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.

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.

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.

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.

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.

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.

Dysregulation of mitochondrial dynamics and mitophagy are involved in high-fat diet-induced steroidogenesis inhibition.

Male obesity is a pandemic health issue and can disrupt testicular steroidogenesis. Here, we explored the mechanism by which a high-fat diet (HFD) induced steroidogenic inhibition. As expected, HFD induced lipid droplet accumulation and reduced the expression of StAR, P450scc, and 3ß-HSD, three steroidogenic enzymes, in mouse testes. Palmitic acid (PA), a saturated fatty acid usually used to trigger lipotoxicity in vitro, induced greater accumulation of lipid droplets and the downregulation of steroidogenic enzymes in TM3 cells. Mechanistically, both HFD and PA disturbed mitochondrial fusion/fission dynamics and then induced mitochondrial dysfunction and mitophagy inhibition in mouse Leydig cells. Additionally, mitochondrial fusion promoter M1 attenuated PA-induced imbalance of mitochondrial dynamics, mitophagy inhibition, mitochondrial reactive oxygen species (ROS) production, and mitochondrial dysfunction in TM3 cells. Mitofusin 2 (Mfn2) knock-down further aggravated the PA-induced imbalance of mitochondrial dynamics, mitochondrial ROS production, and mitochondrial dysfunction in TM3 cells. Importantly, M1 rescued PA-induced downregulation of steroidogenic enzymes, whereas Mfn2 knock-down further aggravated PA-induced downregulation of steroidogenic enzymes in TM3 cells. Overall, our results provide laboratory evidence that mitochondrial dysfunction and mitophagy inhibition caused by dysregulation of mitochondrial fusion may be involved in HFD-induced steroidogenesis inhibition in mouse Leydig cells.

Designing a model to estimate the burden of COVID-19 in Iran.

The novel coronavirus disease 2019 (COVID-19) is the latest evidence of an epidemic disease resulting in an extraordinary number of infections and claimed several lives, along with extensive economic and social consequences. In response to the emergency situation, countries introduced different policies to address the situation, with different levels of efficacy. This paper outlines the protocol for developing a model to analyze the burden of COVID-19 in Iran and the effect of policies on the incidence and cumulative death of the disease. The importance of the model lies in the fact that no study, according to the authors' best knowledge, tried to quantify the impact of the disease on Iran society and the impact of various implemented interventions on disease control. Based on a systematic review of COVID-19 prediction models and expert interviews, we developed a system dynamics model that not only includes an epidemic part but also considers the impact of various policies implemented by the Ministry of Health. The epidemic model estimates the incidence and mortality of COVID-19 in Iran. The model also intends to evaluate the effect of implemented policies on these outcomes. The model reflects the continuum of COVID-19 infection and care in Iran (of which some of its elements are unique) and key activities and decisions in delivering care. The model is calibrated and validated using data published by the Ministry of Health of Iran. Finally, the study aims to provide evidence of the impact of interventions intended to curb COVID-19 in Iran. Insights provided by the model will be necessary for controlling either future waves of the disease or similar future pandemics.

Reducing mental health emergency visits: population-level strategies from participatory modelling.

BACKGROUND: Emergency departments (EDs) are often the front door for urgent mental health care, especially when demand exceeds capacity. Long waits in EDs exert strain on hospital resources and worsen distress for individuals experiencing a mental health crisis. We used as a test case the Australian Capital Territory (ACT), with a population surge of over 27% across 2011-2021 and a lagging increase in mental health care capacity, to evaluate population-based approaches to reduce mental health-related ED presentations. METHODS: We developed a system dynamics model for the ACT region using a participatory approach involving local stakeholders, including health planners, health providers and young people with lived experience of mental health disorders. Outcomes were projected over 2023-2032 for youth (aged 15-24) and for the general population. RESULTS: Improving the overall mental health care system through strategies such as doubling the annual capacity growth rate of mental health services or leveraging digital technologies for triage and care coordination is projected to decrease youth mental health-related ED visits by 4.3% and 4.8% respectively. Implementation of mobile crisis response teams (consisting of a mental health nurse accompanying police or ambulance officers) is projected to reduce youth mental health-related ED visits by 10.2% by de-escalating some emergency situations and directly transferring selected individuals to community mental health centres. Other effective interventions include limiting re-presentations to ED by screening for suicide risk and following up with calls post-discharge (6.4% reduction), and limiting presentations of frequent users of ED by providing psychosocial education to families of people with schizophrenia (5.1% reduction). Finally, combining these five approaches is projected to reduce youth mental health-related ED presentations by 26.6% by the end of 2032. CONCLUSIONS: Policies to decrease youth mental health-related ED presentations should not be limited to increasing mental health care capacity, but also include structural reforms.

A joint-threshold Filippov model describing the effect of intermittent androgen-deprivation therapy in controlling prostate cancer.

Intermittent androgen-deprivation therapy (IADT) can be beneficial to delay the occurrence of treatment resistance and cancer relapse compared to the standard continuous therapy. To study the effect of IADT in controlling prostate cancer, we developed a Filippov prostate cancer model with a joint threshold function: therapy is implemented once the total population of androgen-dependent cells (AC-Ds) and androgen-independent cells (AC-Is) is greater than the threshold value ET, and it is suspended once the population is less than ET. As the parameters vary, our model undergoes a series of sliding bifurcations, including boundary node, focus, saddle, saddle-node and tangency bifurcations. We also obtained the coexistence of one, two or three real equilibria and the bistability of two equilibria. Our results demonstrate that the population of AC-Is can be contained at a predetermined level if the initial population of AC-Is is less than this level, and we choose a suitable threshold value.

Multispectral and molecular simulation of the interaction of human α1-acid glycoprotein with palbociclib.

Palbociclib, a selective CDK4/6 inhibitor with potent anti-tumor effects, was investigated for its interaction with human α1-acid glycoprotein (HAG). Spectral analysis revealed that palbociclib forms a ground state complex with HAG, exhibiting binding constant (Kb) of 104 M-1 at the used temperature range. The interaction between the two was determined to be driven mainly by hydrogen bonding and hydrophobic forces. Multispectral studies indicated that the bound palbociclib altered the secondary structure of HAG and reduced polarity around Trp and Tyr amino acids. And, molecular docking and dynamics simulations verified the experimental findings. Finally, most of the metal ions present in plasma, such as K+, Cu2+, Ca2+, Mg2+, Ni2+, Fe3+, and Co2+, are detrimental to the binding of palbociclib to HAG, with the exception of Zn2+, which is favorable.

Size-dependent Curie temperature of Ni nanoparticles from spin-lattice dynamics simulations.

The magnetic properties of Ni nanoparticles (NPs) with diameter D are investigated using spin-lattice dynamics (SLD) simulations. Using exchange interactions fitted to ab-initio results we obtain a Curie temperature, T c , similar, but lower, than experiments. In order to reproduce quantitatively the bulk Curie temperature and the experimental results, the exchange energy has to be increased by 25% compared to the ab-initio value. During the simulated time, Ni NPs remain ferromagnetic down to the smallest sizes investigated here, containing around 500 atoms. The average magnetic moment of the NPs is slightly smaller than that determined experimentally. By considering a core-shell model for NPs, in which the shell atoms are assigned a larger magnetic moment, this discrepancy can be removed. T c is lower for a moving lattice than for a frozen lattice, as expected, but this difference decreases with NP size because smaller NPs include higher surface disorder which dominates the transition. For NPs, T c decreases with the NP diameter D by at most 10% at D = 2  nm, in agreement with several experiments, and unlike some modeling or theoretical scaling results which predict a considerably larger decrease. The decrease of T c is well described by finite-size scaling models, with a critical exponent that depends on the SLD settings for a frozen or moving lattice, and also depends on the procedure for determining T c . Extrapolating the inverse of the magnetization as function of temperature near T c gives a lower T c than the maximum of the susceptibility.

Starvation increases susceptibility to bacterial infection and promotes systemic pathogen proliferation in Drosophila melanogaster females.

Defense against pathogens and parasites requires substantial investment of energy and resources on part of the host. This makes the host immune function dependent on availability and accessibility of resources. A resource deprived host is therefore expected to be more susceptible to infections, although empirical results do not always align with this prediction. Limiting host access to resources can additionally impact within-host pathogen numbers, either directly by altering the amount of resources available to the pathogens for proliferation or indirectly by altering the efficiency of the host immune system. We tested for the effects of host starvation (complete deprivation of resources) on susceptibility to bacterial pathogens, and within-host pathogen proliferation, in Drosophila melanogaster females. Our results show that starvation increases post-infection mortality of the host, but in a pathogen-specific manner. This increase in mortality is always accompanied by increased within-host pathogen proliferation. We therefore propose that starvation compromises host resistance to bacterial infections in Drosophila melanogaster females thereby increasing susceptibility to infections.

Expanding the food environment framework to include family dynamics: A systematic synthesis of qualitative evidence using HIV as a case study.

Food environment changes in low- and middle-income countries are increasing diet-related noncommunicable diseases (NCDs). This paper synthesizes the qualitative evidence about how family dynamics shape food choices within the context of HIV (Prospero: CRD42021226283). Guided by structuration theory and food environment framework, we used best-fit framework analysis to develop the Family Dynamics Food Environment Framework (FDF) comprising three interacting dimensions (resources, characteristics, and action orientation). Findings show how the three food environment domains (personal, family, external) interact to affect food choices within families affected by HIV. Given the growing prevalence of noncommunicable and chronic diseases, the FDF can be applied beyond the context of HIV to guide effective and optimal nutritional policies for the whole family.

Bouts, Pauses, and Units of Operant Performance: A Primer.

Operant behavior typically occurs in bouts and pauses. The microstructural analysis of bouts and pauses reveals important and separable information about the physical characteristics of the operant and the motivation behind it. An analysis of interresponse times (IRTs) often reveals a mixture of two exponential distributions. One corresponds to short IRTs within ongoing response bouts, reflecting motor properties of the operant, and the other corresponds to longer intervals between bouts, reflecting the motivation behind the response. Partitioning responses into bout initiations and within-bout responses via this two-mode framework reveals the mechanisms underlying behavior maintenance and change. This approach is used in the fields of neurotoxicology, behavioral pharmacology, and behavioral neuroscience to disentangle the contribution of motivational and motoric variables to the pattern of operant behavior. In this article, we present a primer aimed at providing essential concepts related to the analysis of response bouts and temporal dynamics of operant performance.

A new understanding of coronary curvature and haemodynamic impact on the course of plaque onset and progression.

The strong link between atherosclerosis and luminal biomechanical stresses is well established. Yet, this understanding has not translated into preventative coronary diagnostic imaging, particularly due to the under-explored role of coronary anatomy and haemodynamics in plaque onset, which we aim to address with this work. The left coronary trees of 20 non-stenosed (%diameter stenosis [%DS] = 0), 12 moderately (0 < %DS < 70) and 7 severely (%DS ≥ 70) stenosed cases were dissected into bifurcating and non-bifurcating segments for whole-tree and segment-specific comparisons, correlating nine three-dimensional coronary anatomical features, topological shear variation index (TSVI) and luminal areas subject to low time-average endothelial shear stress (%LowTAESS), high oscillatory shear index (%HighOSI) and high relative residence time (%HighRRT). We found that TSVI is the only metric consistently differing between non-stenosed and stenosed cases across the whole tree, bifurcating and non-bifurcating segments (p < 0.002, AUC = 0.876), whereas average curvature and %HighOSI differed only for the whole trees (p < 0.024) and non-bifurcating segments (p < 0.027), with AUC > 0.711. Coronary trees with moderate or severe stenoses differed only in %LowTAESS (p = 0.009) and %HighRRT (p = 0.012). This suggests TSVI, curvature and %HighOSI are potential factors driving plaque onset, with greater predictive performance than the previously recognized %LowTAESS and %HighRRT, which appears to play a role in plaque progression.

Breaking Rossby waves drive extreme precipitation in the world's arid regions.

More than a third of the world's population lives in drylands and is disproportionately at risk from hydrometeorological hazards such as drought and flooding. While weather systems governing precipitation formation in humid regions have been widely explored, our understanding of the atmospheric processes generating precipitation in arid regions remains fragmented at best. Here we show, using a variety of precipitation datasets, that Rossby wave breaking is a key atmospheric driver of precipitation in arid regions worldwide. Rossby wave breaking contributes up to 90% of daily precipitation extremes and up to 80% of total precipitation amounts in arid regions equatorward and downstream of the midlatitude storm tracks. The relevance of Rossby wave breaking for precipitation increases with increasing land aridity. Contributions of wave breaking to precipitation dominate in the poleward and westward portions of arid subtropical regions during the cool season. Our findings imply that Rossby wave breaking plays a crucial role in projections and uncertainties of future precipitation changes in societally vulnerable regions that are exposed to both freshwater shortages and flood hazards.

Dendrites contribute to the gradient of intrinsic timescales encompassing cortical and subcortical brain networks.

Introduction: Cytoarchitectonic studies have uncovered a correlation between higher levels of cortical hierarchy and reduced dendritic size. This hierarchical organization extends to the brain's timescales, revealing longer intrinsic timescales at higher hierarchical levels. However, estimating the contribution of single-neuron dendritic morphology to the hierarchy of timescales, which is typically characterized at a macroscopic level, remains challenging. Method: Here we mapped the intrinsic timescales of six functional networks using functional magnetic resonance imaging (fMRI) data, and characterized the influence of neuronal dendritic size on intrinsic timescales of brain regions, utilizing a multicompartmental neuronal modeling approach based on digitally reconstructed neurons. Results: The fMRI results revealed a hierarchy of intrinsic timescales encompassing both cortical and subcortical brain regions. The neuronal modeling indicated that neurons with larger dendritic structures exhibit shorter intrinsic timescales. Together these findings highlight the contribution of dendrites at the neuronal level to the hierarchy of intrinsic timescales at the whole-brain level. Discussion: This study sheds light on the intricate relationship between neuronal structure, cytoarchitectonic maps, and the hierarchy of timescales in the brain.