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We combine on-the-fly trajectory surface hopping simulations and the doorway–window representation of nonlinear optical response functions to create an efficient protocol for the evaluation of time- and frequency-resolved fluorescence (TFRF) spectra and anisotropies of the realistic polyatomic systems. This approach gives the effective description of the proper (e.g., experimental) pulse envelopes, laser field polarizations, and the proper orientational averaging of TFRF signals directly from the well-established on-the-fly nonadiabatic dynamic simulations without extra computational cost. To discuss the implementation details of the developed protocol, we chose cis-azobenzene as a prototype to simulate the time evolution of the TFRF spectra governed by its nonadiabatic dynamics. The results show that the TFRF is determined by the interplay of several key factors, i.e., decays of excited-state populations, evolution of the transition dipole moments along with the dynamic propagation, and scaling factor of the TFRF signals associated with the cube of emission frequency. This work not only provides an efficient and effective approach to simulate the TFRF and anisotropies of realistic polyatomic systems but also discusses the important relationship between the TFRF signals and the underlining nonadiabatic dynamics. [ABSTRACT FROM AUTHOR]

This article presents methodological advances in the state-of-the-art for making time-dependent, thermochemical measurements within kilogram-scale explosive post-detonation fireballs utilizing tunable laser absorption spectroscopy. This measurement capability is critical for validating multi-scale, multi-physics models of post-detonation dynamics. The technique is based on hardened gauges built around rapidly-tunable lasers and custom post-processing algorithms that provide quantitative thermochemical data interior to large and opaque explosive fireballs. The authors present a holistic overview of the technique including gauge design, the laser absorption diagnostic, and the custom data processing algorithms. Additionally, fielding high-bandwidth laser absorption probes at stand-off ranges presents new challenges in data processing that must compensate for long distance signal transmission effects. We highlight representative data from a hardened gauge measurement at 0.81 m stand-off from a 2.78 kg LX-14 explosive charge detonated in an outdoor test arena. We discuss progress in all-optical measurement of temperature, pressure, and water vapor number density at a 100 kHz repetition rate during the first 10 ms of the fireball evolution. We conclude the article with a brief discussion on our current approach for comparing hardened gauge measurements with computational fluid dynamic simulations. [ABSTRACT FROM AUTHOR]

Modelling of many real-world processes, such as drug delivery, wastewater treatment, and pharmaceutical production, requires accurate descriptions of the dynamics of hard particles confined in complicated domains. In particular, when modelling sedimentation processes or systems with driven flows, it is important to accurately capture volume exclusion effects. This work applies Dynamic Density Functional Theory to the evolution of a particle density under diffusion, external forces, particle–particle interaction, and volume exclusion. Using a spectral element framework, for the first time it is possible to include all of these effects in dynamic simulations on complex domains. Moreover, this allows one to apply complicated no-flux, and other non-local, non-linear, boundary conditions. The methodology is also extended to control problems, addressing questions of how to enhance production set-up in industrially-motivated processes. In this work the relevant models are introduced, numerical methods are discussed, and several example problems are solved to demonstrate the methods' versatility. It is shown that incorporating volume exclusion is crucial for simulation accuracy and we illustrate that the choice of boundary conditions significantly impacts the dynamics. [ABSTRACT FROM AUTHOR]

Parkinson's disease is accompanied by the presence of amyloids in the brain that are formed of α-synuclein chains. The correlation between COVID-19 and the onset of Parkinson's disease led to the idea that amyloidogenic segments in SARS-COV-2 proteins can induce aggregation of α-synuclein. Using molecular dynamic simulations, we show that the fragment FKNIDGYFKI of the spike protein, which is unique for SARS-COV-2, preferentially shifts the ensemble of α-synuclein monomer toward rod-like fibril seeding conformations and, at the same time, differentially stabilizes this polymorph over the competing twister-like structure. Our results are compared with earlier work relying on a different protein fragment that is not specific for SARS-COV-2. [ABSTRACT FROM AUTHOR]

In this work, we investigate the water capture process for functionalized carbon nanocones (CNCs) through molecular dynamic simulations in the following three scenarios: a single CNC in contact with a reservoir containing liquid water, a single CNC in contact with a water vapor reservoir, and a combination of more than one CNC in contact with vapor. We found that water flows through the nanocones when in contact with the liquid reservoir if the nanocone tip presents hydrophilic functionalization. In contact with steam, we observed the formation of droplets at the base of the nanocone only when hydrophilic functionalization is present. Then, water flows through in a linear manner, a process that is more efficient than that in the liquid reservoir regime. The scalability of the process is tested by analyzing the water flow through more than one nanocone. The results suggest that the distance between the nanocones is a fundamental ingredient for the efficiency of water harvesting. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the ejection production from twice-shocked Sn using molecular dynamic simulations in regimes where the metal undergoes complete shock melting after the first shock. A new description form of a bubble shape is proposed to fit the interface during the whole stage, which overcomes the inapplicability of the flycut profile in later stages. We then explore the ejection on second shock with the dimensionless intervals of ∼3.8 and ∼96 between the two shocks. Surprisingly, the results show that the ejecta model can well predict the second ejecta mass with a shock interval of ∼3.8 while far underestimated that with a shock interval of ∼96. We find that in the presence of the first ejecta, the high-speed secondary interface interacts with the low-speed first ejecta, resulting in the movement of liquid metals to the secondary ejecta, thereby promoting the increase of secondary ejecta mass. These findings are further validated by our smoothed particle hydrodynamics simulations at a macroscale. [ABSTRACT FROM AUTHOR]

Large-scale nonequilibrium molecular dynamics simulation is used to study the effect of grain size and Cr segregation at the twin boundary (TB) on the spalling fracture mechanism of nickel based alloys. In particular, loading waves are designed so that the maximum tensile stress first appears in the grain interior for all the crystals with different grain sizes. In contrast to traditional understandings, no monotonous relationship between the spall strength and the grain size appears in our results. The spall strength is found to depend on the wave attenuation distance measured from the first maximum tensile stress position to the spalled TB as well as the accompanied microstructure evolutions. The number of spalling plane increases with the increase of TB or the decrease of the grain size. As the grain size continues to decrease, a greater impact strength is required to cause spallation fracture at multiple TBs. In this case, the spall strength becomes insensitive to the first maximum tensile stress position. With the increment of solute atom concentration, the number of the spalling plane increases when the solution is segregated. But it decreases when the solution is uniformly distributed. Such a result is explained by segregation-enhanced energy dissipation and interactions between the waves and the microstructures nearby TBs. In particular, the shock wave would induce a local lattice reorientation nearby the TB depending on its segregation degree and the lattice reorientation would modify the slip manner of stacking faults and, thus, affect void nucleation and growth. The lattice reorientation would also contribute to the generation of sub-grain boundaries inside the grains in terms of the movement of stacking faults. Void nucleation at the sub-GB is the main cause of fracture at the grain interior. [ABSTRACT FROM AUTHOR]

Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis. Pentamidine and melarsoprol are drugs used to treat sleeping sickness caused by Trypanosoma brucei. Here, authors present cryo-EM structures of TbAQP2 with molecular dynamic simulations, revealing mechanisms shaping substrate specificity and drug permeation. [ABSTRACT FROM AUTHOR]

Context: SHP2 is a non-receptor protein tyrosine phosphatase to remove tyrosine phosphorylation. Functionally, SHP2 is an essential bridge to connect numerous oncogenic cell-signaling cascades including RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1 pathways. This study aims to discover novel and potent SHP2 inhibitors using a hierarchical structure-based virtual screening strategy that combines molecular docking and the fragment molecular orbital method (FMO) for calculating binding affinity (referred to as the Dock-FMO protocol). For the SHP2 target, the FMO method prediction has a high correlation between the binding affinity of the protein–ligand interaction and experimental values (R2 = 0.55), demonstrating a significant advantage over the MM/PBSA (R2 = 0.02) and MM/GBSA (R2 = 0.15) methods. Therefore, we employed Dock-FMO virtual screening of ChemDiv database of ∼2,990,000 compounds to identify a novel SHP2 allosteric inhibitor bearing hydroxyimino acetamide scaffold. Experimental validation demonstrated that the new compound (E)-2-(hydroxyimino)-2-phenyl-N-(piperidin-4-ylmethyl)acetamide (7188–0011) effectively inhibited SHP2 in a dose-dependent manner. Molecular dynamics (MD) simulation analysis revealed the binding stability of compound 7188–0011 and the SHP2 protein, along with the key interacting residues in the allosteric binding site. Overall, our work has identified a novel and promising allosteric inhibitor that targets SHP2, providing a new starting point for further optimization to develop more potent inhibitors. Methods: All the molecular docking studies were employed to identify potential leads with Maestro v10.1. The protein–ligand binding affinities of potential leads were further predicted by FMO calculations at MP2/6-31G* level using GAMESS v2020 system. MD simulations were carried out with AmberTools18 by applying the FF14SB force field. MD trajectories were analyzed using VMD v1.9.3. MM/GB(PB)SA binding free energy analysis was carried out with the mmpbsa.py tool of AmberTools18. The docking and MD simulation results were visualized through PyMOL v2.5.0. [ABSTRACT FROM AUTHOR]

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5‐a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02–99.13 against 15 cancer cell lines at 10 μM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI‐38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib. [ABSTRACT FROM AUTHOR]

Food supplements have become beneficial as adjuvant therapies for many chronic disorders, including cancer. Genistein, a natural isoflavone enriched in soybeans, has gained potential interest as an anticancer agent for various cancers, primarily by modulating apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. However, in lung cancer, the exact impact and mechanism of action of genistein still require clarification. To provide more insight into the mechanism of action of genistein, network pharmacology was employed to identify the key targets and their roles in lung cancer pathogenesis. Based on the degree score, the hub genes AKT1, CASP3, EGFR, STAT3, ESR1, SRC, PTGS2, MMP9, PRAG, and AR were significantly correlated with genistein treatment. AKT1, EGFR, and STAT3 were enriched in the non-small cell lung cancer (NSCLC) pathway according to Kyoto Encyclopedia of Genes and Genomes analysis, indicating a significant connection to lung cancer development. Moreover, the binding affinity of genistein to NSCLC target proteins was further verified by molecular docking and molecular dynamics simulations. Genistein exhibited potential binding to AKT1, which is involved in apoptosis, cell migration, and metastasis, thus holding promise for modulating AKT1 function. Therefore, this study aimed to investigate the mechanism of action of genistein and its therapeutic potential for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: GNAO1 encephalopathy is characterized by severe hypotonia, psychomotor retardation, epilepsy, and movement disorders. Genetic variations in GNAO1 have been linked to neurological symptoms including movement disorders like dystonia. The correlation between the E246K mutation in the Gα subunit and aberrant signal transduction of G proteins has been established but no data are reported regarding the efficacy of medical treatment with tetrabenazine. Methods: Molecular modeling studies were performed to elucidate the molecular mechanisms underlying this mutation. We developed drug efficacy models using molecular dynamic simulations that replicated the behavior of wild-type and mutated proteins in the presence or absence of ligands. Results and discussion: We demonstrated that the absence of the mutation leads to normal signal transduction upon receptor activation by the endogenous ligand, but not in the presence of tetrabenazine. In contrast, the presence of the mutation resulted in abnormal signal transduction in the presence of the endogenous ligand, which was corrected by the drug tetrabenazine. Tetrabenazine was identified as a promising therapeutic option for pediatric patients suffering from encephalopathy due to an E246K mutation in the GNAO1 gene validated through molecular dynamics. This is a potential first example of the use of this technique in a rare neurological pediatric disease. [ABSTRACT FROM AUTHOR]

The catalyst is crucial in enhancing productivity within the Fischer-Tropsch synthesis (FTS). The metal support interaction (MSI) plays a pivotal role in the FTS catalyst performance, impacting activity, stability, and selectivity. he configuration and composition of the catalyst dramatically impact MSI, with a strong MSI (SMSI) specified for the core-shell structure. In this study, two methods consisting of chemical treatment of etching and adding a promoter (Ru) for tuning the SMSI of the FTS catalyst are presented, and their footprints on the catalysts' performance are screened by utilizing various characterization tests, molecular dynamic simulation, and catalytic tests. It is recognized that the silica interfacial perimeter acts as a barrier that restricts the charge transfer and boosts the SMSI in the silica-coated catalyst. Conversely, the etched catalyst exhibits a moderate MSI, contributing to increased reducibility, stability, and activity. Furthermore, the Ru-doped etched catalyst represents the optimum MSI, resulting in the highest overall performance. [Display omitted] • The catalyst's structure, configuration, and composition significantly affect the metal support interaction (MSI). • Chemical etching and a promoter (Ru) are used to tune the SMSI of the FTS catalyst and intensify its performance. • The etched catalyst exhibits a moderate MSI, increasing ease of reduction, stability, and activity. • The etched catalyst undergoing doping with Ru with the outer shell of ceria promotes the formation of oxygen vacancies. • Ru NPs have a significant effect on the electron charge surface density of the catalyst. [ABSTRACT FROM AUTHOR]

Fluid simulation is an essential tool to produce realistic looking animations. In particular, Lagrangian simulations offer interactive computation times with an easy integration of the two-way interaction with rigid bodies. However, the interactivity is lost for larger scenes even if only the areas around the bodies have any visual interest. In this paper, we present a novel approach to quickly initialize additional fluid in a rest state in simulations with any 3D boundary shape and able to preserve any already existing fluid. Our approach only uses the density property of the particles to allow compatibility with any smoothed-particle hydrodynamics (SPH) simulation scheme and any boundaries model. This initialization method is fast enough to allow the initialization of new fluid volumes interactively while the simulation is running. We showcase our approach by proposing a method to create a dynamic simulation window, allowing the restriction of simulating the fluid only around moving objects. We propose multiple experiments to demonstrate the capabilities and performance of our approach. [ABSTRACT FROM AUTHOR]

The launcher recovery method known as 'In-Air Capturing' is an innovative approach where a winged rocket stage is captured mid-air by an aircraft and subsequently towed back to the launch site. To achieve this, a capturing device attached to a tether is released from the towing aircraft. This device autonomously connects the reusable launch vehicle to the aircraft, while the two vehicles are in proximity. The tether's flexible dynamics have a strong influence on the maneuverability of the capturing device. Thus, it is critical to model the dynamics of the tether to get a realistic understanding and to evaluate feasibility of the concept. However, precise modelling and control of highly flexible systems with large deformations is both challenging and computationally intensive. For engineering applications which involve closed-loop simulations, finding a trade-off between accuracy and computational effort is crucial. In this paper, the tether is modelled as a discretized chain of rigid bodies connected by rotational springs at the joints. The tether along with the capture system is integrated in a simulation model and open loop tests are performed to analyse the system characteristics. The tether properties are studied to find a suited configuration for 'In-Air Capturing'. • Multibody modelling approach for long cable like bodies with large deformation. • Capture system dynamics for the unique 'In-Air Capturing' launcher recovery concept. • Dynamic modelling for the complete capturing system including towing aircraft, capturing device and tether. • Assessment of tether properties suited for 'In-Air Capturing' with sensitivity studies. [ABSTRACT FROM AUTHOR]

This study developed a finite element method (FEM) dynamic simulation to visualize the deployment behavior of thin membrane structures in the space environment. The proliferation of space debris resulting from accelerated space development threatens the future of space. Numerous researchers have explored strategies to prevent artificial structures from remaining in space and becoming space debris. One such method involves utilizing a drag sail device to de-orbit artificial structures, which reduces their kinetic energy by inducing additional atmospheric drag, allowing them to re-enter the Earth's atmosphere. Tohoku University and Nakashimada Engineering Works, Ltd. have successfully developed a deployable membrane structure for de-orbit purposes and demonstrated its effectiveness in space. Space structures, such as membranes, exhibit highly nonlinear behavior due to their flexible properties, and ground tests by actual devices cannot fully demonstrate their deployment stability in a microgravity environment. Therefore, evaluating the deployment behavior using simulation methods instead of relying solely on hardware development is crucial. In this study, we employed FEM to establish a simulation environment, which enables us to consider nonlinear oscillations of flexible structures, such as the membrane. The simulation results closely reproduce the deployment motion observed in ground tests by appropriately incorporating constraint conditions related to deployment forces and hardware interactions, such as a hub component initially wrapped by the membrane. The simulation facilitated an assessment of the impact of membrane properties on deployment without the need for physically developing an actual hardware device. We proposed evaluation methods for determining membrane properties in terms of the trend of propagation of deployed surface area and the tendency of deployment motion. This established simulation technique can be utilized to develop future flexible space structures. • De-orbit Membrane Mechanism (DOM) was developed as a satellite de-orbit application. • Formulate nonlinear FEM analysis of non-spin type deployable structures. • Modeling techniques of the membrane in simulation. • Evaluation of the membrane deployment between simulation and ground experiments. • Proposed methods can be used to predict the deployment behavior of the actual membrane. [ABSTRACT FROM AUTHOR]

Shimmy is one of the important factors affecting the ride comfort and lateral stability of straddle-type monorail vehicles with single-axle bogies (SMVS). To obtain the main parameters affecting SMVS shimmy, a global sensitivity analysis strategy for SMVS shimmy is proposed. The shimmy response surface model is constructed, and the sensitivity analysis of the shimmy response surface model is carried out by the Sobol method. Based on this, the shimmy factor model of SMVS is established by factor analysis method. A novel SMVS shimmy analysis method based on factor model is proposed. The shimmy factor model is verified by the dynamic model of SMVS. The results show that 11 main factors affecting the shimmy are obtained by sensitivity analysis. Through the dimension reduction technology of factor analysis, four main factors affecting SMVS shimmy are extracted. The complex coupling relationship between the shimmy factors of SMVS is revealed. The established shimmy factor model can effectively analyse the shimmy state of SMVS, and the dynamic simulation results also show consistency. This study not only proposes a new perspective to understand the SMVS shimmy mechanism, but also provides the foundation for further optimal design of monorail vehicle stability. [ABSTRACT FROM AUTHOR]

Unveiling the mechanisms and process of the interfacial reaction between transition metal oxides and metals have far-reaching implications for their superior application. Herein, the interfacial reaction between ZrO 2 and metals was comparatively studied, and the interfacial reactions between three types of ZrO 2 and Zr were systematically investigated by MD simulations. Comparative experiments show that the c -ZrO 2 reacts more vigorously with the active metal than the m -ZrO 2 under the same conditions, and modified c -ZrO 2 nanoparticles have core-shell structures due to the resulting oxygen concentration gradient. The MD simulations reveal that the crystal structure of ZrO 2 has a great influence on its oxygen loss rate (5.14 %–6.46 %) and oxygen distribution induced by the ZrO 2 /metal interface reaction. Meanwhile, the differences in ZrO 2 properties lead to two modes of ZrO 2 /metal interfacial reactions, which are distinguished by the characteristics of the oxygen distribution in the modified ZrO 2. One is that there is no obvious oxygen concentration gradient inside the ZrO 2 during the interfacial reaction, and the crystal defects in the modified ZrO 2 are uniformly distributed, such as c -ZrO 2 and t-ZrO 2. Another reaction mode is that only the region immediately adjacent to the interface in ZrO 2 undergoes diffusion of oxygen ions to the metal, and the interfacial reaction process proceeds layer by layer, such as m -ZrO 2. In addition, when the oxygen density and V O density of ZrO 2 are both low while the oxygen conductivity is high, the ZrO 2 /metal interfacial reaction tends to proceed according to mode A, resulting in modified ZrO 2 with uniformly distributed defects. [ABSTRACT FROM AUTHOR]

Population heterogeneity is due to intrinsic and extrinsic noises; cell to cell variability is related to cell partitioning at division and external forcing by the environment. In this article, a Monte‐Carlo calculation of integral source terms is coupled to a compartment approach. The biological phase is represented by an ensemble of discrete particles which are equipped with a coarse‐grained model that describes the intracellular response to extracellular conditions. The redistribution of cell properties at division generates unbalanced cells and introduces additional time scales into the population dynamics. Using this fully two‐way coupled approach, the consequences of repeated exposure to feast and famine events on both the reactor and the population heterogenities are investigated in a CSTR+PFR scale‐down bioreactor. It is shown that the integration of intrinsic noise due to cell division continuously produces cells that are not at equilibrium with their environment and this contributes to population heterogeneity, even in homogeneous environments. [ABSTRACT FROM AUTHOR]

Real-time hybrid simulation (RTHS) is an economical and reliable method for the evaluation of structural dynamic performances, and the fixed analytical substructure model is often used in RTHS which may affect the accuracy of results. In this study, a real-time hybrid simulation platform (RTHSP) developed by configuring a generic National Instruments (NI) controller with hybrid programming strategy is presented in detail. The dynamic performances of a scaled base isolated structure, where the unscented Kalman filter (UKF) was used to update the analytical substructure Bouc–Wen model during the RTHSs was evaluated by presented RTHSP. RTHS of a base-isolated structure was performed where a lead rubber bearing (LRB) was tested physically as the experimental substructure of a part of the isolation layer and the superstructure with the rest of the isolation layer model updated by UKF was considered as the analytical substructure. Under the excitation of three natural earthquakes, the RTHSs with and without UKF updating were compared and analyzed the differences between the two. The results indicated that the displacements of experimental substructure generated by RTHS with UKF updating are the largest, while the relative displacements and acceleration of superstructure are the smallest overall, and the dynamic characteristics of the isolation layer of the analysis substructure updated by UKF are different from that without updated, which reflected the more authentic dynamic mechanical performance of the base-isolated structure under earthquake excitation. In addition, the RTHSP and the hybrid programming strategy are verified to be reliable in tests and experiments, and the components and implementation of a RTHSP for base-isolated structures is described in detail, providing a reference for research on RTHS method. [ABSTRACT FROM AUTHOR]

The maximum utilization of hydrocracking tail oil becomes increasingly important for petrochemical industry. The aim of this work is to develop optimized distillation processes to achieve various high‐valued qualified oil products from hydrocracking tail oil. Six different oil products is produced and the steady‐state distillation process, which aims to fractionate six qualified narrow distillates is established. The algorithm method incorporating divided‐wall column (DWC) configuration was introduced into the steady‐state design. Compared with traditional separation sequences, the DWC configuration leads to an energy‐saving potential up to 11.17%. Furthermore, effective dynamic control strategies were proposed, demonstrating precise and efficient control performance. In the presence of a 15% feed disturbance, the dynamic control structure is capable of maintaining the product distillation range near the set value. This comprehensive study provides a thorough investigation into the efficient utilization of hydrocracking tail oil, establishing a robust theoretical foundation for its industrial application. [ABSTRACT FROM AUTHOR]

Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large simulation system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop a hierarchical domain decomposition scheme with dynamic load balancing for heterogeneous biomolecular systems to keep computational efficiency even after drastic changes in particle distribution. These schemes are applied to the dynamics of intrinsically disordered protein (IDP) droplets. During the fusion of two droplets, we find that the changes in droplet shape correlate with the mixing of IDP chains. Additionally, we simulate large systems with multiple IDP droplets, achieving simulation sizes comparable to those observed in microscopy. In our MD simulations, we directly observe Ostwald ripening, a phenomenon where small droplets dissolve and their molecules redeposit into larger droplets. These methods have been implemented in CGDYN of the GENESIS software, offering a tool for investigating mesoscopic biological processes using the residue-level CG models. Here, the authors report the development of heterogeneous domain decomposition with load balancing for large biological molecular dynamics simulations using residue-level coarse-grained models. [ABSTRACT FROM AUTHOR]

Virtual product design (VPD) of the refrigeration cycle has long been a major subject of many engineers and manufacturers. Issues should be the question of how simulation gets close to the real world in virtual ways. It is especially true when we consider variable refrigerant flow (VRF) heat pumps, having various types of indoor unit combinations, long and complicated piping configurations, and simultaneous cooling and heating functions under extreme weather conditions. In this regard, model-based systems engineering (MBSE) or model-based design (MBD) guides a methodology to make a virtual model easily. Now, there are plenty of engineering platforms and tools to make a strong simulation model, which provides interfacing technology among multiple physics, different dimensions, and codes in different languages. In the study, the authors share their experience in the virtual design for a VRF heat pump system including the architecture, multiple physics, and the connection with the control SW. Modelica, an acausal and object-oriented modeling language, constructs the backbone of the model to describe the dynamic behavior of refrigerants and to combine external components in the form of functional mock-up units (FMUs). The developed virtual model is validated against measured data, showing it can reproduce all the essential physics of interest both in qualitative and quantitative ways. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the exact solutions of a modified generalized multidimensional fractional Kadomtsev–Petviashvili (KP) equation by the bifurcation method. First, the equation is converted into a planar dynamical system through fractional complex wave transformation. The phase portraits of the equation and qualitative analysis are presented under different bifurcation conditions. Then, the bounded and unbounded traveling wave solutions, including periodic, kink, anti-kink, dark-solitary, bright-solitary and breaking wave solutions, are acquired by integrating along different orbits. Finally, numerical simulations of the dynamic behaviors of the solutions obtained are graphically illustrated by choosing appropriate parameters. [ABSTRACT FROM AUTHOR]

Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules. [ABSTRACT FROM AUTHOR]

Shale oil in China is widely distributed and has enormous resource potential. The pores of shale are at the nanoscale, and traditional research methods encounter difficulty in accurately describing the fluid flow mechanism, which has become a bottleneck restricting the industrial development of shale oil in China. To clarify the distribution and migration laws of fluid microstructure in shale nanopores, we constructed a heterogeneous inorganic composite shale model and explored the fluid behavior in different regions of heterogeneous surfaces. The results revealed the adsorption capacity for alkanes in the quartz region was stronger than that in the illite region. When the aperture was small, solid–liquid interactions dominated; as the aperture increased, the bulk fluid achieved a more uniform and higher flow rate. Under conditions of small aperture/low temperature/low pressure gradient, the quartz region maintained a negative slip boundary. Illite was more hydrophilic than quartz; when the water content was low, water molecules formed a "liquid film" on the illite surface, and the oil flux percentages in the illite and quartz regions were 87% and 99%, respectively. At 50% water content, the adsorbed water in the illite region reached saturation, the quartz region remained unsaturated, and the difference in the oil flux percentage of the two regions decreased. At 70% water content, the adsorbed water in the two regions reached a fully saturated state, and a layered structure of "water–two-phase region–water" was formed in the heterogeneous nanopore. This study is of great significance for understanding the occurrence characteristics and flow mechanism of shale oil within inorganic nanopores. [ABSTRACT FROM AUTHOR]

Acellular fish swim bladders (AFSBs) are a promising biomaterial in tissue engineering, however, they may suffer from rapid degradation due to enzyme invasion. In this work, natural polyphenols, including epigallocatechin gallate (EGCG), proanthocyanidin (PC), tannic acid (TA) and protocatechuic acid (PCA), were utilized to improve the properties of AFSBs through crosslinking modifications. Fourier transform infrared (FTIR) results indicate that the triple helix of the collagen in AFSBs is well preserved after crosslinking. The differential scanning calorimetry (DSC), water contact angle (WCA) and in vitro degradation tests indicate that the polyphenol-crosslinked AFSBs exhibit improved thermal stability, enzymatic stability, hydrophilicity and mechanical properties. Among them, EGCG with multiple phenolic hydroxyl groups and low potential resistance is more favorable for the improvement of the mechanical properties and enzymatic stability of AFSBs, as well as their biocompatibility and integrity with the collagen triple helix. Moreover, the crosslinking mechanism was demonstrated to be due to the hydrogen bonds between polyphenols and AFSBs, and was affected by the molecular size, molecular weight and the hydroxyl groups activity of polyphenol molecules, as clarified by molecular dynamic (MD) simulations. The approach presented in this work paves a path for improving the properties of collagen materials. [ABSTRACT FROM AUTHOR]

This work deals with doubly fed induction generator (DFIG) modeling and stability when connected to weak AC grids. A detailed state-space model that includes the phase-locked loop (PLL) is developed. This work aims to determine the influence of the network's strength on DFIG stability through the short-circuit ratio (SCR). The critical values of the proportional control parameters of the grid-side and rotor-side converters (RSC and GSC), as well as PLL, which make the system unstable, are calculated for different SCR values. Finally, PSCAD/EMTDC dynamic simulations are used to validate the critical control parameters obtained by studying the eigenvalues of the DFIG state-space model regarding system stability. [ABSTRACT FROM AUTHOR]

The diterpene 7α-acetoxy-6β-hydroxyroyleanone isolated from Plectranthus grandidentatus demonstrates promising antibacterial, anti-inflammatory and anticancer properties. However, its bioactivity may be enhanced via strategic structural modifications of such natural products through semisynthesis. The anticancer potential of 7α-acetoxy-6β-hydroxyroyleanone and five derivatives was analyzed in silico via the prediction of chemicals absorption, distribution, metabolism, excretion, and toxicity (ADMET), quantum mechanical calculations, molecular docking and molecular dynamic simulation. The protein targets included regulators of apoptosis and cell proliferation. Additionally, network pharmacology was used to identify potential targets and signaling pathways. Derivatives 7α-acetoxy-6β-hydroxy-12-O-(2-fluoryl)royleanone and 7α-acetoxy-6β-(4-fluoro)benzoxy-12-O-(4-fluoro)benzoylroyleanone achieved high predicted binding affinities towards their respective protein panels, with stable molecular dynamics trajectories. Both compounds demonstrated favorable ADMET parameters and toxicity profiles. Their stability and reactivity were confirmed via geometry optimization. Network analysis revealed their involvement in cancer-related pathways. Our findings justify the inclusion of 7α-acetoxy-6β-hydroxy-12-O-(2-fluoryl)royleanone and 7α-acetoxy-6β-(4-fluoro)benzoxy-12-O-(4-fluoro)benzoylroyleanone in in vitro analyses as prospective anticancer agents. Our binding mode analysis and stability simulations indicate their potential as selective inhibitors. The data will guide studies into their structure optimization, enhancing efficacy and drug-likeness. [ABSTRACT FROM AUTHOR]

Introduction: The CXCR4 chemokine receptor is a G protein-coupled receptor that plays a role in many physiological processes and diseases, such as cancer metastasis, HIV infection, and immune response. Because of this, it may be possible to target it therapeutically. In addition, the active ingredient of Phaseolus vulgaris L (PVL) has been reported to have anti-inflammatory, antioxidant, and anticancer properties. Novel CXCR4 antagonists from natural resources can be a promising drug development product using a computational approach. This study aims to explore the active compound in PVL that has the responsibility to inhibit CXCR4 using molecular docking and dynamics simulation. Materials and methods: Pharmacokinetic analysis were performed using the pkCSM, OSIRIS for toxicity risk analysis, and the PerMM for membrane permeability assessment. Molecular docking was performed using PyRx software to determine the interaction between the CXCR4 target protein from the PDB database and the active component of PVL from the PubChem database. A molecular dynamics (MD) simulation was performed to determine the stability of the interaction using the WEBGRO Macromolecular Simulations online server. The analysis were performed by comparing the results with plerixafor as a control ligand. Results and discussion: The pharmacokinetic analysis of quercetin, kaempferol, myricetin, catechin, 3,4-dihydroxybenzoic acid, and daidzin in PVL showed that they met the drug-like criteria. These chemicals were expected to have medium-risk effects on mutagenesis and tumorigenesis, with the exception of catechin, which has no risk of toxicity, and daidzin, which has high-risk effects on mutagenesis and reproduction. Molecular docking identified that quercetin (− 6.6 kcal/mol), myricetin (− 6.6 kcal/mol), catechin (− 6.5 kcal/mol), and 3,4-dihydroxybenzoic acid (− 5.4 kcal/mol) bind to CXCR4 with the highest affinity compared to plerixafor (− 5.0 kcal/mol) and can bind to the same binding pocket with key residues Asp187, Asp97, and Glu288. The MD simulation analysis showed that quercetin has a similar stability interaction compared to the control. Conclusions: Considering the pharmacokinetic analysis, molecular docking, and MD simulations, quercetin, myricetin, and 3,4-dihydroxybenzoic acid have the potential to become CXCR4 agonists with their good oral bioavailability and safety properties for the novel drug candidates. Future studies are needed to consider the molecular docking result. [ABSTRACT FROM AUTHOR]

Introduction: Coleoptera is the most species-rich order of animals with the widest distribution area; however, little is known about its global suitability distribution, and a substantial number of species are experiencing silent extinction. Most of Earth's biocommunities are concentrated in biodiversity hotspots, and these hotspots receive the largest investment of conservation funds. The survival of beetles is closely related to the richness of biodiversity, so habitat loss in hotspots results in a high extinction risk for beetles. Methods: We used the MaxEnt model to simulate the spatial suitable distribution in six time periods (1970-1980,1980-1990,1990-2000, 2000-2010, 2010-2020, and 1970-2020). Furthermore, we determined the priority suitable regions in hotspots after coupling the current biodiversity zones and evaluated the congruence between the suitable habitat of beetles and hotspots. Results: The results revealed that less than 30% of suitable regions were located in hotspots, and approximately 49.08% of the suitable habitat remained constant in all six periods, and can be regarded as climatically stable refugia. The Mediterranean Basin had the largest suitable area in each period and was always ranked first; other regions, such as Indo-Burma, Irano-Anatolian, and Mesoamerica, also had large areas of suitable habitat. Nine excellent, ten stable, and seventeen lower hotspots were identified based on their dynamic changes in 36 hotspots. Discussion: Based on these results, corresponding planning and management measures should be implemented in different biodiversity hotspots according to the changes in geographic distribution. In this paper, we propose practical advice for different regions to improve isolated and fragmented habitats, which will support the conservation of Coleoptera taxa and the restoration of biodiversity. [ABSTRACT FROM AUTHOR]

Capillary wicking characteristics play an important role in two-phase thermal management devices including heat pipes and vapor chambers, yet three-dimensional (3D) pore-scale simulations of the dynamic capillary wicking process on various micro-structured surfaces have been rare. In this paper, we conduct 3D pore-scale simulations of capillary wicking on three commonly used micro-structured wicks including micro-pillar array, micro-channel, and sintered particles. The micro-scale liquid propagation dynamics and the "stick-slip" behavior of the propagating liquid front are captured using a 3D pseudo-potential multiple-relaxation-time lattice Boltzmann method. Based on the Lucus–Washburn approach and a work-energy approach, we theoretically analyze wickabilities of different micro-structured wicks. Effects of wick geometry and structural parameters on the capillary wicking characteristics are discussed. We demonstrate that an optimal pillar pitch distance exists, which maximizes the wickability of the micro-pillar array. We show that when the porosity is relatively low, the wickability of the micro-channel is higher than that of the micro-pillar array and the sintered particles. When the porosity is large, however, the sintered particles exhibit higher wickability than the micro-pillar array and the micro-channel. We also demonstrate that the capillary pressure of the sintered particles is always higher than that of the micro-pillar array and the micro-channel throughout the porosity range investigated. The numerical simulation results are compared with theoretical predictions. Findings in this work provide guidelines for the designs of porous wick in various two-phase thermal management systems for high heat flux devices. [ABSTRACT FROM AUTHOR]

All instrumented basaltic caldera collapses have generated Mw > 5 very long period earthquakes. However, previous studies of source dynamics have been limited to lumped models treating the caldera block as rigid, leaving open questions related to how ruptures initiate and propagate around the ring fault, and the seismic expressions of those dynamics. We present the first 3D numerical model capturing the nucleation and propagation of ring fault rupture, the mechanical coupling to the underlying viscoelastic magma, and the associated seismic wavefield. We demonstrate that seismic radiation, neglected in previous models, acts as a damping mechanism reducing coseismic slip by up to half, with effects most pronounced for large magma chamber volume/ring fault radius or highly compliant crust/compressible magma. Viscosity of basaltic magma has negligible effect on collapse dynamics. In contrast, viscosity of silicic magma significantly reduces ring fault slip. We use the model to simulate the 2018 Kı̄lauea caldera collapse. Three stages of collapse, characterized by ring fault rupture initiation and propagation, deceleration of the downward‐moving caldera block and magma column, and post‐collapse resonant oscillations, in addition to chamber pressurization, are identified in simulated and observed (unfiltered) near‐field seismograms. A detailed comparison of simulated and observed displacement waveforms corresponding to collapse earthquakes with hypocenters at various azimuths of the ring fault reveals a complex nucleation phase for earthquakes initiated on the northwest. Our numerical simulation framework will enhance future efforts to reconcile seismic and geodetic observations of caldera collapse with conceptual models of ring fault and magma chamber dynamics. Plain Language Summary: Caldera collapse manifests as the rapid subsidence of a kilometer‐scale block of crust circumscribed by a near‐circular fault on top of a volcano. The subsidence of the caldera block is caused by the eruption‐induced withdrawal of magma and reduction in pressure in the underlying magma chamber. All scientifically instrumented caldera collapses at volcanoes with low‐viscosity magma are accompanied by earthquakes of magnitude 5 and above. How do magma viscosity and the seismic wave radiation influence the amount of slip per earthquake on the fault? What can we learn about the dynamics of these earthquakes from seismic records? We address these questions by performing computer simulations of caldera collapse earthquakes and compare the results to the seismic records from the Kı̄lauea caldera collapse of 2018. Key Points: Seismic wave radiation through ring fault and magma, as well as high magma viscosity, reduce fault slip by up to half during collapseRupture propagation, downward momentum transfer via magma pressure waves, and chamber pressurization are identified in unfiltered seismogramsComparison between simulated and observed near‐field seismograms from Kı̄lauea 2018 reveals complex nucleation phase on the ring fault [ABSTRACT FROM AUTHOR]

In order to effectively improve safety and stability during transportation, a shock absorber with buffering and self-locking functions was designed. Based on the rigid flexible coupling technology, the working state and dynamic response of the shock absorber were simulated and analyzed. The linear spring was treated as a flexible body, and the cam button, guide pillar, and base were treated as rigid bodies. The modal neutral files required for the rigid flexible coupling dynamic analysis were generated. Based on ADAMS, a dynamic simulation model was established, replacing a part of the rigid model with a flexible model and conducting load response analysis on it. To further improve the vibration reduction effect, the performance of the contact material of the shock absorber was analyzed. Through the calculation of dynamic characteristics, it could be known that the self-locking mechanism had no dead points, and the vibration reduction force response stability was high, meeting the working requirements. [ABSTRACT FROM AUTHOR]

Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57 kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and − 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder. [ABSTRACT FROM AUTHOR]

As the development of well types for low permeability reservoirs shifts from vertical to highly inclined/horizontal wells, targeted studies of oil and gas reservoir damage must be conducted for such well types to improve the science and effectiveness of acidification conversion. Taking into account the formation of mud cake and the dynamic damage factors caused by drilling fluid on the reservoir during horizontal well drilling, a refined dynamic description model for nonuniform damage in horizontal wells was established. The coupled simulation accounts for the dynamical destruction of the skin factor of the reservoir and the dynamical generation of the slurry. The coupled model consists of a radial mud cake dynamic formation model, a reservoir damage radius model, a permeability distribution model, and a horizontal well inhomogeneous skin factor model. It captures the dynamic evolution of reservoir damage due to drilling fluid contamination during horizontal well drilling and provides a real‐time representation of changes in the reservoir skin factor of horizontal wells, measuring the depth and extent of radial reservoir damage. Clarifying the extent of reservoir damage and its impact in horizontal well sections can help select appropriate acidification methods, improve acid distribution processes, and ultimately improve the effectiveness of mitigating reservoir damage and increasing oil and gas well productivity. [ABSTRACT FROM AUTHOR]

Reductions of carbon dioxide emissions from the building sector are mandatory for climate protection. This calls for both a reduction of the construction material and energy as well as a reduction of the operational energy. Against this background, a novel facade-integrated adsorption system for solar cooling of lightweight buildings is proposed and theoretically investigated in this work. For this purpose, a detailed simulation model is developed to analyze both the processes in the single components as well as the overall system behavior. The proposed system consists of the three components adsorber, condenser and evaporator, which are connected vacuum-tight and are coupled by vapor transfer. The simulation results of a defined reference case yield cooling rates of 54   W per installed square meter of adsorber facade. The cooling power can be maintained for 12 h, confirming the applicability of the proposed system. Furthermore, a comprehensive parametric study is carried out in order to identify an optimum set of parameter values for maximum cooling rate under the assumed conditions. The results reveal that controlled constant cooling rates of 105   W per square meter of adsorber facade can be reached and a maximum peak power of 145   W per square meter of adsorber facade is possible. [ABSTRACT FROM AUTHOR]

Our laboratory has shown that calpain‐2 activation in the brain following acute injury is directly related to neuronal damage and the long‐term functional consequences of the injury, while calpain‐1 activation is generally neuroprotective and calpain‐1 deletion exacerbates neuronal injury. We have also shown that a relatively selective calpain‐2 inhibitor, referred to as C2I, enhanced long‐term potentiation and learning and memory, and provided neuroprotection in the controlled cortical impact (CCI) model of traumatic brain injury (TBI) in mice. Using molecular dynamic simulation and Site Identification by Ligand Competitive Saturation (SILCS) software, we generated about 130 analogs of C2I and tested them in a number of in vitro and in vivo assays. These led to the identification of two interesting compounds, NA‐112 and NA‐184. Further analyses indicated that NA‐184, (S)‐2‐(3‐benzylureido)‐N‐((R,S)‐1‐((3‐chloro‐2‐methoxybenzyl)amino)‐1,2‐dioxopentan‐3‐yl)‐4‐methylpentanamide, selectively and dose‐dependent inhibited calpain‐2 activity without evident inhibition of calpain‐1 at the tested concentrations in mouse brain tissues and human cell lines. Like NA‐112, NA‐184 inhibited TBI‐induced calpain‐2 activation and cell death in mice and rats, both male and females. Pharmacokinetic and pharmacodynamic analyses indicated that NA‐184 exhibited properties, including stability in plasma and liver and blood–brain barrier permeability, that make it a good clinical candidate for the treatment of TBI. [ABSTRACT FROM AUTHOR]

Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure‐response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure‐response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure‐response analysis, as well as longitudinal adverse event (AE) analysis using discrete‐time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure‐response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE‐based personalized dosing is the most effective approach for optimizing the benefit–risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows. [ABSTRACT FROM AUTHOR]