Search Results (96)

Background/Objectives: The neonatal Fc receptor (FcRn) plays a crucial role in extending the systemic half-life of monoclonal antibodies (mAbs), but its influence on ocular distribution remains incompletely understood. This study investigated the impact of FcRn on the ocular disposition of mAbs following systemic administration in rabbits. Methods: New Zealand White rabbits received a single intravenous dose (1 mg/kg) of either wild-type trastuzumab (TS-WT) or its FcRn non-binding variant (IHH). Plasma and ocular tissues (retina, iris–ciliary body, vitreous humor, aqueous humor, cornea, conjunctiva, and tears) were collected at terminal time points up to 336 h for TS-WT and 168 h for IHH. Antibody concentrations were quantified using a validated sandwich ELISA. Pharmacokinetic parameters and antibody biodistribution coefficients (ABC) were calculated to assess the FcRn-mediated effects on ocular distribution. Results: TS-WT demonstrated 2-fold higher systemic exposure compared to IHH. The iris–ciliary body exhibited the highest absolute exposure for both antibodies, with TS-WT showing significantly higher accumulation (ABC_0–168h: 14.95% vs. 8.89%). Retinal distribution remained comparable between antibodies (5.96% vs. 5.51%). Both antibodies were detectable in tears, with ABC value of ~4% reported for TS-WT. TS-WT also demonstrated markedly increased distribution in vitreous humor and tear fluid (3.5- and 5.5-fold higher ABC values, respectively) compared to IHH. The cornea (5.76% vs. 5.57%) and conjunctiva (7.71% vs. 7.21%) showed comparable relative distribution between TS-WT and IHH, while aqueous humor showed minimal differences (0.44% vs. 0.52%). Conclusions: This investigation reveals distinct tissue-specific patterns of FcRn-mediated mAb distribution within the eye. FcRn binding significantly enhanced antibody distribution in ocular tissues, such as the iris–ciliary body, and tears, with less pronounced effects on the retina, cornea, conjunctiva and aqueous humor. These findings provide mechanistic insights for optimizing mAb-based therapeutics for ocular disease and understanding the ocular toxicity of mAb-based therapeutics, such as antibody–drug conjugates. Full article

To improve crop yields and incomes, farmers consistently adapt their practices to climate and market fluctuations, resulting in highly variable crop field distribution and coverage in space and time. As these dynamics illustrate farmers’ challenges, up-to-date crop-type mapping is essential for understanding farmers’ needs and supporting their adoption of sustainable practices. With global coverage and frequent temporal observations, remote sensing data are generally integrated into machine learning models to monitor crop dynamics. Unlike physical-based models that rely on straightforward use, implementing machine learning models requires extensive user interaction. In this context, this study assesses how sensitive the models’ outputs are to feature selection and hyperparameter tuning, as both processes rely on user judgment. To achieve this, Sentinel-1 (S1) and Sentinel-2 (S2) features are integrated into five distinct models (Random Forest (RF), Support Vector Machine (SVM), Light Gradient Boosting (LGB), Histogram-based Gradient Boosting (HGB), and Extreme Gradient Boosting (XGB)), considering several features selection (Variance Inflation Factor (VIF) and Sequential Feature Selector (SFS)) and hyperparameter tuning (Grid-Search) setup. Results show that the preprocess modeling feature selection (VIF) discards the features that the wrapped method (SFS) keeps, resulting in less reliable crop-type mapping. Additionally, hyperparameter tuning appears to be sensitive to the input features, and considering it after any feature selection improved the crop-type mapping. In this context a three-step nested modeling setup, including first hyperparameter tuning, followed by a wrapped feature selection (SFS) and additional hyperparameter tuning, leads to the most reliable model outputs. For the study region, LGB and XGB (SVM) are the most (least) suitable models for crop-type mapping, and model reliability improves when integrating S1 and S2 features rather than considering S1 or S2 alone. Finally, crop-type maps are derived across different regions and time periods to highlight the benefits of the proposed method for monitoring crop dynamics in space and time. Full article

Carbon dots (CDs) have emerged as a promising non-viral gene delivery vector due to their excellent biocompatibility and tunable surface properties. In this study, four CDs with gradient-positive zeta potentials (7.23 mV, 16.7 mV, 25.3 mV, 34.5 mV) were synthesized via a hydrothermal method. Among these, CDs-3 with an optimal zeta potential of 25.3 mV stood out, exhibiting ultra-low cytotoxicity (cell viability > 80% even at 50 μg/mL) and a transfection efficiency of nearly 100% (for GFP plasmid delivery), significantly outperforming commercial vectors Lipo2000 and PEI. A stable CDs-3/siIhh delivery system was constructed at a mass ratio of 2:1. In vitro evaluations confirmed that CDs-3/siIhh could efficiently regulate the Indian Hedgehog (Ihh) signaling pathway and osteoarthritis (OA)-related markers in both normal and IL-1β-induced inflammatory ATDC5 chondrocytes. Its regulatory effect was significantly superior to that of the commercial Lipo2000/siIhh and PEI/siIhh systems. This consistent “transcription–translation” regulation, combined with the carrier’s safety and excellent cellular internalization capacity in chondrocytes, highlights its potential for OA gene therapy. Collectively, our work develops a novel, safe, and efficient positive-potential CD-based gene delivery vector, providing a promising gene regulatory capacity by leveraging optimized surface charge engineering. Full article

Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9⁺/Fgfr3⁺ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1⁺ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5⁺ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a–Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh–PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint. Full article

High-quality agricultural products from the Lambayeque region have contributed to the growth of Peru’s agro-export sector and increased international trade. However, the need for agricultural exports to be more resilient and sustainable is demonstrated by the fact that markets are still concentrated, logistical costs are high, and global demand is constantly shifting. The purpose of this study is to use a gravity-based trade model and market intelligence techniques to analyse the agricultural exports from the Lambayeque region between 2015 and 2024. Using official data from the World Bank, AZATRADE, CEPII, and MINCETUR, we employed a quantitative explanatory approach. The results show that the concentration of businesses has significantly decreased while the value of exports has increased steadily. The Herfindahl–Hirschman Index increased from 6209 in 2015 to 1349 in 2024, and export destinations have become slightly more diverse. Exports are negatively impacted by geographic distance, but free trade agreements greatly benefit them. There is a lot of export potential in markets like Finland, Indonesia, Austria, Bolivia, and Vietnam. However, Israel and Hong Kong appear to be full. Overall, the findings indicate that Lambayeque’s export performance has improved, but it still runs the risk of becoming overly focused on a single sector. Long-term sustainability of the region’s agricultural exports depends on enhancing logistical infrastructure, bolstering market intelligence, and promoting regional diversity. Full article

Background/Objectives: Intermittent hypobaric hypoxia (IHH) induces various physiological and metabolic adaptations. This study aimed to investigate the effects of a seven-day IHH exposure on nutritional status, body composition, gut microbiota, movement intensity, and energy expenditure in 10 workers. Methods: A pre–post comparative design was employed, with measurements taken at the beginning and end of the exposure period. Nutritional status, body composition, and phase angle (PhA) were assessed via bioelectrical impedance analysis (BIA). Gut microbiota composition was analyzed through fecal DNA extraction and qPCR for specific bacterial families. Movement intensity and energy expenditure were monitored using accelerometry. An initial statistical analysis was performed, which included paired t-tests and Wilcoxon signed-rank tests. Results: A significant increase in PhA (mean difference: 0.40; p = 0.0053 for t-test, p = 0.0136 for Wilcoxon) and a significant decrease in BMI (mean difference: −0.38; p = 0.0311 for t-test, p = 0.0546 for Wilcoxon). Conclusions: While the original paper reported no significant changes in nutritional status or body composition, our re-analysis suggests a significant change in BMI. The original paper also reported significant changes in specific gut bacterial families (butyrate-producing bacteria, p = 0.037; Lactobacillus species, p = 0.006). Physical activity levels remained consistently low. Full article

This study investigates the genetic architecture of Salsk sheep—a long-established Russian Merino-type breed from the southern steppes—highlighting their broad genetic diversity, resilience to cold and drought, and dual-purpose (wool and meat) productivity as a unique gene pool shaped by natural and artificial selection. The study used data from 96 sheep. Genotyping was carried out on the Illumina Ovine Infinium^® HD BeadChip platform, and after filtering, 511,145 SNPs were retained. We assessed population structure and genetic diversity using principal component analysis (PCA), Fst, and linkage disequilibrium (LD) in comparison with four reference European breeds. To detect selection signatures, we employed a combination of complementary methods, including intra-population statistics (iHS, nSL, iHH12) and inter-population comparisons (XP-EHH). This integrated approach identified genomic regions under positive selection, reflecting the breed’s evolutionary response to both natural and artificial selection pressures. Strong selection signals were detected in genes associated with production traits like fertility and growth (CCSER1, SOX6), as well as fundamental adaptive functions, including immune response (IL6R, NLRP1) and energy metabolism (ACSL5, FANCA). These results elucidate the genetic basis of the Salsk breed’s high resilience and highlight its potential as a valuable genetic resource for improving this trait in other sheep populations. Full article

Hepatocellular carcinoma (HCC) remains a global health issue due to high incidence and mortality, complicated by limited therapeutic options and evolution of de novo resistance to conventional chemotherapy. In this study, we investigated the antiproliferative activity of RDD-142, a synthetic precursor of the HIV-1 protease inhibitor (HIV-PI) Darunavir analog, on the human hepatocellular carcinoma line (HepG2) and healthy hepatocyte line (IHH), both as a free molecule and in liposomal formulation. RDD-142 demonstrated a selective cytostatic effect on HepG2, preserving healthy IHH cells. Mechanistically, RDD-142 delayed cancer cell proliferation by attenuating the ERK1/2 signaling pathway, and concurrently, it activated the autophagic process via p62 up-regulation. These effects were linked to RDD-142 inhibitory activity on the chymotrypsin-like subunit of the proteasome, triggering a UPR-mediated stress response. Notably, the liposomal formulation of RDD-142 significantly enhanced intracellular intake and cytotoxic efficacy. RDD-142 demonstrated promising potential as a therapeutic agent for HCC. Its antitumor activity may be further amplified through liposomal nanoformulation, offering a successful strategy to reduce effective dosage and minimize adverse effects. Full article

Soil moisture content (SMC) is a critical parameter for agricultural productivity, particularly in semi-arid regions, where irrigation practices are extensively used to offset water deficits and ensure decent yields. Yet, the socio-economic and remote context of these regions prevents sufficiently dense SMC monitoring in space and time to support farmers in their work to avoid unsustainable irrigation practices and preserve water resource availability. In this context, our study addresses the challenge of high spatial resolution (i.e., 20 m) SMC estimation by integrating remote sensing datasets in machine learning models. For this purpose, a dataset made of 166 soil samples’ SMC along with corresponding SMC, precipitation, and radar signal derived from Soil Moisture Active Passive (SMAP), Integrated Multi-satellitE Retrievals for GPM (IMERG), and Sentinel-1 (S1), respectively, was used to assess four machine learning models’ (Decision Tree—DT, Random Forest—RF, Gradient Boosting—GB, Extreme Gradient Boosting—XGB) reliability for SMC mapping. First, each model was trained/validated using only the coarse spatial resolution (i.e., 10 km) SMAP SMC and IMERG precipitation estimates as independent features, and, second, S1 information (i.e., 20 m) derived from single scenes and/or composite images was added as independent features to highlight the benefit of information (i.e., S1 information) for SMC mapping at high spatial resolution (i.e., 20 m). Results show that integrating S1 information from both single scenes and composite images to SMAP SMC and IMERG precipitation data significantly improves model reliability, as R² increased by 12% to 16%, while RMSE decreased by 10% to 18%, depending on the considered model (i.e., RF, XGB, DT, GB). Overall, all models provided reliable SMC estimates at 20 m spatial resolution, with the GB model performing the best (R² = 0.86, RMSE = 2.55%). Full article

Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder with variable penetrance caused by GnRH deficiency, leading to delayed puberty and infertility. In 50–60% of cases, CHH is associated with non-reproductive abnormalities, most commonly anosmia/hyposmia (Kallmann syndrome, KS). Over 60 genes have been implicated in CHH pathogenesis. We aimed to perform genetic screening in a cohort of 14 patients (10 males, 4 females; mean age 22 ± 7.72 years) with suspected or diagnosed HH/KS. Genetic analysis was conducted using next-generation sequencing (NGS) with a custom panel of 46 candidate genes. Variant interpretation followed ACMG standards and guidelines. Multiple tools were used to predict the structural effects of variants on tertiary protein structure, assessing their pathogenicity. Novel variants were functionally characterized by qRT-PCR on mRNA extracted from peripheral leukocytes. NGS identified nine rare variants and four novel variants in genes previously associated with normosmic isolated HH (nHH) and/or KS (FGFR1, PROK2, TAC3R, DCC, WDR11, IL17RD, DUSP6, KAL1, FGF8, IL17RD and DCC). The variant in TAC3R (p.Trp275Ter) was pathogenic; variants in ANOS1 (c.541+1G>A), IL17RD (c.1303_1304dup, p.Lys436ThrfsTer58), and TAC3R (p.Lys361Ter) were likely pathogenic. Nine variants were classified as variants of uncertain significance (VUS). Our study identified a possible genetic cause in 71% of the CHH/KS cohort, emphasizing the importance of genetic screening and functional characterization of genetic variants in patients with a phenotypically and genetically heterogeneous disorder like CHH. Full article

Although the roles of proteoglycans (PGs) have been well documented in the development and homeostasis of the temporomandibular joint (TMJ), how the glycosaminoglycan (GAG) chains of PGs contribute to TMJ chondrogenesis and osteogenesis still requires explication. In this study, we found that FAM20B, a hexokinase essential for attaching GAG chains to the core proteins of PGs, was robustly activated in the condylar mesenchyme during TMJ development. The inactivation of Fam20b in craniofacial neural crest cells (CNCCs) dramatically reduced the synthesis and accumulation of GAG chains rather than core proteins in the condylar cartilage, which resulted in a hypoplastic condylar cartilage by severely promoting chondrocyte hypertrophy and perichondral ossification. In the condyles of Wnt1-Cre;Fam20b^f/f mouse embryos, enlarged Ihh- and COL10-expressing domains indicated premature hypertrophy resulting from an attenuated IHH-PTHRP negative feedback in condylar chondrocytes, while increased osteogenic markers, canonical Wnt activity, and type-H angiogenesis verified the enhanced osteogenesis in the perichondrium. Further ex vivo investigations revealed that the loss of Fam20b decreased the domain area but increased the activity of HH signaling in the embryonic condylar mesenchyme. Moreover, the abrogation of GAG chains in heparan sulfate and chondroitin sulfate proteoglycans led to a rapid up- and then downregulation of HH signaling in condylar chondrocytes, implicating a “slow-release” manner of growth factors controlled by GAG chains. Overall, this study revealed a comprehensive role of the FAM20B-catalyzed GAG chain synthesis in the chondrogenic and osteogenic differentiation of the embryonic TMJ condyle. Full article

Rare diseases (RDs) often have a genetic basis, yet conventional diagnostic techniques fail to identify causative genetic variations in up to 50% of cases. Structural variants (SVs), including balanced rearrangements, frequently evade detection by karyotyping, microarray, and exome sequencing. The present study utilized optical genome mapping (OGM) to investigate two patients with RDs whose genetic etiology remained unresolved despite prior genomic analyses. Patient 1 exhibited a balanced reciprocal translocation disrupting the BCL11A gene, associated with Dias-Logan syndrome. Patient 2 had a mosaic 682 kb deletion near the IHH gene, causing ectopic enhancer–promoter interactions and polydactyly, mirroring phenotypes observed in mouse models and similar human cases. These findings highlight OGM’s efficacy in identifying complex SVs and underline novel pathogenic mechanisms in rare genetic disorders. Consequently, the incorporation of OGM into routine diagnostic procedures will enhance genetic diagnosis, discover new syndromes of currently unknown cause, and eventually improve the clinical management of numerous patients with rare diseases. Full article

The hedgehog (Hh) signalling pathway plays a key role in both embryonic and postnatal development of the intestine and is responsible for gut homeostasis. It regulates stem cell renewal, formation of the villous–crypt axis, differentiation of goblet and Paneth cells, the cell cycle, apoptosis, development of gut innervation, and lipid metabolism. Ligands of the Hh pathway, i.e., Indian hedgehog (Ihh) and Sonic hedgehog (Shh), are expressed by superficial enterocytes but act in the mesenchyme, where they are bound by a Patched receptor localised on myofibroblasts and smooth muscle cells. This activates a cascade leading to the transcription of target genes, including those encoding G1/S-specific cyclin-D2 and -E1, B-cell lymphoma 2, fibroblast growth factor 4, and bone morphogenetic protein 4. The Hh pathway is tightly connected to Wnt signalling. Ihh is the major ligand in the Hh pathway. Its activation inhibits proliferation, while its blocking induces hyperproliferation and triggers a wound-healing response. Thus, Ihh is a negative feedback regulator of cell proliferation. There are data indicating that diet composition may affect the expression of the Hh pathway genes and proteins, which in turn, induces changes in mucosal architecture. This was shown for fat, vitamin A, haem, berberine, and ovotransferrin. The Hh signalling is also affected by the intestinal microbiota, which affects the intestinal barrier integrity. This review highlights the critical importance of the Hh pathway in shaping the intestinal mucosa and summarises the results obtained so far in research on the effect of dietary constituents on the activity of this pathway. Full article

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is increasing throughout the world. Nevertheless, no specific diagnostic or even risk assessment marker is available. Combining more than one marker can improve the diagnostic value of each marker alone and maximize the AUC for ROC curve. Hedgehog (Hh) signaling modulates both intestinal inflammation and immunity. Cyclooxygenase-2 (COX-2) is required for inflammation, and it has been related to epileptic seizures. COX-2 generates prostaglandins-EP2 (PGE2) in the brain, which plays a major role in neuropathology and epilepsy. This study aims to understand the pathophysiology of ASD by investigating the diagnostic value of COX-2 and IHh using independent and combined ROC curves. Methods: COX-2 and IHh were measured in 40 children with ASD and 41 age and sex-matched controls using ELISA. Statistical analyses were performed using ROC curves, odds ratios, and multiple logistic regression models. Results: Higher levels of COX-2 and IHh were observed in the plasma of patients with autism than in controls. The ROC curve of HIh and COX-2 independently showed poor and fair AUCs of 0.662 and 0.776, respectively, while the combined ROC for both variables in relation to the control group increased the AUC = 0.831 significantly (p < 0.001). Conclusions: Thus, combining these variables could be a useful diagnostic marker for ASD. Full article

This study assesses the relative performance of Sentinel-1 and -2 and their combination with topographic information for plow agricultural land soil salinity mapping. A learning database made of 255 soil samples’ electrical conductivity (EC) along with corresponding radar (R), optical (O), and topographic (T) information derived from Sentinel-2 (S2), Sentinel-1 (S1), and the SRTM digital elevation model, respectively, was used to train four machine learning models (Decision tree—DT, Random Forest—RF, Gradient Boosting—GB, Extreme Gradient Boosting—XGB). Each model was separately trained/validated for four scenarios based on four combinations of R, O, and T (R, O, R+O, R+O+T), with and without feature selection. The Recursive Feature Elimination with k-fold cross validation (RFEcv 10-fold) and the Variance Inflation Factor (VIF) were used for the feature selection process to minimize multicollinearity by selecting the most relevant features. The most reliable salinity estimates are obtained for the R+O+T scenario, considering the feature selection process, with R² of 0.73, 0.74, 0.75, and 0.76 for DT, GB, RF, and XGB, respectively. Conversely, models based on R information led to unreliable soil salinity estimates due to the saturation of the C-band signal in plowed lands. Full article