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Register a new userRate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model
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State-dependent Na+ channel blockers are often prescribed to treat cardiac arrhythmias, but many Na+ channel blockers are known to have pro-arrhythmic side effects. While the anti and proarrhythmic potential of a Na+ channel blocker is thought to depend on the characteristics of its rate-dependent block, the mechanisms linking these two attributes are unclear. Furthermore, how specific properties of rate-dependent block arise from the binding kinetics of a particular drug is poorly understood. Here, we examine the rate-dependent effects of the Na+ channel blocker lidocaine by constructing and analyzing a novel drug-channel interaction model. First, we identify the predominant mode of lidocaine binding in a 24 variable Markov model for lidocaine-Na+ channel interaction by Moreno et al. We then develop a novel 3-variable lidocaine-Na+ channel interaction model that incorporates only the predominant mode of drug binding. Our low-dimensional model replicates the extensive voltage-clamp data used to parameterize the Moreno et al. model. Furthermore, the effects of lidocaine on action potential upstroke velocity and conduction velocity in our model are similar to those predicted by the Moreno et al. model. By exploiting the low-dimensionality of our model, we derive an algebraic expression for level of rate-dependent block as a function of pacing frequency, restitution properties, diastolic and plateau potentials, and drug binding rate constants. Our model predicts that the level of rate-dependent block is sensitive to alterations in restitution properties and increases in diastolic potential, but it is insensitive to variations in the shape of the action potential waveform and lidocaine binding rates.
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Brain tissue is a heterogeneous material, constituted by a soft matrix filled with cerebrospinal fluid. The interactions between, and the complexity of each of these components are responsible for the non-linear rate-dependent behaviour that characterizes what is one of the most complex tissue in nature. Here, we investigate the influence of the cutting rate on the fracture properties of brain, through wire cutting experiments. We also present a model for the rate-dependent behaviour of fracture propagation in soft materials, which comprises the effects of fluid interaction through a poro-hyperelastic formulation. The method is developed in the framework of finite strain continuum mechanics, implemented in a commercial finite element code, and applied to the case of an edge-crack remotely loaded by a controlled displacement. Experimental and numerical results both show a toughening effect with increasing rates, which is linked to the energy dissipated by the fluid-solid interactions in the process zone ahead of the crack.
To enable personalized cancer treatment, machine learning models have been developed to predict drug response as a function of tumor and drug features. However, most algorithm development efforts have relied on cross validation within a single study to assess model accuracy. While an essential first step, cross validation within a biological data set typically provides an overly optimistic estimate of the prediction performance on independent test sets. To provide a more rigorous assessment of model generalizability between different studies, we use machine learning to analyze five publicly available cell line-based data sets: NCI60, CTRP, GDSC, CCLE and gCSI. Based on observed experimental variability across studies, we explore estimates of prediction upper bounds. We report performance results of a variety of machine learning models, with a multitasking deep neural network achieving the best cross-study generalizability. By multiple measures, models trained on CTRP yield the most accurate predictions on the remaining testing data, and gCSI is the most predictable among the cell line data sets included in this study. With these experiments and further simulations on partial data, two lessons emerge: (1) differences in viability assays can limit model generalizability across studies, and (2) drug diversity, more than tumor diversity, is crucial for raising model generalizability in preclinical screening.
Motivation: Predicting Drug-Target Interaction (DTI) is a well-studied topic in bioinformatics due to its relevance in the fields of proteomics and pharmaceutical research. Although many machine learning methods have been successfully applied in this task, few of them aim at leveraging the inherent heterogeneous graph structure in the DTI network to address the challenge. For better learning and interpreting the DTI topological structure and the similarity, it is desirable to have methods specifically for predicting interactions from the graph structure. Results: We present an end-to-end framework, DTI-GAT (Drug-Target Interaction prediction with Graph Attention networks) for DTI predictions. DTI-GAT incorporates a deep neural network architecture that operates on graph-structured data with the attention mechanism, which leverages both the interaction patterns and the features of drug and protein sequences. DTI-GAT facilitates the interpretation of the DTI topological structure by assigning different attention weights to each node with the self-attention mechanism. Experimental evaluations show that DTI-GAT outperforms various state-of-the-art systems on the binary DTI prediction problem. Moreover, the independent study results further demonstrate that our model can be generalized better than other conventional methods. Availability: The source code and all datasets are available at https://github.com/Haiyang-W/DTI-GRAPH
Microbial-Induced Carbonate Precipitation (MICP) has been explored for more than a decade as a promising soil improvement technique. However, it is still challenging to predict and control the growth rate and characteristics of CaCO3 precipitates, which directly affect the engineering performance of MICP-treated soils. In this study, we employ a microfluidics-based pore scale model to observe the effect of bacterial density on the growth rate and characteristics of CaCO3 precipitates during MICP processes occurring at the sand particle scale. Results show that the precipitation rate of CaCO3 increases with bacterial density in the range between 0.6e8 and 5.2e8 cells/ml. Bacterial density also affects both the size and number of CaCO3 crystals. A low bacterial density of 0.6e8 cells/ml produced 1.1e6 crystals/ml with an average crystal volume of 8,000 um3, whereas a high bacterial density of 5.2e8 cells/ml resulted in more crystals (2.0e7 crystals/ml) but with a smaller average crystal volume of 450 um3. The produced CaCO3 crystals were stable when the bacterial density was 0.6e8 cells/ml. When the bacterial density was 4-10 times higher, the crystals were first unstable and then transformed into more stable CaCO3 crystals. This suggests that bacterial density should be an important consideration in the design of MICP protocols.
Although the open-field test has been widely used, its reliability and compatibility are frequently questioned. Although many indicating parameters were introduced for this test, they did not take data distributions into consideration. This oversight may have caused the problems mentioned above. Here, an exploratory approach for the analysis of video records of tests of elderly mice was taken that described the distributions using the least number of parameters. First, the locomotor activity of the animals was separated into two clusters: dash and search. The accelerations found in each of the clusters were distributed normally. The speed and the duration of the clusters exhibited an exponential distribution. Although the exponential model includes a single parameter, an additional parameter that indicated instability of the behaviour was required in many cases for fitting to the data. As this instability parameter exhibited an inverse correlation with speed, the function of the brain that maintained stability would be required for a better performance. According to the distributions, the travel distance, which has been regarded as an important indicator, was not a robust estimator of the animals condition.
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