Now and future of mouse mutagenesis for human disease models

One of the major objectives of the Human Genome Project is to understand the biological function of the gene and genome as well as to develop clinical applications for human diseases. For this purpose, the experimental validations and preclinical trails by using animal models are indispensable. The mouse (Mus musculus) is one of the best animal models because genetics is well established in the mouse and embryonic manipulation technologies are also well developed. Large-scale mouse mutagenesis projects have been conducted to de-velop various mouse models since 1997. Originally, the phenotype-driven mutagenesis with N-ethyl-N-nitrosourea (ENU) has been the major efforts internationally then knockout/conditional mouse projects and gene-driven mutagenesis have been following. At the beginning, simple monogenic traits in the experimental condition have been elucidated. Then, more complex traits with variety of environmental interactions and gene-to-gene interactions (epistasis) have been challenged with mutant mice. In addition, chromosomal substitution swains and collaborative cross strains are also available to elucidate the complex Waits in the mouse. Altogether, mouse models with mutagenesis and various laboratory strains will accelerate the studies of functional genomics in the mouse as well as in human.     

基于RAGA的PPC模型在城市公园绿地景观生态美学评价中的应用

基于公众对生态环境的日益重视,以生态美学思想为指导,提出城市公园绿地景观生态美学评价的指标体系;同时利用基于RAGA的PPC模型,将高维数据转换到低维子空间,通过寻求最优投影方向及投影函数值来实现对城市公园绿地景观的生态美学评价。选取大庆市10个具有代表性的公园绿地为研究对象,运用该评价指标体系及模型进行景观生态美学评价。结果表明:总体景观空间多样性、植被色彩多样性、建筑与小品分布合理性、树种多样性、水体可亲近性、植被长势自然性、地形自然度、建筑与小品体量适宜度指标对大庆市公园绿地景观生态美学效果的影响较大,是今后大庆市公园绿地景观生态建设、改造与管理上应作为重点考虑的因素;在10个公园绿地中,油田乐园、城市森林公园最具生态美,而乘风广场、世纪大道(高新技术开发区段)附属带状绿地的生态美较差。应用该模型可以避免传统方法存在的一些不足,也为处理景观评价中具有模糊性、不确定性的高维数据的综合评判、排序、寻优等方面研究提供了新的思路与方法。     

生命科学研究中常用模式生物

模式生物是生命科学研究的重要材料,目前公认的用于生命科学研究的常见模式生物有噬菌体、大肠杆菌、酵母、线虫、果蝇、斑马鱼、小鼠、拟南芥等.这8种常用模式生物对生命现象的揭密和人类疾病治疗的探索等都所做出了重大贡献,对其在生命科学研究中的历史轨迹、各自优势、技术手段、热点研究、发展前景等系统而又简要的了解,有助于具体而又生动地体察到模式生物在今天生命科学发展中的重要地位和推动生命科学及医学进步的不可替代的巨大潜力.     

Methods for Culturing Human Femur Tissue Explants to Study Breast Cancer Cell Colonization of the Metastatic Niche

Bone is the most common site of breast cancer metastasis. Although it is widely accepted that the microenvironment influences cancer cell behavior, little is known about breast cancer cell properties and behaviors within the native microenvironment of human bone tissue.We have developed approaches to track, quantify and modulate human breast cancer cells within the microenvironment of cultured human bone tissue fragments isolated from discarded femoral heads following total hip replacement surgeries. Using breast cancer cells engineered for luciferase and enhanced green fluorescent protein (EGFP) expression, we are able to reproducibly quantitate migration and proliferation patterns using bioluminescence imaging (BLI), track cell interactions within the bone fragments using fluorescence microscopy, and evaluate breast cells after colonization with flow cytometry. The key advantages of this model include: 1) a native, architecturally intact tissue microenvironment that includes relevant human cell types, and 2) direct access to the microenvironment, which facilitates rapid quantitative and qualitative monitoring and perturbation of breast and bone cell properties, behaviors and interactions. A primary limitation, at present, is the finite viability of the tissue fragments, which confines the window of study to short-term culture. Applications of the model system include studying the basic biology of breast cancer and other bone-seeking malignancies within the metastatic niche, and developing therapeutic strategies to effectively target breast cancer cells in bone tissues.     

Using Pharmacokinetic Profiles and Digital Quantification of Stained Tissue Microarrays as a Medium-Throughput,Quantitative Method for Measuring the Kinetics of Early Signaling Changes Following Integrin-Linked Kinase Inhibition in an In Vivo Model of Cancer

A small molecule inhibitor (QLT0267) targeting integrin-linked kinase is able to slow breast tumor growth in vivo; however, the mechanism of action remains unknown. Understanding how targeting molecules involved in intersecting signaling pathways impact disease is challenging. To facilitate this understanding, we used tumor tissue microarrays (TMA) and digital image analysis for quantification of immunohistochemistry (IHC) in order to investigate how QLT0267 affects signaling pathways in an orthotopic model of breast cancer over time. Female NCR nude mice were inoculated with luciferase-positive human breast tumor cells (LCC6^Luc) and tumor growth was assessed by bioluminescent imaging (BLI). The plasma levels of QLT0267 were determined by LC-MS/MS methods following oral dosing of QLT0267 (200 mg/kg). A TMA was constructed using tumor tissue collected at 2, 4, 6, 24, 78 and 168 hr after treatment. IHC methods were used to assess changes in ILK-related signaling. The TMA was digitized, and Aperio ScanScope and ImageScope software were used to provide semi-quantitative assessments of staining levels. Using medium-throughput IHC quantitation, we show that ILK targeting by QLT0267 in vivo influences tumor physiology through transient changes in pathways involving AKT, GSK-3 and TWIST accompanied by the translocation of the pro-apoptotic protein BAD and an increase in Caspase-3 activity.     

A review of global potentially available cropland estimates and their consequences for model‐based assessments

The world's population is growing and demand for food, feed, fiber, and fuel is increasing, placing greater demand on land and its resources for crop production. We review previously published estimates of global scale cropland availability, discuss the underlying assumptions that lead to differences between estimates, and illustrate the consequences of applying different estimates in model‐based assessments of land‐use change. The review estimates a range from 1552 to 5131 Mha, which includes 1550 Mha that is already cropland. Hence, the lowest estimates indicate that there is almost no room for cropland expansion, while the highest estimates indicate that cropland could potentially expand to over three times its current area. Differences can largely be attributed to institutional assumptions, i.e. which land covers/uses (e.g. forests or grasslands) are societally or governmentally allowed to convert to cropland, while there was little variation in biophysical assumptions. Estimates based on comparable assumptions showed a variation of up to 84%, which originated mainly from different underlying data sources. On the basis of this synthesis of the assumptions underlying these estimates, we constructed a high, a medium, and a low estimate of cropland availability that are representative of the range of estimates in the reviewed studies. We apply these estimates in a land‐change model to illustrate the consequences on cropland expansion and intensification as well as deforestation. While uncertainty in cropland availability is hardly addressed in global land‐use change assessments, the results indicate a large range of estimates with important consequences for model‐based assessments.     

Sustainable limits to crop residue harvest for bioenergy: maintaining soil carbon in Australia's agricultural lands

The use of crop residues for bioenergy production needs to be carefully assessed because of the potential negative impact on the level of soil organic carbon (SOC) stocks. The impact varies with environmental conditions and crop management practices and needs to be considered when harvesting the residue for bioenergy productions. Here, we defined the sustainable harvest limits as the maximum rates that do not diminish SOC and quantified sustainable harvest limits for wheat residue across Australia's agricultural lands. We divided the study area into 9432 climate‐soil (CS) units and simulated the dynamics of SOC in a continuous wheat cropping system over 122 years (1889 – 2010) using the Agricultural Production Systems sIMulator (APSIM). We simulated management practices including six fertilization rates (0, 25, 50, 75, 100, and 200 kg N ha^?1) and five residue harvest rates (0, 25, 50, 75, and 100%). We mapped the sustainable limits for each fertilization rate and assessed the effects of fertilization and three key environmental variables – initial SOC, temperature, and precipitation – on sustainable residue harvest rates. We found that, with up to 75 kg N ha^?1 fertilization, up to 75% and 50% of crop residue could be sustainably harvested in south‐western and south‐eastern Australia, respectively. Higher fertilization rates achieved little further increase in sustainable residue harvest rates. Sustainable residue harvest rates were principally determined by climate and soil conditions, especially the initial SOC content and temperature. We conclude that environmental conditions and management practices should be considered to guide the harvest of crop residue for bioenergy production and thereby reduce greenhouse gas emissions during the life cycle of bioenergy production.     

入侵害虫菊方翅网蝽在中国的潜在分布预测

菊方翅网蝽Corythucha marmorata(Uhler,1878)是我国新近发现的外来入侵害虫,研究明确菊方翅网蝽在我国的潜在分布范围对其监测预警及科学防控具有重要意义。本研究根据菊方翅网蝽的地理分布数据及相关环境变量,运用Maxent生态位模型与ArcGIS预测了菊方翅网蝽在中国的潜在地理分布范围。预测结果表明:菊方翅网蝽在我国的适生区主要分布于100°～125°E,20°～40°N的亚热带、暖温带区域,其中高适生区主要集中在长江中下游地区,包括浙江、江苏、湖南、上海大部分地区、安徽南部、湖北南部、江西西部及南部、贵州东部、福建东部、广西北部、山东中部、河南南部以及重庆、台湾局部;此外,极端气温、平均气温、最干月份降雨量对菊方翅网蝽的潜在分布影响较大。菊方翅网蝽已在我国成功入侵并迅速蔓延成灾,应在疫区边缘地带加强监测,并采取措施防止其进一步扩散。     

Co‐occurrence patterns of trees along macro‐climatic gradients and their potential influence on the present and future distribution of Fagus sylvatica L.

Aim During recent and future climate change, shifts in large‐scale species ranges are expected due to the hypothesized major role of climatic factors in regulating species distributions. The stress‐gradient hypothesis suggests that biotic interactions may act as major constraints on species distributions under more favourable growing conditions, while climatic constraints may dominate under unfavourable conditions. We tested this hypothesis for one focal tree species having three major competitors using broad‐scale environmental data. We evaluated the variation of species co‐occurrence patterns in climate space and estimated the influence of these patterns on the distribution of the focal species for current and projected future climates. Location Europe. Methods We used ICP Forest Level 1 data as well as climatic, topographic and edaphic variables. First, correlations between the relative abundance of European beech (Fagus sylvatica) and three major competitor species (Picea abies, Pinus sylvestris and Quercus robur) were analysed in environmental space, and then projected to geographic space. Second, a sensitivity analysis was performed using generalized additive models (GAM) to evaluate where and how much the predicted F. sylvatica distribution varied under current and future climates if potential competitor species were included or excluded. We evaluated if these areas coincide with current species co‐occurrence patterns. Results Correlation analyses supported the stress‐gradient hypothesis: towards favourable growing conditions of F. sylvatica, its abundance was strongly linked to the abundance of its competitors, while this link weakened towards unfavourable growing conditions, with stronger correlations in the south and at low elevations than in the north and at high elevations. The sensitivity analysis showed a potential spatial segregation of species with changing climate and a pronounced shift of zones where co‐occurrence patterns may play a major role. Main conclusions Our results demonstrate the importance of species co‐occurrence patterns for calibrating improved species distribution models for use in projections of climate effects. The correlation approach is able to localize European areas where inclusion of biotic predictors is effective. The climate‐induced spatial segregation of the major tree species could have ecological and economic consequences.     

Modelling biome shifts and tree cover change for 2050 in West Africa

Aim Africa is expected to face severe changes in climatic conditions. Our objectives are: (1) to model trends and the extent of future biome shifts that may occur by 2050, (2) to model a trend in tree cover change, while accounting for human impact, and (3) to evaluate uncertainty in future climate projections. Location West Africa. Methods We modelled the potential future spatial distribution of desert, grassland, savanna, deciduous and evergreen forest in West Africa using six bioclimatic models. Future tree cover change was analysed with generalized additive models (GAMs). We used climate data from 17 general circulation models (GCMs) and included human population density and fire intensity to model tree cover. Consensus projections were derived via weighted averages to: (1) reduce inter‐model variability, and (2) describe trends extracted from different GCM projections. Results The strongest predicted effect of climate change was on desert and grasslands, where the bioclimatic envelope of grassland is projected to expand into the desert by an area of 2 million km². While savannas are predicted to contract in the south (by 54 ± 22 × 10⁴ km²), deciduous and evergreen forest biomes are expected to expand (64 ± 13 × 10⁴ km² and 77 ± 26 × 10⁴ km²). However, uncertainty due to different GCMs was particularly high for the grassland and the evergreen biome shift. Increasing tree cover (1–10%) was projected for large parts of Benin, Burkina Faso, Côte d’Ivoire, Ghana and Togo, but a decrease was projected for coastal areas (1–20%). Furthermore, human impact negatively affected tree cover and partly changed the direction of the projected change from increase to decrease. Main conclusions Considering climate change alone, the model results of potential vegetation (biomes) show a ‘greening’ trend by 2050. However, the modelled effects of human impact suggest future forest degradation. Thus, it is essential to consider both climate change and human impact in order to generate realistic future tree cover projections.