PFAS-Biomolecule Interactions: Case Study Using Asclepios Nodes and Automated Workflows in KNIME for Drug Discovery and Toxicology.

The Asclepios suite of KNIME nodes represents an innovative solution for conducting cheminformatics and computational chemistry tasks, specifically tailored for applications in drug discovery and computational toxicology. This suite has been developed using open-source and publicly accessible software. In this chapter, we introduce and explore the Asclepios suite through the lens of a case study. This case study revolves around investigating the interactions between per- and polyfluorinated alkyl substances (PFAS) and biomolecules, such as nuclear receptors. The objective is to characterize the potential toxicity of PFAS and gain insights into their chemical mode of action at the molecular level. The Asclepios KNIME nodes have been designed as versatile tools capable of addressing a wide range of computational toxicology challenges. Furthermore, they can be adapted and customized to accomodate the specific needs of individual users, spanning various domains such as nanoinformatics, biomedical research, and other related applications. This chapter provides an in-depth examination of the technical underpinnings and foundations of these tools. It is accompanied by a practical case study that demonstrates the utilization of Asclepios nodes in a computational toxicology investigation. This showcases the extendable functionalities that can be applied in diverse computational chemistry contexts. By the end of this chapter, we aim for readers to have a comprehensive understanding of the effectiveness of the Asclepios node functions. These functions hold significant potential for enhancing a wide spectrum of cheminformatics applications.

Role of urea in the retention of DON in soil by clay minerals: Analysis based upon molecular weight.

As a widely used fertilizer, urea significantly promotes the leaching of dissolved organic nitrogen (DON) in soils and aggravates nitrogen contamination in groundwater. Clay minerals are considered the most important factor in retaining DON. However, the effect of urea on the retention of DON with different molecular weights by clay minerals is unknown. In this study, the retention of both low-molecular weight DON (LMWD) and high-molecular weight DON (HMWD) by clay minerals in the presence of urea was investigated. For this purpose, batch adsorption and soil column leaching experiments, characterization analysis (Fourier transform infrared spectroscopy X-ray diffraction, and X-ray photoelectron spectroscopy), and molecular dynamics simulations were carried out. Urea had a positive effect on the adsorption of LMWD, whereas a competitive effect existed for the adsorption of HMWD. The dominant interactions among DON, urea, and clay minerals included H-bonding, ligand exchange, and cation exchange. The urea was preferentially adsorbed on clay minerals and formed a complex, which provided more adsorption sites to LMWD and only a few to HMWD. The presence of urea increased the retention of LMWD and decreased the retention of HMWD in clay minerals. The retention capacity of LMWD increased by 6.9%-12.8%, while that of HMWD decreased by 6.7%-53.1%. These findings suggest that LMWD tended to be trapped in soils, while HMWD was prone to be leached into groundwater, which can be used to evaluate the leaching of DON from soil to groundwater.

gRNAde: A Geometric Deep Learning Pipeline for 3D RNA Inverse Design.

Fundamental to the diverse biological functions of RNA are its 3D structure and conformational flexibility, which enable single sequences to adopt a variety of distinct 3D states. Currently, computational RNA design tasks are often posed as inverse problems, where sequences are designed based on adopting a single desired secondary structure without considering 3D geometry and conformational diversity. In this tutorial, we present gRNAde, a geometric RNA design pipeline operating on sets of 3D RNA backbone structures to design sequences that explicitly account for RNA 3D structure and dynamics. gRNAde is a graph neural network that uses an SE (3) equivariant encoder-decoder framework for generating RNA sequences conditioned on backbone structures where the identities of the bases are unknown. We demonstrate the utility of gRNAde for fixed-backbone re-design of existing RNA structures of interest from the PDB, including riboswitches, aptamers, and ribozymes. gRNAde is more accurate in terms of native sequence recovery while being significantly faster compared to existing physics-based tools for 3D RNA inverse design, such as Rosetta.

Uncovering the pharmacological mechanisms of Patchouli essential oil for treating ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Pogostemonis Herba has long been used in traditional Chinese medicine to treat inflammatory disorders. Patchouli essential oil (PEO) is the primary component of Pogostemonis Herba, and it has been suggested to offer curative potential when applied to treat ulcerative colitis (UC). However, the pharmacological mechanisms of PEO for treating UC remain to be clarified. AIM OF THE STUDY: To elucidate the pharmacological mechanisms of PEO for treating UC. METHODS AND RESULTS: In the present study, transcriptomic and network pharmacology approaches were combined to clarify the mechanisms of PEO for treating UC. Our results reveal that rectal PEO administration in UC model mice significantly alleviated symptoms of UC. In addition, PEO effectively suppressed colonic inflammation and oxidative stress. Mechanistically, PEO can ameliorate UC mice by modulating gut microbiota, inhibiting inflammatory targets (OPTC, PTN, IFIT3, EGFR, and TLR4), and inhibiting the PI3K-AKT pathway. Next, the 11 potential bioactive components that play a role in PEO's anti-UC mechanism were identified, and the therapeutic efficacy of the pogostone (a bioactive component) in UC mice was partially validated. CONCLUSION: This study highlights the mechanisms through which PEO can treat UC, providing a rigorous scientific foundation for future efforts to develop and apply PEO for treating UC.

Hypotensive effect of potent angiotensin-I-converting enzyme inhibitory peptides from corn gluten meal hydrolysate: Gastrointestinal digestion and transepithelial transportation modifications.

The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (Ki) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with -7.83 and - 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide.

Construction of Coarse-Grained Molecular Dynamics Model of Nuclear Global Chromosomes Dynamics in Mammalian Cells.

Biomolecules contain various heterogeneities in their structures and local chemical properties, and their functions emerge through the dynamics encoded by these heterogeneities. Molecular dynamics model-based studies will greatly contribute to the elucidation of such chemical/mechanical structure-dynamics-function relationships and the mechanisms that generate them. Coarse-grained molecular dynamics models with appropriately designed nonuniform local interactions play an important role in considering the various phenomena caused by large molecular complexes consisting of various proteins and DNA such as nuclear chromosomes. Therefore, in this chapter, we will introduce a method for constructing a coarse-grained molecular dynamics model that simulates the global behavior of each chromosome in the nucleus of a mammalian cell containing many giant chromosomes.

Integrative Modeling of 3D Genome Organization by Bayesian Molecular Dynamics Simulations with Hi-C Metainference.

Polymer modeling has been playing an increasingly important role in complementing 3D genome experiments, both to aid their interpretation and to reveal the underlying molecular mechanisms. This chapter illustrates an application of Hi-C metainference, a Bayesian approach to explore the 3D organization of a target genomic region by integrating experimental contact frequencies into a prior model of chromatin. The method reconstructs the conformational ensemble of the target locus by combining molecular dynamics simulation and Monte Carlo sampling from the posterior probability distribution given the data. Using prior chromatin models at both 1 kb and nucleosome resolution, we apply this approach to a 30 kb locus of mouse embryonic stem cells consisting of two well-defined domains linking several gene promoters together. Retaining the advantages of both physics-based and data-driven strategies, Hi-C metainference can provide an experimentally consistent representation of the system while at the same time retaining molecular details necessary to derive physical insights.

Perspectives on label-free microscopy of heterogeneous and dynamic biological systems.

Significance: Advancements in label-free microscopy could provide real-time, non-invasive imaging with unique sources of contrast and automated standardized analysis to characterize heterogeneous and dynamic biological processes. These tools would overcome challenges with widely used methods that are destructive (e.g., histology, flow cytometry) or lack cellular resolution (e.g., plate-based assays, whole animal bioluminescence imaging). Aim: This perspective aims to (1) justify the need for label-free microscopy to track heterogeneous cellular functions over time and space within unperturbed systems and (2) recommend improvements regarding instrumentation, image analysis, and image interpretation to address these needs. Approach: Three key research areas (cancer research, autoimmune disease, and tissue and cell engineering) are considered to support the need for label-free microscopy to characterize heterogeneity and dynamics within biological systems. Based on the strengths (e.g., multiple sources of molecular contrast, non-invasive monitoring) and weaknesses (e.g., imaging depth, image interpretation) of several label-free microscopy modalities, improvements for future imaging systems are recommended. Conclusion: Improvements in instrumentation including strategies that increase resolution and imaging speed, standardization and centralization of image analysis tools, and robust data validation and interpretation will expand the applications of label-free microscopy to study heterogeneous and dynamic biological systems.

Mathematical Modeling of Mating Probability and Fertile Egg Production in Helminth Parasites.

In this work, we obtained a general formulation for the mating probability and fertile egg production in helminth parasites, focusing on the reproductive behavior of polygamous parasites and its implications for transmission dynamics. By exploring various reproductive variables in parasites with density-dependent fecundity, such as helminth parasites, we departed from the traditional assumptions of Poisson and negative binomial distributions to adopt an arbitrary distribution model. Our analysis considered critical factors such as mating probability, fertile egg production, and the distribution of female and male parasites among hosts, whether they are distributed together or separately. We show that the distribution of parasites within hosts significantly influences transmission dynamics, with implications for parasite persistence and, therefore, with implications in parasite control. Using statistical models and empirical data from Monte Carlo simulations, we provide insights into the complex interplay of reproductive variables in helminth parasites, enhancing our understanding of parasite dynamics and the transmission of parasitic diseases.

Molecular Dynamics Simulation Combined with Neural Relationship Inference and Markov Model to Reveal the Relationship between Conformational Regulation and Bioluminescence Properties of Gaussia Luciferase.

Gaussia luciferase (Gluc) is currently known as the smallest naturally secreted luciferase. Due to its small molecular size, high sensitivity, short half-life, and high secretion efficiency, it has become an ideal reporter gene and is widely used in monitoring promoter activity, studying protein-protein interactions, protein localization, high-throughput drug screening, and real-time monitoring of tumor occurrence and development. Although studies have shown that different Gluc mutations exhibit different bioluminescent properties, their mechanisms have not been further investigated. The purpose of this study is to reveal the relationship between the conformational changes of Gluc mutants and their bioluminescent properties through molecular dynamics simulation combined with neural relationship inference (NRI) and Markov models. Our results indicate that, after binding to the luciferin coelenterazine (CTZ), the α-helices of the 109-119 residues of the Gluc Mutant2 (GlucM2, the flash-type mutant) are partially unraveled, while the α-helices of the same part of the Gluc Mutant1 (GlucM1, the glow-type mutant) are clearly formed. The results of Markov flux analysis indicate that the conformational differences between glow-type and flash-type mutants when combined with luciferin substrate CTZ mainly involve the helicity change of α7. The most representative conformation and active pocket distance analysis indicate that compared to the flash-type mutant GlucM2, the glow-type mutant GlucM1 has a higher degree of active site closure and tighter binding. In summary, we provide a theoretical basis for exploring the relationship between the conformational changes of Gluc mutants and their bioluminescent properties, which can serve as a reference for the modification and evolution of luciferases.

Structural Insights into Endostatin-Heparan Sulfate Interactions Using Modeling Approaches.

Glycosaminoglycans (GAGs) play a key role in a variety of biological processes in the extracellular matrix (ECM) via interactions with their protein targets. Due to their high flexibility, periodicity and electrostatics-driven interactions, GAG-containing complexes are very challenging to characterize both experimentally and in silico. In this study, we, for the first time, systematically analyzed the interactions of endostatin, a proteolytic fragment of collagen XVIII known to be anti-angiogenic and anti-tumoral, with heparin (HP) and representative heparan sulfate (HS) oligosaccharides of various lengths, sequences and sulfation patterns. We first used conventional molecular docking and a docking approach based on a repulsive scaling-replica exchange molecular dynamics technique, as well as unbiased molecular dynamic simulations, to obtain dynamically stable GAG binding poses. Then, the corresponding free energies of binding were calculated and the amino acid residues that contribute the most to GAG binding were identified. We also investigated the potential influence of Zn2+ on endostatin-HP complexes using computational approaches. These data provide new atomistic details of the molecular mechanism of HP's binding to endostatin, which will contribute to a better understanding of its interplay with proteoglycans at the cell surface and in the extracellular matrix.

Langevin Dynamics Study on the Driven Translocation of Polymer Chains with a Hairpin Structure.

The hairpin structure is a common and fundamental secondary structure in macromolecules. In this work, the process of the translocation of a model polymer chain with a hairpin structure is studied using Langevin dynamics simulations. The simulation results show that the dynamics of hairpin polymer translocation through a nanopore are influenced by the hairpin structure. Hairpin polymers can be classified into three categories, namely, linear-like, unsteady hairpin, and steady hairpin, according to the interaction with the stem structure. The translocation behavior of linear-like polymers is similar to that of a linear polymer chain. The time taken for the translocation of unsteady hairpin polymers is longer than that for a linear chain because it takes a long time to unfold the hairpin structure, and this time increases with stem interaction and decreases with the driving force. The translocation of steady hairpin polymers is distinct, especially under a weak driving force; the difficulty of unfolding the hairpin structure leads to a low translocation probability and a short translocation time. The translocation behavior of hairpin polymers can be explained by the theory of the free-energy landscape.

Structural and Electronic Properties of Novel Azothiophene Dyes: A Multilevel Study Incorporating Explicit Solvation Effects.

Among azobenzene derivatives, azothiophenes represent a relatively recent family of compounds that exhibit similar characteristics as dyes and photoreactive systems. Their technological applications are extensive thanks to the additional design flexibility conferred by the heteroaromatic ring. In this study, we present a comprehensive investigation of the structural and electronic properties of novel dyes derived from 3-thiophenamine, utilizing a multilevel approach. We thoroughly examined the potential energy surfaces of the E and Z isomers for three molecules, each bearing different substituents on the phenyl ring at the para position relative to the diazo group. This exploration was conducted through quantum chemistry calculations at various levels of theory, employing a continuum solvent model. Subsequently, we incorporated an explicit solvent (a dimethyl sulfoxide-water mixture) to simulate the most stable isomers using classical molecular dynamics, delivering a clear picture of the local solvation structure and intermolecular interactions. Finally, a hybrid quantum mechanics/molecular mechanics (QM/MM) approach was employed to accurately describe the evolution of the solutes' properties within their environment, accounting for finite temperature effects.

Time-Resolved Circular Dichroism in Molecules: Experimental and Theoretical Advances.

Following changes in chirality can give access to relevant information on the function or reactivity of molecular systems. Time-resolved circular dichroism (TRCD) spectroscopy proves to be a valid tool to achieve this goal. Depending on the class of molecules, different temporal ranges, spanning from seconds to femtoseconds, need to be investigated to observe such chiroptical changes. Therefore, over the years, several approaches have been adopted to cover the timescale of interest, especially based on pump-probe schemes. Moreover, various theoretical approaches have been proposed to simulate and explain TRCD spectra, including linear and non-linear response methods as well as non-adiabatic molecular dynamics. In this review, an overview on both experimental and theoretical advances in the TRCD field is provided, together with selected applications. A discussion on future theoretical developments for TRCD is also given.

Investigation on the Synergy between Membrane Permeabilizing Amphiphilic α-Hydrazido Acids and Commonly Used Antibiotics against Drug-Resistant Bacteria.

The growth of (multi)drug resistance in bacteria is among the most urgent global health issues. Monocationic amphiphilic α-hydrazido acid derivatives are structurally simple mimics of antimicrobial peptides (AMPs) with fewer drawbacks. Their mechanism of membrane permeabilization at subtoxic concentrations was found to begin with an initial electrostatic attraction of isolated amphiphile molecules to the phospholipid heads, followed by a rapid insertion of the apolar portions. As the accumulation into the bilayer proceeded, the membrane increased its fluidity and permeability without being subjected to major structural damage. After having ascertained that α-hydrazido acid amphiphiles do not interact with bacterial DNA, they were subjected to synergy evaluation for combinations with conventional antibiotics. Synergy was observed for combinations with tetracycline against sensitive S. aureus and E. coli, as well as with ciprofloxacin and colistin against resistant strains. Additivity with a remarkable recovery in activity of conventional antibiotics (from 2-fold to ≥32-fold) together with largely subtoxic concentrations of α-hydrazido acid derivatives was found for combinations with ciprofloxacin toward susceptible S. aureus and methicillin toward MRSa. However, no potentiation of conventional antibiotics was observed for combinations with linezolid and gentamicin against the corresponding resistant S. aureus and E. coli strains.

Synthesis and Kinetics of CO2-Responsive Gemini Surfactants.

Surfactants are hailed as "industrial monosodium glutamate", and are widely used as emulsifiers, demulsifiers, water treatment agents, etc., in the petroleum industry. However, due to the unidirectivity of conventional surfactants, the difficulty in demulsifying petroleum emulsions generated after emulsification with such surfactants increases sharply. Therefore, it is of great significance and application value to design and develop a novel switchable surfactant for oil exploitation. In this study, a CO2-switchable Gemini surfactant of N,N'-dimethyl-N,N'-didodecyl butylene diamine (DMDBA) was synthesized from 1, 4-dibromobutane, dodecylamine, formic acid, and formaldehyde. Then, the synthesized surfactant was structurally characterized by infrared (IR) spectroscopy, hydrogen nuclear magnetic resonance (1H NMR) spectroscopy, and electrospray ionization mass spectrometry (ESI-MS); the changes in conductivity and Zeta potential of DMDBA before and after CO2/N2 injection were also studied. The results show that DMDBA had a good CO2 response and cycle reversibility. The critical micelle concentration (CMC) of cationic surfactant obtained from DMDBA by injecting CO2 was 1.45 × 10-4 mol/L, the surface tension at CMC was 33.4 mN·m-1, and the contact angle with paraffin was less than 90°, indicating that it had a good surface activity and wettability. In addition, the kinetic law of the process of producing surfactant by injecting CO2 was studied, and it was found that the process was a second-order reaction. The influence of temperature and gas velocity on the reaction dynamics was explored. The calculated values from the equation were in good agreement with the measured values, with a correlation coefficient greater than 0.9950. The activation energy measured during the formation of surfactant was Ea = 91.16 kJ/mol.

Fisheries shocks provide an opportunity to reveal multiple recruitment sources of sardine in the Sea of Japan.

The abrupt decline in sardine catches in the Sea of Japan and the East China Sea (SJ-ECS) in 2014 and 2019 and the recovery in the following years call into question the current assumption that sardines in the SJ-ECS form a self-recruiting subpopulation. To test this hypothesis, we analysed otolith stable oxygen and carbon isotope profiles (δ18O, δ13C) of age-0 and age-1 sardines from 2010 and 2013-2015 year-classes captured in the SJ-ECS, as geographic markers for nursery areas. Age-0 sardines generally showed a significant ontogenetic decrease in otolith δ18O from larval to juvenile stages. However, the majority of age-1 captured in spring 2011, 2015 and 2016 showed non-decreasing otolith δ18O profiles, suggesting that the age-0 off the Japanese coast were not the main source of recruitment. Different migration groups were thus indicated: the "locals" growing up off the Japanese coast and the migrating "nonlocals". The isotope profiles of the "nonlocals" overlapped with those of age-0 captured in the subarctic North Pacific, suggesting that they may be migrants from the Pacific, or perhaps an unobserved northward migration group in the SJ-ECS. Our results highlight the considerable uncertainty in the population structure assumed in current stock assessment models for Japanese sardine.

Multiple benefits of new-energy vehicle power battery recycling strategies based on the theory of planned behavior and stimulus organism response.

With the yearly increasing market penetration of new-energy vehicles in China, the retirement of power batteries has gradually become a scale, and most of the waste batteries have entered informal recycling channels, which has induced a series of environmental problems. Considering this issue, we introduced the system dynamics (SD), stimulus organism response (SOR), and the theory of planned behavior (TPB) in behavioral economics to establish the environmental economic benefit evaluation model of power battery recycling strategies, and we performed a dynamic simulation analysis on the effect of government subsidy policy, policy advocacy, and other recycling strategies. The results show that: (1) the recovery subsidy policy can improve the formal recycling quantity and economic benefits of recovery, but the effect on the degree of environmental pollution is limited. (2) The combination of environmental awareness promotion strategy and subsidy policy can overcome the shortcomings of subsidy policy and has significant environmental and economic performance. (3) Compared with the benchmark scenario, the formal recycling quantity, the CO2 emission reduction, and the economic benefits of recovery in scenario 4 (high subsidy-high policy propaganda strategy) increased by approximately 112 %, 208 %, and 223 %, respectively, and the degree of environmental pollution decreased by approximately 65 %.

Effects of developmental stages, sex difference, and diet types of the host marmalade hoverfly (Episyrphus balteatus) on symbiotic bacteria.

Introduction: Symbiotic bacteria play key roles in a variety of important life processes of insects such as development, reproduction and environmental adaptation, and the elucidation of symbiont population structure and dynamics is crucial for revealing the underlying regulatory mechanisms. The marmalade hoverfly (Episyrphus balteatus) is not only a remarkable aphid predator, but also a worldwide pollinator second to honeybees. However, its symbiont composition and dynamics remain unclear. Methods: Herein, we investigate the symbiotic bacterial dynamics in marmalade hoverfly throughout whole life cycle, across two sexes, and in its prey Megoura crassicauda by 16S rRNA sequencing. Results: In general, the dominant phyla were Proteobacteria and Firmicutes, and the dominant genera were Serratia and Wolbachia. Serratia mainly existed in the larval stage of hoverfly with the highest relative abundance of 86.24% in the 1st instar larvae. Wolbachia was found in adults and eggs with the highest relative abundance of 62.80% in eggs. Significant difference in species diversity was observed between the adults feeding on pollen and larvae feeding on M. crassicauda, in which the dominant symbiotic bacteria were Asaia and Serratia, respectively. However, between two sexes, the symbionts exhibited high similarity in species composition. In addition, our results suggested that E. balteatus obtainded Serratia mainly through horizontal transmission by feeding on prey aphids, whereas it acquired Wolbachia mainly through intergeneration vertical transmission. Taken together, our study revealed the effects of development stages, diet types and genders of E. balteatus on symbionts, and explored transmission modes of dominant bacteria Serratia and Wolbachia. Discussion: Our findings lay a foundation for further studying the roles of symbiotic bacteria in E. balteatus life cycle, which will benefit for revealing the co-adaptation mechanisms of insects and symbiotic bacteria.

Probing Surface Dynamics of SiOx Thin-Film Electrodes during Cycling through X-Ray Photoemission Spectroscopy and Operando X-Ray Reflectivity.

SiOx electrodes are promising for high-energy-density lithium-ion batteries (LIBs) due to their ability to mitigate volume expansion-induced degradation. Here, we investigate the surface dynamics of SiOx thin-film electrodes cycled in different carbonate-based electrolytes using a combination of ex situ X-ray photoelectron spectroscopy (XPS) and operando synchrotron X-ray reflectivity analyses. The thin-film geometry allows us to probe the depth-dependent chemical composition and electron density from surface to current collector through the solid electrolyte interphase (SEI), the active material, and the thickness evolution during cycling. Results reveal that SiOx lithiation initiates below 0.4 V vs Li+/Li and indicate a close relationship between SEI formation and SiOx electrode lithiation, likely due to the high resistivity of SiOx. We find similar chemical compositions for the SEI in FEC-containing and FEC-free electrolytes but observe a reduced thickness in the former case. In both cases, the SEI thickness decreases during delithiation due to the removal or dissolution of some carbonate species. These findings give insights into the (de)lithiation of SiOx, in particular, during the formation stage, and the effect of the presence of FEC in the electrolyte on the evolution of the SEI during cycling.