Optimising Bioprinting Nozzles through Computational Modelling and Design of Experiments.

3D bioprinting is a promising technique for creating artificial tissues and organs. One of the main challenges of bioprinting is cell damage, due to high pressures and tensions. During the biofabrication process, extrusion bioprinting usually results in low cell viability, typically ranging from 40% to 80%, although better printing performance with higher cell viability can be achieved by optimising the experimental design and operating conditions, with nozzle geometry being a key factor. This article presents a review of studies that have used computational fluid dynamics (CFD) to optimise nozzle geometry. They show that the optimal ranges for diameter and length are 0.2 mm to 1 mm and 8 mm to 10 mm, respectively. In addition, it is recommended that the nozzle should have an internal angle of 20 to 30 degrees, an internal coating of ethylenediaminetetraacetic acid (EDTA), and a shear stress of less than 10 kPa. In addition, a design of experiments technique to obtain an optimal 3D bioprinting configuration for a bioink is also presented. This experimental design would identify bioprinting conditions that minimise cell damage and improve the viability of the printed cells.

Computational Simulation of Virtual Patients Reduces Dataset Bias and Improves Machine Learning-Based Detection of ARDS from Noisy Heterogeneous ICU Datasets.

Goal: Machine learning (ML) technologies that leverage large-scale patient data are promising tools predicting disease evolution in individual patients. However, the limited generalizability of ML models developed on single-center datasets, and their unproven performance in real-world settings, remain significant constraints to their widespread adoption in clinical practice. One approach to tackle this issue is to base learning on large multi-center datasets. However, such heterogeneous datasets can introduce further biases driven by data origin, as data structures and patient cohorts may differ between hospitals. Methods: In this paper, we demonstrate how mechanistic virtual patient (VP) modeling can be used to capture specific features of patients' states and dynamics, while reducing biases introduced by heterogeneous datasets. We show how VP modeling can be used for data augmentation through identification of individualized model parameters approximating disease states of patients with suspected acute respiratory distress syndrome (ARDS) from observational data of mixed origin. We compare the results of an unsupervised learning method (clustering) in two cases: where the learning is based on original patient data and on data derived in the matching procedure of the VP model to real patient data. Results: More robust cluster configurations were observed in clustering using the model-derived data. VP model-based clustering also reduced biases introduced by the inclusion of data from different hospitals and was able to discover an additional cluster with significant ARDS enrichment. Conclusions: Our results indicate that mechanistic VP modeling can be used to significantly reduce biases introduced by learning from heterogeneous datasets and to allow improved discovery of patient cohorts driven exclusively by medical conditions.

Computational simulation-assisted template selection of magnetic MOFs molecularly imprinted materials applying the adsorption and detection of multiple fluoroquinolones.

This study utilized computational simulation and surface molecular imprinting technology to develop a magnetic metal-organic framework molecularly imprinted polymer (Fe3O4@ZIF-8@SMIP) capable of selectively recognizing and detecting multiple fluoroquinolones (FQs). The Fe3O4@ZIF-8@SMIP material was synthesized using the "common" template-ofloxacin, identified by computational simulation, demonstrating notable adsorption capacity (88.61-212.93 mg g-1) and rapid mass-transfer features (equilibration time: 2-3 min) for all tested FQs, consistent with Langmuir adsorption model. Subsequently, this material was employed as a magnetic solid-phase-extraction adsorbent for adsorption and detection of multiple FQs by combining with high performance liquid chromatography. The developed method exhibited good linearity for various FQs within the concentration range of 0.1-500 µg L-1, with low limit of detection (0.0605-0.1529 µg L-1) and limit of quantitation (0.2017-0.5097 µg L-1). Satisfactory recoveries (88.38-103.44%) were obtained when applied to spiked food samples, demonstrating the substantial potential of this Fe3O4@ZIF-8@SMIP material for rapid enrichment and identification for multiple FQs residues.

Ascorbic acid and ascorbyl palmitate-loaded liposomes: Development, characterization, stability evaluation, in vitro security profile, antimicrobial and antioxidant activities.

The objective of this work was to prepare and characterize liposomes containing co-encapsulated ascorbic acid (AA) and ascorbyl palmitate (AP), as well as to evaluate their stability, cytotoxicity, antioxidant, and antimicrobial activity. Through the pre-formulation studies, it was possible to improve the formulation, as leaving it more stable and with a greater antioxidant activity, resulting in a formulation designated LIP-AAP, with 161 nm vesicle size, 0.215 polydispersity index, -31.7 mV zeta potential, and pH of 3.34. Encapsulation efficiencies were 37% for AA and 79% for AP, and the content was 1 mg/mL for each compound. The optimized liposomes demonstrated stability under refrigeration for 60 days, significant antioxidant activity (31.4 µMol of TE/mL), and non-toxicity, but no antimicrobial effects against bacteria and fungi were observed. These findings confirm that the co-encapsulated liposomes are potent, stable antioxidants that maintain their physical and chemical properties under optimal storage conditions.

Photochemical transformation of liquid crystal monomers in simulated environmental media: Kinetics, mechanism, toxicity variation and QSAR modeling.

Liquid crystal monomers (LCMs) are a new class of emerging pollutants with high octanol-water partition coefficients; however, their transformation behavior and associated risk to environments with high organic matter content has rarely been reported. In this study, we investigated the photodegradation kinetics, mechanism, and toxicity variation of 23 LCMs on leaf wax models (e.g., organic solvents methanol and n-hexane). The order of the photolysis rates of these LCMs were biphenylethyne LCMs > phenylbenzoate LCMs > diphenyl/terphenyl LCMs under simulated sunlight, while the phenylcyclohexane LCMs were resistant to photodegradation. The phenylbenzoate and biphenylethyne LCMs mainly undergo direct photolysis, while the diphenyl/terphenyl LCMs mainly undergo self-sensitized photolysis. The main photolysis pathways are the cleavage of ester bonds for phenylbenzoate LCMs, the addition, oxidation and cleavage of alkynyl groups for biphenylethyne LCMs, and the cleavage/oxidation of chains attached to phenyls and the benzene ring opening for diphenyl/terphenyls LCMs. Most photolysis products remained toxic to aquatic organisms to some degree. Additionally, two quantitative structure-activity relationship models for predicting kobs of LCMs in methanol and n-hexane were developed, and employed to predict kobs of 93 LCMs to fill the kobs data gap in systems mimicking leaf surfaces. These results can be helpful for evaluating the fate and risk of LCMs in environments with high content of organic phase.

Comprehending the inhibition mechanism of indole-based bis-acylhydrazone compounds on α-glucosidase: Spectral and theoretical approaches.

Indole-based bis-acylhydrazone compounds can inhibit the activity of α-glucosidase and control the concentration of blood glucose. In this paper, the characteristics of three indole-based bis-acylhydrazone compounds with different inhibitory activities of α-glucosidase as well as the interaction with α-glucosidase were studied by experiments and computational simulation techniques. Enzyme kinetic and spectral experiments showed that the indole-based bis-acylhydrazone compounds were able to inhibit enzyme activity through mixed inhibition dominated by competitive inhibition, and during the binding reaction, indole-based bis-acylhydrazone compounds can quench the intrinsic fluorescence of α-glucosidase through static quenching and an aggregation of the indole-based bis-acylhydrazone with α-glucosidase produces a stable complex with a molar ratio of 1:1, and the combination of indole-based bis-acylhydrazone compounds could lead to slight change in the conformation of α-glucosidase. The theoretical simulation demonstrated that the stability of the complex systems was positively correlated with the inhibitory activity of indole-based bis-acylhydrazone compounds, and the indole-based bis-acylhydrazone compounds occupied the active site in the multi-ligand system, resulting in a significant decrease in the binding ability of starch to active amino acids. These results suggested that indole-based bis-acylhydrazone compound was expected to be a new type of α-glucosidase inhibitor.

Inversion of Left Ventricular Axial Shortening: In Silico Proof of Concept for Treatment of HFpEF.

Left ventricular (LV) longitudinal function is mechanically coupled to the elasticity of the ascending aorta (AA). The pathophysiologic link between a stiff AA and reduced longitudinal strain and the subsequent deterioration in longitudinal LV systolic function is likely relevant in heart failure with preserved ejection fraction (HFpEF). The proposed therapeutic effect of freeing the LV apex and allowing for LV inverse longitudinal shortening was studied in silico utilizing the Living Left Heart Human Model (Dassault Systémes Simulia Corporation). LV function was evaluated in a model with (A) an elastic AA, (B) a stiff AA, and (C) a stiff AA with a free LV apex. The cardiac model simulation demonstrated that freeing the apex caused inverse LV longitudinal shortening that could abolish the deleterious mechanical effect of a stiff AA on LV function. A stiff AA and impairment of the LV longitudinal strain are common in patients with HFpEF. The hypothesis-generating model strongly suggests that freeing the apex and inverse longitudinal shortening may improve LV function in HFpEF patients with a stiff AA.

Advancement in computational simulation and validation of congenital heart disease: a review.

The improvement in congenital heart disease (CHD) treatment and management has increased the life expectancy in infants. However, the long-term efficacy is difficult to assess and thus, computational modelling has been applied for evaluating this. Here, we provide an overview of the applications of computational modelling in CHD based on three categories; CHD involving large blood vessels only, heart chambers only, and CHD that occurs at multiple heart structures. We highlight the advancement of computational simulation of CHD that uses multiscale and multiphysics modelling to ensure a complete representation of the heart and circulation. We provide a brief future direction of computational modelling of CHD such as to include growth and remodelling, detailed conduction system, and occurrence of myocardial infarction. We also proposed validation technique using advanced three-dimensional (3D) printing and particle image velocimetry (PIV) technologies to improve the model accuracy.

Three-Dimensional Bowing Measurement of Distal Femur at Actual Size and Clinical Implications of Total Knee Arthroplasty.

Background and Objectives: To assess femoral shaft bowing (FSB) in coronal and sagittal planes and introduce the clinical implications of total knee arthroplasty (TKA) by analyzing a three-dimensional (3D) model with virtual implantation of the femoral component. Materials and Methods: Sixty-eight patients (average age: 69.1 years) underwent 3D model reconstruction of medullary canals using computed tomography (CT) data imported into Mimics® software (version 21.0). A mechanical axis (MA) line was drawn from the midportion of the femoral head to the center of the intercondylar notch. Proximal/distal straight centerlines (length, 60 mm; diameter, 1 mm) were placed in the medullary canal's center. Acute angles between these centerlines were measured to assess lateral and anterior bowing. The acute angle between the distal centerline and MA line was measured for distal coronal and sagittal alignment in both anteroposterior (AP) and lateral views. The diameter of curve (DOC) along the posterior border of the medulla was measured. Results: The mean lateral bowing in the AP view was 3.71°, and the mean anterior bowing in the lateral view was 11.82°. The average DOC of the medullary canal was 1501.68 mm. The average distal coronal alignment of all femurs was 6.40°, while the distal sagittal alignment was 2.66°. Overall, 22 femurs had coronal bowing, 42 had sagittal bowing, and 15 had both. Conclusions: In Asian populations, FSB can occur in coronal, sagittal, or both planes. Increased anterolateral FSB may lead to cortical abutment in the sagittal plane, despite limited space in the coronal plane. During TKA, distal coronal alignment guides the distal femoral valgus cut angle, whereas distal sagittal alignment aids in predicting femoral component positioning to avoid anterior notching. However, osteotomies along the anterior cortical bone intended to prevent notching may result in outliers due to differences between the distal sagittal alignment and the distal anterior cortical axis.

The Stiffness of the Ascending Aorta Has a Direct Impact on Left Ventricular Function: An In Silico Model.

During systole, longitudinal shortening of the left ventricle (LV) displaces the aortic root toward the apex of the heart and stretches the ascending aorta (AA). An in silico study (Living Left Heart Human Model, Dassault Systèmes Simulia Corporation) demonstrated that stiffening of the AA affects myocardial stress and LV strain patterns. With AA stiffening, myofiber stress increased overall in the LV, with particularly high-stress areas at the septum. The most pronounced reduction in strain was noted along the septal longitudinal region. The pressure-volume loops showed that AA stiffening caused a deterioration in LV function, with increased end-systolic volume, reduced systolic LV pressure, decreased stroke volume and effective stroke work, but elevated end-diastolic pressure. An increase in myofiber contractility indicated that stroke volume and effective stroke work could be recovered, with an increase in LV end-systolic pressure and a decrease in end-diastolic pressure. Longitudinal and radial strains remained reduced, but circumferential strains increased over baseline, compensating for lost longitudinal LV function. Myofiber stress increased overall, with the most dramatic increase in the septal region and the LV apex. We demonstrate a direct mechanical pathophysiologic link between stiff AA and reduced longitudinal left ventricular strain which are common in patients with HFpEF.

Computerized analysis of haptens for the ultrasensitive and specific detection of Pyriftalid.

Pyriftalid (Pyr) is one of the most commonly used herbicides and due to its widespread and improper use, it has led to serious pollution of groundwater, soil and other ecosystems, threatening human health. A rapid method to detect Pyr was urgently needed. A high specific monoclonal antibody (mAb) against Pyr with IC50 values of 4.7 ng/mL was obtained by mAb screening technique and method with enhanced matrix effect. The study firstly proposed colloidal gold immunochromatographic test strips (CGIA) for Pyr, which enables rapid qualitative and quantitative determination of a large number of samples anytime and anywhere, so as to effectively monitor Pyr in environment and grain samples. Based on the properties of the desired Pyr antibody, the hapten Pyr-hapten-4 with high structural similarity to Pyr molecule, similar electrostatic potential distribution, and the ability to expose Pyr functional groups was screened out from five different Pyr haptens, which was consistent with mouse antiserum test. The CGIA quickly analyze the Pyr content in positive samples such as water samples, soil samples, paddy samples, brown rice samples within 10 min, the LOD for Pyr by CGIA as low as 1.84 ng/g, the v LOD value as low as 6 ng/g, and the extinction value as low as 25 ng/g. The content of positive samples detected by CGIA was consistent with the quantitative results of LC-MS/MS, the relative accuracy was within the range of 97-103 %. The recovery rate range for Pyr by CGIA was 92.0-99.7 %, and the coefficient of variation was between 1.30-8.56 %. It indicated Pyr-targeted CGIA test strip was an efficient and fast detection method to detect real environment and food samples.

Anti-Melanogenic Effects of Takifugu flavidus Muscle Hydrolysate in B16F10 Melanoma Cells and Zebrafish.

Abnormal melanogenesis can lead to hyperpigmentation. Tyrosinase (TYR), a key rate-limiting enzyme in melanin production, is an important therapeutic target for these disorders. We investigated the TYR inhibitory activity of hydrolysates extracted from the muscle tissue of Takifugu flavidus (TFMH). We used computer-aided virtual screening to identify a novel peptide that potently inhibited melanin synthesis, simulated its binding mode to TYR, and evaluated functional efficacy in vitro and in vivo. TFMH inhibited the diphenolase activities of mTYR, reducing TYR substrate binding activity and effectively inhibiting melanin synthesis. TFMH indirectly reduced cAMP response element-binding protein phosphorylation in vitro by downregulating melanocortin 1 receptor expression, thereby inhibiting expression of the microphthalmia-associated transcription factor, further decreasing TYR, tyrosinase related protein 1, and dopachrome tautomerase expression and ultimately impeding melanin synthesis. In zebrafish, TFMH significantly reduced black spot formation. TFMH (200 µg/mL) decreased zebrafish TYR activity by 43% and melanin content by 52%. Molecular dynamics simulations over 100 ns revealed that the FGFRSP (T-6) peptide stably binds mushroom TYR via hydrogen bonds and ionic interactions. T-6 (400 µmol/L) reduced melanin content in B16F10 melanoma cells by 71% and TYR activity by 79%. In zebrafish, T-6 (200 µmol/L) inhibited melanin production by 64%. TFMH and T-6 exhibit good potential for the development of natural skin-whitening cosmetic products.

Computed Simulation of Transcatheter Edge-to-Edge Mitral Valve Repair - A Proof of Concept Study.

AIMS: As transcatheter mitral valve (MV) interventions are expanding and more device types and sizes become available, a tool supporting operators in preprocedural planning and the clinical decision-making process is highly desirable. We sought to develop a finite element (FE) computational simulation model to predict results of transcatheter edge-to-edge (TEER) interventions. METHODS AND RESULTS: We prospectively enrolled patients with secondary mitral regurgitation (MR) referred for a clinically indicated TEER. Three-dimensional (3D) transesophageal echocardiograms performed at the beginning of the procedure were used to perform the simulation. On the 3D dynamic model of the MV that was first obtained, we simulated the clip implantation using the same clip(s) type, size, number, and implantation location that was used during the intervention. The 3D model of the MV obtained after simulation of the clip implantation was compared to the clinical results obtained at the end of the intervention. We analyzed the degree and location of residual MR and the shape and area of the diastolic mitral valve area. We performed computational simulation on 5 patients. Overall, the simulated models predicted well the degree and location of the residual regurgitant orifice(s) but tended to underestimate the diastolic mitral orifice area. CONCLUSIONS: In this proof-of-concept study, we present preliminary results on our algorithm simulating clip implantation in 5 patients with functional MR. We show promising results regarding the feasibility and accuracy in terms of predicting residual MR and the need to improve the estimation of the diastolic mitral valve area.

Deep eutectic solvent self-assembled reverse nanomicelles for transdermal delivery of sparingly soluble drugs.

BACKGROUND: Transdermal delivery of sparingly soluble drugs is challenging due to their low solubility and poor permeability. Deep eutectic solvent (DES)/or ionic liquid (IL)-mediated nanocarriers are attracting increasing attention. However, most of them require the addition of auxiliary materials (such as surfactants or organic solvents) to maintain the stability of formulations, which may cause skin irritation and potential toxicity. RESULTS: We fabricated an amphiphilic DES using natural oxymatrine and lauric acid and constructed a novel self-assembled reverse nanomicelle system (DES-RM) based on the features of this DES. Synthesized DESs showed the broad liquid window and significantly solubilized a series of sparingly soluble drugs, and quantitative structure-activity relationship (QSAR) models with good prediction ability were further built. The experimental and molecular dynamics simulation elucidated that the self-assembly of DES-RM was adjusted by noncovalent intermolecular forces. Choosing triamcinolone acetonide (TA) as a model drug, the skin penetration studies revealed that DES-RM significantly enhanced TA penetration and retention in comparison with their corresponding DES and oil. Furthermore, in vivo animal experiments demonstrated that TA@DES-RM exhibited good anti-psoriasis therapeutic efficacy as well as biocompatibility. CONCLUSIONS: The present study offers innovative insights into the optimal design of micellar nanodelivery system based on DES combining experiments and computational simulations and provides a promising strategy for developing efficient transdermal delivery systems for sparingly soluble drugs.

Integrating physical experiments with computational fluid dynamics to transform mosque minarets into efficient solar chimneys.

This study explores the potential of repurposing mosque minarets as solar chimneys in hot arid regions to facilitate natural ventilation and diminish the reliance on energy-intensive cooling systems. Originating as a means to call the faithful to prayer, minarets have become iconic landmarks within Islamic cities. This research focuses on Cairo, Egypt, as a representative hot arid environment. The paper traces the evolution of the minaret, underscoring the variations in form that influence the experimental design. The investigation proceeded in two stages: the construction of physical mosque models with variably positioned minarets for laboratory testing, ensuring standardized measurements, followed by computational fluid dynamics (CFD) simulations for comparison. Findings indicate that mosque minarets can be effectively adapted for passive ventilation, with their performance significantly influenced by orientation and placement. This study concludes that traditional mosque minarets offer a viable, sustainable option for passive cooling in hot climates.

Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1ß, IL-18), in which the order of cytotoxicity was dichlorvos > dipterex > dibrom > paraoxon > fenthion > dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566 µM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1ß, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate > paraoxon > dichlorvos > dibrom > (fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690 µM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.

Photochemical behaviour and toxicity evolution of phenylbenzoate liquid crystal monomers in water.

Liquid crystal monomers (LCMs) are a group of emerging pollutants that pose potential environmental risks because of their ubiquitous occurrence and toxicity. Understanding their environmental transformation is essential for assessing the ecological risk. In this study, we investigated the photochemical transformation kinetics, mechanism, and photo-induced toxicity of three phenylbenzoate LCMs in water. Their apparent photolytic rate constants were within (0.023 - 0.058) min-1, and the half-lives were < 30.0 min, showing lower persistence in water. Dissolved organic matter significantly inhibited their photolysis because of light-shielding effect and quenching of excited triplet states of LCMs. Their photolysis mainly occurred through excited triplet states, and the reactive oxygen species (i.e., ⋅OH, 1O2 and ⋅O2-) contributed to their degradation. The main photolysis pathways were ester bond cleavage, ⋅OH substitution/addition, and defluorination. Experiments and computational simulation revealed that some ·OH addition/substitution products have similar toxicity with LCMs. Additionally, the ∙OH reaction rate constants (kOH) of LCMs were determined to be > 1 × 109 M-1 s-1, evidence for their high reactivity toward ⋅OH. We have further developed reliable methods to estimate kOH of other phenylbenzoate-like LCMs with quantum chemical calculations. These results are useful for understanding the transformation and fate of LCMs in aquatic environments.

Evaluation of the impact of two C5 genetic variants on C5-eculizumab complex stability at the molecular level.

Complement C5 is the target of the monoclonal antibody eculizumab, used in complement dysregulating disorders, like the rare disease Paroxysmal Nocturnal Hemoglobinuria (PNH). PNH is an acquired hematopoietic stem cell condition characterized by aberrant destruction of erythrocytes, chronic hemolytic anemia, and thromboembolism propensity. C5 is a protein component of the complement system which is part of the immune system of the body and plays a prominent role in the destruction of red blood cells, misidentifying them as a threat. This work describes the application of molecular dynamics simulations to the study of the underlying interactions between complement C5 and eculizumab. This study also reveals the importance of single nucleotide polymorphisms on C5 protein concerning the effective inhibition of the mAB, involving the mechanistic events taking place at the interface spots of the complex. The predicted conformational change in the C5 Arg885/His/Cys mutation has implications on the protein's interaction with eculizumab, compromising their compatibility. The acquired insights into the conformational changes, dynamics, flexibility, and interactions shed light on the knowledge of the function of this biomolecule providing answers about the poor response to the treatment in PNH patient carriers of the mutations. By investigating the intricate dynamics, significant connections between C5 and eculizumab can be uncovered. Such insights may aid in the creation of novel compounds or lead to the enhancement of eculizumab's efficacy.Communicated by Ramaswamy H. Sarma.