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911.
Fan Zhang Haoting Chen Li Na Zhao Hui Liu Teresa M. Przytycka Jie Zheng 《BMC systems biology》2016,10(Z1):S7
Background
Cellular responses to extracellular perturbations require signaling pathways to capture and transmit the signals. However, the underlying molecular mechanisms of signal transduction are not yet fully understood, thus detailed and comprehensive models may not be available for all the signaling pathways. In particular, insufficient knowledge of parameters, which is a long-standing hindrance for quantitative kinetic modeling necessitates the use of parameter-free methods for modeling and simulation to capture dynamic properties of signaling pathways.Results
We present a computational model that is able to simulate the graded responses to degradations, the sigmoidal biological relationships between signaling molecules and the effects of scheduled perturbations to the cells. The simulation results are validated using experimental data of protein phosphorylation, demonstrating that the proposed model is capable of capturing the main trend of protein activities during the process of signal transduction. Compared with existing simulators, our model has better performance on predicting the state transitions of signaling networks.Conclusion
The proposed simulation tool provides a valuable resource for modeling cellular signaling pathways using a knowledge-based method.912.
Hasun Yu Sungji Choo Junseok Park Jinmyung Jung Yeeok Kang Doheon Lee 《BMC systems biology》2016,10(Z1):S2
Background
Developing novel uses of approved drugs, called drug repositioning, can reduce costs and times in traditional drug development. Network-based approaches have presented promising results in this field. However, even though various types of interactions such as activation or inhibition exist in drug-target interactions and molecular pathways, most of previous network-based studies disregarded this information.Methods
We developed a novel computational method, Prediction of Drugs having Opposite effects on Disease genes (PDOD), for identifying drugs having opposite effects on altered states of disease genes. PDOD utilized drug-drug target interactions with ‘effect type’, an integrated directed molecular network with ‘effect type’ and ‘effect direction’, and disease genes with regulated states in disease patients. With this information, we proposed a scoring function to discover drugs likely to restore altered states of disease genes using the path from a drug to a disease through the drug-drug target interactions, shortest paths from drug targets to disease genes in molecular pathways, and disease gene-disease associations.Results
We collected drug-drug target interactions, molecular pathways, and disease genes with their regulated states in the diseases. PDOD is applied to 898 drugs with known drug-drug target interactions and nine diseases. We compared performance of PDOD for predicting known therapeutic drug-disease associations with the previous methods. PDOD outperformed other previous approaches which do not exploit directional information in molecular network. In addition, we provide a simple web service that researchers can submit genes of interest with their altered states and will obtain drugs seeming to have opposite effects on altered states of input genes at http://gto.kaist.ac.kr/pdod/index.php/main.Conclusions
Our results showed that ‘effect type’ and ‘effect direction’ information in the network based approaches can be utilized to identify drugs having opposite effects on diseases. Our study can offer a novel insight into the field of network-based drug repositioning.913.
This study investigated the seasonal change in xylem growth of Japanese red pine (Pinus densiflora). Wood cores were sampled at 2-week intervals from April to November in 2012 using the microcoring method. Daily increment rates of tracheid number and tree-ring width were compared with seasonal changes in daily mean temperature and photoperiod. Xylem growth started in early to late May and stopped in late October to early November. The maximum daily increment rates of tracheid number and tree-ring width were in early July. The 95 % confidence intervals of the timing of the maximum daily increment rates included the summer solstice (23 June) with the longest photoperiod, but not the warmest day (30 July). The maximum daily increment rate of xylem growth is thought to be controlled by the photoperiod rather than by temperature. The daily mean temperature exceeded 20 °C after the summer solstice, indicating that temperature is not a limiting factor for xylem growth. This study suggests that the timing of maximum daily increment rates of xylem growth of P. densiflora is controlled by the photoperiod. 相似文献
914.
Crossover trials are used in a variety of fields, such as medicine, biology, psychology, and some commercial goods investigations. The aim of this paper is to extend a methodology for multiple comparisons to the problem of testing in crossover trials with two treatments. These two treatments are given in two orderings, treatment A first or treatment B first. We perform inference on the effect of one treatment relative to the effect of the other, without assuming that these effects are independent of treatment ordering, using techniques from order-restricted inference and multiple comparisons, and compare to some existing multiple comparison tests. 相似文献
915.
Targeted therapies based on biomarker profiling are becoming a mainstream direction of cancer research and treatment. Depending on the expression of specific prognostic biomarkers, targeted therapies assign different cancer drugs to subgroups of patients even if they are diagnosed with the same type of cancer by traditional means, such as tumor location. For example, Herceptin is only indicated for the subgroup of patients with HER2+ breast cancer, but not other types of breast cancer. However, subgroups like HER2+ breast cancer with effective targeted therapies are rare, and most cancer drugs are still being applied to large patient populations that include many patients who might not respond or benefit. Also, the response to targeted agents in humans is usually unpredictable. To address these issues, we propose subgroup-based adaptive (SUBA), designs that simultaneously search for prognostic subgroups and allocate patients adaptively to the best subgroup-specific treatments throughout the course of the trial. The main features of SUBA include the continuous reclassification of patient subgroups based on a random partition model and the adaptive allocation of patients to the best treatment arm based on posterior predictive probabilities. We compare the SUBA design with three alternative designs including equal randomization, outcome-adaptive randomization, and a design based on a probit regression. In simulation studies, we find that SUBA compares favorably against the alternatives. 相似文献
916.
Gilbert S. Omenn 《Statistics in biosciences》2016,8(1):1-7
Omics-based technology platforms have made new kinds of cancer profiling tests feasible. There are several valuable examples in clinical practice, and many more under development. A concerted, transparent process of discovery with lock-down of candidate assays and classifiers and clear specification of intended clinical use is essential. The Institute of Medicine has now proposed a three-stage scheme of confirming and validating analytical findings, validating performance on clinical specimens, and demonstrating explicit clinical utility for an approvable test (Micheel et al., Evolution of translational omics: lessons learned and path forward, 2012). 相似文献
917.
918.
Dynamic light scattering (DLS), also known as photon correlation spectroscopy (PCS), is a very powerful tool for studying the diffusion behaviour of macromolecules in solution. The diffusion coefficient, and hence the hydrodynamic radii calculated from it, depends on the size and shape of macromolecules. In this review, we provide evidence of the usefulness of DLS to study the homogeneity of proteins, nucleic acids, and complexes of protein–protein or protein–nucleic acid preparations, as well as to study protein–small molecule interactions. Further, we provide examples of DLS’s application both as a complementary method to analytical ultracentrifugation studies and as a screening tool to validate solution scattering models using determined hydrodynamic radii. 相似文献
919.
920.
Molecular dynamics (MD) simulations using all-atom and explicit solvent models provide valuable information on the detailed behavior of protein–partner substrate binding at the atomic level. As the power of computational resources increase, MD simulations are being used more widely and easily. However, it is still difficult to investigate the thermodynamic properties of protein–partner substrate binding and protein folding with conventional MD simulations. Enhanced sampling methods have been developed to sample conformations that reflect equilibrium conditions in a more efficient manner than conventional MD simulations, thereby allowing the construction of accurate free-energy landscapes. In this review, we discuss these enhanced sampling methods using a series of case-by-case examples. In particular, we review enhanced sampling methods conforming to trivial trajectory parallelization, virtual-system coupled multicanonical MD, and adaptive lambda square dynamics. These methods have been recently developed based on the existing method of multicanonical MD simulation. Their applications are reviewed with an emphasis on describing their practical implementation. In our concluding remarks we explore extensions of the enhanced sampling methods that may allow for even more efficient sampling. 相似文献