MDPI - Publisher of Open Access Journals

31 pages, 1323 KB

Open AccessReview

Pharmacokinetic Landscape and Interaction Potential of SGLT2 Inhibitors: Bridging In Vitro Findings and Clinical Implications

by Nahyun Koo, Eun Ji Lee, Ji-Eun Chang, Kyeong-Ryoon Lee and Yoon-Jee Chae

Pharmaceutics 2025, 17(12), 1604; https://doi.org/10.3390/pharmaceutics17121604 (registering DOI) - 12 Dec 2025

Abstract

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes and cardiometabolic diseases, and their pharmacokinetic characteristics generally confer a low risk of clinically relevant drug–drug interactions (DDIs). Most clinical studies demonstrate that these agents can be co-administered safely with commonly [...] Read more.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes and cardiometabolic diseases, and their pharmacokinetic characteristics generally confer a low risk of clinically relevant drug–drug interactions (DDIs). Most clinical studies demonstrate that these agents can be co-administered safely with commonly prescribed medications without dose adjustment, although strong enzyme inducers such as rifampin can reduce systemic exposure, and pharmacodynamic interactions may still arise. However, existing evidence is largely derived from short-term studies in healthy volunteers, with limited data in special populations and minimal evaluation of metabolite- or transporter-mediated interactions. This review summarizes the available in vitro and in vivo pharmacokinetic and DDI data for SGLT2 inhibitors, identifies key knowledge gaps related to polypharmacy, metabolite effects, and vulnerable patient groups, and outlines future research priorities to ensure their safe and effective use in real-world clinical practice. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics and Drug Interactions)

19 pages, 1555 KB

Open AccessArticle

Screening of Lactic Acid Bacteria Tolerant to Antimicrobial Substances and Their Effects on the Quality of Cyperus esculentus Silage

by Hui Wang, Weiqi Liu, Shengyi Li, Shuan Jia and Xuzhe Wang

Microorganisms 2025, 13(12), 2833; https://doi.org/10.3390/microorganisms13122833 (registering DOI) - 12 Dec 2025

Abstract

This study investigated the inhibitory effects of endogenous compounds from Cyperus esculentus on lactic acid bacteria and examined whether inoculation with selected strains could enhance silage fermentation quality. Lactic acid bacteria were isolated and identified from C. esculentus silage, and antibacterial assays were [...] Read more.

This study investigated the inhibitory effects of endogenous compounds from Cyperus esculentus on lactic acid bacteria and examined whether inoculation with selected strains could enhance silage fermentation quality. Lactic acid bacteria were isolated and identified from C. esculentus silage, and antibacterial assays were performed to screen strains suitable for inoculation. Results indicated that the endogenous compounds inhibited lactic acid bacteria, with sensitivity ranked as Lentilactobacillus buchneri > Lactiplantibacillus plantarum > Lacticaseibacillus rhamnosus. Scanning electron microscopy revealed no significant structural damage to bacterial cells caused by the inhibitory compounds. Metabolomic analysis suggested that these compounds may alter lactic acid bacterial metabolism by modulating key pathways, including amino acid and energy metabolism. Among the tested strains, Lcb. rhamnosus exhibited the highest tolerance to the endogenous compounds. Inoculation experiments demonstrated that the addition of Lcb. rhamnosus significantly enhanced the fermentation quality of C. esculentus silage. Full article

(This article belongs to the Special Issue Microorganisms in Silage)

34 pages, 19352 KB

Open AccessReview

Gas Turbine Blade Failures Repaired Using Laser Metal Additive Remanufacturing

by Changjun Chen, Min Zhang, Haodong Liu and Qingfeng Yang

Materials 2025, 18(24), 5590; https://doi.org/10.3390/ma18245590 (registering DOI) - 12 Dec 2025

Abstract

The production of reliable turbo machinery, particularly gas turbine blades, is a major global challenge. This capability serves as a key indicator of a nation’s industrial base, technological prowess, and comprehensive strength. Critical components in aircraft engines and gas turbines operate under extreme [...] Read more.

The production of reliable turbo machinery, particularly gas turbine blades, is a major global challenge. This capability serves as a key indicator of a nation’s industrial base, technological prowess, and comprehensive strength. Critical components in aircraft engines and gas turbines operate under extreme conditions, including high temperatures, high pressures, and substantial mechanical stresses. Consequently, there is a growing urgency to develop cost-effective and time-efficient repair strategies to enhance engine performance and efficiency. However, many mission-critical parts, especially high-pressure (HP) blades, are prone to severe damage. Moreover, taking equipment offline for blade maintenance and repair is a time-consuming process. It is also highly costly to restore these essential components to full functionality. Since 1996, researchers have focused on applying laser metal deposition (LMD) additive manufacturing technology for high-performance repair and remanufacturing of aerospace engines and industrial gas turbine (IGT) blades. Empirical studies have demonstrated that depositing a high-quality, erosion-resistant protective coating on the leading edge of HP blades effectively extends the service life of turbine blades in both aircraft engines and industrial gas turbines. This study systematically outlines the technical workflow of the proposed methodology and provides a concise perspective on emerging development trends. Full article

(This article belongs to the Section Manufacturing Processes and Systems)

21 pages, 1552 KB

Open AccessArticle

Navigating Risk Aversion in Green Supply Chains: The Retailer Competition Perspective

by Zhen Chen, Kaveh Khalilpour, Qingzhen Yao, Lijuan Li and Sinan Xu

Sustainability 2025, 17(24), 11165; https://doi.org/10.3390/su172411165 (registering DOI) - 12 Dec 2025

Abstract

This study examines the intricate pricing and coordination issues shaped by risk-averse behavior and retailer competition in the green supply chain. Firstly, we derive equilibrium strategies for stakeholders by employing models. The impact of the risk aversion level on pricing and greenness is [...] Read more.

This study examines the intricate pricing and coordination issues shaped by risk-averse behavior and retailer competition in the green supply chain. Firstly, we derive equilibrium strategies for stakeholders by employing models. The impact of the risk aversion level on pricing and greenness is analyzed. Secondly, we conduct comparative analyses of optimal decisions under the three models. Finally, we discuss the coordination of cost-sharing contracts and validate the relevant conclusions through numerical simulation analysis. By linking firms’ decision-making behaviors with product greenness, the study further shows how operational choices influence the overall sustainability performance of the supply chain. Our findings reveal a downward trend in wholesale price, greenness, and retail price as risk aversion levels escalate. Additionally, we uncover the dual effect of cost-sharing contracts: while they enhance environmental sustainability by boosting greenness, they also bolster supply chain profitability and facilitate coordination efforts. These insights offer practical guidance for establishing more sustainable green supply chains in competitive and risk-sensitive environments. Full article

(This article belongs to the Special Issue Sustainable Operations and Green Supply Chain)

25 pages, 3882 KB

Open AccessSystematic Review

Oncologic and Reproductive Outcomes After Fertility-Sparing Treatments for Endometrial Hyperplasia with Atypia: A Systematic Review and Meta-Analysis

by Pál Sebok, Márton Keszthelyi, Balázs Vida, Lotti Lőczi, Barbara Sebők, Petra Merkely, Nándor Ács, Attila Keszthelyi, Szabolcs Várbíró, Balázs Lintner and Richárd Tóth

Cancers 2025, 17(24), 3966; https://doi.org/10.3390/cancers17243966 (registering DOI) - 12 Dec 2025

Abstract

Background: Atypical endometrial hyperplasia is a precursor of endometrial carcinoma, increasingly diagnosed in reproductive-aged women. Standard hysterectomy may constitute overtreatment. Fertility-sparing approaches, oral or local progestins, hysteroscopic resection, and combined regimens are widely used, though evidence largely derives from early-stage carcinoma. Methods [...] Read more.

Background: Atypical endometrial hyperplasia is a precursor of endometrial carcinoma, increasingly diagnosed in reproductive-aged women. Standard hysterectomy may constitute overtreatment. Fertility-sparing approaches, oral or local progestins, hysteroscopic resection, and combined regimens are widely used, though evidence largely derives from early-stage carcinoma. Methods: CENTRAL, EMBASE, Scopus, Web of Science, and PubMed were searched from inception to 13 April 2025. Eligible studies included premenopausal women with AEH treated with oral progestins, levonorgestrel intrauterine devices (LNG-IUDs), hysteroscopic resection, or combination regimens (e.g., oral progestins + metformin, LNG-IUD + GnRH analogues). Random-effects meta-analyses with multilevel modeling were applied. Risk of bias was assessed using RoB-2 and ROBINS-I; certainty of evidence was graded with GRADE-PRO. Results: Forty-nine studies (2313 women) were included. The pooled complete response (CR) rate was 85% (95% CI 80–89%). LNG-IUDs resulted in 88% CR and oral progestins in 80%. Combination therapies achieved up to 95% CR, though data were limited. Hysteroscopic resection combined with hormonal therapy reported high CR rates (96–97%) but relied on small, heterogeneous cohorts with uncertain reproducibility. The pooled recurrence rate was 19% (95% CI, 13–25%), lower with LNG-IUDs (14%) compared with oral progestins (22%). No response occurred in 14% overall and was lower with LNG-IUDs (13%) than oral progestins (19%). Among women attempting conception, the pooled pregnancy rate was 41%, and the live birth rate was 30%. The mean time to achieve CR was 5.6 months, whereas the mean time to recurrence was approximately 33 months. Conclusions: LNG-IUDs provide the most effective and well-supported fertility-sparing treatment for AEH, ensuring high remission with low recurrence. Despite favorable numerical outcomes, the evidence for hysteroscopic resection is limited and inconsistent, not supporting its routine use. Combination regimens may improve response but require confirmation in larger studies. Full article

(This article belongs to the Special Issue Gynecological Cancer: Prevention, Diagnosis, Prognosis and Treatment)

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16 pages, 1102 KB

Open AccessArticle

Associations of Lactoferrin-Fortified Formula with Infant Growth and Gut Microbiota: A Real-World Observational Study

by Xiaojin Shi, Biao Liu, Wenhui Ye, Xuanjing Qi, Menglu Xi, Shuqi Liu, Qihan Zhu, Lutong Zheng and Ai Zhao

Nutrients 2025, 17(24), 3896; https://doi.org/10.3390/nu17243896 (registering DOI) - 12 Dec 2025

Abstract

Background/Objectives: Lactoferrin, a key bioactive component in human milk, may bridge functional gaps in infant formula; however, its long-term effects on growth and the gut microbiota in term infants remain underexplored, particularly in real-world settings. Methods: This real-world evidence (RWE) study assessed the [...] Read more.

Background/Objectives: Lactoferrin, a key bioactive component in human milk, may bridge functional gaps in infant formula; however, its long-term effects on growth and the gut microbiota in term infants remain underexplored, particularly in real-world settings. Methods: This real-world evidence (RWE) study assessed the impact of lactoferrin-fortified formula (LF) on infant growth, the gut microbiota, and feeding tolerance compared with control formula (CF) and exclusive breastfeeding (BF). After propensity score matching (PSM) for maternal education level and infant age, 111 matched Chinese infants (37 per group: LF, CF, and BF; age: 6–12 months) were analyzed. Growth was evaluated using WHO Z-scores (WAZ, LAZ, WLZ, and zBMI). The gut microbiota was profiled via 16S rRNA sequencing (n = 81). Feeding challenges were quantified using the Montreal Children’s Hospital Feeding Scale (MCH-FS). Results: The LF group exhibited significantly higher length-for-age Z-scores (LAZ) compared with both the BF and CF groups (p < 0.001), indicating superior linear growth. LF infants also showed reduced MCH-FS scores (18.0 vs. 36.2 in CF; p < 0.001), signifying fewer feeding difficulties. Gut microbiota analysis revealed enrichment of Bifidobacterium breve and butyrate-producing taxa (e.g., Faecalibacterium and Ruminococcaceae), higher alpha diversity, and metabolic divergence, involving enhanced lysine fermentation to acetate/butyrate in LF infants, suggesting a higher level of short-chain fatty acid (SCFA) production. Beta diversity analysis demonstrated that the LF microbiota clustered close to BF. Conclusions: Lactoferrin-fortified formula was associated with improved linear growth and feeding tolerance while shaping a healthy gut microbiota, showing similarities to breastfed infants’ microbiota. These findings support LF fortification as a strategy to improve functional outcomes in formula-fed infants. Full article

(This article belongs to the Section Pediatric Nutrition)

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20 pages, 1581 KB

Open AccessArticle

An Improved Variable Step-Size Normalized Subband Adaptive Filtering Algorithm for Signal Clipping Distortion

by Jiapeng Duan and Bo Zhang

Signals 2025, 6(4), 74; https://doi.org/10.3390/signals6040074 (registering DOI) - 12 Dec 2025

Abstract

The safe and stable operation of power systems and other dynamic systems relies on accurate perception of their dynamic processes. Voltage, current, and other measurement signals carry critical information about the system’s state. However, under conditions such as equipment damage, aging, and non-ideal [...] Read more.

The safe and stable operation of power systems and other dynamic systems relies on accurate perception of their dynamic processes. Voltage, current, and other measurement signals carry critical information about the system’s state. However, under conditions such as equipment damage, aging, and non-ideal operational conditions of devices under test, over-range phenomena may occur, leading to biased estimation issues in adaptive filters. To address this problem, this paper proposes a variable-parameter subband adaptive filtering algorithm with signal clipping distortion awareness. The algorithm first uses the Expectation-Maximization (EM) process to achieve high-fidelity restoration of damaged signals. Then, by integrating an intelligent steady-state detector and a dual-mode control mechanism, the adaptive filter can adjust key parameters such as step-size, forgetting factor, and regularization parameter based on state perception results. Finally, theoretical analysis proves the unbiased nature of the proposed method. Validation using real-world data from a high-penetration renewable energy power system shows that the algorithm achieves fast tracking during transient events and provides high-precision estimation during steady-state operation, offering an effective solution for real-time, high-accuracy processing of dynamic measurement data in power systems. Full article

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32 pages, 1599 KB

Open AccessArticle

Early-Cycle Lifetime Prediction of LFP Batteries Using a Semi-Empirical Model and Chaotic Musical-Chairs Optimization

by Zeyad A. Almutairi, Hady A. Bheyan, H. Al-Ansary and Ali M. Eltamaly

Energies 2025, 18(24), 6528; https://doi.org/10.3390/en18246528 (registering DOI) - 12 Dec 2025

Abstract

Efficiently predicting the lifespan of lithium iron phosphate (LFP) batteries early in their operational life is critical to accelerating the development of energy storage systems while reducing testing time, cost, and resource consumption. Traditional degradation models rely on full-cycle testing to estimate long-term [...] Read more.

Efficiently predicting the lifespan of lithium iron phosphate (LFP) batteries early in their operational life is critical to accelerating the development of energy storage systems while reducing testing time, cost, and resource consumption. Traditional degradation models rely on full-cycle testing to estimate long-term performance, which is both time- and resource-intensive. This study proposes a novel semi-empirical degradation model that leverages a small fraction of early-cycle data with just 5% to accurately forecast full-lifetime performance with high accuracy, with less than 1.5% mean absolute percentage error. The model integrates fundamental degradation physics with data-driven calibration, using an improved musical chairs algorithm modified with chaotic map dynamics to optimize model parameters efficiently. Trained and validated on a diverse dataset of 27 LFP cells cycled under varying depths of discharge, current rates, and temperatures, the proposed method demonstrates superior convergence speed, robustness across LFP operating conditions, and predictive accuracy compared to traditional approaches. These results provide a scalable framework for rapid battery evaluation and deployment, supporting advances in electric mobility and grid-scale storage. Full article

(This article belongs to the Section D: Energy Storage and Application)

33 pages, 353 KB

Open AccessArticle

Integration of Artificial Intelligence into Criminal Procedure Law and Practice in Kazakhstan

by Gulzhan Nusupzhanovna Mukhamadieva, Akynkozha Kalenovich Zhanibekov, Nurdaulet Mukhamediyaruly Apsimet and Yerbol Temirkhanovich Alimkulov

Laws 2025, 14(6), 98; https://doi.org/10.3390/laws14060098 (registering DOI) - 12 Dec 2025

Abstract

Legal regulation and practical implementation of artificial intelligence (AI) in Kazakhstan’s criminal procedure are considered within the context of judicial digital transformation. Risks arise for fundamental procedural principles, including the presumption of innocence, adversarial process, and protection of individual rights and freedoms. Legislative [...] Read more.

Legal regulation and practical implementation of artificial intelligence (AI) in Kazakhstan’s criminal procedure are considered within the context of judicial digital transformation. Risks arise for fundamental procedural principles, including the presumption of innocence, adversarial process, and protection of individual rights and freedoms. Legislative mechanisms ensuring lawful and rights-based application of AI in criminal proceedings are required to maintain procedural balance. Comparative legal analysis, formal legal research, and a systemic approach reveal gaps in existing legislation: absence of clear definitions, insufficient regulation, and lack of accountability for AI use. Legal recognition of AI and the establishment of procedural safeguards are essential. The novelty of the study lies in the development of concrete approaches to the introduction of artificial intelligence technologies into criminal procedure, taking into account Kazakhstan’s practical experience with the digitalization of criminal case management. Unlike existing research, which examines AI in the legal profession primarily from a theoretical perspective, this work proposes detailed mechanisms for integrating models and algorithms into the processing of criminal cases. The implementation of AI in criminal justice enhances the efficiency, transparency, and accuracy of case handling by automating document preparation, data analysis, and monitoring compliance with procedural deadlines. At the same time, several constraints persist, including dependence on the quality of training datasets, the impossibility of fully replacing human legal judgment, and the need to uphold the principles of the presumption of innocence, the right to privacy, and algorithmic transparency. The findings of the study underscore the potential of AI, provided that procedural safeguards are strictly observed and competent authorities exercise appropriate oversight. Two potential approaches are outlined: selective amendments to the Criminal Procedure Code concerning rights protection, privacy, and judicial powers; or adoption of a separate provision on digital technologies and AI. Implementation of these measures would create a balanced legal framework that enables effective use of AI while preserving core procedural guarantees. Full article

(This article belongs to the Special Issue Criminal Justice: Rights and Practice)

23 pages, 1101 KB

Open AccessArticle

Hybrid AI Intrusion Detection: Balancing Accuracy and Efficiency

by Vandit R Joshi, Kwame Assa-Agyei, Tawfik Al-Hadhrami and Sultan Noman Qasem

Sensors 2025, 25(24), 7564; https://doi.org/10.3390/s25247564 (registering DOI) - 12 Dec 2025

Abstract

The Internet of Things (IoT) has transformed industries, healthcare, and smart environments, but introduces severe security threats due to resource constraints, weak protocols, and heterogeneous infrastructures. Traditional Intrusion Detection Systems (IDS) fail to address critical challenges including scalability across billions of devices, interoperability [...] Read more.

The Internet of Things (IoT) has transformed industries, healthcare, and smart environments, but introduces severe security threats due to resource constraints, weak protocols, and heterogeneous infrastructures. Traditional Intrusion Detection Systems (IDS) fail to address critical challenges including scalability across billions of devices, interoperability among diverse protocols, real-time responsiveness under strict latency, data privacy in distributed edge networks, and high false positives in imbalanced traffic. This study provides a systematic comparative evaluation of three representative AI models, CNN-BiLSTM, Random Forest, and XGBoost for IoT intrusion detection on the NSL-KDD and UNSW-NB15 datasets. The analysis quantifies the achievable detection performance and inference latency of each approach, revealing a clear accuracy–latency trade-off that can guide practical model selection: CNN-BiLSTM offers the highest detection capability (F1 up to 0.986) at the cost of higher computational overhead, whereas XGBoost and Random Forest deliver competitive accuracy with significantly lower inference latency (sub-millisecond on conventional hardware). These empirical insights support informed deployment decisions in heterogeneous IoT environments where accuracy-critical gateways and latency-critical sensors coexist. Full article

(This article belongs to the Special Issue AI-Empowered Internet of Things)

28 pages, 37154 KB

Open AccessArticle

Parliamentary Alchemists and Electric Colossi: The Scientific and the Nostalgic Past in Sir John Tenniel’s Punch Cartoons

by Grayson C. V. Van Beuren

Arts 2025, 14(6), 172; https://doi.org/10.3390/arts14060172 (registering DOI) - 12 Dec 2025

Abstract

The modern world has had a long and uneasy relationship with the nostalgic past, with the line between the harmless and the harmful in this relationship often difficult to parse. This article looks at a particular microcosm of nostalgic medievalism in nineteenth century [...] Read more.

The modern world has had a long and uneasy relationship with the nostalgic past, with the line between the harmless and the harmful in this relationship often difficult to parse. This article looks at a particular microcosm of nostalgic medievalism in nineteenth century popular culture—selections from the work of prominent editorial cartoonist Sir John Tenniel in Punch that combine gothic imagery with depictions of modern science and technology—through the literary critical theoretical framework of nostalgia theory, connecting it with strong societal forces in his time. Full article

(This article belongs to the Special Issue Early Modern Global Materials, Materiality, and Material Culture)

29 pages, 2125 KB

Open AccessArticle

Caffeine Protects Against Hyperoxia-Induced Structural Lung Injury and Restores Alveolar Development in Neonatal Rats

by Stefanie Endesfelder and Christoph Bührer

Antioxidants 2025, 14(12), 1497; https://doi.org/10.3390/antiox14121497 (registering DOI) - 12 Dec 2025

Abstract

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and [...] Read more.

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and vascular maturation. In a postnatal high-oxygen-induced rat model of BPD-associated lung injury, three or five days of exposure to 80% oxygen was found to disrupt developmental signaling pathways, downregulating genes essential for alveolarization and angiogenesis while inducing profibrotic mediators and collagen expression (Sirius Red staining). These changes resulted in simplified alveolar architecture, as quantified by toluidine blue staining and mean linear intercept analysis of normalized volumes of parenchyma, non-parenchyma, airspaces, septa, and edema. Acting as a multifunctional antioxidant with antifibrotic activity, caffeine mitigated structural lung damage and normalized the transcription of angiogenic and fibrotic genes. It counteracted TGF-β/CTGF-driven fibrogenic signaling and promoted recovery of normal lung morphology following hyperoxic injury. Under normoxic conditions, however, caffeine transiently upregulated profibrotic mediators. Overall, caffeine mitigates hyperoxia-induced lung injury and may actively promote physiological lung maturation, warranting future studies to define optimal dosing windows, clarify context-dependent fibrotic signaling, and translate gene-level effects into long-term clinical outcomes. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

14 pages, 1784 KB

Open AccessArticle

Forecasting Future Earthquakes with Machine Learning Models Based on Seismic Prediction Zoning

by Xiaolin Chen, Daicheng Peng and Li Li

Appl. Sci. 2025, 15(24), 13116; https://doi.org/10.3390/app152413116 (registering DOI) - 12 Dec 2025

Abstract

Predicting future seismic trends and occurrence of earthquakes remains a long-standing challenge in seismology. Despite substantial efforts to unravel the physical mechanisms underlying earthquake occurrence, currently, no well-defined physical or statistical model is capable of reliably predicting major earthquakes. However, machine learning methods [...] Read more.

Predicting future seismic trends and occurrence of earthquakes remains a long-standing challenge in seismology. Despite substantial efforts to unravel the physical mechanisms underlying earthquake occurrence, currently, no well-defined physical or statistical model is capable of reliably predicting major earthquakes. However, machine learning methods have demonstrated exceptional proficiency in identifying patterns within large-scale datasets, offering a promising avenue for enhancing earthquake prediction performance. Within the framework of machine learning, this study has developed a feature extraction method based on seismic prediction zoning, improving the effectiveness of machine learning-based earthquake prediction. The research findings indicate that the ensemble learning Stacking method, which is based on seismic prediction zoning, exhibits superior performance and high robustness in predicting the annual maximum earthquake magnitude. Additionally, the long short-term memory (LSTM) method demonstrates commendable performance within specific tectonic zones (e.g., the southwestern Yunnan region), providing valuable guidance for analyzing seismic trends in these regions. Full article

(This article belongs to the Special Issue Artificial Intelligence Applications in Earthquake Science)

17 pages, 7695 KB

Open AccessArticle

Composite Structure as a Stress Wave Barrier Zone Under Impulse Loading: Microscale Numerical Analysis of Attenuation

by Zuzana Murčinková, Dominik Sabol and Petr Baron

Materials 2025, 18(24), 5599; https://doi.org/10.3390/ma18245599 (registering DOI) - 12 Dec 2025

Abstract

This study investigates the design factors of stress wave barrier zones intended for manufacturing machines under impulse loading, using polymer discontinuously reinforced composites with specified internal microstructures, which effectively suppress stress at the wave front, promote uniform stress distribution, improve impact resistance, and [...] Read more.

This study investigates the design factors of stress wave barrier zones intended for manufacturing machines under impulse loading, using polymer discontinuously reinforced composites with specified internal microstructures, which effectively suppress stress at the wave front, promote uniform stress distribution, improve impact resistance, and reduce vibrations and noise. Two-dimensional representative unit cells and explicit finite element simulations were used to analyze stress wave propagation under impulse loading. The effects of inclusion shape, orientation, distribution, interlayer, and size of the interface on stress wave scattering and attenuation were examined. In our models, hollow inclusions demonstrated 20.6% higher attenuation compared to solid inclusions, with the hollow fiber inclusion showing the most significant improvement. Inclusion orientation relative to the stress wave direction affected attenuation by 18.5%, while redistribution of inclusions and addition of a compliant interlayer contributed additional increments of 3–11%. These results highlight the critical role of microscale topology in stress barrier zone designing, such that the combined adjustment of inclusion shape, orientation, interlayer presence, and spatial distribution provides an effective strategy to maximize stress wave attenuation. Full article

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15 pages, 1730 KB

Open AccessArticle

Research on Printed Circuit Board (PCB) Defect Detection Algorithm Based on Convolutional Neural Networks (CNN)

by Zhiduan Ni and Yeonhee Kim

Appl. Sci. 2025, 15(24), 13115; https://doi.org/10.3390/app152413115 (registering DOI) - 12 Dec 2025

Abstract

Printed Circuit Board (PCB) defect detection is critical for quality control in electronics manufacturing. Traditional manual inspection and classical Automated Optical Inspection (AOI) methods face challenges in speed, consistency, and flexibility. This paper proposes a CNN-based approach for automatic PCB defect detection using [...] Read more.

Printed Circuit Board (PCB) defect detection is critical for quality control in electronics manufacturing. Traditional manual inspection and classical Automated Optical Inspection (AOI) methods face challenges in speed, consistency, and flexibility. This paper proposes a CNN-based approach for automatic PCB defect detection using the YOLOv5 model. The method leverages a Convolutional Neural Network to identify various PCB defect types (e.g., open circuits, short circuits, and missing holes) from board images. In this study, a model was trained on a PCB image dataset with detailed annotations. Data augmentation techniques, such as sharpening and noise filtering, were applied to improve robustness. The experimental results showed that the proposed approach could locate and classify multiple defect types on PCBs, with overall detection precision and recall above 90% and 91%, respectively, enabling reliable automated inspection. A brief comparison with the latest YOLOv8 model is also presented, showing that the proposed CNN-based detector offers competitive performance. This study shows that deep learning-based defect detection can improve the PCB inspection efficiency and accuracy significantly, paving the way for intelligent manufacturing and quality assurance in PCB production. From a sensing perspective, we frame the system around an industrial RGB camera and controlled illumination, emphasizing how imaging-sensor choices and settings shape defect visibility and model robustness, and sketching future sensor-fusion directions. Full article

(This article belongs to the Special Issue Applications in Computer Vision and Image Processing)

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15 pages, 2761 KB

Open AccessArticle

Influence of FeSiB Layer Thickness on Magnetoelectric Response of Asymmetric and Symmetric Structures ofMagnetostrictive/Piezoelectric Composites

by Lei Chen, Yingjie Cheng and Fujian Qin

J. Compos. Sci. 2025, 9(12), 693; https://doi.org/10.3390/jcs9120693 (registering DOI) - 12 Dec 2025

Abstract

Asymmetric and symmetric magnetoelectric (ME)-laminated composites with magnetostrictive layer FeNi and piezoelectric layer PZT are prepared. The longitudinal resonance ME voltage coefficient in the symmetric composite is approximately 1.57 times that in the asymmetric composite with same constituents due to the flexural deformation [...] Read more.

Asymmetric and symmetric magnetoelectric (ME)-laminated composites with magnetostrictive layer FeNi and piezoelectric layer PZT are prepared. The longitudinal resonance ME voltage coefficient in the symmetric composite is approximately 1.57 times that in the asymmetric composite with same constituents due to the flexural deformation and asymmetric stress distribution in the asymmetric structure. By bonding an additional high-permeability FeSiB, combining FeSiB with FeNi forms magnetization-graded ferromagnetic materials. A stronger maximum ME voltage coefficient, a dual-peak phenomenon, and a self-bias ME effect are observed. The maximum ME voltage coefficients for asymmetric and symmetric composites reach 3.10 V/Oe and 5.67 V/Oe by adjusting the thickness of the FeCuNbSiB layer. The maximum zero-bias ME voltage coefficients for asymmetrical and symmetrical composite materials reach 2.19 V/Oe at 25 µm thickness of FeSiB and 2.87 V/Oe at 75 µm thickness of FeSiB. Such high performances enable the ME composites to possess ideal sensing and make them promising for self-bias current sensor applications. Full article

(This article belongs to the Section Composites Applications)

19 pages, 2730 KB

Open AccessArticle

Impact of Combined Rootstock Cultivar and Grafting Method on Growth, Yield, and Quality of Soilless-Grown Cucumber (Cucumis sativus L.) in a Non-Temperature-Controlled High Tunnel

by Takgoa A. Phalakatshela, Puffy Soundy, Sanele F. Kubheka and Martin M. Maboko

Plants 2025, 14(24), 3792; https://doi.org/10.3390/plants14243792 (registering DOI) - 12 Dec 2025

Abstract

Growers rarely use the grafting method on a double-root system due to limited information on the added advantages for increased plant vigour and yield of soilless-grown cucumber (Cucumis sativus L.). The study aimed to investigate the effect of combining rootstock cultivar and [...] Read more.

Growers rarely use the grafting method on a double-root system due to limited information on the added advantages for increased plant vigour and yield of soilless-grown cucumber (Cucumis sativus L.). The study aimed to investigate the effect of combining rootstock cultivar and the grafting method on the growth, yield, and quality of soilless-grown cucumber in a non-temperature-controlled (NTC) tunnel. Two rootstock cultivars, Flexifort (Flex) (Cucurbita maxima × Cucurbita moschata) and Ferro (Fer) (C. maxima × C. moschata), were grafted with scion cultivar Hoplita (H) to either single- (1R) or double- (2R) root systems, and the original scion root system was combined with either a Flexifort or Ferro rootstock (O1R) to two root systems and a non-grafted plant (Hoplita). Plants were grown in 10 L containers filled with sawdust as a growing medium. The leaf number was higher in ‘HO1RFlex’ combinations, while the non-grafted plants had a significantly lower leaf number. Thicker stem diameter was obtained from non-grafted plants. The tallest plants were obtained from HO1Fer combinations at 39, 53, and 101 days after transplanting (DAT), while non-grafted plants at 25 and 101 DAT were the shortest plants. Plants grafted to single- or double-root systems, regardless of rootstock cultivar, had higher early, marketable, and total yield compared to non-grafted cucumber. Many medium-sized fruits were obtained in ‘HO1RFlex’ combinations during the early harvest. The total soluble solids (TSSs) of cucumber juice were higher in ‘H1RFer’ while fruit mineral content was not affected by the combined rootstock cultivar and grafting method. Grafting to a double-root system using the original scion roots combined with rootstock or double rootstock had a limited effect compared to plants grafted to a single-root system. It is recommended that scion be grafted to a single-root system of either rootstock Ferro or Flexifort compared to a double-root system, particularly for the cost effectiveness of seeds and labour used in grafting, as well as for improved vegetative growth, including early marketable and total yield of cucumber. The growing containers of various sizes need further investigation to allow for the root extension and growth of grafted plants. Full article

(This article belongs to the Section Crop Physiology and Crop Production)

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24 pages, 2878 KB

Open AccessArticle

Investigation of Mechanical Behavior and Damage Mechanisms in Synthetic and Bio-Based Sandwich Composites Using Acoustic Emission

by Hana Driss, Abderrahim El Mahi, Mourad Bentahar, Moez Beyaoui and Mohamed Haddar

Appl. Mech. 2025, 6(4), 90; https://doi.org/10.3390/applmech6040090 (registering DOI) - 12 Dec 2025

Abstract

This paper presents the mechanical characterisation of sandwich composites. Different specimen configurations have been tested with a three-point bending load and their mechanical behavior has been discussed. In addition, the acoustic emission technique was used to detect the onset of damage mechanisms and [...] Read more.

This paper presents the mechanical characterisation of sandwich composites. Different specimen configurations have been tested with a three-point bending load and their mechanical behavior has been discussed. In addition, the acoustic emission technique was used to detect the onset of damage mechanisms and to monitor their evolution. The proposed analysis is based on processing recorded acoustic emission bursts. An unsupervised classification approach, combining the k-means algorithm with Principal Component Analysis (PCA), is used to group the detected acoustic events. The cluster analysis of the acquired data allows for correlation with the damage mechanisms occurring in sandwich composites. In addition to the advantages of multivariate data analysis, the results highlight the influence of sensor placement on the analysis of damage mechanisms is investigated. A suitable sensor configuration is proposed to improve the detection of acoustic emission activity. The originality of this work lies in the combined mechanical–AE interpretation that provides new insight into the damage behaviour of both a synthetic and a bio-based sandwich material. The comparative analysis of these two types of materials, coupled with a dedicated evaluation of sensor placement effects on defect detection, offers a contribution not previously reported in the literature. Full article

(This article belongs to the Collection Fracture, Fatigue, and Wear)

24 pages, 1196 KB

Open AccessArticle

Long-Term Straw Return Combined with Chemical Fertilizer Enhances Crop Yields in Wheat-Maize Rotation Systems by Improving Soil Nutrients Stoichiometry and Aggregate Stability in the Shajiang Black Soil (Vertisol) Region of North China Plain

by Xian Tang, Yangfan Qu, Yu Wu, Shasha Li, Fuwei Wang, Dongxue Li, Xiaoliang Li, Jianfei Wang and Jianrong Zhao

Agronomy 2025, 15(12), 2861; https://doi.org/10.3390/agronomy15122861 (registering DOI) - 12 Dec 2025

Abstract

The sustainability of wheat-maize rotation systems in the North China Plain is challenged by the over-reliance on chemical fertilizers, which leads to the decline of soil organic matter and structural degradation, particularly in the unique Shajiang black soil (Vertisol). While straw return is [...] Read more.

The sustainability of wheat-maize rotation systems in the North China Plain is challenged by the over-reliance on chemical fertilizers, which leads to the decline of soil organic matter and structural degradation, particularly in the unique Shajiang black soil (Vertisol). While straw return is widely recommended to mitigate these issues, the synergistic mechanisms of its long-term combination with chemical fertilizers on soil nutrient stoichiometry and aggregate stability remain inadequately quantified. A long-term field experiment was conducted with the five fertilization treatments including: (1) no fertilizer or straw (CK), (2) chemical fertilizer alone (NPK), (3) straw return chemical fertilizer (NPKS), (4) straw return with 10% straw-decomposing microbial inoculant combined with chemical fertilizer (10%NPKS), and (5) straw return with 20% straw-decomposing microbial inoculant combined with chemical fertilizer (20%NPKS) in the Shajiang black soil (Vertisol) region to investigate the effects of straw return combined with chemical fertilizers on soil organic carbon (SOC), total nitrogen (TN) and total phosphorus (TP) stoichiometry, aggregate stability, and crop yield in winter wheat-summer maize rotation systems of North China Plain. Our study demonstrated that the co-application of straw with a straw-decomposing microbial inoculant is a highly effective strategy for enhancing soil health and crop productivity, with its efficacy being critically dose-dependent. Our results identified the 10%NPKS treatment as the optimal practice. It most effectively improved soil physical structure by significantly increasing the content of large macroaggregates (>0.5 mm) and key stability indices (MWD, GMD, WA), while concurrently enhancing nutrient cycling, as evidenced by elevated SOC, TN, and shifted C/P and N/P stoichiometry. Multivariate analyses confirmed strong positive correlations among these soil properties, indicating a synergistic improvement in soil quality. Crucially, these enhancements translated into significant yield gains, with a notable crop-specific response: maize yield was maximized under the 10%NPKS treatment, whereas wheat yield benefited sufficiently from NPKS treatment. A key mechanistic insight was that 20%NPKS treatment, despite leading to the highest SOC and TN, induced a relative phosphorus limitation and likely caused transient nutrient immobilization, thereby attenuating its benefits for soil structure and yield. We conclude that co-applying straw with a 10% microbial inoculant combined with chemical fertilizer represents the superior strategy, offering a sustainable pathway to synergistically improve soil structure, nutrient availability, and crop productivity, particularly in maize-dominated systems. Full article

(This article belongs to the Special Issue Plant Nutrition Eco-Physiology and Nutrient Management)

20 pages, 549 KB

Open AccessReview

How the Intake of Pulses May Impact Metabolic Disorders and Dementia Risk: A Narrative Review

by Lisa M. B. Salinas, Maricarmen Marroquin, Mariana Mendez, Isabel Omaña-Guzmán and Juan C. Lopez-Alvarenga

Nutrients 2025, 17(24), 3898; https://doi.org/10.3390/nu17243898 (registering DOI) - 12 Dec 2025

Abstract

We present a narrative review focusing on pulses’ geographical origin and distribution, their impact on human evolution and history, and their influence on human health. Pulses, including dry peas, beans, and lentils, are renowned for their richness in chemical antioxidants. Despite containing antinutrients, [...] Read more.

We present a narrative review focusing on pulses’ geographical origin and distribution, their impact on human evolution and history, and their influence on human health. Pulses, including dry peas, beans, and lentils, are renowned for their richness in chemical antioxidants. Despite containing antinutrients, processing techniques preserve their health advantages. Epidemiological research has consistently demonstrated that the consumption of pulses is associated with favorable effects on metabolism. This evidence is further supported by molecular and clinical research, which has elucidated potential nutrigenomic mechanisms and effects on gut microbiota composition underlying their health benefits. However, the literature lacks randomized controlled clinical trials investigating the effects of pulses on health outcomes. Despite this limitation, our review provides valuable insights into the potential beneficial effects of pulses in ameliorating metabolic disorders and reducing the risk of dementia and Alzheimer’s disease. Acknowledging the current limitations, we identify areas for further research to generate additional evidence. Specifically, well-designed randomized controlled trials are needed to thoroughly assess the efficacy of pulses in preventing metabolic diseases. Addressing these research gaps will enhance our understanding of the health benefits associated with pulse consumption and facilitate evidence-based dietary recommendations to improve public health outcomes. Full article

(This article belongs to the Special Issue Nutrition, Genes, and Biological Pathways Influencing Metabolism and Obesity)

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12 pages, 710 KB

Open AccessArticle

Causal Association Between Psoriasis and Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study

by Young Lee, Soojin Kim and Je Hyun Seo

Genes 2025, 16(12), 1489; https://doi.org/10.3390/genes16121489 (registering DOI) - 12 Dec 2025

Abstract

Background/Objectives: Psoriasis and age-related macular degeneration (AMD) may share immune-related pathophysiologic characteristics. However, few studies have investigated the relationship between psoriasis and AMD. We assessed the possible causal link between psoriasis and AMD in European populations. Methods: Single-nucleotide polymorphisms associated with psoriasis exposure [...] Read more.

Background/Objectives: Psoriasis and age-related macular degeneration (AMD) may share immune-related pathophysiologic characteristics. However, few studies have investigated the relationship between psoriasis and AMD. We assessed the possible causal link between psoriasis and AMD in European populations. Methods: Single-nucleotide polymorphisms associated with psoriasis exposure were employed as instrumental variables (IVs) based on genome-wide significance (p < 5.0 × 10⁻⁸) in the FinnGen genome-wide association study (GWAS). The GWAS data for AMD were obtained from 11 studies performed by the International AMD Genomics Consortium. We performed a two-sample Mendelian randomisation (MR) study to estimate causal effects using the inverse-variance weighted, weighted median, and MR-Egger methods, as well as the MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) test. Results: We observed significant causal associations of psoriasis with AMD. Using the weighted median method, the odds ratio (OR) was 1.09 (95% CI = [1.03–1.16] and p = 0.005), and using the MR-PRESSO test, the OR was 1.04 (95% CI = [1.00–1.09] and p = 0.043). Conclusions: A potential causal association between psoriasis and AMD underscores the need to investigate inflammation as a risk factor for AMD. Full article

(This article belongs to the Special Issue Genetic Diagnosis and Therapeutics of Eye Diseases)

31 pages, 1823 KB

Open AccessReview

Sea Urchin Gonad Enhancement and Coloration: Nutritional Strategies and Ecological Considerations

by Jeremie Bauer and Jorge Olmos

Animals 2025, 15(24), 3583; https://doi.org/10.3390/ani15243583 (registering DOI) - 12 Dec 2025

Abstract

This review analyzes current research on short-term culture of sea urchin from barrens through formulated feed, addressing the need for sustainable aquaculture practices and ecological restoration of kelp forests. We compare the results of multiple studies to identify the optimal feed composition to [...] Read more.

This review analyzes current research on short-term culture of sea urchin from barrens through formulated feed, addressing the need for sustainable aquaculture practices and ecological restoration of kelp forests. We compare the results of multiple studies to identify the optimal feed composition to induce gonad growth and coloration. Our analysis suggests that macroalgae are the best feed ingredients to improve gonad growth and coloration; however, environmental and economic challenges persist in expanding sea urchin production with these types of ingredients. Plant-based protein sources like soy have emerged as a potential cost-effective alternative to fish products; nevertheless, the presence of antinutritional factors in soy products limits their inclusion in formulated feed. Regarding the composition and amount of lipids, we found that they are critical macronutrients in gonad development. The review also explores the potential of sea urchin aquaculture in mitigating urchin barrens and restoring kelp forests, highlighting the interplay between ecological and economic factors. We identify key knowledge gaps and propose future research directions, including large-scale economic viability assessments, novel feed additives, and integrated multitrophic aquaculture systems. These findings have significant implications for developing sustainable and economically viable sea urchin aquaculture, potentially transforming urchin barrens into productive ecosystems while meeting market demand for roe. Full article

(This article belongs to the Special Issue New Nutritional Strategies for Inducing Growth and Controlling Diseases in Aquaculture)

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18 pages, 1760 KB

Open AccessArticle

Implementing the One Water Concept in Greece: Evidence from Case Studies and Policy Pathways

by Nektarios N. Kourgialas, Andreas N. Angelakis and George Tchobanoglous

Water 2025, 17(24), 3525; https://doi.org/10.3390/w17243525 (registering DOI) - 12 Dec 2025

Abstract

A prominent development in environmental engineering and water resource management is the growing adoption of the term “One Water,” which encompasses all categories of water. In practical terms, One Water Concept (OWC) suggests that some municipalities could benefit from combining their traditionally separate [...] Read more.

A prominent development in environmental engineering and water resource management is the growing adoption of the term “One Water,” which encompasses all categories of water. In practical terms, One Water Concept (OWC) suggests that some municipalities could benefit from combining their traditionally separate water supply and wastewater divisions into a single, unified department. This integration is believed to enable more strategic, efficient, and economically viable approaches to addressing future water challenges. The OWC promotes an integrated approach to water resource management, emphasizing the interconnectedness of water systems and the need for holistic governance. The focus of this paper is on an examination of the implementation of OWC in Greece based on an analysis of recent international case studies, and the identification of the methodological and epistemological challenges. Through critical engagement with current literature and policy frameworks, the study highlights the successes and obstacles in adopting OWC, offering insights into future directions for sustainable water management. The study identifies key challenges such as institutional fragmentation, insufficient reuse infrastructure, and fragmented policy frameworks, while also highlighting opportunities related to digital monitoring, stakeholder collaboration, and investment in green infrastructure. These findings underscore the need for coordinated strategies to advance the One Water approach in Greece. Full article

(This article belongs to the Special Issue Climate–Water Effects in Agriculture: Adaptation and Mitigation Approaches)

16 pages, 1619 KB

Open AccessArticle

Intra-Articular Injection of Adipose-Derived-MSC Exosomes and Hyaluronic Acid in Sheep Knee Osteoarthritic Models Enhances Hyaline Cartilage Regeneration

by Auliya Akbar, Ismail Hadisoebroto Dilogo, Radiana Dhewayani Antarianto, Iqra Kousar, Angela Jennifer Tantry and Anissa Feby Canintika

Biomedicines 2025, 13(12), 3070; https://doi.org/10.3390/biomedicines13123070 (registering DOI) - 12 Dec 2025

Abstract

Background: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage damage. The limited regenerative capability of articular cartilage poses a therapeutic challenge. Adipose mesenchymal stem cell (MSC) exosomes have shown potential in regenerating cartilage structure in previous in vivo studies on [...] Read more.

Background: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage damage. The limited regenerative capability of articular cartilage poses a therapeutic challenge. Adipose mesenchymal stem cell (MSC) exosomes have shown potential in regenerating cartilage structure in previous in vivo studies on small animals. This study aims to compare the effectiveness of intra-articular injections of adipose-derived MSC exosomes and hyaluronic acid (HA) on cartilage regeneration in a sheep osteoarthritis model. Methods: This in vivo study involved 18 male sheep that were induced to develop OA via meniscectomy. The sheep were randomized and divided into three groups: Group 1 (adipose MSC exosomes + HA), Group 2 (adipose MSC exosomes), and Group 3 (HA). Microscopic evaluation using histological scoring with the Pineda score, cartilage regeneration assessment through histochemical and immunohistochemical examinations, and microtopographic examination using a scanning electron microscope (SEM) were performed 6 weeks post-intervention. Results: Cartilage regeneration in the combination group (Group 1) exhibited a larger area of hyaline cartilage (Group 1 vs. Group 2 [40.38 ± 9.35% vs. 34.93 ± 2.32% vs. 31.08 ± 3.47%; p = 0.034]) and a smaller area of fibrocartilage compared to adipose MSC exosomes (Group 2) or HA alone (Group 3) (13.06 ± 2.21% vs. 18.67 ± 3.13% vs. 28.14 ± 3.67%; p = 0.037). Microtopographic examination also showed a more homogeneous and smoother cartilage surface in the combination group (Group 1) of adipose MSC exosomes and HA. Conclusions: In a sheep knee osteoarthritis model, intra-articular injection of a combination of adipose-derived MSC exosomes and HA significantly enhances cartilage regeneration compared to injections of adipose-derived MSC exosomes or HA alone. Full article

(This article belongs to the Section Gene and Cell Therapy)

16 pages, 3889 KB

Open AccessArticle

Assessment of 15 CMIP6 Models in Simulating the East Asian Winter Monsoon and Its Relationship with ENSO

by Yiqiong Tang and Mengyu Li

Atmosphere 2025, 16(12), 1400; https://doi.org/10.3390/atmos16121400 (registering DOI) - 12 Dec 2025

Abstract

The East Asian winter monsoon (EAWM) is a critical component of the boreal winter global climate system, exerting profound influences on weather and climate anomalies across East Asia. This study systematically evaluates the capability of 15 Coupled Model Intercomparison Project Phase 6 (CMIP6) [...] Read more.

The East Asian winter monsoon (EAWM) is a critical component of the boreal winter global climate system, exerting profound influences on weather and climate anomalies across East Asia. This study systematically evaluates the capability of 15 Coupled Model Intercomparison Project Phase 6 (CMIP6) models in simulating the typical associated circulation, temporal characteristics, and the relationship with the El Niño–Southern Oscillation (ENSO) during the historical period of 1951–2013. Results indicate that the multi-model ensemble demonstrates considerable fidelity in reproducing the climatological spatial patterns of key EAWM systems, including the Siberian High, Aleutian Low, and low-level meridional winds. However, a systematic eastward shift is identified in the simulated sea level pressure anomaly centers over the North Pacific. In terms of temporal variability, most models realistically capture the dominant interdecadal periodicity of 15–20 years found in observations after 11-year low-passed filter. Four models reproduce a similar bimodal periodicity. Regarding the ENSO–EAWM relationship, approximately 80% of the evaluated models successfully capture the observed negative correlation, although its strength is consistently underestimated across the model ensemble. More notably, only three CMIP6 models faithfully capture the observed intrinsic asymmetry in the ENSO–EAWM relationship (i.e., the stronger impact of El Niño compared to La Niña). Full article

(This article belongs to the Special Issue Numerical Modeling Applications of Extreme Weather Events and Climate Change)

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21 pages, 26913 KB

Open AccessArticle

Role of the Insulin Receptor in Mediating Cytosolic Delivery of Proteins by a Modified Cell-Penetrating Peptide

by Keito Sugai and Akiko Okuda

Pharmaceuticals 2025, 18(12), 1885; https://doi.org/10.3390/ph18121885 (registering DOI) - 12 Dec 2025

Abstract

Background: Intracellular delivery of high-molecular-weight proteins is limited by the cell membrane. Cell-penetrating peptides (CPPs) offer a potential solution, but effective cytosolic delivery remains hindered by endosomal sequestration. Pas2r12, a CPP-derived peptide, facilitates cytosolic delivery of proteins including immunoglobulin G. Because Pas2r12 internalization [...] Read more.

Background: Intracellular delivery of high-molecular-weight proteins is limited by the cell membrane. Cell-penetrating peptides (CPPs) offer a potential solution, but effective cytosolic delivery remains hindered by endosomal sequestration. Pas2r12, a CPP-derived peptide, facilitates cytosolic delivery of proteins including immunoglobulin G. Because Pas2r12 internalization occurs via caveolae-dependent endocytosis, we hypothesized that cell-surface receptors contribute to uptake. Methods: HEK293 cells were treated with Pas2r12 alone or complexed with enhanced green fluorescent protein (EGFP). Phosphorylation of insulin receptor (INSR), insulin-like growth factor 1 receptor (IGF1R), and extracellular signal–regulated kinase 1/2 (ERK1/2) was analyzed by Western blot. Linsitinib was used to inhibit INSR/IGF1R kinase activity. Cytosolic delivery was assessed by confocal microscopy, and receptor involvement was evaluated using siRNA-mediated knockdown and receptor overexpression. Results: Pas2r12 alone transiently increased INSR/IGF1R phosphorylation at 2 min (6.6-fold), which was suppressed by linsitinib (1.3-fold), and strongly increased ERK1/2 phosphorylation (6.2-fold), which was not inhibited by linsitinib. Pas2r12–EGFP did not induce detectable INSR/IGF1R phosphorylation in parental cells but increased ERK1/2 phosphorylation (3.4-fold). Linsitinib markedly reduced cytosolic EGFP delivery to 16% of control. INSR knockdown decreased delivery to 13–16%, and IGF1R knockdown to 19–65%. In INSR-overexpressing lines, Pas2r12–EGFP induced INSR/IGF1R phosphorylation (6.0-fold) and enhanced delivery (230–270%). In IGF1R-overexpressing lines, Pas2r12–EGFP did not induce phosphorylation, and delivery decreased to 60–69%. Conclusions: Pas2r12-mediated cytosolic delivery involves both INSR and IGF1R, with INSR contributing more prominently. These findings, including the largely INSR/IGF1R-independent ERK1/2 activation, provide mechanistic insight into Pas2r12-mediated protein delivery. Full article

(This article belongs to the Special Issue Protein and Peptide-Based Drug Delivery)

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