Search Results (186)

Background/Objectives: The major question that confronts a pathologist when evaluating a lymph node biopsy is whether the process is benign or malignant, and the differential diagnosis between follicular lymphoma and reactive lymphoid tissue can be challenging. Methods: This study designed a convolutional neural network based on ResNet architecture to classify a large series of 221 cases, including 177 follicular lymphoma and 44 reactive lymphoid tissue/lymphoid hyperplasia, which were stained with hematoxylin and eosin (H&E). Explainable artificial intelligence (XAI) methods were used for interpretability. Results: The series included 1,004,509 follicular lymphoma and 490,506 reactive lymphoid tissue image-patches at 224 × 244 × 3, and was partitioned into training (70%), validation (10%), and testing (20%) sets. The performance of the training (training and validation sets) had an accuracy of 99.81%. In the testing set, the performance metrics achieved an accuracy of 99.80% at the image-patch level for follicular lymphoma. The other performance parameters were precision (99.8%), recall (99.8%), false positive rate (0.35%), specificity (99.7%), and F1 score (99.9%). Interpretability was analyzed using three methods: grad-CAM, image LIME, and occlusion sensitivity. Additionally, hybrid partitioning was performed to avoid information leakage using a patient-level independent validation set that confirmed high classification performance. Conclusions: Narrow artificial intelligence (AI) can perform differential diagnosis between follicular lymphoma and reactive lymphoma tissue, but it is task-specific and operates within limited constraints. The trained ResNet convolutional neural network (CNN) may be used as transfer learning for larger series of cases and lymphoma diagnoses in the future. Full article

This review investigates recent developments in cardiac mechano-electrical-fluid interaction (MEFI) modeling, with a focus on multiphysics simulation platforms and digital twin frameworks developed between 2015 and 2025. The purpose of the study is to assess how computational modeling methods—particularly finite element and immersed boundary techniques, monolithic and partitioned coupling schemes, and artificial intelligence (AI)-enhanced surrogate modeling—capture the integrated dynamics of cardiac electrophysiology, tissue mechanics, and hemodynamics. The goal is to evaluate the translational potential of MEFI models in clinical applications such as cardiac resynchronization therapy (CRT), arrhythmia classification, atrial fibrillation ablation, and surgical planning. Quantitative results from the literature demonstrate <5% error in pressure–volume loop predictions, >0.90 F1 scores in machine-learning-based arrhythmia detection, and <10% deviation in myocardial strain relative to MRI-based ground truth. These findings highlight both the promise and limitations of current MEFI approaches. While recent advances improve physiological fidelity and predictive accuracy, key challenges remain in achieving multiscale integration, model validation across diverse populations, and real-time clinical applicability. The review concludes by identifying future milestones for clinical translation, including regulatory model certification, standardization of validation protocols, and integration of patient-specific digital twins into electronic health record (EHR) systems. Full article

As potable water becomes limited, alternative water sources, such as reclaimed wastewater, for crop irrigation have gained attention. However, reclaimed wastewater for irrigation may expose edible crops to compounds of emerging concern (CECs), which may include pharmaceutics, hazardous waste, and volatile substances. Of these CECs, carbamazepine (CBZ) is of particular interest because only 7% of CBZ is filtered out during traditional wastewater treatment processing methods. Two trials were designed to evaluate the uptake and partitioning of CBZ in lettuce grown in a deep-water culture system (DWC) at low and high concentrations. The first trial (0 µg L⁻¹, 12.5 µg L⁻¹, 25 µg L⁻¹, and 50 µg L⁻¹) of CBZ had few effects on lettuce (Lactuca sativa var. capitata) growth, and low concentrations of accumulated CBZ were found in lettuce tissues. As a result, increased concentrations of CBZ were used in the second trial (0 mg L⁻¹, 21 mg L⁻¹, 41 mg L⁻¹, and 83 mg L⁻¹). Greater amounts of CBZ accumulated in plant tissues and the application of higher rates of CBZ negatively affected the growth and overall health of the lettuce. Further research is needed to determine the impacts of CECs on plant uptake and growth, as well as the environmental conditions. Full article

Objectives: Innate lymphoid cells (ILCs) and natural killer (NK) cells represent a diverse group of innate immune populations that modulate immune responses and tissue equilibrium across various diseases, including cancer. In the present study, we analyzed single-cell RNA sequencing (scRNA-seq) data to explore the landscape and functional status of ILC subsets in patients with head and neck squamous cell carcinoma (HNSCC). Methods: The GSE164690 dataset, which includes preprocessed scRNA-seq and clinical data, was acquired from the Gene Expression Omnibus database. The Cancer Genome Atlas database was used to develop the survival prediction model. Results: A total of 95,809 immune cells were clustered into 16 immune cell clusters, among which 7278 NK cells were further subdivided into 11 clusters. Among the 11 clusters, eight NK cell clusters, two intraepithelial ILC1 (ieILC1) clusters, and one ieILC1–NK-intermediate (ieILC1-NK-int) cluster were identified. Among the ieILC1/NK clusters, ieILC1-1 exhibited the highest immunological activity and was mainly derived from human papillomavirus-positive samples. Further, ieILC1s showed higher enrichment of pathways related to inflammation and effector functions—such as inflammatory response, interferon-gamma response, and interferon-alpha response—compared to the other clusters. Moreover, we developed prognostic prediction models based on differentially expressed genes in the ieILC1/NK clusters. Risk scores of the ieILC1-1, ieILC1-NK-int, and NK clusters were identified as independent prognostic factors for shorter overall survival (OS) and progression-free survival (PFS). Recursive partitioning revealed that combining ieILC1-1 and the NK clusters strongly predicted shorter OS and PFS. Conclusions: Our findings highlight the diverse landscape and prognostic significance of ieILC1/NK cells in patients with HNSCC. Full article

To investigate the role of potassium in the regulation of potato growth, dynamic changes in starch–sugar metabolism, and processing quality. In this study, “Gannong Potato No. 9” was used as the test material, and five potassium concentration treatments of 0, 9.4, 23.5, 28.5, and 37.6 mmol/L were set. The results showed that moderate application of potassium (23.5 mmol/L) significantly enhanced plant height, stem thickness, and tuber yield. It also promotes starch accumulation in all tissues and reduces sucrose, fructose, and glucose content, thus optimizing processing quality. Dynamic analyses showed that potassium affects carbohydrate transport and partitioning among tissues by regulating the direction of carbon partitioning and the rate of conversion. Correlation analysis confirmed the synergistic effect of starch–sugar metabolism among tissues, forming a spatio-temporally linked carbon allocation network. This study reveals the pivotal role of potash in potato starch–sugar metabolism and provides a theoretical basis for precision potassium application and quality improvement. Full article

Yam (Dioscorea cayennensis subsp. rotundata,hereafter referred to as Dioscorea rotundata) is a staple tropical tuber crop with notable nutritional and economic value. Its development and yield depend on efficient sucrose allocation from source tissues. Sucrose transporters (SUTs), a conserved family of membrane proteins, mediate sucrose loading, translocation, and unloading. Although well-studied in model plants and cereals, SUTs in yam remain largely uncharacterized. This study aims to identify and characterize the SUT gene family in yam and explore their roles in sucrose transport and tuber development. We conducted a genome-wide analysis of yam SUT genes, including gene structure, subcellular localization, and phylogeny. Molecular docking was used to predict sucrose-binding residues, and qRT-PCR assessed gene expression across tissues and tuber developmental stages. Eight SUT genes were identified and classified based on sequence similarity and domain structure. Docking analysis revealed key residues involved in sucrose binding and possible conformational shifts influencing transport. Expression profiling showed that most SUT genes, especially in the tuber apex, were progressively upregulated during development, suggesting roles in sucrose unloading and cell expansion. Additionally, functional validation of DrSUT1 in Arabidopsis thaliana confirmed its involvement in sucrose transport, supporting its role in yam sucrose partitioning. Yam SUT genes, especially those highly expressed in sink tissues, are involved in sucrose partitioning and tuber development. These findings provide structural and functional insights into SUT-mediated sugar transport and lay a foundation for improving sucrose utilization and yield in yam and other tuber crops. Full article

Background/Objectives: As a monocyclic β-lactam antibiotic, aztreonam has regained attention recently because combining it with β-lactamase inhibitors helps fight drug-resistant bacteria. This study aimed to systematically characterize the plasma and tissue concentration-time profiles of aztreonam in rats, mice, dogs, monkeys, and humans by developing a multi-species, physiologically based pharmacokinetic (PBPK) model. Methods: A rat PBPK model was optimized and validated using plasma concentration-time curves determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS) following intravenous administration, with reliability confirmed through another dose experiment. The rat model characteristics, modeling experience, ADMET Predictor (11.0) software prediction results, and allometric scaling were used to extrapolate to mouse, human, dog, and monkey models. The tissue-to-plasma partition coefficients (K_p values) were predicted using GastroPlus (9.0) software, and the sensitivity analyses of key parameters were evaluated. Finally, the cross-species validation was performed using the average fold error (AFE) and absolute relative error (ARE). Results: The cross-species validation showed that the model predictions were highly consistent with the experimental data (AFE < 2, ARE < 30%), but the deviation of the volume of distribution (V_ss) in dogs and monkeys suggested the need to supplement the species-specific parameters to optimize the prediction accuracy. The K_p values revealed a high distribution of aztreonam in the kidneys (K_p = 2.0–3.0), which was consistent with its clearance mechanism dominated by renal excretion. Conclusions: The PBPK model developed in this study can be used to predict aztreonam pharmacokinetics across species, elucidating its renal-targeted distribution and providing key theoretical support for the clinical dose optimization of aztreonam, the assessment of target tissue exposure in drug-resistant bacterial infections, and the development of combination therapy strategies. Full article

In perennial trees, wood development is a carbon-demanding process, pivotal for secondary cell wall (SCW) formation and xylem development. Sugars, functioning both as carbon substrates and signaling molecules, orchestrate cambial proliferation and xylem differentiation. However, few molecular candidates involved in the sugar-mediated regulation of wood development have been characterized. Cell wall invertases (CWINs), a subclass of the invertase enzyme family localized in the apoplastic space, catalyze the irreversible hydrolysis of sucrose into glucose and fructose, thereby governing carbon allocation in sink tissues. Here, PtoCWIN4 shows preferential expression in the stem of Populus tomentosa and has a high efficiency in sucrose cleavage activity. We demonstrated that the knockout of PtoCWIN4 results in stunted growth, aberrant branching patterns, and compromised secondary xylem formation. In contrast, mutant lines displayed enhanced SCW thickness accompanied by elevated cellulose and hemicellulose accumulation. Following this, the knockout of PtoCWIN4 led to impaired carbon partitioning from sucrose to hexose metabolites during wood development, corroborating the enzyme’s role in sustaining sucrose hydrolysis. Collectively, these findings establish PtoCWIN4 as a master regulator of sucrose-to-hexose conversion, a metabolic gateway critical for balancing structural biomass production and developmental growth during wood formation. Full article

Background/Objectives: Iron overload is a serious condition that can increase the production of reactive oxygen species (ROS), leading to oxidative tissue damage and organ dysfunction. While current pharmaceutical drugs for iron chelation have limitations, the search for natural herbs with iron-chelating properties is crucial. This study aimed to explore the various biological functions of the Perilla frutescens seed, regarding antioxidant activity and hepatoprotective and iron-chelating properties. Methods:Perilla frutescens seeds were subjected to extraction using a solvent-partitioning technique. Each fraction was evaluated for total phenolic content (TPC), total flavonoid content (TFC), and rosmarinic acid (RA) content by Folin–Ciocalteu assay, aluminum chloride colorimetric assay, and ultra-high-performance liquid chromatography (UHPLC), respectively. Antioxidant activity was assessed using DPPH, ABTS, and FRAP assays. The inhibition of lipid peroxidation was evaluated using the TBARS assay in HepG2 cells and an egg yolk model. The iron-chelating activity was examined using a ferric nitrilotriacetate (Fe³⁺-NTA)-binding assay, labile iron pool (LIP) level assessment, and the transferrin receptor (TfR) expression in HepG2 cells. Results: Phytochemical analysis indicated that the ethyl acetate (EtOAc) fraction had the highest TPC, TFC, and RA. This fraction demonstrated strong antioxidant properties and attenuated lipid peroxidation in HepG2 cells and egg yolk. In addition, this fraction exhibited iron-binding activity, decreased LIP levels, and induced TfR expression in iron-loaded HepG2 cells similar to the rosmarinic acid standard. Conclusions: These findings suggest that the EtOAc fraction of the Perilla frutescens seed possesses promising potential as a therapeutic agent for treating iron overload. Full article

Objectives: There is growing concern over tyrosine kinase inhibitor (TKI)-induced cardiotoxicity, particularly regarding left ventricular dysfunction and heart failure in clinical treatment. These adverse effects often lead to treatment discontinuation, severely impacting patient outcomes. Therefore, there is an urgent need for more precise risk assessment methods. This study aimed to assess the cardiotoxicity of TKIs, refine in vitro to in vivo extrapolation (IVIVE) methodologies to improve predictive accuracy, and identify critical in vitro parameters for assessment. Methods: By leveraging high-throughput cardiotoxicity screening with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), a mechanism-based toxicodynamic (TD) model for TKIs was constructed. A QSP-PK-TD model was developed by integrating pharmacokinetic (PK) and quantitative systems pharmacology (QSP) models. This model incorporates critical drug exposure factors, such as plasma protein binding, tissue–plasma partitioning, and drug distribution heterogeneity to enhance extrapolation accuracy. Results: The QSP-PK-TD model validated the reliability of IVIVE and identified the area under the curve of drug effects on mitochondrial membrane potential (AEMMP) and cardiomyocyte contractility (AEAAC) as key in vitro parameters for assessing TKI-induced cardiotoxicity. Incorporating critical drug exposure factors obviously improved qualitative and quantitative extrapolation accuracy. Conclusions: This study established a framework for predicting in vivo cardiotoxicity from in vitro parameters, enabling efficient translation of preclinical data into clinical risk assessment. These findings provide valuable insights for drug development and regulatory decision-making, offering a powerful tool for evaluating TKI-induced cardiotoxicity. Full article

Mangrove ecosystems are globally significant for their biodiversity and ecosystem services but face persistent threats from invasive species and anthropogenic disturbances. This study investigates the interactions between Cyperus rotundus, a widespread invasive weed, and fungal communities in the mangrove-adjacent wetlands of Isla Santay, Ecuador. Using metagenomic sequencing of the ITS region, we analyzed fungal diversity in samples from an anthropogenically pressured area and a non-impacted site. Results revealed significant differences in microbial assemblages: the rhizosphere sample from the disturbed area exhibited lower fungal richness and was dominated by Magnaporthaceae (9%) and Aureobasidium melanogenum (5%), both associated with stress-tolerant traits. In contrast, the rhizosphere sample from the non-impacted site showed higher species diversity, with Cladosporium dominicanum (62%) and Talaromyces (11%) as dominant endophytic taxa. Principal Coordinates Analysis (PCoA) and co-occurrence networks highlighted distinct fungal partitioning between the two sample tissues, indicating that C. rotundus mediates microbial composition in response to environmental gradients. These findings underscore the role of microbial communities in the plant’s invasive success and suggest that leveraging beneficial fungi could enhance ecosystem resilience and support wetland restoration. By integrating molecular approaches with ecological insights, this work contributes to a deeper understanding of microbial dynamics in coastal wetlands and informs targeted management strategies to preserve mangrove habitats. Full article

The present study employed a ⁶⁵Zn radioactive isotope as a tracer to investigate the foliar uptake and distribution patterns of ZnO concentrated suspension- and ZnSO₄ solution-sprayed on soybean plant leaves. The radiolabeled foliar treatments were sprayed on the leaves at V4 and V8 phenological stages. The radioactivity of ⁶⁵Zn in the leaves, roots, stems, and pods was determined using γ-ray spectrometry. After the first foliar spray, V4, the partition of radiolabeled Zn in plants treated with ZnO and ZnSO₄ was 99.22% and 98.12% in treated leaves, 0.15% and 0.39% in stems, 0.16% and 0.29% in roots, and 0.47% and 1.19% in newly expanded non-treated leaves, respectively. After two sprayings, V4 and V8, the partition of radiolabeled Zn in plants treated with ZnO and ZnSO₄ was 92.56% and 92.18% in treated leaves, 0.92% and 0.70% in stems, 0.52% and 0.39% in roots, 5.60% and 6.15% in newly expanded non-treated leaves, and 0.43% and 0.61% in grains, respectively. The total fraction translocated from the application tissue was 0.79% and 1.91% for ZnO and ZnSO₄, respectively, after 12 days and 8.03% and 8.48% for ZnO and ZnSO₄, respectively, after 72 days. An anatomical analysis revealed that plants cultivated in a nutrition solution with 10% ionic strength had 63% fewer stomata, and the xylem vessels were 63% smaller compared to plants grown in a solution with 100% Zn ionic. One can conclude that after a short period, 12 days, the absorption and translocation of ZnSO₄ was higher and faster than ZnO, and after the long period, 72 days, their performance was similar. Full article

Background/Objectives: Following tooth extraction, resveratrol (RSV) can support healing by reducing inflammation and microbial risks, though its poor solubility limits its effectiveness. This study aims to develop a solid nanocomposite by embedding RSV in lipid nanoparticles (mLNP) within a hydrophilic matrix, to the scope of improving local delivery and enhancing healing. Hydroxyapatite (HXA), often used as a bone substitute, was added to prevent post-extraction alveolus volume reduction. Methods: The mLNP-RSV dispersion was mixed with seven different polymers in various mLNP/polymer ratios. Following freeze-drying, the powders were redispersed, and the resulting dispersions were tested by DLS experiments. Then, the best two nanocomposites underwent extensive characterization by SEM, XRD, FTIR, Raman spectroscopy, and thermal analysis as well as in vitro partitioning studies aimed at verifying their ability to yield the mLNP-RSV from the hydrophilic matrix to a lipophilic tissue. The characterizations led to identify the best nanocomposite, which was further combined with HXA to obtain hybrid nanocomposites, further evaluated as pharmaceutical powders or in form of mini-tablets. Results: PEG-based nanocomposites emerged as optimal and, following HXA insertion, the resulting powders revealed adequate bulk properties, making them useful as a pharmaceutical intermediate to produce ≈59 mm³ mini-tablets, compliant with the post-extraction socket. Moreover, they were proven ex vivo to be able to promote RSV and GA accumulation into the buccal tissue over time. Conclusions: The here-proposed mini-tablet offers an innovative therapeutic approach for alveolar wound healing promotion as they led to a standardized dose administration, while being handy and stable in terms of physical solid identity as long as it takes to suture the wound. Full article

This paper proposes a mathematical model based on a mechanistic approach and previous research findings for the bacterial canker disease development in kiwifruit vines. This disease is a leading cause of severe damage to kiwifruit vines, particularly in humid regions, and contributes to significant economic challenges for growers in many countries. The proposed model contains three parts. The first one is the model of the kiwifruit vine describing its light interception, its carbon acquisition, and the partitioning dynamics. The carbon resource represents the chemical energy required for maintaining the necessary respiration of the living organs and their growth processes. The second part of the model is the dynamics of the pathogenic bacterial population living within the vine’s tissues and competing with them for the carbon resource required for their proliferation. The third part of the model is the carbon dynamics described by a mass conservation formula which computes the remaining amount of carbon available for competition. The model was validated by comparing simulations with experimental results obtained from growth chambers. The results show that the proposed model can simulate reasonably well the functional part of the vine in both the healthy case and the disease case without plant defense mechanisms in which the bacteria are always dominant under favorable environmental conditions. They also show that the environmental effects on the vine’s growth and the infection progress are taken into account and align with the previous studies. The model can be used to simulate the infection process, predict its outcomes, test disease management techniques, and support experimental analyses. Full article

Background: Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at the identification of the molecular factors associated with disease relapse and their further investigation as therapeutically exploitable targets. Methods: Analyses were conducted on formalin-fixed paraffin-embedded tissues of the primary tumors of relapsed (cases) and not relapsed (controls) HER2+ BC patients treated with adjuvant trastuzumab. The nCounter Human Breast Cancer Panel 360 was used. Logistic regression and partitioning around medoids were employed to identify the genes associated with disease recurrence. Cytotoxicity experiments using trastuzumab-resistant cell lines and a network pharmacology approach were carried out to investigate drug efficacy. Results: A total of 52 patients (26 relapsed and 26 not relapsed) were analyzed. We found that a higher expression of HDAC6 was significantly associated with an increased risk of recurrence, with an adjusted OR of 3.20 (95% CI 1.38–9.91, p = 0.016). Then, we investigated the cytotoxic activity of the selective HDAC6 inhibitor Nexturastat A (NextA) on HER2+ cell lines, which were both sensitive and trastuzumab-resistant. A sub-cytotoxic concentration of NextA, combined with trastuzumab, showed a synergistic effect on BC cell lines. Finally, using a network pharmacology approach, we identified HSP90AA1 as the putative molecular candidate responsible for the synergism observed in vitro. Conclusions: Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance. Full article