Predicting pharmacodynamic effects through early drug discovery with artificial intelligence-physiologically based pharmacokinetic (AI-PBPK) modelling

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model links the concentration-time profile of a drug with its therapeutic effects based on the underlying biological or physiological processes. Clinical endpoints play a pivotal role in drug development. Despite the substantial time and effort invested in screening drugs for favourable pharmacokinetic (PK) properties, they may not consistently yield optimal clinical outcomes. Furthermore, in the virtual compound screening phase, researchers cannot observe clinical outcomes in humans directly. These uncertainties prolong the process of drug development. As incorporation of Artificial Intelligence (AI) into the physiologically based pharmacokinetic/pharmacodynamic (PBPK) model can assist in forecasting pharmacodynamic (PD) effects within the human body, we introduce a methodology for utilizing the AI-PBPK platform to predict the PK and PD outcomes of target compounds in the early drug discovery stage. In this integrated platform, machine learning is used to predict the parameters for the model, and the mechanism-based PD model is used to predict the PD outcome through the PK results. This platform enables researchers to align the PK profile of a drug with desired PD effects at the early drug discovery stage. Case studies are presented to assess and compare five potassium-competitive acid blocker (P-CAB) compounds, after calibration and verification using vonoprazan and revaprazan

Unveiling the neuroprotective potential of dietary polysaccharides: a systematic review

Central nervous system (CNS) disorders present a growing and costly global health challenge, accounting for over 11% of the diseases burden in high-income countries. Despite current treatments, patients often experience persistent symptoms that significantly affect their quality of life. Dietary polysaccharides have garnered attention for their potential as interventions for CNS disorders due to their diverse mechanisms of action, including antioxidant, anti-inflammatory, and neuroprotective effects. Through an analysis of research articles published between January 5, 2013 and August 30, 2023, encompassing the intervention effects of dietary polysaccharides on Alzheimer’s disease, Parkinson’s disease, depression, anxiety disorders, autism spectrum disorder, epilepsy, and stroke, we have conducted a comprehensive review with the aim of elucidating the role and mechanisms of dietary polysaccharides in various CNS diseases, spanning neurodegenerative, psychiatric, neurodevelopmental disorders, and neurological dysfunctions. At least four categories of mechanistic bases are included in the dietary polysaccharides’ intervention against CNS disease, which involves oxidative stress reduction, neuronal production, metabolic regulation, and gut barrier integrity. Notably, the ability of dietary polysaccharides to resist oxidation and modulate gut microbiota not only helps to curb the development of these diseases at an early stage, but also holds promise for the development of novel therapeutic agents for CNS diseases. In conclusion, this comprehensive review strives to advance therapeutic strategies for CNS disorders by elucidating the potential of dietary polysaccharides and advocating interdisciplinary collaboration to propel further research in this realm

Acute Ethanol Inhibition of γ Oscillations Is Mediated by Akt and GSK3β

Hippocampal network oscillations at gamma band frequency (γ, 30–80 Hz) are closely associated with higher brain functions such as learning and memory. Acute ethanol exposure at intoxicating concentrations (≥50 mM) impairs cognitive function. This study aimed to determine the effects and the mechanisms of acute ethanol exposure on γ oscillations in an in vitro model. Ethanol (25–100 mM) suppressed kainate-induced γ oscillations in CA3 area of the rat hippocampal slices, in a concentration-dependent, reversible manner. The ethanol-induced suppression was reduced by the D1R antagonist SCH23390 or the PKA inhibitor H89, was prevented by the Akt inhibitor triciribine or the GSk3β inhibitor SB415286, was enhanced by the NMDA receptor antagonist D-AP5, but was not affected by the MAPK inhibitor U0126 or PI3K inhibitor wortmanin. Our results indicate that the intracellular kinases Akt and GSk3β play a critical role in the ethanol-induced suppression of γ oscillations and reveal new cellular pathways involved in the ethanol-induced cognitive impairment

Ship structural component contribution evaluation based on grey target theory

[Objectives] A concept named ‘component contribution rate’ is proposed to solve problems concerning the influence of ship structure components on ship structure performance.[Methods] First, a hierarchical structure is elaborated and mapped from structural components to structural performance. Second, the component contribution rate is defined in order to describe the contribution rate for a component in structural performance to fulfill its structural purpose. Next, the grey target theory is applied to quantify the component contribution rate.[Results] Finally, the application of the proposed method is demonstrated through a SWATH case study.[Conclusions] This method can be applied in the evaluation of the ship structural schemes,in order to support the optimal design of ship structure

AHR regulates the immunomodulatory function of human adipose-derived mesenchymal stem cells

Objective To explore the effect of aryl hydrocarbon receptor(AHR) on the immunomodulatory function of human adipose derived mesenchymal stem cells (MSCs). Methods RT-qPCR and immunofluorescence staining were used to detect the expression levels of indoleamine 2,3-dioxygenase 1 (IDO1), interleukin-4-inducible gene 1 (IL4I1) and AHR in MSCs before and after inflammatory cytokine stimulation; siCtrl, siIDO1, siIL4I1 and siAHR were transfected into MSCs and blocked the AHR signaling pathway; conditioned medium from MSCs was co-incubated with macrophages, RT-qPCR and ELISA were performed to detect the level of IL-6, IL-1β, TNF-α. Results MSCs without cytokine stimulation highly expressed AHR and hardly expressed IDO1 and IL4I1 proteins; IDO1, IL4I1 and AHR were up-regulated after different cytokine stimulation(P＜0.05), the expression of IDO1 and IL4I1 was most significantly up-regulated after stimulation by IFN-γ(P＜0.001), AHR entering the nucleus was increased; down-regulation of AHR expression could inhibit the immunomodulatory effect of MSCs(P＜0.05). Conclusions AHR regulates the immune function of MSCs, downregulates expression of AHR could inhibit the immunomodulatory effects of MSCs

Research on the Contact Pressure Calculation Method for the Misaligned Elastomeric Journal Bearing

The pressure distribution of a misaligned elastomeric journal bearing is crucial for analyzing the uneven excessive wearing of the propulsion shaft bearing. However, analysis of the misaligned bearing is usually mainly based on the finite element method (FEM), which lacks a convenient and effective calculation method. This paper uses the influence coefficient factors (ICs) method to analyze the contact pressure of the misaligned bearing. First, the elastic displacement of the cylindrical shell subjected to a single point of concentrated force is derived and used to attain the new influence coefficient factors. Then, the geometric boundary conditions of planar conformal cylindrical contact are extended to the case of non-planar contact. Finally, the proposed method is applied and compared with other methods. The results show that the influence coefficient factors are greatly affected by the shape and constraints of the contact object. The proposed method is suitable for cylindrical shell contact analysis and has the same accuracy as FEM with half of the time consumption. In addition, the bearing capacity and contact stiffness are decreased as the effective contact area decreases due to misalignment

Study on wave slamming characteristics of a typical floating wind turbine under freak waves

Freak waves can cause serious damage to offshore structures because of their characteristics of high peak energy, short duration, and great contingency. In this study, the slamming pressure characteristics of a typical floating wind turbine under freak waves are studied by numerical simulation and experiment. The computational fluid dynamics (CFD) method is used to establish the numerical tank. The experimental test of a typical float wind turbine is implemented at Jiangsu University of Science and Technology. The numerical model of a floating wind turbine system is modified based on an experimental test. The slamming characteristics of a floating wind turbine under the freak wave are studied using the modified numerical model. The combined wave focusing model and the push pedal wave-making theory are adopted to simulate the freak wave. Results show that the slamming pressure of a floating wind turbine under a freak wave is much larger than that under a conventional random wave with the same significant wave height. Meanwhile, the evident phenomenon of double-peak slamming is observed in the wave slamming of the floating wind turbine. The impact period at different locations varies although the floating wind turbine is a monolithic structure

Optimizing Printing Fidelity Of The Single-Nozzle Based Multimaterial Direct Ink Writing For 3D Food Printing

Single-nozzle based multimaterial direct ink writing enables voxel-based fabrication with superior printing efficiency than multi-nozzle protocol. This is attractive for food 3D printing process where efficiency matters for its application. However, for single-nozzle based process, the presence of residual material in the shared channel can affect its printing fidelity. In this study, we propose a path planning algorithm that can address this issue by incorporating (i) advance distance to compensate the extrusion delay when switching materials, and (ii) in-process printhead motion adjustments to stabilise the extrusion process. Our approach demonstrated a substantial improvement in printing fidelity, where the switching point offset was reduced to ±0.5 mm. Similarly, the unstable extrusion behaviours (bulging and necking) during switching materials were suppressed, where the printing fidelity was improved by 27 ± 5% (bulging) and 19 ± 3% (necking) respectively. Additionally, we provide an open-source slicing programme that empowers users to implement the above two algorithms