Transverse Spin Diffusion in a Dilute Spin-Polarized Degenerate Fermi Gas

We re-examine the calculation of the transverse spin-diffusion coefficient in a dilute degenerate spin-polarized Fermi gas, for the case of s-wave scattering. The special feature of this limit is that the dependence of the spin diffusion coefficient on temperature and field can be calculated explicitly with no further approximations. This exact solution uncovers a novel intermediate behavior between the high field spin-rotation dominated regime in which $D_{\bot} \propto H^{-2}$, $D_{\parallel} \propto T^{-2}$, and the low-field isotropic, collision dominated regime with $D_{\bot} = D_{\parallel} \propto T^{-2}$. In this intermediate regime, $D_{\bot ,\parallel} \propto T^{-2}$ but $D_{\bot} \neq D_{\parallel}$. We also present an analytical calculation of the self-energy in the s-wave approximation for a dilute spin-polarized Fermi gas, at zero temperature. This emphasizes the failure of the conventional Fermi-liquid phase space arguments for processes involving spin flips. We close by reviewing the evidence for the existence of the intermediate regime in experiments on weakly spin-polarized $^3{\rm He}$ and $^3{\rm He} - ^4{\rm He}$ mixtures.Comment: 38 pages, Latex-Revtex, 9 PostScript figures. Minor revisions, misprints corrected, references adde

Assessment and control of geodynamical risks under the conditions of a rock-bump hazardous complex deposit

Research has been carried out to study the peculiarities of rockbump hazards and induced seismic manifestations at the Nikolaevskoe deposit, and their close correlation with the tectonic structure of the rock massif has been established. In order to strengthen control over the rock-bump hazard in the TN-3 high-angle fault, in 2019 the observation network was expanded and continuous seismoacoustic monitoring of the rock mass at the deep levels of Nikolaevskoe deposit was organized. Monitoring data is verified by local geoacoustic method using the portable device “Prognoz L”. The results of the monitoring revealed major acoustically active zone with the main amount of seismic and acoustic events recorded during the last 5 years and occurring dynamic rock pressure manifestations. Nikolaevskoe deposit was the site of execution of the industrial experiment on regional discharge of a potentially rock-bump hazardous section of a shock blasting massif

Benchmarking tools for in silico cysteine pKa prediction

Accurate estimation of the pKa’s of cysteine residues in proteins could inform targeted approaches in hit discovery. The pKa of a targetable cysteine residue in a disease-related protein is an important physiochemical parameter in covalent drug discovery, as it influences the fraction of nucleophilic thiolate amenable to chemical protein modification. Traditional structure-based in silico tools are limited in their predictive accuracy of cysteine pKa’s relative to other titratable residues. Additionally, there are limited comprehensive benchmark assessments for cysteine pKa predictive tools. This raises the need for exten-sive assessment and evaluation of methods for cysteine pKa prediction. Here, we report the performance of several computa-tional pKa methods, including structure-based and ensemble-based sampling approaches, on a diverse test set of experimental cysteine pKa’s retrieved from the PKAD database. The dataset consisted of 16 wildtype and 10 mutant proteins with experimentally measured cysteine pKa values. Our results highlight that these methods are varied in their overall predictive accura-cies. Among the test set of wildtype proteins evaluated, the best method yielded a mean absolute error of 2.3 pK units — highlighting the need for improvement of existing pKa methods for accurate cysteine pKa estimation. Given the limited accuracy of these methods, further development is needed before these approaches can be routinely employed to drive design decisions in early drug discovery efforts

Benchmarking in silico Tools for Cysteine pKa Prediction

Accurate estimation of the pKas of cysteine residues in proteins could inform targeted approaches in hit discovery. The pKa of a targetable cysteine residue in a disease-related protein is an important physiochemical parameter in covalent drug dis- covery, as it influences the fraction of nucleophilic thiolate amenable to chemical protein modification. Traditional structure-based in silico tools are limited in their predictive accuracy of cysteine pKas relative to other titratable residues. Additionally, there are limited comprehensive benchmark assessments for cysteine pKa predictive tools. This raises the need for extensive assessment and evaluation of methods for cysteine pKa prediction. Here, we report the performance of several computational pKa methods, including single structure and ensemble-based approaches, on a diverse test set of experimental cysteine pKas retrieved from the PKAD data- base. The dataset consisted of 16 wildtype and 10 mutant proteins with experimentally measured cysteine pKa values. Our results highlight that these methods are varied in their overall predictive accuracies. Among the test set of wildtype proteins evaluated, the best method yielded a mean absolute error of 2.3 pK units highlighting the need for improvement of existing pKa methods for accurate cysteine pKa estimation. Given the limited accuracy of these methods, further development is needed before these approaches can be routinely employed to drive design decisions in early drug discovery efforts

Data processing method for experimental studies of deformation in a rock sample under uniaxial compression

As a result of experimental and theoretical studies, the patterns of behavior of rocks in a condition close to destructive are the focal nature of the preparation of macrocracking, which allowed us to include the mesocrack structure of the material, which is the main element in the preparation of macrocracking. Differences in this new approach to mathematical modeling will let adequately describe dissipative mesocrack structures of various hierarchical levels of geodesy, predict dynamic changes, structures and mechanical properties of both rock samples and massif, which also lead to resource-intensive experimental studies. In this paper, with usage of the methods of cluster, factor, and statistical analysis, we set the task of processing the data of experimental studies of the laws of deformation and preparing macro-fracture of rock samples by various methods, including acoustic and deformation observations

Molecular Insights into the Binding Interaction of the First Class of Potent Small Molecules Disrupting the YAP-TEAD Protein-Protein Interaction

Disruption of the YAP-TEAD protein-protein interaction is an attractive therapeutic strategy for oncology to suppress tumour progression and cancer metastasis. YAP binds to TEAD at a large flat binding interface (~3500 2) devoid of a well-defined druggable pocket, so it has been difficult to design low molecular weight compounds to abrogate this protein-protein interaction directly. Recently, work by Furet and coworkers (ChemMedChem 2022, DOI: 10.1002/cmdc.202200303) reported the discovery of the first class of small molecules able to efficiently disrupt the transcriptional activity of TEAD by binding to a specific interaction site of the YAP-TEAD binding interface. Using high-throughput in silico docking and structure-based drug design, they identified a virtual screening hit from a hot-spot derived from their previously rationally designed peptidic inhibitor. Given advances in rapid high-throughput screening and rational approaches to peptidic ligand discovery for challenging targets, we analyzed the pharmacophore features involved in transferring from their peptidic to small molecule inhibitor that could enable small molecule discovery for such targets. Here, we show that pharmacophore analysis augmented by solvation analysis of molecular dynamics trajectories can guide the designs while binding free energy calculations provide greater insight into the binding conformation and energetics accompanying the association event. The computed binding free energy estimates agree with experimental findings and offer useful insight into structural determinants that influence ligand binding to the TEAD interaction surface, even for such a shallow binding site. In general, our results provide rationale for the structure-based design efforts in compound optimization that led to a significant gain in potency among the first class of potent small molecule YAP:TEAD protein-protein inhibitors

Molecular Insights into the Binding Interaction of the First Class of Potent Small Molecules Disrupting the YAP-TEAD Protein-Protein Interaction

Disruption of the YAP-TEAD protein-protein interaction is an attractive therapeutic strategy for oncology to suppress tumour progression and cancer metastasis. YAP binds to TEAD at a large flat binding interface (~3500 Å2) devoid of a well-defined druggable pocket, so it has been difficult to design low molecular weight compounds to abrogate this protein-protein interaction directly. Recently, work by Furet and coworkers (ChemMedChem 2022, DOI: 10.1002/cmdc.202200303) reported the discovery of the first class of small molecules able to efficiently disrupt the transcriptional activity of TEAD by binding to a specific interaction site of the YAP-TEAD binding interface. Using high-throughput in-silico docking and structure-based drug design, they identified a virtual screening hit from a hot-spot derived from their previously rationally designed peptidic inhibitor. Given the advances in rapid high-throughput screening and rational approaches to peptidic ligand discovery for challenging targets, we analyzed the pharmacophore features involved in transferring from their peptidic to small molecule inhibitor that could enable small molecule discovery for such targets. Here, we show that pharmacophore analysis augmented by solvation analysis of molecular dynamics trajectories can guide the designs while binding free energy calculations provide greater insight into the binding conformation and energetics accompanying the association event. The computed binding free energy estimates agree with experimental findings and offer useful insight into structural determinants that influence ligand binding to the TEAD interaction surface, even for such a shallow binding site. In general, our results provide rationale for the structure-based design efforts in compound optimization that led to a significant gain in potency among the first class of potent small molecule YAP:TEAD protein-protein inhibitors

Ultrasonic Spectrum Analysis of Granite Damage Evolution Based on Dry-Coupled Ultrasonic Monitoring Technology

The self-developed dry-coupled rock ultrasonic monitoring system is adopted to set up a multidirectional and multiwaveform ultrasonic monitoring network, which aims to analyse the evolution law of acoustic spectrum parameters in the process of granite loading failure under uniaxial compression, to explore the dominant acoustic spectrum characteristic information at different stages of granite loading, and to verify in situ the damage monitoring of time-effect deformation. The results show that the wave velocity, amplitude, and amplitude-frequency of the first wave and the velocity of P-wave and S-wave show a significant upward trend in the rock compaction section. After entering the elastic stage, the three spectral parameters become peacefully stable, and the stage transformation is obvious. In the stable crack growth stage, with the initiation of the crack, the dominant frequency of S-wave shows a significant stage transition compared with the global ultrasonic wave velocity and the first arrived amplitude, and the dominant frequency decreases by 6%. In the unstable crack growth stage, the three acoustic spectrum parameters present obvious downward trend, and the first arrived wave amplitude of S-wave is found to have a significant decline of 39.1%. On the eve of failure, the amplitude-frequency of S-wave shows different feature from the P-wave; that is, S-wave transfers from the state of multipeak in wide frequency to the state of single peak in low frequency, which is the failure precursor of the rock sample

Building new bridges between in vitro and in vivo in early drug discovery: Where molecular modeling meets systems biology

Cellular drug targets exist within networked function-generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e. inputs). Cellular phenotypic behaviors are manifested through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations. We propose that cells act as analog computers, “solving” sets of coupled “molecular differential equations” (i.e. represented by populations of interacting species) via “integration” of the dynamic state probability distributions among those populations. Disconnects between biochemical and functional/phenotypic assays (cellular/in vivo) may arise with targetcontaining systems that operate far from equilibrium, and/or when coupled contributions (including target-cognate partner binding and drug pharmacokinetics) are neglected in the analysis of biochemical results. The transformation of drug discovery from a trial-and-error endeavor to one based on reliable design criteria depends on improved understanding of the dynamic mechanisms powering cellular function/dysfunction at the systems level. Here, we address the general mechanisms of molecular and cellular function and pharmacological modulation thereof. We outline a first principles theory on the mechanisms by which free energy is stored and transduced into biological function, and by which biological function is modulated by drug-target binding. We propose that cellular function depends on dynamic counter-balanced molecular systems necessitated by the exponential behavior of molecular state transitions under non-equilibrium conditions, including positive versus negative mass action kinetics and solute-induced perturbations to the hydrogen bonds of solvating water versus kT