Residence Time Research Articles

Abstract 2997: Cell-based assay platforms for NLRP3 inflammasome drug discovery

Abstract Inflammasomes have recently emerged as the exciting and promising drug targets for inflammatory disease therapy. The best characterized is the NLRP3 inflammasome. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3, adapter protein ASC, and inflammatory protease caspase-1 that responds to microbial infection, endogenous danger signals, and environmental stimuli. The assembled NLRP3 inflammasome can activate the protease caspase-1 to induce gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18, which contribute to innate immune defense and homeostatic maintenance. We have established cell-based Caspase-Glo 1 Inflammasome Assay and NanoBRET target engagement intracellular NLRP3 assay for high throughput screening of inflammasome inhibitors. MCC950 is a cell-permeable, bioavailable, non-toxic sulfonylurea-derived compound. Here, we demonstrate that MCC950 inhibits LPS/Nigericin-induced caspase-1 activation and pyroptotic cell death in dose response mode in PMA primed THP-1 cells in Caspase-Glo 1 inflammasome and CellTiter-Glo viability assays. Our NanoBRET target engagement NLRP3 assay results show that MCC950 binds to cellular NLRP3 within 2 hours of incubation. Interestingly, NanoBRET NLRP3 residence time analysis in living cells indicates that a slow dissociation kinetics (long residence time) is observed for MCC950. Furthermore, Western blot analysis confirms that MCC950 blocks LPS/Nigericin-induced caspase-1 cleavage and activation in PMA primed THP-1 cells. Taken together, our results indicate Caspase-Glo 1 inflammasome and NanoBRET target engagement NLRP3 assays serve as great cell-based assay platforms to facilitate inflammasome drug discovery against inflammatory diseases. Citation Format: Jianghong Wu, Li Liang, Peter Gallagher, Yong Wan, Haiching Ma. Cell-based assay platforms for NLRP3 inflammasome drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2997.

Abstract 5496: Target density matters: Binding kinetics of antibody-based therapeutics are highly influenced by target expression levels

Understanding antibody-based therapeutic behaviour under varying target expression levels iscrucial for effective tissue and cell-specific targeting. Traditional in vitro evaluations often relyon cancer cell line panels with differing receptor levels, which can be logistically challengingand yield inconsistent results. Standard techniques like SPR are poorly suited for analyzingmolecule binding to eukaryotic cells, as detection depth (∼200 nm) covers only ∼2% of a typical10-20 µm cell and unstable immobilization limits SPR to cell attachment studies. Similarlimitations apply to BLI and QCM. Other cell-based binding technologies have not gainedwidespread adoption due to challenges in automation, sensitivity, and throughput. Measuringhow binding is influenced by differential target expression is critical for tumor-targetingtherapeutics, as antigen density impacts safety through on-target, off-tumor toxicities andaffects efficacy by enabling tumor escape at low target expression levels.The purpose of this study was to investigate how target antigen density influences the bindingkinetics of therapeutic molecules under physiologically relevant conditions, addressinglimitations inherent to traditional kinetic assays. To achieve this, we utilized the novel IndEx-2system, which employs CHO-K1 cells engineered for tuneable expression of one or two targetantigens via chemically induced proximity-mediated induction. This was paired with single-cellInteraction Cytometry (scIC), a unique biosensor-based technology that measures real-timebinding directly on captured cells. By combining these two systems, we examined the bindingkinetics of trastuzumab to HER2 expressed at varying levels, serving as a model for tumourheterogeneity. HER2 expression was quantified using flow cytometry, while scIC was used toperform kinetic measurements on the same cells. The analysis revealed that higher HER2expression levels prolonged trastuzumab residence time due to avidity effects. Notably,differences in affinity (Kd) across HER2 densities were driven by variations in the dissociationrate (koff), rather than the association rate (kon), underscoring the critical influence of targetdensity on binding kinetics.This study demonstrates how target density can affect therapeutic binding kinetics, offeringcritical insights into drug efficacy and duration of action. By integrating scIC with the IndEx-2platform, we provide a robust framework for assessing kinetic behaviour of targetedtherapeutics in a cellular context, including bispecific binders and receptor internalisationstudies. These results pave the way for safer, more effective therapeutics, selected in morecomplex, and more relevant, biological systems. Citation Format: Eric Cruickshank, Nichole Cerutti, Hannah Findlay, Timothy London, Vivien Hafner, Andreas Kratzert. Target density matters: Binding kinetics of antibody-based therapeutics are highly influenced by target expression levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5496.

Abstract 5614: Advancing treatment for brain tumors and metastases with brain permeable SHP2 inhibitor I-1000233

Background: SHP2, a non-receptor protein tyrosine phosphatase encoded by PTPN11, plays a pivotal role as a downstream effector of receptor tyrosine kinases (RTKs) in the MAPK signaling cascade. We report the discovery of I-1000233, a potent and selective SHP2 allosteric inhibitor that is orally bioavailable and penetrates the blood-brain barrier (BBB). This compound holds great potential for treating primary brain tumors and brain metastases associated with dysregulated RTK/RAS/ERK signaling pathways. Experimental Procedures: Through iterative optimization of the physicochemical and pharmacological properties of a lead compound series, we identified I-1000233 as a SHP2 inhibitor with excellent drug-like characteristics. Preclinical studies included in vitro assays to assess potency, in vivo pharmacokinetics to confirm BBB penetration, and proof-of-concept studies in orthotopic xenograft models of glioblastoma and brain metastases. Combination studies were conducted using other brain-penetrant agents targeting the MAPK pathway. Additionally, patient-derived glioblastoma stem cell (GSC) models were collected to refine a responder identification (ID) strategy for potential application in personalized medicine. Results: I-1000233 demonstrated potent in vitro inhibition of SHP2 activity (IC50 = 2 nM) with prolonged target residence time. In vivo, the compound exhibited strong anti-tumor activity in orthotopic glioblastoma and brain metastasis models, both as a monotherapy and in combination with other brain-permeable inhibitors, underscoring its versatility and potential for combination treatment regimens. Moreover, I-1000233 showed efficacy not only in targeting tumor cells bearing EGFR/RAS/MAPK mutations but also in modulating the tumor microenvironment (TME), enhancing the overall anti-tumor response. Further studies using patient-derived GSC models were conducted to identify biomarkers predictive of response, facilitating the development of precision medicine approaches for SHP2-targeted therapies. Conclusions: I-1000233 is a potent, selective, and orally available SHP2 inhibitor with demonstrated efficacy in preclinical models of primary brain tumors and metastases. Its ability to penetrate the BBB, modulate the tumor microenvironment, and provide combinatory potential with other agents highlights its promise as a therapeutic candidate for treating SHP2-responsive brain cancers. Citation Format: Francesca Puca, Alina Ciammaichella, Danilo Fabbrini, Martina Nibbio, Antonino Cucinotta, Giulio Auciello, Francesco Scalabrì, Christian Montalbetti, Alessia Petrocchi, Alessandro Carugo, Carlo Toniatti. Advancing treatment for brain tumors and metastases with brain permeable SHP2 inhibitor I-1000233 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5614.

Legacy of severe soil degradation hinders the buildup of mineral-associated soil organic carbon.

Legacy of severe soil degradation hinders the buildup of mineral-associated soil organic carbon.

Eliminating Bimolecular Decomposition to Address Sustainability in Cross-Coupling: Supported Pd-PEPPSI-IPentCl.

Fine-chemical manufacturing, with its dismal E-factors, has been known for decades as being one of the worst contributors to the well-being of the environment. Further, mining practices that pursue precious metals used in catalysis lead to considerable destruction of the environment. Further contributing to this is the necessity for high catalyst loads due to the limited mortality of organometallic complexes in solution. Bimolecular decomposition (BD), in particular, is a significant contributor to this problem. Assisting in the sustainability of chemical synthesis is flow chemistry, whose "just-in-time" nature produces chemicals as needed, eliminating vast stockpiles of chemicals associated with batch manufacturing. In this work, Pd-PEPPSI-IPentCl, a high-reactivity, high-selectivity Pd catalyst, has been mounted onto the surface of silica, of which the spacing has eliminated BD. This material has been loaded into packed beds and used in Negishi coupling and Buchwald-Hartwig amination, where the active catalyst has shown tremendous resiliency while producing valuable small-molecule products with deft selectivity and speed with residence time in the order of minutes under mild conditions (e.g., Negishi couplings conducted at room temperature).

Contradictions in Dissolved Black Carbon Research: A Critical Review of its Sources, Structures, Analytical Methods, and Environmental Behaviors.

Contradictions in Dissolved Black Carbon Research: A Critical Review of its Sources, Structures, Analytical Methods, and Environmental Behaviors.

Investigation of Nano Spray-Dried, Hyaluronic Acid-Modified Polymeric Micelles for Nasal Administration

Background/Objectives: The combination of nanomedicine with nasal administration is of paramount importance in current research and development. Polymeric micelles coated with hyaluronic acid may be a suitable solution to enhance drug release and permeation whilst properly adhering to the nasal mucosa, increasing residence time. Methods: Solid state characterization included morphology and laser diffraction-based size analysis and X-ray powder diffraction. The characterization of dispersed polymeric micelles in aqueous media was performed based on dynamic light scattering and determining the solubility enhancement related factors such as encapsulation efficiency and thermodynamic solubility. In vitro nasal drug release and permeability studies were also conducted to characterize the different hyaluronic acid-modified polymeric micelles. Quantitative measurements were carried out via liquid chromatography. Results: Concentration dependence on hyaluronic acid was found during all measurements, with one formulation candidate overcoming the others. With a high yield above 80%, monodispersed particles were formulated with an approximately 4 µm particle size in uniform distribution and spherical morphology. The small micelle size (107.3 nm) in uniform manner led to a high encapsulation efficiency above 80% and released the drug amount above 70% in 15 min. High drug permeation was also achieved compared with the initial active substance by itself. Conclusions: A value-added polymeric micelle formulation was developed with rapid drug release and permeation kinetics alongside its high mucoadhesion.

Cyclosporine a Eluting Nano Drug Reservoir Film for the Management of Dry Eye Disease

Cyclosporine A (CsA) is widely used to treat dry eye disease (DED), and ocular morbidity is on the rise and is a growing concern globally. However, several drug and formulation challenges, such as poor drug solubility, short pre-corneal residence time, and poor patient compliance, have limited the ocular bioavailability of CsA to < 5%. A CsA cyclodextrin-based ternary complex loaded dissolvable nano drug reservoir films were developed to overcome these limitations and efficiently manage DED. Drug-loaded nano-reservoir films were fabricated via lithography using silicone and poly (dimethyl siloxane) (PDMS) molds. Different physicochemical characterizations were performed to confirm the formation of stable CsA-cyclodextrin-based ternary complexes. Formation of nanoreservoirs on the films was confirmed using SEM and AFM. Optimized CsA-complex-loaded nano-reservoir films were evaluated for in vitro drug release, ex vivo corneal permeation, and in vivo precorneal retention. Preclinical efficacy studies were performed to assess the efficacy of CsA-complex-loaded nano-reservoirs in an experimental dry-eye mouse model. Physicochemical characterization confirmed the formation of a stable complex and the improved solubility of CsA. In vitro release and ex vivo permeation studies indicated a controlled drug release and improved permeation, respectively. Furthermore, tear volume measurement and corneal damage assessment using slit-lamp imaging suggested decreased dry eye symptoms, significantly increasing tear volume in the drug-loaded nano-reservoir-treated group. Moreover, histopathological studies corroborated the tear volume and slit-lamp imaging results, with reduced inflammation and neovascularization. The poorly water-soluble drug with cyclodextrin complex incorporated nanoreservoir films presents a potential alternative for managing various ocular diseases.Graphical

Dynamics of nanoparticles in a 3D breathing lung-on-a-chip.

The"Breathing Lung-on-a-Chip,"a novel microfluidic device featuring a stretchable membrane, replicates the natural expansion and contraction of the human lung. It provides a more realistic in-vitro platform to study respiratory diseases, particle deposition, and drug delivery mechanisms. This device enables investigations into the effects of inhaled nanoparticles (NPs) on lung tissue and supports the development of advanced inhalation therapies. Uniform and optimal concentration delivery of NPs to cultured cells within the chip is critical, particularly as membrane stretching significantly influences particle dynamics. To address this, we developed a 3D numerical model that accurately simulates NP behavior under dynamic conditions, overcoming experimental limitations. The model, validated against experimental data, explores the effects of flow dynamics, particle size, membrane porosity, and stretching frequency/intensity on NP deposition in the air channel and transfer through the porous membrane into the medium channel. The results indicate that increased membrane stretch enhances the sedimentation rate of NPs in the air channel, thereby promoting their transfer to the medium channel, particularly in membranes with initially low porosity. Additionally, excessive stretching frequencies or intensities can introduce reverse flow and stagnation, leading to a longer residence time for NPs and altering their sedimentation patterns. These insights advance our understanding of NP transport in dynamic lung environments, paving the way for more effective applications of lung-on-a-chip technology in toxicological assessments and respiratory therapy innovations.

Optimizing Hyaluronan-Based Lubricants for Treating Thoracolumbar Fascia Pathologies: Insights from Tribological and Pharmacokinetic Studies

In a world where the incidence of non-specific lower back pain (LBP) is steadily increasing, researchers are still searching for effective solutions for patients. Hyaluronic acid (HA) viscosupplementation is commonly used to restore lubrication in osteoarthritis (OA) and other medical applications, but its rapid metabolism limits efficacy. This study evaluates whether an HA derivative can replace native HA for the treatment of non-specific LBP while maintaining or enhancing its frictional properties and improving in vivo stability. Six HA-based lubricants, both native and derivatized, were tested in a tribological rabbit fascia model and a new synthetic model. Reduced HA derivative showed better tribological properties and longer in vivo residence time compared to native HA, as demonstrated in pharmacokinetic studies in rabbits. The 316 kDa HA and reduced HA exhibited the most stable tribological properties, which were influenced by their molecular weight and concentration. These findings suggest that both native and reduced HA are promising viscosupplements for intrafascial injection in the treatment of LBP, with reduced HA potentially enhancing effectiveness through a prolonged effect.

Development and optimization of an innovative raft-forming antiemetic gastro-retentive system

Gastro-retentive drug delivery systems are vital for enhancing bioavailability and prolonging gastric residence time, especially for drugs with a short half-life like Ondansetron HCl. This study developed a raft-forming gastroretentive drug delivery system using a polyelectrolyte complex (PEC) of Chitosan and anionic polymers to improve stomach retention, regulate drug release, and enhance therapeutic efficacy. Various formulations were optimized based on polymer type, ratio, cross-linking agent concentration, and hydroxypropyl methylcellulose (HPMC K100M). The best formulation (F12: Chitosan: Carbopol 934) showed high entrapment efficiency (98%), drug loading (11.5%), buoyancy (&amp;gt;12 hours), extended drug release (over 12 hours), and a swelling ratio of 1584% at 8 hours. FTIR and DSC confirmed PEC formation and stability, while FE-SEM demonstrated homogeneity. Drug release followed non-Fickian kinetics, indicating that both diffusion and matrix relaxation contributed to the drug release. This PEC-based system shows promise for sustained stomach delivery of Ondansetron HCl, improving therapeutic efficacy and patient adherence.

Predictors of pre-hospital delay among stroke patients in Yekatit-12 hospital Addis Ababa, Ethiopia: unmatched case-control study

BackgroundTimely detection and early medical interventions are critical in reducing complications and mortality related to stroke. The duration from onset to hospital presentation is an essential factor in determining the outcome of stroke treatment. The sooner a stroke patient receives medical attention, the better the chances of preventing long-term complications. Pre-hospitalization delays can significantly decrease the chances of successful therapy and recovery from stroke.ObjectiveThe study aims to assess predictors of delayed hospital presentation after a stroke attack.MethodAn unmatched case-control study was conducted from September 2021 to November 2023 at Yekatit 12 Hospital Medical College. Descriptive statistics were used to describe study variables. Bivariable and multivariable logistic regression were used to identify the predictors of delay hospital presentation after stroke attack. All statistical tests were run with a significance threshold of 5%.ResultA total of 83 cases (presenting after four hours) and 166 controls (presenting within four or fewer hours) of an acute stroke patients were included in this study. The median duration of symptoms from the onset of stroke to hospital arrival were 24 h (IQR, 12 h) and 2 h(IQR,1 h) for cases and controls respectively. The study found that age 60 or less (AOR 1.75, 95% CI 1–3.09, p < 0.05), living outside of Addis Ababa (AOR 3.55, 95% CI 1.33–9.46, p < 0.011), onset of stroke happening at night (AOR 1.75, 95% CI 1.2–3.1, p < 0.05) and not having health insurance (AOR 0.43, 95% CI 0.23–0.8,p < 0.007) were identified as predicting factors of late presentation to hospital in stroke patients.ConclusionThis study highlights key predictors of delayed hospital presentation in stroke patients. Specifically, age, place of residence, health insurance, and stroke onset time were significantly influence the timeliness of seeking medical care. Recognizing and addressing the predicting factors can improve the health care treatment outcome and help to design targeted health policies that reduce barriers to timely presentation of stroke patients.

The NET-DNA-CCDC25 inhibitor di-Pal-MTO suppresses tumor progression and promotes the innate immune response.

The DNA component of neutrophil extracellular traps (NET-DNA) is associated with cancer metastasis and chemotherapy resistance. However, recent studies have suggested that NET-DNA contributes to the activation of dendritic cells (DCs) and promotes the innate immune response to anticancer immunity. Therefore, exploring therapeutic approaches to inhibit NET-mediated tumor progression while maintaining antitumor immunity is essential. Our groups recently identified CCDC25 as a specific NET-DNA sensor on the cytoplasmic membrane of cancer cells that promotes cancer metastasis. In this study, we performed small-molecule compound screening and revealed that mitoxantrone (MTO) could block the interaction between NET-DNA and CCDC25. Molecular docking results indicated that MTO competed with NET-DNA by binding with the amino acid residues Tyr24 (Y24), Glu25 (E25), and Asp28 (D28) of the crystal structure of CCDC25. More importantly, we conjugated MTO with palmitoleic acids such as di-Pal-MTO to increase its residence time on the cytoplasmic membrane, which increased its inhibitory efficiency and decreased its cytotoxicity. In addition, di-Pal-MTO markedly inhibited the RAC1-CDC42 cascade to alleviate the NET-induced cytoskeleton arrangement and chemotactic migration of cancer cells. In multiple mouse models, di-Pal-MTO can suppress breast cancer metastasis and have synergistic effects with chemotherapeutics. Moreover, di-Pal-MTO promotes NET-DNA-dependent DC activation, leading to the subsequent expression of various chemokines that facilitate the infiltration of CD8+ T cells. Overall, we successfully identified a small molecule inhibitor, di-Pal-MTO, with dual effects on tumor repression and the antitumor immune response, which provides a novel therapeutic strategy against breast cancer.

Long‐range transport of terrestrial particulate organic carbon to the open ocean by sediment resuspension

AbstractThe transport of particulate organic carbon (POC) from land to deep‐sea sediments is a critical component of the global carbon cycle. However, the transport processes of terrestrial POC across continental shelves remain poorly understood due to the complexity of these systems. In this study, we investigated the vertical fluxes and fates of terrestrial vs. marine POC using stable carbon isotope ratios (δ13C) and 234Th tracers along two transects in the southern coastal region of Korea. The POC concentrations were highest in the surface layer and decreased with depth, with a slight increase near the seafloor. The δ13C values revealed that terrestrial POC contributed 29% ± 24% of the total POC, with higher contributions at the innermost stations and in the bottom layer. Based on 234Th–238U disequilibria, the residence times of particulate 234Th (8.1 ± 3.6 d) were significantly longer than those of dissolved 234Th (3.7 ± 2.2 d). The much higher vertical fluxes of terrestrial POC in the deeper layer relative to the upper layer suggest that terrestrial POC undergoes multiple turnover cycles through sediment resuspension before burial, while marine POC degrades preferentially in the course of settling. These findings highlight that effective sediment resuspension and the refractory nature of terrestrial POC allow for its long‐range transport (&gt; 200 km) to the deep Ulleung Basin in the East Sea (Japan Sea). This study sheds new light on the mechanisms driving the transport of terrestrial POC from coastal regions to the deep ocean.

Computational Estimation of Residence Time on Roniciclib and Its Derivatives against CDK2: Extending the Use of Classical and Enhanced Molecular Dynamics Simulations

Computational Estimation of Residence Time on Roniciclib and Its Derivatives against CDK2: Extending the Use of Classical and Enhanced Molecular Dynamics Simulations

A New Aerosol-Based Photobioreactor for the Cultivation of Cyanobacteria on Luffa.

Cyanobacteria are promising organisms for sustainable biotechnology due to their ability to grow photoautotrophically and their wide range of products. Many cyanobacteria grow in the form of biofilms, which is why the development of photobioreactors (PBR) for the cultivation of cyanobacteria in the form of biofilms is of great interest. However, these biofilm PBR are mostly based on artificial growth surfaces, whereas biodegradable growth surfaces would be favored in terms of sustainable production and application. Luffa sponges (the dried fruit of Luffa cylindrica) are excellent biodegradable growth surfaces for cyanobacteria. Therefore, a biofilm PBR for cultivation of cyanobacteria on Luffa was developed in this study. Since many cyanobacteria grow naturally as biofilms in an air-exposed form and this should be imitated to improve growth, an aerosol-based PBR (abPBR) should be used for cultivation. This involves supplying the cyanobacteria with a nutrient mist. The abPBR was comprehensively characterized by determining the distribution of light, humidity and temperature inside the reactor. In addition, the residence time distribution of the aerosol was determined both experimentally and simulatively. In final cultivation experiments, it was shown that the abPBR is ideal for cultivating cyanobacteria and at the same time the aerosol system enables a simple imitation of drought stress. With the cyanobacteria Nostoc spec. and Desmonostoc muscorum, maximum area-time-yields (ATY) in relation to the growth surface of 6.34 and 4.19 g m-2 d-1, respectively, were achieved. Compared to previously developed abPBR, the ATY has been increased by a factor of 2.3.

Effect of liquid phase dispersion on the performance of water distillation column

ABSTRACT Effect of the axial dispersion in the liquid phase on the performance of a vacuum distillation column for heavy water production has been investigated in this study. Axial dispersion in the liquid phase and liquid phase holdup in the distillation column were evaluated by carrying out Residence Time Distribution (RTD) studies using the radiotracer technique. To simulate the measured RTD data, a two Plug flow with Axial Dispersion Model (PF-ADM) in parallel was used. A steady-state process model using rate-based modeling was developed to determine the effect of axial dispersion in the liquid phase on the overall performance of the water distillation column for heavy water separation. Validation of the process model was carried out using the plant operating data. The model was further used to study the effect of axial dispersion in the liquid phase on the performance of distillation columns in terms of Height Equivalent to a Theoretical Plate (HETP).

Assessment of biomechanical properties in pulmonary arterial hypertension: a computational fluid dynamics study of the extensive pulmonary arterial tree

Biomechanical forces play a central role in the pathophysiology of pulmonary arterial hypertension (PAH). Due to the numerous branches and complex structure of the pulmonary arteries, three-dimensional reconstruction poses significant challenges, resulting in a lack of comprehensive hemodynamic studies encompassing the entire pulmonary arterial tree in PAH. This study employs computational fluid dynamics (CFD) to evaluate the biomechanical properties of the extensive pulmonary artery tree (segmented up to 6 th-generation branches) in PAH. Key hemodynamic parameters, including velocity, wall shear stress (WSS), time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT), were meticulously computed. Results revealed a significant decrease in outlet cross-sectional area (p < 0.0001) and a notable increase in outlet velocity compared to the inlet (p < 0.05) and main body (p < 0.001). WSS in the proximal pulmonary artery was consistently lower than in the distal pulmonary artery for all subjects, with low TAWSS observed in proximal arteries. Helical flow patterns were predominantly seen in proximal pulmonary arteries of PAH subjects. Additionally, high OSI and RRT values were noted within the proximal arteries. This study provides a comprehensive evaluation of hemodynamic parameters in PAH, identifying velocity, WSS, OSI, and RRT as valuable markers of its distinct biomechanical characteristics. These findings shed light on the complex interplay of biomechanical forces in PAH.

Development of performance evaluation framework considering structural and non-structural factors in water distribution systems

This study proposes an integrated performance evaluation system to prioritize the repair and reinforcement of water distribution systems (WDSs). Recognizing that aging infrastructure poses risks such as pipe failures and water quality degradation, the integrated performance evaluation system offers a comprehensive assessment approach, addressing the limitations of traditional evaluation methods that are constrained by time and cost. The system integrates both direct and indirect performance evaluations, focusing on factors such as pipeline aging, hydraulic stability, and water quality safety. The system also evaluates hydraulic stability by simulating pressure fluctuations and water quality through the analysis of water residence times under varying demand conditions. To systematically determine repair and reinforcement priorities, the analytic hierarchy process is applied, assigning weights to each evaluation factor based on its relative importance. By simulating hypothetical abnormal scenarios, such as pipeline failures, the system estimates potential damage and the risk to water supply blocks. These evaluations provide valuable insights into the vulnerability of different sections of the WDSs, supporting informed decision-making for maintenance planning. The integrated approach of the integrated performance evaluation system not only ensures a more reliable and data-driven prioritization process but also enhances preparedness for abnormal system conditions. The framework is validated through applications in real-world water distribution networks, demonstrating its effectiveness in guiding resource allocation and maintenance efforts for long-term system stability.

Intraoral Drug Delivery: Bridging the Gap Between Academic Research and Industrial Innovations

AbstractIntraoral delivery of active pharmaceutical ingredients (API) is an attractive approach to improve their local therapeutic efficacy or to enable their systemic delivery. It offers several advantages, such as high drug concentration at the intraoral target site and rapid access to the systemic circulation due to high vascularization of the oral cavity, bypassing first‐pass metabolism. However, several limitations need to be addressed, such as the relatively short residence time of formulations applied in the oral cavity due to salivation, swallowing reflex, and tongue movement, as well as poor membrane permeability of, in particular, hydrophilic drugs. Within this review, a comprehensive summary of the latest strategies and formulation approaches in the field of intraoral drug delivery is provided, focusing on those pursued by academia and industry to overcome those challenges. An overview is provided of excipients that are generally recognized as safe (GRAS) and utilized to enhance the efficacy of intraoral drug delivery systems, such as mucoadhesive materials, enzyme inhibitors, and permeation enhancers. Innovative pharmaceutical dosage forms are outlined, covering solid, semi‐solid, and liquid delivery systems as well as aerosols. Future trends, including self‐emulsifying systems, microneedles, and in situ bioprinting, are explored, presenting new opportunities for intraoral drug delivery.