Binding Modes of Peptidomimetics Designed to Inhibit STAT3

STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers. Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities. Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions involving the SH2 domain and phosphotyrosine(pTyr)-based inhibitors. We also discovered a stable novel binding mode that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing dimerization of cancer target protein STAT3

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Enhanced SOGI controller for weak grid integrated solar PV system

This paper presents a two-stage three-phase solar photovoltaic (PV) system, which is controlled through a novel enhanced second order generalized integrator (ESOGI) based control technique. The proposed ESOGI is used for fundamental component extraction from nonlinear load current and distorted grid voltages. The proposed integrator effectively and simultaneously manages to address the DC offset, inter-harmonic and integrator delay problems of the traditional SOGI. In addition, the proposed control technique provides power factor correction, harmonic elimination, and load balancing functionalities. The ESOGI controller is used to generate reference grid currents for controlling the voltage source converter (VSC), interfacing the PV panel with the grid. Extensive simulation and experimental results, on a developed prototype in the laboratory, depict that the total harmonic distortion (THD) of the grid injected currents and voltages are found well under IEEE-519 standard

Prediction interval estimation for electricity price and demand using support vector machines

Uncertainty is known to be a concomitant factor of almost all the real world commodities such as oil prices, stock prices, sales and demand of products. As a consequence, forecasting problems are becoming more and more challenging and ridden with uncertainty. Such uncertainties are generally quantified by statistical tools such as prediction intervals (Pis). Pis quantify the uncertainty related to forecasts by estimating the ranges of the targeted quantities. Pis generated by traditional neural network based approaches are limited by high computational burden and impractical assumptions about the distribution of the data. A novel technique for constructing high quality Pis using support vector machines (SVMs) is being proposed in this paper. The proposed technique directly estimates the upper and lower bounds of the PI in a short time and without any assumptions about the data distribution. The SVM parameters are tuned using particle swarm optimization technique by minimization of a modified Pi-based objective function. Electricity price and demand data of the Ontario electricity market is used to validate the performance of the proposed technique. Several case studies for different months indicate the superior performance of the proposed method in terms of high quality PI generation and shorter computational times

Automated error correction in IBM quantum computer and explicit generalization

Construction of a fault-tolerant quantum computer remains a challenging problem due to unavoidable noise and fragile quantum states. However, this goal can be achieved by introducing quantum error-correcting codes. Here, we experimentally realize an automated error correction code and demonstrate the nondestructive discrimination of GHZ states in IBM 5-qubit quantum computer. After performing quantum state tomography, we obtain the experimental results with a high fidelity. Finally, we generalize the investigated code for maximally entangled n-qudit case, which could both detect and automatically correct any arbitrary phase-change error, or any phase-flip error, or any bit-flip error, or combined error of all types of error

Pattern mining approaches used in social media data

Social media conveys a reachable platform for users to share information. The inescapable practice of social media has produced remarkable volumes of social data. Social media gathers the data in both structured-unstructured and formal-informal ways as users are not concerned with the exact grammatical structure and spelling when interacting with each other by means of various social networking websites (Twitter, Facebook, YouTube, LinkedIn, etc.). People are increasingly involved in and dependent on social media networks for data, news and opinions of other handlers on a variety of topics. The strong dependence on social media network sites contributes to enormous data generation characterized by three issues: scale, noise, and variety. Such problems also hinder social network data to be evaluated manually, resulting in the correct use of statistical analytical methods. Mining social media data can extract significant patterns that can be advantageous for consumers, users, and business. Pattern mining offers a wide variety of methods to detect valuable knowledge from huge datasets, such as patterns, trends, and rules. In this work, data was collected comprised of users’ opinions and sentiments and then processed using a significant number of pattern mining methods. The results were then further analyzed to attain meaningful information. The aim of this paper is to deliver a summary and a set of strategies for utilizing the ubiquitous pattern mining approaches, and to recognize the challenges and future research guidelines of dealing out social media data