A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies

1. Download : Download high-res image (203KB)
2. Download : Download full-size image

     

Testing parameter sensitivities and uncertainty analysis of Biome-BGC model in simulating carbon and water fluxes in broadleaved-Korean pine forests

生态过程模型的发展为研究者在长时间序列和区域尺度的研究提供了便利, 但模型模拟的准确性受到模型自身结构、模型参数估计合理性的影响。敏感性分析能够定量或定性筛选出对模型模拟结果影响较大的敏感参数, 是模型参数校准过程中的重要工具, 也是建模和应用的先决条件。该文以阔叶红松林为研究对象, 采用全局敏感性分析方法——傅里叶幅度灵敏度检验扩展法(EFAST)对Biome-BGC模型的生理生态参数进行了敏感性分析, 分别分析了红松(Pinus koraiensis)和阔叶树的净初级生产力(NPP)、蒸散(ET)对参数变化的敏感性。结果表明: (1)模拟红松NPP的不确定性高于阔叶树, 但二者的模拟ET的不确定性均较小。阔叶树的NPP和ET对生理生态参数的敏感性总体上都小于红松。(2)无论是红松、阔叶或其他植被类型, 模拟NPP均表现出对叶片碳氮比、细根碳氮比、比叶面积(SLA)和冠层截留系数的敏感性, 这4个参数的高敏感性主要是由模型自身结构所决定的, 与植被类型和研究地区的关系较小。对模拟ET而言, 细根与叶片碳分配比、新茎与新叶碳分配比和SLA均是影响红松和阔叶树ET的敏感参数, 但红松ET主要受参数与参数间的二阶或多阶交互作用的间接影响, 而阔叶树ET则主要是受到敏感参数直接效应的影响。(3)除了上述影响红松和阔叶树碳水通量的共性参数外, 诸如核酮糖-1,5-二磷酸羧化酶中叶氮含量、叶片与细根周转率、所有叶面积与投影叶面积之比等也是对模拟结果有影响的重要参数, 但是其敏感程度随物种不同和研究区不同而不同, 所以这类参数可以根据具体情况进行参数本地化, 对于其他不敏感参数则可以采用模型缺省值。     

Gene order and recombination rates in the linkage group S-Phi-Hal-H-(Po2)-Pgd in pigs

Families of Czech Landrace (94 litters and 636 offspring) were tested for halothane sensitivity, A-O (S), H, PHI and PGD phenotypes. Informative matings for the estimation of recombination rates between marker loci were selected. The following recombination frequencies were established: S-Phi = 4.8 % (2.5 % -10.7 %);S-H = 6.8 % (4.3 %-11.7 %); Phi-H = 2.6 % (0.9 %-5.3 9%); H-Pgd = 4.4 % (1.6 %-8.0 %). CCCC-overs were observed also between S- Hal, Hal-H andHal - Pgd, but were not found between Phi - Hal. On the basis of these results it has been possible to revise the position of the S locus in this linkage group. The most probable gene order would be: S - Phi - Hal (or Hal - Phi) -H- (P02) - Pgd.
A striking difference was found between the number of halothane-sensitive pigs (87) and HalⁿHal ⁿ genotypes determined by haplotyping (123). Segregation rates in 19 backcross matings and experimental matings of the animals proved that this difference is mostly due to incomplete CCC or low expression of halothane sensitivity.     

Diagnostic accuracy of fine-needle aspiration cytology in histological grade 1 breast carcinomas: are we good enough?

Background: Fine-needle aspiration cytology (FNAC) of both palpable and non-palpable breast carcinomas has a high accuracy and sensitivity in dedicated centres. It is generally thought that low-grade carcinomas have a distinctly lower sensitivity due to discrete cellular atypia that may be difficult to appreciate. Grade 1 carcinomas make up about 45% of screening-detected breast carcinomas and about 20% of symptomatic breast cancers. The aim of this study was to evaluate the diagnostic sensitivity of grade 1 carcinomas and identify the critical features in the cytological diagnostic work-up of these tumours. Methods: There were FNAC smears from 494 histologically confirmed grade 1 carcinomas diagnosed during 1996–2004. The cytological diagnoses were compared with the histology. Results: A definitive malignant diagnosis (absolute sensitivity) was given in 382 cases (77.3%). Equivocal or suspicious diagnoses were given in 75 (15.2%), benign or probably benign (false negative) in 24 (4.8%). Thirteen cases (2.6%) were unsatisfactory. Complete sensitivity was 92.7%. Invasive ductal carcinomas comprised 81.3% of all cases; absolute sensitivity for these was 80.9%. Invasive lobular and tubular carcinomas comprised 7.3% and 5.9% of cases, respectively; absolute sensitivity for these diagnosis was 50.0% and 57.1%, respectively, significantly lower than for other subtypes (P ≤ 0.0001) whereas the difference for complete sensitivity was less but still significant (P = 0.017). Absolute and complete sensitivities were lower for tumours less than 1 cm size compared with more than 1 cm (P ≤ 0.00001). Conclusion: Preoperative FNAC diagnosis of grade 1 breast carcinoma has a high sensitivity, especially in ductal carcinomas. Invasive lobular and tubular carcinomas were less likely to receive a definite preoperative diagnosis. The main reason for not reaching a definitive malignant diagnosis was sampling error due to small tumours less than 1 cm in diameter, irrespective of tumour subtype.     

不同剂量熊果酸干预糖尿病小鼠视网膜病变的作用及机制研究

目的:探究不同剂量熊果酸(UA)干预糖尿病小鼠视网膜病变的作用及机制。方法:选取雄性健康C57BL/6小鼠60只,其中50只按50 mg/kg的剂量一次性往小鼠尾静脉注射新鲜配置的四氯嘧啶生理盐水溶液构建小鼠糖尿病视网膜病变模型,随机分为5组,每组10只,分别为模型组、阳性对照组(小鼠玻璃体注射3μL 40 mg/m L的曲安奈德),低剂量UA干扰组(小鼠玻璃体注射3μL剂量为0.5μg/μL的UA)、中剂量UA干扰组(小鼠玻璃体注射3μL剂量为1.0μg/μL的UA),高剂量UA干扰组(小鼠玻璃体注射3μL剂量为2.0μg/μL的UA),余下10只小鼠作为正常对照组。观察各组小鼠对胰岛素敏感性、视网膜内糖代谢情况、小鼠视网膜神经节细胞(RGCs)凋亡情况,比较各组小鼠视网膜组织中血管内皮生长因子(VEGF)、环氧化酶-2(COX-2)、基质金属蛋白酶2(MMP-2)蛋白及其mRNA的表达情况。结果:建模后,正常对照组胰岛素抵抗指数(HOMA-IR)、视网膜含糖量、葡萄糖转运体-1(GLUT-1)与葡萄糖转运体-3(GLUT-3)含量、RGCs凋亡率、视网膜组织中VEGF、COX-2、MMP-2蛋白及其mRNA的表达量低于模型组(P0.05);经干扰后,阳性对照组、不同剂量UA干扰组HOMA-IR、视网膜含糖量、GLUT-1、GLUT-3的含量、RGCs凋亡率、视网膜组织中VEGF、COX-2、MMP-2蛋白及其mRNA的表达量低于模型组(P0.05),且随UA干扰剂量的升高而降低(P0.05)。结论:UA能够降低HOMA-IR和视网膜糖代谢能力,抑制RGCs的凋亡,对VEGF、COX-2、MMP-2蛋白及其mRNA的表达具有一定的抑制作用,高剂量UA对糖尿病小鼠视网膜病预防治疗效果较好。     

Reduced caloric intake and periodic fasting independently contribute to metabolic effects of caloric restriction

Caloric restriction (CR) has positive effects on health and longevity. CR in mammals implements time‐restricted (TR) feeding, a short period of feeding followed by prolonged fasting. Periodic fasting, in the form of TR or mealtime, improves metabolism without reduction in caloric intake. In order to understand the relative contribution of reduced food intake and periodic fasting to the health benefits of CR, we compared physiological and metabolic changes induced by CR and TR (without reduced food intake) in mice. CR significantly reduced blood glucose and insulin around the clock, improved glucose tolerance, and increased insulin sensitivity (IS). TR reduced blood insulin and increased insulin sensitivity, but in contrast to CR, TR did not improve glucose homeostasis. Liver expression of circadian clock genes was affected by both diets while the mRNA expression of glucose metabolism genes was significantly induced by CR, and not by TR, which is in agreement with the minor effect of TR on glucose metabolism. Thus, periodic fasting contributes to some metabolic benefits of CR, but TR is metabolically different from CR. This difference might contribute to differential effects of CR and TR on longevity.     

Modeling of exposure to mercury in different environmental media over a 30-year period: A case study of Shimen reservoir,northern Taiwan

Abstract

Mercury is affected by the movement mechanisms in the environmental media and is normally present in dry and wet depositions and surface and water vapor, among other things. The rapid growth of mercury-related industries in the past two decades reflects the result of its increased use in water sources such as in the Shimen reservoir, northern Taiwan. Consequently, residents living nearby are exposed to mercury almost every day. In light of the effects of continued exposure to the deleterious properties of mercury, this study provides modeling results of the atmosphere, soil, and freshwater over a 30-year period (2016–2046). The associated influences in the media and mercury contamination during this period will be determined via sensitivity analysis. Finally, the results of this study facilitate the assessment of potential health hazards associated with mercury inhalation and the ingestion of MeHg-contaminated fish. The mean daily dose (mg/kg) and hazard quotient (HQ) in the children and adult were 3.52E-13 (HQ = 4.10E-09) and 1.19E-13 (HQ = 1.39E-09) for Hg inhalation and 6.38E-05 (HQ = 6.38E-01) and 4.47E-05 (HQ = 4.47E-01) for ingestion of MeHg+-contaminated fish.     

Traits mediate drought effects on wood carbon fluxes

CO₂ fluxes from wood decomposition represent an important source of carbon from forest ecosystems to the atmosphere, which are determined by both wood traits and climate influencing the metabolic rates of decomposers. Previous studies have quantified the effects of moisture and temperature on wood decomposition, but these effects were not separated from the potential influence of wood traits. Indeed, it is not well understood how traits and climate interact to influence wood CO₂ fluxes. Here, we examined the responses of CO₂ fluxes from dead wood with different traits (angiosperm and gymnosperm) to 0%, 35%, and 70% rainfall reduction across seasonal temperature gradients. Our results showed that drought significantly decreased wood CO₂ fluxes, but its effects varied with both taxonomical group and drought intensity. Drought‐induced reduction in wood CO₂ fluxes was larger in angiosperms than gymnosperms for the 35% rainfall reduction treatment, but there was no significant difference between these groups for the 70% reduction treatment. This is because wood nitrogen density and carbon quality were significantly higher in angiosperms than gymnosperms, yielding a higher moisture sensitivity of wood decomposition. These findings were demonstrated by a significant positive interaction effect between wood nitrogen and moisture on CO₂ fluxes in a structural equation model. Additionally, we ascertained that a constant temperature sensitivity of CO₂ fluxes was independent of wood traits and consistent with previous estimates for extracellular enzyme kinetics. Our results highlight the key role of wood traits in regulating drought responses of wood carbon fluxes. Given that both climate and forest management might extensively modify taxonomic compositions in the future, it is critical for carbon cycle models to account for such interactions between wood traits and climate in driving dynamics of wood decomposition.     

松栎林天然更新模拟与不确定性分析

森林天然更新的复杂性和不确定性是森林生态系统动态预测中的关键问题。本研究引入贝叶斯技术和全局敏感性分析,构建基于竞争、气候和地形3类因子的秦岭松栎林天然更新模型。备选模型形式以泊松(Poisson)模型、负二项(negative binomial,NB)模型、零膨胀泊松(zero-inflated Poisson,ZIP)模型和零膨胀负二项(zero-inflated negative binomial,ZINB)模型为基础。同时,根据模型参数传递的不确定性量化分析结果,阐释影响森林更新小概率事件的主导因子。结果表明: ZINB模型在油松和锐齿栎更新模拟中均优于其他模型。林分总断面积、光截留、坡位和生长季最低温是影响松栎林中油松天然更新的最关键因子;而林分总断面积、坡向与海拔的组合、年均温和最热季节降水量则是影响松栎林中锐齿栎天然更新的关键因子。油松更新模拟中,各类因子对模型输出的不确定性贡献率从小到大依次为: 竞争因子(25%)＜气候因子(29%)＜地形因子(46%);锐齿栎更新模拟中为: 气候因子(12%)＜竞争因子(24%)＜地形因子(64%)。油松天然更新数量对生长季最低温和最干季节降水量为正响应,对最干季节均温为负响应;锐齿栎天然更新数量对年均温、生长季最低温和最热季节降水量为正响应,对最干季节均温为负响应。基于贝叶斯技术的ZINB模型可以量化森林更新的影响因子,并解释参数传递的不确定性,是预测森林天然更新的有力工具。