Project description:Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.
Project description:Fluids of charged particles act as the supporting medium for chemical reactions and physical, dynamical, and biological processes. The local structure in an electrolytic background is deformed by micro- and nanoscopic polarizable objects. Vice versa, the forces between the objects are regulated by the cohesive properties of the background. We study here the range and strength of these forces and the microscopic origin from which they emerge. We find the forces to be sensitively dependent on the material properties of the charged fluid and the immersed solutes. The induced interactions can be varied over decades, offering high tunability and aided by accurate theory, control in experiments and applications. To distinguish correlational effects from simple ionic screening, we describe electrolyte-induced forces between neutral objects. The interplay of thermal motion, short-range repulsions, and electrostatic forces is responsible for a soft structure in the fluid. This structure changes near polarizable interfaces and causes diverse attractions between confining walls that seem well-exploited by microbiological systems. For parameters that correspond to monovalent electrolytes in biologically and technologically relevant aqueous environments, we find induced forces between nanoscopic areas of the order of piconewtons over a few nanometers.
Project description:Metasurfaces as artificially nanostructured interfaces hold significant potential for multi-functionality, which may play a pivotal role in the next-generation compact nano-devices. The majority of multi-tasked metasurfaces encode or encrypt multi-information either into the carefully tailored metasurfaces or in pre-set complex incident beam arrays. Here, we propose and demonstrate a multi-momentum transformation metasurface (i.e., meta-transformer), by fully synergizing intrinsic properties of light, e.g., orbital angular momentum (OAM) and linear momentum (LM), with a fixed phase profile imparted by a metasurface. The OAM meta-transformer reconstructs different topologically charged beams into on-axis distinct patterns in the same plane. The LM meta-transformer converts red, green and blue illuminations to the on-axis images of "R", "G" and "B" as well as vivid color holograms, respectively. Thanks to the infinite states of light-metasurface phase combinations, such ultra-compact meta-transformer has potential in information storage, nanophotonics, optical integration and optical encryption.
Project description:An accelerated thermal aging process was used to simulate the condition of paper insulation in transformer oil-paper systems. Optical parameters of the insulation paper after various aging intervals were analyzed with terahertz time-domain spectroscopy (THz-TDS) over the range 0.1~1.8 THz. The result shows that the paper had seven absorption peaks at 0.19, 0.49, 0.82, 1.19, 1.43, 1.53, and 1.74 THz, and density functional theory of B3LYP/6-311G+ (d, p) was used to simulate the molecular dynamics of the repeating component (cellobiose) of the cellulose paper. Theoretical spectra were consistent with experiment, which had absorption peaks at 0.18, 0.82, 1.47, and 1.53 THz in the same frequency range. At the same time, the paper samples after various aging intervals had different refractive indexes, and least squares fitting revealed a linear relationship between the degree of polymerization and the refractive index of the paper. Hence, this paper demonstrates that THz-TDS could be used to analyze the aging condition of transformer insulation paper and provides the theoretical and experimental basis for detection.
Project description:The poorly physical and psychological conditions of the patients make the body thermal protection crucial in the perioperative context, due to the risk of hypothermia. The lack of evidence regarding the effectiveness of textile coverings in protecting patients in the operating room, underscores the recommendation of the forced warming system using non-woven fabric for ensuring the best thermal protection in the perioperative context. This study is part of a development process of a three-layered thermal insulation system, a blanket for use in the perioperative context. After previous selection of two fabrics for the mid and outer layers, in this study three fabric samples for the inner layer with same soft tactile sensation and different textile compositions were tested to find its effect on increasing the thermal insulation of the whole set, using a thermal manikin. The serial method was used to calculate the thermal insulation properties of the sets. The best thermal insulation and thermal comfort performance was obtained by the set using an inner layer composed of polypropylene, polyamide, and elastane whose results were the highest thermal conductivity and thickness and the lowest maximum stationary heat flow density. The results indicated that this fabric influenced positively the values of the whole set once increased its thermal protection effectiveness when compared to the other tested sets. This set is more suitable for future testing in patients during their stay in the perioperative setting.
Project description:Polymer dielectrics, an insulating material ubiquitous in electrical power systems, must be ultralight, mechanically and dielectrically strong, and very thermally conductive. However, electric and thermal transport parameters are intercorrelated in a way that works against the occurrence of thermally conductive polymer electric insulators. Here, we describe how solution gel-shearing–strained polyethylene yields an electric insulating material with an outstanding in-plane thermal conductivity of 10.74 W m−1 K−1 and an average dielectric constant of 4.1. The dielectric constant and loss of such sheared polymer electric insulators are nearly independent of the frequency and a wide temperature range. The gel-shearing aligns ultrahigh–molecular weight polymer crystalline chains for the formation of separated and aligned nanoscale fibrous arrays. Together with lattice strains and the presence of boron nitride nanosheets, the dielectric polymer shows high current density carrying and high operating temperature, which is attributed to greatly enhanced heat conduction.
Project description:Janus kinase 2 (JAK2) inhibitors represent a promising therapeutic class of anticancer agents against many myeloproliferative disorders. Bioactivity data on pIC 50 of 2229 JAK2 inhibitors were employed in the construction of quantitative structure-activity relationship (QSAR) models. The models were built from 100 data splits using decision tree (DT), support vector machine (SVM), deep neural network (DNN) and random forest (RF). The predictive power of RF models were assessed via 10-fold cross validation, which afforded excellent predictive performance with R 2 and RMSE of 0.74 ± 0.05 and 0.63 ± 0.05, respectively. Moreover, test set has excellent performance of R 2 (0.75 ± 0.03) and RMSE (0.62 ± 0.04). In addition, Y-scrambling was utilized to evaluate the possibility of chance correlation of the predictive model. A thorough analysis of the substructure fingerprint count was conducted to provide insights on the inhibitory properties of JAK2 inhibitors. Molecular cluster analysis revealed that pyrazine scaffolds have nanomolar potency against JAK2.
Project description:Quantitative structure-activity relationship (QSAR) models are useful in understanding how chemical structure relates to the biological activity of natural and synthetic chemicals and for design of newer and better therapeutics. In the present study, 46 flavonoids and related polyphenols were evaluated for direct/indirect antioxidant activity in three different assay systems of increasing complexity (chemical, enzymatic, and intact phagocytes). Based on these data, two different QSAR models were developed using (i) physicochemical and structural (PC&S) descriptors to generate multiparameter partial least squares (PLS) regression equations derived from optimized molecular structures of the tested compounds and (ii) a partial 3D comparison of the 46 compounds with local fingerprints obtained from fragments of the molecules by the frontal polygon (FP) method. We obtained much higher QSAR correlation coefficients (r) for flavonoid end-point antioxidant activity in all three assay systems using the FP method (0.966, 0.948, and 0.965 for datasets evaluated in the biochemical, enzymatic, and whole cell assay systems, respectively). Furthermore, high leave-one-out cross-validation coefficients (q2) of 0.907, 0.821, and 0.897 for these datasets, respectively, indicated enhanced predictive ability and robustness of the model. Using the FP method, structural fragments (submolecules) responsible for the end-point antioxidant activity in the three assay systems were also identified. To our knowledge, this is the first QSAR model derived for description of flavonoid direct/indirect antioxidant effects in a cellular system, and this model could form the basis for further drug development of flavonoid-like antioxidant compounds with therapeutic potential.
Project description:In vivo and ex vivo sensors have the potential to aid tracking and anti-poaching endeavours and provide new insights into rhinoceros physiology and environment. However, the propagation of electromagnetic signals in rhinoceros tissue is currently not known. We present simulation and agar models of the rhinoceros that allow the investigation of electromagnetic propagation by in vivo and ex vivo devices without the need for surgery. Since the dielectric properties of rhinoceros tissue have not been documented, the conductivity and permittivity of the skin, fat, muscle, blood and other organs are first approximated by means of a meta-analysis that includes animals with similar physical properties. Subsequently, we develop anatomical models that include dermal layers, internal organs and a skeleton. We also develop a flank model that serves as an approximation of the anatomical model in certain situations. These models are used to determine the viability of communication between an in vivo device and an ex vivo device attached to the hind leg of the animal. Two types of antenna (microstrip-fed planar elliptical monopole antenna and printed inverted-F antenna) and three feasible implant locations (back, neck and chest) are considered. In addition to the computer models, phantom recipes using salt, sugar and agar are developed to match the dielectric properties of each tissue type at the industrial, scientific and medical (ISM) frequencies of 403MHz, 910MHz and 2.4GHz. The average error between the measured and theoretically predicted dielectric values was 6.22% over all recipes and 4.49% for the 2.4 GHz recipe specifically. When considering the predicted efficiency of the transmitting and receiving antennas, an agreement of 67.38% was demonstrated between the computer simulations and laboratory measurements using the agar rhinoceros flank models. Computer simulations using the anatomical model of the rhinoceros indicate that the chest is the optimal implant location and that best signal propagation is achieved using the planar inverted-F antenna (PIFA). Using this configuration, the simulations indicate that communication between the implant and an ex vivo device attached to the hind leg is challenging but possible. Furthermore, we find that the inclusion of factors such as the density and temperature of the phantom materials were found to be critical to the achievement of good agreement between practice and simulation.