Search Results (452)

Optimizing olive orchard management requires timely, per-tree data to enhance productivity and sustainability. Unoccupied aerial vehicle (UAV)-based red, green, and blue (RGB) imagery offers a low-cost solution for acquiring high-resolution spatiotemporal insights for orchard management, which are not yet common in Tunisia. This study monitored tree structural parameters, leaf area index (LAI), and leaf nitrogen content (%N DW) in two Tunisian olive orchards during 2022 and 2023. UAV-derived imagery was photogrammetrically processed into 3D point clouds and analyzed using an automated approach. Target variables of the automated approach included tree-wise estimates of height, projected crown area, and crown volume, as well as raster cell counts of the canopy cloud and spectral indices such as the normalized green-red difference index (NGRDI) and green leaf index (GLI). In addition, the estimated parameters per tree were used to model LAI and leaf nitrogen content. Analyses were conducted separately for trees represented by a high and a low number of points in the dense point cloud. Outcomes were compared to reference data collected in the field on dates close to the UAV flights. The findings showed strong relationships for the projected crown area (R² = 0.82 and 0.91) and tree height (R² = 0.89 and 0.88) when compared to reference values. Linear regression models for LAI (R² = 0.73 and 0.68) and crown volume (R² = 0.85 and 0.91) estimation also show strong relationships. However, leaf nitrogen estimation was not feasible from RGB spectral index values, as it showed a weak relationship (R² = 0.34). A dataset with multispectral imagery could overcome this limitation but would increase costs, making it less suitable for the low-budget approach required in price-sensitive farming contexts, particularly in low-income regions. Full article

Grain quality in bread wheat is a complex trait determined by multiple genetic factors and their interaction with environmental conditions. This study investigated the genetic architecture of key grain quality traits in the Avalon × Cadenza double haploid (DH) population under contrasting climatic conditions in Kazakhstan. A set of 101 spring-type DH lines was evaluated over three years in three major wheat-growing regions of Kazakhstan, representing northern, central, and southern environments. Grain yield and nine grain quality traits were assessed, including amylose content (Amc, %), test weight per liter (TWL, g/L), grain protein content (GPC, %), gliadin content (Gli, %), glutenin content (Glu, %), grain hardness (GH, %), grain vitreousness (GV, %), falling number (FN, s), and sedimentation value determined in a 2% acetic acid solution (SV, mL). The objectives were to characterize phenotypic variation, examine trait relationships, and identify major and environmentally stable quantitative trait loci (QTLs) controlling grain quality. QTL mapping identified 89 QTLs associated with the nine studied traits, including 82 major QTLs explaining more than 10% of phenotypic variation and 16 stable QTLs detected in two or more environments. The largest numbers of QTLs were found for GPC, SV, and TWL. Stable QTLs were distributed across all three wheat genomes, with important regions detected on chromosomes 1A, 1B, 2D, 4A, 4D, 5A, 6A, and 7D. Several stable QTLs co-localized with genomic regions previously associated with grain quality and developmental regulation, including loci near Wx-B1, Rht-D1, and Ppd-D1, suggesting biologically meaningful links among gluten composition, starch biosynthesis, plant development, and grain physical properties. These results improve understanding of the genetic control of wheat grain quality across diverse environments in Kazakhstan and provide promising targets for marker-assisted selection to combine improved end-use quality with wide environmental adaptation. Full article

Non-small-cell lung cancer (NSCLC) constitutes approximately all lung cancers (LCs), and metastasis remains a major challenge in its treatment, thus necessitating the detection of novel molecular players involved in this process. In this study, we performed a comprehensive analysis of microarray and RNA-seq cohorts extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) and associated them with metastasis-related genes involved in brain metastasis (BM) in NSCLC. We thus identified differentially expressed metastatic genes (DEMGs) and constructed a protein–protein interaction network (PPIN) using these DEMGs. These DEMGs were further analyzed for associations with patient age, gender, and tumor stage, and the significant impact of specific genes on overall survival (OS) was assessed to determine the prognostic significance of the identified targets. We finally constructed a three-node microRNA (miRNA) feed-forward loop (FFL) involving miR-23b-3p, CD44, and five transcription factors (TFs) [EOMES, FOS, FOSL1, GLIS3, TP63] specific to NSCLC metastasis. Further mutational analysis of these FFL elements revealed that all were altered in the patient samples analyzed. Thus, our study identified potential genomic drivers that may play crucial roles in NSCLC BM. Overall, it provides valuable insights for the discovery of novel therapeutic targets in the management of NSCLC metastasis. However, further in vitro and in vivo experimentations are needed to justify the prognostic role of NSCLC biomarkers in BM pathogenesis. Full article

Background/Objectives: Craniofacial malformations such as orofacial clefts affect ~1 in 700 births; 40–60% lack clear genetic etiology, and many exhibit asymmetry and variable expressivity unexplained by classical Sonic Hedgehog (SHH) morphogen gradient models. We investigated whether integrated molecular modules linking morphogen signaling with metabolic stress responses may better account for craniofacial developmental outcomes. Methods: Sequential UniProt gene set integration identified 186 candidate craniofacial regulators. STRING network analysis revealed modular architecture. Molecular docking profiled 17 compounds against SMO, CK1δ, PINK1, and TIE2 (control). Pathway reconstruction integrated the SHH–CK1δ–HIF1A–HEY1–PINK1 axis with in-silico-predicted CK1δ phosphorylation sites on SMO (S615, T593, S751), HIF1A (Ser247), and GLI1/2/3 transcription factors. A developmental decision tree mapped affinity profiles to node-specific phenotype hypotheses. Results: CK1δ and PINK1 emerged as candidate nodes coupling morphogen signaling with mitochondrial quality control. Cross-docking showed preferential binding to developmental kinases (CK1δ: −8.34 kcal/mol; PINK1: −8.80 kcal/mol) versus TIE2 control (−6.76 kcal/mol; p < 0.001). Pathway reconstruction suggested that CK1δ-mediated Ser247 phosphorylation of HIF1A disrupts ARNT dimerization, redirecting HIF1A toward ARNT-independent HEY1 induction and consequent PINK1 suppression. Based on computed profiles, node-specific associations were proposed as computational hypotheses: SMO perturbation → midline defects; CK1δ → facial asymmetry/clefting; PINK1 → mandibular hypoplasia. Multi-target compounds (e.g., purmorphamine, taladegib) generated composite phenotype predictions consistent with clinical complexity. Conclusions: This strictly in silico study identifies candidate integrated morphogenic modules whose multi-node perturbation may underlie anatomically specific craniofacial malformation patterns. Node–phenotype associations are prioritized computational hypotheses requiring experimental validation; if confirmed, the framework could inform developmental toxicity assessment, therapeutic design, and reclassification of idiopathic craniofacial anomalies. Full article

The temporomandibular joint (TMJ) relies on specialized progenitor cells for tissue maintenance and repair. We characterized TMJ-derived progenitor cells in mice and investigated the role of Evc2-mediated Hedgehog signaling. Progenitor cells from the anterior TMJ exhibited greater colony-forming capacity and an elongated morphology, while posterior cells were cuboidal, highlighting regional heterogeneity. TMJ-derived progenitors demonstrated multipotency, differentiating into osteogenic and chondrogenic lineages. Gli1-expressing, slow-cycling cells localized to the ligament attachment regions, initially accumulating there and not overlapping with specialized cells (Col1⁺ cells). Conditional Evc2 disruption in Gli1-expressing cells paradoxically augmented expression of Gli1 and mechanosensors (Yap, Wwtr1, Piezo1), and produced more confluent, rapidly expanding colonies. We hypothesize that these colonies are primarily composed of transit amplifying cells (TACs), which may proliferate robustly but face challenges in terminal differentiation. These results reveal critical roles for EVC2 and regional progenitor cell diversity in TMJ regenerative biology and suggest that targeting cell signaling and mechanical factors may inform novel strategies for TMJ disorder therapies. Full article

Background and Clinical Significance: Plexiform fibromyxoma (PFM) is a rare benign gastric mesenchymal neoplasm characterized by multinodular plexiform growth of bland spindle cells in a myxoid or fibromyxoid stroma. We report a case of the cellular form of PFM with limited myxoid stroma and aberrant KIT expression, resulting in diagnostic difficulty by biopsy. Case Presentation: A 59-year-old woman presented with a slowly enlarging 15 mm gastric antral submucosal tumor. A resected specimen by laparoscopic and endoscopic cooperative surgery revealed spindle cell proliferation forming plexiform nodules with a myxoid background in limited areas. Positive immunoreactivity of a subset of spindle cells for KIT suggested a diagnosis of gastrointestinal stromal tumor (GIST), although DOG1 was negative. In addition, diffuse staining for CD10, smooth muscle actin, and D2-40 was confusing. MALAT1::GLI1 fusion was detected by next-generation sequencing analysis. Consequently, a diagnosis of PFM was established. Conclusions: This case expands the morphologic and immunophenotypic spectrum of PFM and indicates the possible diagnostic utility and biological significance of D2-40 expression. Although molecular confirmation of MALAT1::GLI1 fusion is definitive for the diagnosis of PFM, the findings of the present case may aid diagnosis in challenging cases that mimic GIST. Full article

Photobiomodulation (PBM) has shown promising potential to enhance bone regeneration; however, its optimal delivery parameters and interactions with osteoconductive scaffolds remain insufficiently defined. This preclinical study is the first to incorporate a pilot dosimetry evaluation to standardize 980-nm PBM delivery and ensure that effective irradiance reached the target surface of critical-size calvarial defects in mice. The primary aim was to evaluate the effectiveness of this novel 980-nm PBM protocol delivered using either flat-top (FT) or standard Gaussian (ST) handpieces in enhancing bone regeneration in critical-size defects (CSDs), both with and without Bio-Oss^® grafting. A total of 120 adult mice were allocated into twelve experimental groups (n = 10 per group): untreated (control), Bio-Oss^® alone, PBM alone, and PBM combined with Bio-Oss^®, using either FT or ST handpieces, and evaluated at 30 and 60 days. Animals received 980 nm irradiation at 0.6 W (nominal power output–set on laser interface) in continuous-wave mode for 60 s, three times per week, for two consecutive weeks. Pilot dosimetry included power meter measurements to determine the therapeutic power reaching the defect surface area and temperature monitoring to ensure safe energy delivery. The dosimetry study demonstrated that, after accounting for the optical properties of mouse shaved skin and the Bio-Oss^® graft covered with Bio-Gide^® membrane, the effective irradiance reaching the base of the defect surface area was 1.131 W/cm² for the FT handpiece and 0.413 W/cm² for the ST handpiece. This dose was sufficient to induce significant regenerative effects. Histological, Masson’s trichrome, and immunohistochemical analyses for Runx2, OCN, GLI1, CD34, and CTSK were performed to characterize early and late osteogenic events. The combination of PBM and Bio-Oss^® significantly accelerated bone regeneration compared with PBM alone, with the FT handpiece producing the most uniform and advanced osteogenesis. PBM enhanced progenitor activation, osteoblast differentiation, angiogenesis, matrix deposition, and late-stage remodeling, demonstrating a synergistic effect with the scaffold, whereas Bio-Oss^® alone or defect alone showed limited early regenerative potential. These findings highlight the effectiveness of this novel standardized PBM dosimetry and uniform beam profile (FT), supporting their use as a foundation for future randomized controlled trials in craniofacial bone repair. Full article

Stemness is a critical factor in tumor initiation, progression, metastasis, and resistance to treatment. The AXL receptor and hedgehog (Hh) signaling pathways play significant roles in regulating stemness, making them potential therapeutic targets. This study explores the involvement of AXL and hedgehog signaling in maintaining stemness and contributing to trastuzumab resistance in HER2-positive breast cancer. The expression of AXL and Hh markers was assessed in trastuzumab-resistant SKBR3 and HCC1954 cell lines and their parental counterparts. Trastuzumab resistance was associated with upregulation of AXL expression, with the GAS6/AXL axis identified as a regulator of stemness. Although inhibition of hedgehog signaling using GANT61 did not affect AXL expression, overexpression of AXL led to increased levels of hedgehog markers (e.g., Gli1, Ptch1) and stemness markers (e.g., Sox2, Oct4, Nanog), while silencing AXL resulted in their downregulation. Furthermore, AXL overexpression enhanced stemness in resistant cells, suggesting its role in resistance mechanisms. The combination of AXL inhibition and trastuzumab treatment significantly reduced stemness and hedgehog marker expression, indicating a synergistic effect. These results emphasize the pivotal role of AXL in regulating both stemness and hedgehog signaling in HER2-positive breast cancer. The study suggests that targeting both AXL and HER2 could be a promising strategy to overcome trastuzumab resistance and improve treatment outcomes. Full article

Water scarcity increasingly threatens viticulture in the Macaronesian region due to climatic variability and recurrent droughts. This study evaluated the physiological and productive responses of grapevines (Vitis vinifera L.) to foliar applications of two amino acid-based biostimulants, pyroglutamic acid and pipecolic acid, under contrasting water availability conditions on Madeira Island, Portugal. Three non-irrigated treatments were arranged in a randomized complete block design: T1 (no irrigation and no amino acids), T2 (pyroglutamic acid, without irrigation), and T3 (pipecolic acid, without irrigation), while conventional irrigation (T4) was included as a non-randomized reference. Agronomic parameters and UAV-derived multispectral and thermal data were analyzed during the 2023 (moderate drought) and 2024 (severe drought) growing seasons. Vegetation indices (NDVI, GNDVI, NDRE, NGRDI, and GLI) and the Simplified Crop Water Stress Index (CWSI_si) were used to assess canopy vigor and plant water status. In 2023, T4 showed significantly higher bunch number and total yield, whereas differences among non-irrigated treatments were not statistically significant. Nevertheless, T2 showed consistent numerical trends toward higher yield components and a comparatively more stable canopy thermal response than the untreated control. In 2024, severe drought reduced productivity across all treatments, with no significant difference detected. Yield components were generally strongly correlated, while CWSI_si was negatively associated with vegetation indices, particularly under moderate drought. The NGRDI demonstrated potential as a low-cost RGB-based indicator but requires cautious interpretation. Overall, pyroglutamic acid may represent a complementary strategy to irrigation and UAV-based precision monitoring in drought-prone viticulture, although confirmation through longer-term and higher-powered field studies is required. Full article

Glibenclamide (Gli), widely used in the management of type 2 diabetes mellitus (T2DM), shows low oral bioavailability, while curcumin (Cur) is limited by poor aqueous solubility and instability. This study reports the development of a niosomal co-delivery system combining hypoglycemic and antioxidant agents to improve formulation performance for T2DM. Gli and Cur were co-encapsulated into niosomal vesicles (NIOs) using the thin-film hydration method, followed by surface coating with chitosan (CS). The formulations were characterized by dynamic light scattering, scanning transmission electron microscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy, complemented by in vitro release studies under simulated gastrointestinal conditions. The prepared NIOs exhibited particle sizes between 413.5 and 576.9 nm, with encapsulation efficiency strongly dependent on formulation composition. The optimized system showed high encapsulation efficiency for both Gli (98.95 ± 0.87%) and Cur (91.09 ± 2.00%). In vitro release studies demonstrated enhanced release compared with the physical mixture, providing gastric protection and sustained intestinal delivery. Release kinetics indicated controlled drug release governed by diffusion- and erosion-based mechanisms. Both uncoated and CS-coated NIOs displayed good physical and osmotic stability, with CS coating further reducing drug leakage. These results highlight the potential of niosomal systems for efficient Gli and Cur administration in T2DM. Full article

Background/Objectives: Medication-related safety incidents rank among the most prevalent patient safety concerns globally. In addition to healthcare professionals, patients also play a vital role in ensuring safe medication practices. To effectively engage them, it is essential to gain a deeper understanding of their knowledge and perspectives. Methods: We conducted a netnography-based mixed-method content analysis study within the Hungarian online environment to identify key patient concerns. A total of 5174 relevant comments and discussions were analyzed (from 14 August 2020 to 14 August 2023), utilizing a medication safety framework based on Glies et al. The analysis was confined to publicly accessible online content related to oral medications and did not include demographic information about commenters. Results: The framework was applicable, though its representation was uneven. Patients predominantly focused on issues related to Access to services and Communication. Online discussions were primarily dominated by patients, with contributions from relatives and healthcare professionals being comparatively limited. The majority of concerns pertained to prescription medications, particularly in the fields of gynecology, internal medicine, and gastroenterology. ATC codes G and A were most frequently referenced, corresponding to the healthcare domains discussed. Conclusions: Initiatives aimed at enhancing medication safety should prioritize improving access and communication. Patients must be empowered as active agents in safety efforts; they can aid in preventing errors, reporting incidents, and offering feedback. Their engagement supports organizational learning and promotes safer healthcare delivery. Full article

Precise tumor segmentation in multimodal MRI is crucial for glioma diagnosis and treatment planning; yet, deep learning models still struggle with irregular boundaries and severe class imbalance under computational constraints. An Enhanced 3D DenseNet with CDC architecture was proposed, integrating Central Difference Convolution, attention gates, and Atrous Spatial Pyramid Pooling for brain tumor segmentation on the BraTS 2023-GLI dataset. CDC layers enhance boundary sensitivity by combining intensity-level semantics and gradient-level features. Attention gates selectively emphasize relevant encoder features during skip connections, whereas the ASPP captures the multi-scale context with dilation rates. A hybrid loss function spanning three levels was introduced, consisting of a region-based Dice loss for volumetric overlap, a GPU-native 3D Sobel boundary loss for edge precision, and a class-weighted focal loss for handling class imbalance. The proposed model achieved a mean Dice score of 91.30% (ET: 87.84%, TC: 92.73%, WT: 93.34%) on the test set. Notably, these results were achieved with approximately 3.7 million parameters, representing a 17–76x reduction compared to the 50–200 million parameters required by transformer-based approaches. Enhanced 3D DenseNet with CDC architecture demonstrates that the integration of gradient-sensitive convolutions, attention mechanisms, multi-scale feature extraction, and multi-level loss optimization achieves competitive segmentation performance with significantly reduced computational requirements. Full article

Celiac disease (CeD) is a chronic immune-mediated enteropathy triggered by dietary gluten in genetically predisposed individuals which also entails intestinal dysbiosis. This hallmark microbial imbalance provides a rationale for exploring interventions that could modulate the gut ecosystem. Cocoa is a bioactive food rich in polyphenols, theobromine, and fiber, compounds known to have an influence on both immune function and gut microbiota composition. Here, we investigated the effects of cocoa supplementation on the gut microbial profile and predicted functionality in DQ8-D^d-villin-IL-15tg mice, genetically predisposed to CeD. Animals were assigned to a reference group receiving a gluten-free diet (GFD), a gluten-containing diet group (GLI), or the latter supplemented with defatted cocoa (GLI + COCOA) for 25 days. The cecal microbiota was analyzed via 16S rRNA sequencing, and functional pathways were inferred using PICRUSt2. Goblet cell counts and CeD-relevant autoantibodies were measured and correlated with microbial taxa. Cocoa supplementation partially attenuated gluten-induced dysbiosis, preserving beneficial taxa such as Akkermansia muciniphila and Lactobacillus species while reducing opportunistic and pro-inflammatory bacteria. Functional predictions suggested differences in the predicted microbial metabolic potential related to amino acid, vitamin, and phenolic compound metabolism. Cocoa also mitigated goblet cell loss and was inversely associated with anti-gliadin IgA levels. These findings suggest that cocoa, as an adjuvant to a GFD, could be of help in maintaining microbial homeostasis and intestinal health in CeD, supporting further studies to assess its translational potential. Full article

Vascular function is a direct factor affecting blood pressure, and it is a primary strategy for clinically controlling hypertension by regulating the constriction/relaxation of blood vessels. This study evaluates the vasodilatory and anti-hypertensive effects of norisoboldine (NOR), an isoquinoline alkaloid in Ayurvedic medicine. The rat thoracic aorta was isolated to investigate the vasodilatory effect, and L-NAME-induced hypertensive rats were established, respectively. In the isolated vascular ring, removal of the endothelium resulted in a significant decrease in the vasodilatory effect. Pretreatment with L-NAME, ODQ, KT5823, WT, Tri, Dilt, calcium-free solution, TG, Gd³⁺, 2-APB, Indo, 4-AP, Gli, and BaCl₂ inhibited the vasodilatory effect of NOR. In vascular endothelial cells, NOR promoted eNOS phosphorylation and inhibited TNF-α-induced expression of ICAM-1 and VCAM-1. SBP and DBP were significantly decreased after administration of different doses of NOR in the femoral vein of rats. In addition, NOR significantly reduced the blood pressure of L-NAME-induced hypertensive rats, up-regulated the serum levels of NO, cGMP, and CAT, and down-regulated MDA, IL-6, and TNF-α in hypertensive rats. NOR administration improved pathological changes in the thoracic aorta by regulating the arrangement of thoracic aortic smooth muscle cells, decreasing the thickness of the thoracic aortic wall, and reducing the degree of collagen deposition and fibrosis. In conclusion, the vasodilatory mechanisms of NOR were related to the Ca²⁺-eNOS signaling pathway, including the PGI₂ and various K⁺/Ca²⁺ channels, the inositol triphosphate receptor (IP₃R) calcium release, and the α-adrenergic receptor pathway. The anti-hypertensive mechanism of NOR may be related to increased NO and cGMP bioavailability, inhibition of oxidative stress and inflammatory responses, and improved vascular remodeling. Full article

Neonatal Diabetes Mellitus (NDM) is a rare, heterogeneous monogenic disorder typically presenting within the first six months of life. Unlike type 1 or type 2 diabetes, NDM is caused by single-gene mutations that disrupt pancreatic β-cell function or development. With the advent of next-generation sequencing, the genetic spectrum of NDM has expanded significantly, necessitating a shift from symptomatic management to precision medicine. This narrative review summarizes the genetic basis and pathogenic mechanisms of NDM, categorizing them into three major pathways: (1) ATP-sensitive potassium (K_ATP) channelopathies (e.g., ABCC8, KCNJ11), where gain-of-function mutations inhibit insulin secretion; (2) Transcription factor defects (e.g., GLIS3, PAX6, GATA6), which impair pancreatic development and often present with syndromic features; and (3) Endoplasmic reticulum (ER) stress-mediated β-cell apoptosis, exemplified by WFS1 mutations. Furthermore, we highlight the clinical complexity of these mutations, including the “biphasic phenotype” observed in ABCC8 and HNF1A variants. Understanding these molecular mechanisms is critical for clinical decision-making. We discuss the transformative impact of genetic diagnosis in treatment, particularly the successful transition from insulin to oral sulfonylureas in patients with K_ATP channel mutations, and emphasize the importance of early genetic testing to optimize glycemic control and prevent complications. Full article