Predicting Autoxidation of Sulfides in Drug-like Molecules Using Quantum Mechanical/Density Functional Theory Methods.

Autoxidation of drugs and drug-like molecules is a major concern in the development of safe and effective therapeutics. Because active pharmaceutical ingredients (APIs) that contain sulfur atoms can form sulfoxides under oxidative stress, predicting oxidative susceptibilities within an organic molecule can have a major impact in accelerating the compound's stability assessment. For investigation of a sulfur atom's oxidative stability, density functional theory (DFT) methods were applied to accurately predict S-O estimated bond dissociation enthalpies (BDEs) of sulfoxides. Our process employed B3LYP/6-31+G(d) for geometry optimization and frequency calculation, and we employed B3P86/6-311++G(2df,2p) to obtain electronic energies from single-point energy calculations. A total of 84 drug-like molecules containing 50 different sulfide scaffolds were used to develop a risk scale. Our results showed that when S-O BDE is less than 69 kcal/mol, the sulfur atom has low oxidative susceptibility. High oxidation risk occurs when the S-O BDE is greater than 75 kcal/mol. The risk scale was successful in predicting the relative propensities of sulfide oxidation among the small organic molecules and commercial drugs examined.

Thermally generated spin current in the topological insulator Bi2Se3.

We present measurements of thermally generated transverse spin currents in the topological insulator Bi2Se3, thereby completing measurements of interconversions among the full triad of thermal gradients, charge currents, and spin currents. We accomplish this by comparing the spin Nernst magneto-thermopower to the spin Hall magnetoresistance for bilayers of Bi2Se3/CoFeB. We find that Bi2Se3 does generate substantial thermally driven spin currents. A lower bound for the ratio of spin current density to thermal gradient is [Formula: see text] = (4.9 ± 0.9) × 106 [Formula: see text], and a lower bound for the magnitude of the spin Nernst ratio is -0.61 ± 0.11. The spin Nernst ratio for Bi2Se3 is the largest among all materials measured to date, two to three times larger compared to previous measurements for the heavy metals Pt and W. Strong thermally generated spin currents in Bi2Se3 can be understood via Mott relations to be due to an overall large spin Hall conductivity and its dependence on electron energy.

Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes.

Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. SIGNIFICANCE: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517.

Alkali metal halide-coated perovskite redox catalysts for anaerobic oxidative dehydrogenation of n-butane.

Oxidative dehydrogenation (ODH) of n-butane has the potential to efficiently produce butadiene without equilibrium limitation or coke formation. Despite extensive research efforts, single-pass butadiene yields are limited to <23% in conventional catalytic ODH with gaseous O2. This article reports molten LiBr as an effective promoter to modify a redox-active perovskite oxide, i.e., La0.8Sr0.2FeO3 (LSF), for chemical looping-oxidative dehydrogenation of n-butane (CL-ODHB). Under the working state, the redox catalyst is composed of a molten LiBr layer covering the solid LSF substrate. Characterizations and ab initio molecular dynamics (AIMD) simulations indicate that peroxide species formed on LSF react with molten LiBr to form active atomic Br, which act as reaction intermediates for C─H bond activation. Meanwhile, molten LiBr layer inhibits unselective CO2 formation, leading to 42.5% butadiene yield. The redox catalyst design strategy can be extended to CL-ODH of other light alkanes such as iso-butane conversion to iso-butylene, providing a generalized approach for olefin production.

Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth.

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.

Predicting Total Electron-Ionization Cross Sections and GC-MS Calibration Factors Using Machine Learning.

Concentrations in GC-MS using electron-ionization mass spectrometry can be determined without pure calibration standards through prediction of relative total-ionization cross sections. An atom- and group-based artificial neural network (FF-NN-AG) model is created to generate EI cross sections and calibrations for organic compounds. This model is easy to implement and is more accurate than the widely used atom-additivity-based correlation of Fitch and Sauter (Anal. Chem. 1983). Ninety-two new measurements of experimental EI cross sections (70-75 eV) are joined with different interlaboratory datasets, creating a 396-compound cross-section database, the largest to date. The FF-NN-AG model uses 16 atom-type descriptors, 79 structural-group descriptors, and one hidden layer of 10 nodes, trained 500 times. In each cycle, 96% of the compounds in this database are freshly chosen at random, and then the model is tested with the remaining 4%. The resulting r2 is 0.992 versus 0.904 for the Fitch and Sauter correlation, root mean square deviation is 2.8 versus 9.2, and maximum relative error is 0.30 versus 0.73. As an example of the model's use, a list of cross sections is generated for various sugars and anhydrosugars.

Effects of Anisotropic Strain on Spin-Orbit Torque Produced by the Dirac Nodal Line Semimetal IrO2.

We report spin-torque ferromagnetic resonance studies of the efficiency of the damping-like (ξDL) spin-orbit torque exerted on an adjacent ferromagnet film by current flowing in epitaxial (001) and (110) IrO2 thin films. IrO2 possesses Dirac nodal lines (DNLs) in the band structure that are gapped by spin-orbit coupling, which could enable a very high spin Hall conductivity, σSH. We find that the (001) films do exhibit exceptionally high ξDL ranging from 0.45 at 293 K to 0.65 at 30 K, which sets the lower bounds of σSH to be 1.9 × 105 and 3.75 × 105 Ω-1 m-1, respectively, 10 times higher and of opposite sign than the theoretical prediction. Furthermore, ξDL and σSH are substantially reduced in anisotropically strained (110) films. We suggest that this high sensitivity to anisotropic strain is because of changes in contributions to σSH near the DNLs.

Manipulation of the van der Waals Magnet Cr2Ge2Te6 by Spin-Orbit Torques.

We report measurements of current-induced thermoelectric and spin-orbit torque effects within devices in which multilayers of the semiconducting two-dimensional van der Waals magnet Cr2Ge2Te6 (CGT) are integrated with Pt and Ta metal overlayers. We show that the magnetic orientation of the CGT can be detected accurately either electrically (using an anomalous Hall effect) or optically (using magnetic circular dichroism) with good consistency. The samples exhibit large thermoelectric effects, but nevertheless, the spin-orbit torque can be measured quantitatively using the angle-dependent second harmonic Hall technique. For CGT/Pt, we measure the spin-orbit torque efficiency to be similar to conventional metallic-ferromagnet/Pt devices with the same Pt resistivity. The interfacial transparency for spin currents is therefore similar in both classes of devices. Our results demonstrate the promise of incorporating semiconducting 2D magnets within spin-orbitronic and magneto-thermal devices.

Aurora kinase A-mediated phosphorylation of mPOU at a specific site drives skeletal muscle differentiation.

Aurora kinases are Ser/Thr-directed protein kinases which play pivotal roles in mitosis. Recent evidences highlight the importance of these kinases in multiple biological events including skeletal muscle differentiation. Our earlier study identified the transcription factor POU6F1 (or mPOU) as a novel Aurora kinase (Aurk) A substrate. Here, we report that Aurora kinase A phosphorylates mPOU at Ser197 and inhibit its DNA-binding ability. Delving into mPOU physiology, we find that the phospho-mimic (S197D) mPOU mutant exhibits enhancement, while the wild type or the phospho-deficient mutant shows retardation in C2C12 myoblast differentiation. Interestingly, POU6F1 depletion phenocopies S197D-mPOU overexpression in the differentiation context. Collectively, our results signify mPOU as a negative regulator of skeletal muscle differentiation and strengthen the importance of AurkA in skeletal myogenesis.

Haploinsufficient tumor suppressor Tip60 negatively regulates oncogenic Aurora B kinase.

The Aurora kinases represent a group of serine/threonine kinases which are crucial regulators of mitosis. Dysregulated Aurora kinase B (AurkB) expression, stemming from genomic amplification, increased gene transcription or overexpression of its allosteric activators, is capable of initiating and sustaining malignant phenotypes. Although AurkB level in cells is well-orchestrated, studies that relate to its stability or activity, independent of mitosis, are lacking. We report that AurkB undergoes acetylation in vitro by lysine acetyltransferases (KATs) belonging to different families, namely by p300 and Tip60. The haploinsufficient tumor suppressor Tip60 acetylates two highly conserved lysine residues within the kinase domain of AurkB which not only impinges the protein stability but also its kinase activity. These results signify a probable outcome on the increase in "overall activity" of AurkB upon Tip60 downregulation, as observed under cancerous conditions. The present work, therefore, uncovers an important functional interplay between AurkB and Tip60, frailty of which may be an initial event in carcinogenesis.

Unraveling the role of aurora A beyond centrosomes and spindle assembly: implications in muscle differentiation.

Aurora kinases are critical mitotic serine/threonine kinases and are often implicated in tumorigenesis. Recent studies of the interphase functions for aurora kinase (Aurk)A have considerably expanded our understanding of its role beyond mitosis. To identify the unknown targets of AurkA, we used peptide array-based screening and found E2F4 to be a novel substrate. Phosphorylation of E2F4 by AurkA at Ser75 regulates its DNA binding and subcellular localization. Because E2F4 plays an important role in skeletal muscle differentiation, we attempted to gain insight into E2F4 phosphorylation in this context. We observed that a block in E2F4 phosphorylation retained it better within the nucleus and inhibited muscle differentiation. RNA sequencing analysis revealed a perturbation of the gene network involved in the process of muscle differentiation and mitochondrial biogenesis. Collectively, our findings establish a novel role of AurkA in the process of skeletal muscle differentiation.-Dhanasekaran, K., Bose, A., Rao, V. J., Boopathi, R., Shankar, S. R., Rao, V. K., Swaminathan, A., Vasudevan, M., Taneja, R., Kundu, T. K. Unravelling the role of aurora A beyond centrosomes and spindle assembly: implications in muscle differentiation.

Gyrator Based on Magneto-elastic Coupling at a Ferromagnetic/Piezoelectric Interface.

A gyrator is a non-reciprocal two port device with 180° phase shift in the transmissions between two ports. Though electromagnetic realizations of gyrators have been well studied, devices based on other forms of interaction are relatively unexplored. Here we demonstrate a device in which signal is transmitted via magneto-elastic coupling, can function as a gyrator. The device is built on a piezoelectric substrate: one port of this device has interdigital transducers (IDTs) and the other port has a periodic array of nickel/gold lines. When the magnetizations of Ni lines are excited into precession by magnetic field generated by passing oscillating current through the gold lines, they emit phonons in the form of surface acoustic waves (SAW) due to the magneto-elastic coupling between Ni and substrate. The emitted SAW can be detected at the other end by the IDTs. Conversely, when SAW is incident on Ni lines from IDTs, the magnetization undergoes precession and can be inductively detected by Au lines. The broken time reversal symmetry of the system due to the presence of ferromagnet gives rise to the non-reciprocal transmission between the two ports. These devices could function as novel building blocks for phonon based information processing.

Surface effect on the electromelting behavior of nanoconfined water.

Electric field induced phase transitions of confined water have an important role in cryopreservation and electrocrystallization. In this study, the structural and dynamical properties of nano-confined water in nano-slit pores under the influence of an electric field varying from 0 to 10 V nm(-1) are investigated under ambient conditions using molecular dynamics simulations. In order to replicate the nature of different materials, a systematic approach is adopted, including pore-size and lattice constant variations in different lattice arrangements viz., triangular, square and hexagonal, with hydrophilic and hydrophobic surface-fluid interactions. The structural behavior of water is investigated using radial distribution functions, bond order parameters and hydrogen bond calculations; the dynamical properties are analyzed using lateral and rotational diffusivity calculations. The lateral diffusivity with increasing electric field E increases by order(s) of magnitude during electromelting. The pore-size, lattice constant, lattice arrangement and hydrophobic/hydrophilic nature of the pore surface strongly influence the electromelting behavior for E≤∼7 V nm(-1). Higher values of lattice constants and/or hydrophobic pores enhance the electromelting behavior of nanoconfined water.