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1.
In the area of omics profiling in toxicology, i.e. toxicogenomics, characteristic molecular profiles have previously been incorporated into prediction models for early assessment of a carcinogenic potential and mechanism-based classification of compounds. Traditionally, the biomarker signatures used for model construction were derived from individual high-throughput techniques, such as microarrays designed for monitoring global mRNA expression. In this study, we built predictive models by integrating omics data across complementary microarray platforms and introduced new concepts for modeling of pathway alterations and molecular interactions between multiple biological layers. We trained and evaluated diverse machine learning-based models, differing in the incorporated features and learning algorithms on a cross-omics dataset encompassing mRNA, miRNA, and protein expression profiles obtained from rat liver samples treated with a heterogeneous set of substances. Most of these compounds could be unambiguously classified as genotoxic carcinogens, non-genotoxic carcinogens, or non-hepatocarcinogens based on evidence from published studies. Since mixed characteristics were reported for the compounds Cyproterone acetate, Thioacetamide, and Wy-14643, we reclassified these compounds as either genotoxic or non-genotoxic carcinogens based on their molecular profiles. Evaluating our toxicogenomics models in a repeated external cross-validation procedure, we demonstrated that the prediction accuracy of our models could be increased by joining the biomarker signatures across multiple biological layers and by adding complex features derived from cross-platform integration of the omics data. Furthermore, we found that adding these features resulted in a better separation of the compound classes and a more confident reclassification of the three undefined compounds as non-genotoxic carcinogens.  相似文献   

2.
It is challenging determining whether an ecosystem is impaired. The complexity of direct and indirect interactions between physical, biological and chemical components with their varying temporal and spatial scales generally renders use of multiple assessment approaches mandatory, with a consequent need to integrate different lines-of-evidence. Integration generally involves some form of weight-ofevidence (WOE). WOE approaches reported in the literature vary broadly from subjective and qualitative to quantitative. No standard approach exists and no accepted guidelines exist describing how a WOE process should be conducted. This review summarizes the advantages, limitations, and uncertainties of different WOE approaches, critical issues involved in selecting and executing different lines-ofevidence, and the process for subsequent characterization of the likelihood of impairment.  相似文献   

3.
Surrogate species approaches, including flagship, focal, keystone, indicator, and umbrella, are considered an effective means of conservation planning. For conservation biologists to apply surrogates with confidence, they must have some idea of the effectiveness of surrogates for the circumstances in which they will be applied. We reviewed tests of the effectiveness of surrogate species planning to see if research supports the development of generalized rules for (1) determining when and where surrogate species are an effective conservation tool and (2) how surrogate species should be selected such that the resulting conservation plan will effectively protect biodiversity or achieve other conservation goals. The context and methods of published studies were so diverse that we could not draw general conclusions about the spatial or temporal scales, or ecosystems or taxonomic groups for which surrogate species approaches will succeed. The science of surrogate species can progress by (1) establishing methods to compare diverse measures of effectiveness; (2) taking advantage of data-rich regions to examine the potential effectiveness of surrogate approaches; (3) incorporating spatial scale as an explanatory variable; (4) evaluating surrogate species approaches at broader temporal scales; (5) seeking patterns that will lead to hypothesis driven research; and (6) monitoring surrogate species and their target species.  相似文献   

4.
Viral production estimates show that virioplankton communities turn over rapidly in aquatic ecosystems. Thus, it is likely that the genetic identity of viral populations comprising the virioplankton also change over temporal and spatial scales, reflecting shifts in viral-host interactions. However, there are few approaches that can provide data on the genotypic identity of viral populations at low cost and with the sample throughput necessary to assess dynamic changes in the virioplankton. This study examined two of these approaches—T4-like major capsid protein (g23) gene polymorphism and randomly amplified polymorphic DNA-PCR (RAPD-PCR) fingerprinting—to ask how well each technique could track differences in virioplankton populations over time and geographic location. Seasonal changes in overall virioplankton composition were apparent from pulsed-field gel electrophoresis (PFGE) analysis. T4-like phages containing similar g23 proteins were found within both small- and large-genome populations, including populations from different geographic locations and times. The surprising occurrence of T4-like g23 within small genomic groups (23 to 64 kb) indicated that the genome size range of T4-like phages may be broader than previously believed. In contrast, RAPD-PCR fingerprinting detected high genotypic similarity within PFGE bands from the same location, time, and genome size class without the requirement for DNA sequencing. Unlike g23 polymorphism, RAPD-PCR fingerprints showed a greater temporal than geographic variation. Thus, while polymorphism in a viral signature gene, such as g23, can be a powerful tool for inferring evolutionary relationships, the degree to which this approach can capture fine-scale variability within virioplankton populations is less clear.  相似文献   

5.
Approaches for Integrated Risk Assessment   总被引:1,自引:0,他引:1  
Recognizing the need to enhance the effectiveness and efficiency of risk assessments globally, the World Health Organization's International Programme on Chemical Safety, the U.S. Environmental Protection Agency, the European Commission, and the Organization for Economic Cooperation and Development developed a collaborative partnership to foster integration of assessment approaches used to evaluate human health and ecological risks. The objectives of this effort included: improving understanding of the benefits of integration, identifying obstacles to the integration process, and engaging key agencies, organizations, and scientific societies to promote integration. A framework with supporting documentation was developed to describe an approach for integration. Four case studies were constructed to illustrate how integrated risk assessments might be conducted for chemical and nonchemical stressors. The concepts and approaches developed in the project were evaluated in an international workshop. The goal of this effort was international acceptance of guidance for integrated risk assessment.  相似文献   

6.
7.
Microarray analysis is used for simultaneous measurement of expression of thousands of genes in a given sample and as such extends and deepens our understanding of biological processes. Application of the technique in toxicology is referred to as toxicogenomics. The examples of assessment of immunotoxicity by gene expression profiling presented and discussed here, show that microarray analysis is able to detect known and novel effects of a wide range of immunomodulating agents. Besides the elucidation of mechanisms of action, toxicogenomics is also applied to predict consequences of exposing biological systems to toxic agents. Successful attempts to classify compounds using signature gene expression profiles have been reported. These did, however, not specifically focus on immunotoxicity. Databases containing expression profiles can facilitate the applications of toxicogenomics. Platforms and methodologies for gene expression profiling may vary, however, hampering data compiling across different laboratories. Therefore, attention is paid to standardization of the generation, reporting, and management of microarray data. Obtained gene expression profiles should be anchored to pathological and functional endpoints for correct interpretation of results. These issues are also important when using toxicogenomics in risk assessment. The application of toxicogenomics in evaluation of immunotoxicity is thus not yet without challenges. It already contributes to the understanding of immunotoxic processes and the development of in vitro screening assays, though, and is therefore expected to be of value for mechanistic insight into immunotoxicity and hazard identification of existing and novel compounds.  相似文献   

8.

Introduction

Risk factors for life-threatening cardiovascular events were evaluated in an experimental model of epilepsy, the Wistar Audiogenic Rat (WAR) strain.

Methods

We used long-term ECG recordings in conscious, one year old, WAR and Wistar control counterparts to evaluate spontaneous arrhythmias and heart rate variability, a tool to assess autonomic cardiac control. Ventricular function was also evaluated using the pressure-volume conductance system in anesthetized rats.

Results

Basal RR interval (RRi) was similar between WAR and Wistar rats (188±5 vs 199±6 ms). RRi variability strongly suggests that WAR present an autonomic imbalance with sympathetic overactivity, which is an isolated risk factor for cardiovascular events. Anesthetized WAR showed lower arterial pressure (92±3 vs 115±5 mmHg) and exhibited indices of systolic dysfunction, such as higher ventricle end-diastolic pressure (9.2±0.6 vs 5.6±1 mmHg) and volume (137±9 vs 68±9 μL) as well as lower rate of increase in ventricular pressure (5266±602 vs 7320±538 mmHg.s-1). Indices of diastolic cardiac function, such as lower rate of decrease in ventricular pressure (-5014±780 vs -7766±998 mmHg.s-1) and a higher slope of the linear relationship between end-diastolic pressure and volume (0.078±0.011 vs 0.036±0.011 mmHg.μL), were also found in WAR as compared to Wistar control rats. Moreover, Wistar rats had 3 to 6 ventricular ectopic beats, whereas WAR showed 15 to 30 ectopic beats out of the 20,000 beats analyzed in each rat.

Conclusions

The autonomic imbalance observed previously at younger age is also present in aged WAR and, additionally, a cardiac dysfunction was also observed in the rats. These findings make this experimental model of epilepsy a valuable tool to study risk factors for cardiovascular events in epilepsy.  相似文献   

9.
Transdisciplinary One Health (OH) approaches have been rediscovered as a promising tactic for addressing complex health risks at the human-animal-ecosystem interface. However, there is little evidence of widespread adoption of OH approaches as the new operating normal for addressing these complex health issues. We have used a transformational change model as an evaluation tool and part of an overall assessment of the global adoption of OH approaches. This assessment establishes a point of reference for measuring progress toward OH approaches being the new operating normal. Global adoption of OH approaches will require more strategic efforts to build the case (value proposition), recruiting a broader pool of One Health champions, solidifying partnerships and unifying OH efforts.  相似文献   

10.
Transport Pathways for Therapeutic Concentrations of Lithium in Rat Liver   总被引:1,自引:0,他引:1  
Although both amiloride- and phloretin-sensitive Na+/Li+ exchange activities have been reported in mammalian red blood cells, it is still unclear whether or not the two are mediated by the same pathway. Also, little is known about the relative contribution of these transport mechanisms to the entry of therapeutic concentrations of Li+ (0.2–2 mm) into cells other than erythrocytes. Here, we describe characteristics of these transport systems in rat isolated hepatocytes in suspension. Uptake of Li+ by hepatocytes, preloaded with Na+ and incubated in the presence of ouabain and bumetanide, comprised three components. (a) An amiloride-sensitive component, with apparent K m 1.2 mm Li+, V max 40 μmol · (kg dry wt · min)−1, showed increased activity at low intracellular pH. The relationship of this component to the concentration of intracellular H+ was curvilinear suggesting a modifier role of [H+] i . This system persisted in Na+-depleted cells, although with apparent K m 3.8 mm. (b) A phloretin-sensitive component, with K m 1.2 mm, V max 21 μmol · (kg · min)−1, was unaffected by pH but was inactive in Na+-depleted cells. Phloretin inhibited Li+ uptake and Na+ efflux in parallel. (c) A residual uptake increased linearly with the external Li+ concentration and represented an increasing proportion of the total uptake. The results strongly suggest that the amiloride-sensitive and the phloretin-sensitive Li+ uptake in rat liver are mediated by two separate pathways which can be distinguished by their sensitivity to inhibitors and intracellular [H+]. Received: 8 April 1999/Revised: 19 July 1999  相似文献   

11.
12.
13.
We investigated the gene expression changes in rat hepatic restoration with Rat Genome 230 2.0 chip containing 11,789 known genes and 13,231 unknown genes (taking up 90 percent of rat whole genome) following a 2/3 hepatectomy. The expression profiles and roles of these genes in rat liver regeneration (LR) were assayed using bioinformatics and systems biology method. Among the above genes, 1,004 known genes and 857 unknown genes were found to be associated with rat LR. The numbers of the known genes up-regulated, down-regulated, and up/down-regulated were 622, 443, and 15, respectively; that of the unknown genes were 367, 400, and 14, respectively. Out of the above two groups of genes, the ones up- and down-regulated 20 times or more were 62 and 38, 8, and 14, respectively. Notably, The highest expression level of dehydrogenase/reductase member 7 (DHRS7) was more than 968-fold compared to control, and alpha-1-B glycoprotein (A1BG), the product of gene with the lowest expression abundance, was 58 times lower than control. During rat liver regeneration, 467 up–regulated, 282 down–regulated, 10 up/down-regulated genes, and 1,031 undetected genes in our study interacted with each other and formed a network with a total of 4,014 connectivities. Among them, the genes for the regulation, synthesis, transport, signal transduction, protein modification, and physiological response formed 630, 290, 691, 373, 2010, and 20 connectivities, respectively; and the genes jun, fos, myc, ptgs2, ccna2, ccl2 had relatively higher degree of connectivity. The results indicated that cell apoptosis and inflammatory response were enhanced in the initial phase and the early part of progressive phase in LR.  相似文献   

14.
Due to a USAID-funded study on blood banks, a national policy was instituted in 1994 that set standards for Philippine blood services, promoted voluntary donation, and led to a ban on commercial blood banks. In this follow-up study, we assess the safety of the supply by determining the residual risk for transfusion-transmitted infections (syphilis, hepatitis B and C, HIV). We also identified unsafe facility practices and generated policy recommendations. A 1992 study found that transfusion-ready blood was not safe using the LQAS method (P > 0.05). We found that the 2012 residual risk became 0 to 0.9 percent attributable to the national policy. We noted poor to fair adherence to this policy. We identified unsafe practices such as use of rapid tests and lack of random blood retesting. Training and use of regional networks may improve safety. Despite improvement in safety, facilities complain of funding and logistical issues regarding compliance with the policy.  相似文献   

15.
目的建立大鼠肝移植术后腹腔感染的模型。方法构建DA大鼠到LEW大鼠的肝移植模型,采用腹腔内细菌注射的方法建立感染模型,通过对大鼠肝功、血气、血细胞计数等各项指标的检测对模型进行综合评价。结果肝移植术后5 d注射细菌,大鼠死亡率高,不利后续研究;术后3 d注射细菌,并选定5×105cfu/mL为最终注射浓度,感染后大鼠的7d存活率累计可达到37.5%左右,随之感染的加重,大鼠状态逐渐变差,直肠温度不断升高,WBC计数也随之增加,pH下降,大鼠出现代谢性酸中毒,肝功能损害进行性加重,肝实质的损害重于胆道的损伤,大约在感染5 d左右相继死亡,多器官病理分析表明,大鼠死亡原因为肝损害,不并发肺脏、肾脏损害。结论采用的腹腔内大肠埃希菌注射建立肝移植术后腹腔细菌感染的模型是比较成功的,可用于相关领域的研究。  相似文献   

16.
The reduction of nitroxide free radicals was investigated in detail by Electron Paramagnetic Resonance (EPR) spectroscopy in perfused liver. The nitroxide free radical was rapidly reduced to the corresponding hydroxylamine more efficiently at the lower flow rate of 8 [ml/min], while at higher flow rates, the amount of reduced nitroxide showed a significant decrease. Oxidation of hydroxylamine using hydrogen peroxide provided dynamic information concerning the reduction of the free radical within the liver. In addition, liver homogenates were also investigated to determine the level of nitroxide uptake. The results suggested that a portion of the infused nitroxide was taken up by the liver and cleared from the circulation.  相似文献   

17.
Double Stranded RNA from Rat Liver induces Interferon in Rat Cells   总被引:3,自引:0,他引:3  
Double stranded RNA from rat liver induces interferon in rat ergbryo fibroblasts. This shows that the production of interferon is not only a reaction to “foreign” RNA but can also be obtained with RNA of the same species.  相似文献   

18.
目的 探讨大鼠白介素10(rIL-10)基因是否可通过半乳糖配体介导的脂质体转染法在大鼠肝脏内靶向表达。方法将已构建好的rIL-10基因真核表达质粒与半乳糖配体转染试剂按jetPEI.Gal/DNA(N/P=10)比例混合,通过尾静脉注射转移至大鼠体内。RT—PCR法和ELISA法检测rIL-10基因转移至体内0h、24h、7d和16d后大鼠肝、肾、脾和肺组织及血清中rIL-10的表达情况。结果rIL-10基因转移前大鼠肝、肾、脾和肺组织末扩增出明显rIL-10mRNA表达,转移7d后rIL-10表达主要分布在肝组织。肝组织中rIL-10mRNA表达在基因转移24h和7d时显著升高。血清中的rIL-10浓度在转移后24h和7d浓度分别为(107.92±12.26)pg/ml和(33.2±13.15)pg/ml。结论rIL-10基因通过半乳糖配体介导的脂质体转染法可有效的转移至大鼠体内,并可在肝脏靶向表达一周左右时间。  相似文献   

19.
旨在探索鼠肝中金属硫蛋白(MT)提取工艺并加以改进。按照经典方法工艺提取MT,用中空纤维柱超滤方法加以改进,依据MT自身特点进行分离和鉴定。结果显示,粗品符合MT特点:分子量在6.5kD左右;无280nm特征吸收峰,加酸后紫外吸收(200-300nm)肩峰消失;通过离子交换可以实现MT1、MT2的分离;通过原子吸收测定,含有锌、铜、镉3种金属,锌含量最高,具有重要的病理生理意义。因此,与其它方法比较,改进后方法更适宜实验室制备。  相似文献   

20.
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