Search Results (2,999)

Cadmium (Cd) is a toxic metal that poses a significant threat to crop production and global food security. Transporters play a critical role in mediating the uptake of metal ions, including Cd. However, a substantial number of Cd transporters in rice remain uncharacterized. In this study, we identify OsMDR4, a member of the multidrug resistance protein family, as a mediator of Cd uptake in rice. Heterologous overexpression of OsMDR4 in yeast increased both Cd sensitivity and intracellular Cd accumulation. Consistent with this, the Cd concentrations in both roots and shoots of the mdr4 mutants were significantly lower than those in wild type. Kinetic analysis further revealed that the maximum Cd uptake rate in mdr4 mutants was markedly reduced compared with wild type. Expression analysis showed that OsMDR4 is primarily expressed in the epidermis and root hairs of rice seedlings and in floral organs during the flowering stage. Notably, OsMDR4 expression in seedling roots was upregulated in response to Cd exposure. Subcellular localization analysis revealed that OsMDR4–EGFP was predominantly localized to the plasma membrane in a heterologous Arabidopsis protoplast system. In summary, we have identified and characterized OsMDR4 as a previously uncharacterized protein that contributes to cadmium accumulation in rice. Full article

Nanostructured drug-delivery materials—liposomes, polymeric nanoparticles, dendrimers, and inorganic carriers—have become central to pharmaceutical strategies for crossing the blood–brain barrier (BBB), where most candidate therapeutics fail to reach their targets. Their biological performance hinges on a coupled chain of vascular transport, BBB translocation, tissue diffusion, cellular uptake, and intracellular release, each of which is shaped by the nanocarrier’s size, surface chemistry, charge, and ligand functionalization. Physiologically based pharmacokinetic (PBPK) models describe this chain mechanistically but are limited by parameter uncertainty, simplified representations of the BBB, and coarse regional resolution. Machine learning (ML) can close these gaps by extracting nonlinear structure–transport–exposure relationships from heterogeneous experimental and clinical datasets. This review examines emerging ML–PBPK hybrid frameworks for predicting the brain biodistribution of nanostructured drug carriers. We compare regression, kernel, and deep learning approaches for parameter inference, model correction, and surrogate modeling; assess strategies for feature selection, uncertainty quantification, and interpretability; and discuss documented failure cases that bound the conditions under which these methods can be trusted. The review closes with recommendations on dataset standardization, software platform selection, and the responsible use of generative AI in pharmaceutical modeling, thus providing guidance for translating nanostructured material design into safer, more effective brain-targeted therapies. Full article

Hydrogen (H₂) is expected to play a critical role in modern industry, particularly in ammonia synthesis, petroleum refining, and low-carbon transportation. The safe storage of H₂ remains a major challenge due to its low volumetric density under ambient conditions. Metal–Organic Frameworks (MOFs), highly porous crystalline materials, have emerged as promising H₂ storage candidates owing to their high surface areas and tuneable pore structures. Molecular simulations such as grand canonical Monte Carlo or density functional theory are costly and limited in exploring large material spaces, motivating efficient predictive tools to accelerate discovery. Here, Machine Learning (ML) techniques are compared to an explainable artificial intelligence (XAI) approach using symbolic regression (SR), trained on 10,123 experimentally measured H₂ adsorption datapoints from real-world MOFs. The best performing model achieved a goodness of fit of 0.9986 with lower computational demand, but reduced interpretability, addressed using XAI analysis and clustering. SR achieves a lower goodness of fit of 0.914 but produces a physically meaningful equation highlighting structural features driving high gravimetric efficiencies. These results demonstrate strong ML capability for predicting how MOF properties and environmental conditions affect H₂ uptake. This offers engineers and researchers a practical means of screening potential MOFs for H₂ storage applications, with the XAI analyses providing additional confidence in the predictions. They allow researchers to understand the physical reasoning behind each output, assess the reliability of individual predictions, and make fully informed decisions, enabling predictive models to be acted upon with confidence in real-world contexts. Full article

Milk-derived extracellular vesicles (EVs) transport microRNAs (miRNAs) that are unusually stable and have been proposed to survive digestion and modulate gene expression in the consumer, although their dietary bioavailability and physiological relevance remain debated. How the predicted regulatory potential of these miRNAs differs among the milks of different animals most relevant to human nutrition has not been systematically compared. Here, we performed an integrative in silico analysis of publicly available small-RNA sequencing data from 29 milk and milk-cell samples of human, cow, goat, and donkey origin. miRNAs were quantified against human (hsa) miRBase references—thereby restricting the analysis to evolutionarily conserved miRNAs with human orthologs—and their predicted effect on the human transcriptome was modeled by integrating predicted (mirDIP database) and experimentally supported (TarBase v9 database) miRNA–target interactions into a per-gene, per-species weighted targeting score. Because miRNAs act predominantly as repressors, this score is read as a prediction of which genes would be post-transcriptionally down-regulated in a recipient. miR-148a-3p dominated the exosomal spectrum of all four species (human, cow, goat, and donkey; ≈21.5% of pooled abundance), and the twenty most abundant miRNAs accounted for roughly three quarters of the signal. Of 4577 robustly targeted genes, a 1809-gene conserved “pan-milk” core showed the highest cross-species targeting and was enriched for transcriptional regulation, PI3K–Akt, MAPK, and TGF-β/SMAD signaling, autophagy and—strikingly—the components of the RNA-interference machinery itself. Species-restricted gene sets recapitulated biologically plausible programs, including a human-biased neuronal/axon-guidance and chromatin module, a donkey-biased transcriptional, epithelial, and immune (CD47) module, and a ruminant lipid/cholesterol and insulin–mTOR module. Across categories, we observed a reproducible confidence–exclusivity trade-off. We emphasize that these results are computational predictions that assume dietary miRNA uptake and do not constitute experimental validation. We provide the complete targetome as a hypothesis-generating resource to prioritize candidate genes, pathways, and milk types for future functional, nutritional, and epigenetic investigation. Across the 29 samples from the four species, miRNA composition segregated by species (silhouette width = 0.82, a cluster-separation measure ranging from −1 to 1, with values near 1 indicating well-separated groups) and the category structure exceeded a permutation null, indicating that the between-species signal is robust to differences in dataset origin and milk state. Full article

The tiller number of perennial grasses responds strongly to soil nitrogen availability, and critically governs aboveground biomass production. Plant NRT2 proteins are major components of the high-affinity nitrate transport system, and contribute to nitrate uptake and distribution, with gene-specific functions depending on tissue context, interacting partners, and nitrogen availability. However, few studies have explored the function of the NRT2 proteins in Leymus chinensis. In this study, 28 LcNRT2 genes were first identified in the L. chinensis genome. Phylogenetic analysis indicated that the 28 LcNRT2 genes were classified into four distinct clades. Gene structure analysis demonstrated that 82.1% of LcNRT2 genes were characterized by a lack of introns. While, 17.9% possessed only a single intron. Chromosomal localization indicated that 28 LcNRT2 genes were distributed on 8 of 14 chromosomes of L. chinensis. No LcNRT2 genes were identified on chromosomes 1Ns, 2Ns, 2Xm, 4Ns, 5Ns, and 5Xm. Six LcNRT2 genes were isolated from the nitrogen-induced transcriptome dataset of L. chinensis and exhibited significantly upregulated expression. LcNRT2.21 was significantly upregulated under nitrogen treatment, and was, therefore, studied in more detail. The heterologous overexpression of LcNRT2.21 in rice increased tiller number, decreased plant height, and altered the expression of tillering-related genes OsTB1, OsMOC1, OsYUCCA4 and OsAUX1. These results demonstrated that LcNRT2.21 may play a vital role in improving tiller numbers in plants. Full article

Aquaponic systems couple fish and plant production in recirculating loops, yet quantitatively assessed dynamic models for engineering analysis, scale-up, and operation under realistic conditions remain limited. Here, a modular process-based MATLAB R2026a framework is developed for the recirculating aquaponic system operated at the ASTREDHOR facility (France). The model links hydraulic transport with fish metabolism, nitrification, solids removal, and plant nitrate uptake, using monitoring-derived boundary conditions for temperature, dissolved oxygen, pH, and electrical conductivity. The fish-growth component was calibrated and evaluated against archived, temporally reconstructed biomass trajectories derived from campaign-based biometrics in three production cycles with different fish compositions and environmental regimes. Tank-wise $R^2$ values were 0.865–0.952 in the calibration windows and 0.700–0.921 in the fixed-parameter prediction windows, with prediction-period NRMSE values of 0.64–3.91%. These descriptive metrics quantify agreement on the reconstructed evaluation grid rather than performance over independently retained biometric sampling occasions. Complete corresponding time series were unavailable for TAN, NO${}_2^{-}$, NO${}_3^{-}$, total suspended solids, and plant uptake; these simulated outputs were therefore used only for mechanistic consistency assessment and exploratory scenario analysis, rather than independent validation. Local sensitivity analysis showed limited effects of temperature sensitivity (${\alpha }_T$), optimal temperature ($T_{opt}$), and minimum dissolved oxygen ($D{O}_{min}$) under observed conditions, whereas the feeding ratio ($TR$) and metabolic scaling exponent (n) strongly influenced simulated fish growth and nitrogen loading. Parametric sweeps provided preliminary, model-derived indications of feeding and biofilter-sizing limits under intensified loading; these thresholds require confirmation against independent water-quality measurements. The resulting framework is positioned as an off-line digital shadow with a fish-growth component assessed against reconstructed biomass trajectories and exploratory water-quality simulations. Full article

Iron (Fe) is an essential micronutrient for plant growth, serving as a cofactor in chlorophyll synthesis, photosynthetic electron transport, and redox reactions. Both Fe deficiency and excess disrupt mineral nutrient homeostasis, but the ionomic and transcriptomic mechanisms underlying genotype-specific responses in potato remain elusive. We profiled the ionome and transcriptome of two potato genotypes, 05P and CI5, grown under Fe-deficient, Fe-sufficient and Fe-excess conditions represented by 1, 40.4 and 120 mg L⁻¹ FeNaEDTA, respectively. Ionomic analysis detected significant alterations in Fe, Mn, Zn, Ca, Mg, and Cu concentrations across roots, stems, and leaves, with the direction and magnitude of change varying by organ and genotype. Under Fe deficiency, CI5 showed steeper declines in root and stem Fe than 05P, while 05P retained higher leaf Fe, reflecting genotype-dependent patterns of shoot Fe distribution. Fe excess caused Fe accumulation in both genotypes, but coincided with Mn depletion in shoots, raising Fe/Mn ratios, consistent with potential antagonistic Fe–Mn interactions at the transport level. This pattern is consistent with potential antagonistic Fe–Mn interactions, although alternative mechanisms such as Mn uptake inhibition or dilution effects cannot be ruled out without direct experimental evidence. Transcriptome analysis showed organ-biased responses: Fe deficiency upregulated more genes in stems, whereas Fe excess triggered stronger transcriptional shifts in roots. No KEGG pathways remained significant after false discovery rate (FDR) correction, suggesting that genotype-dependent Fe-responsive divergence was not concentrated in a limited number of canonical KEGG pathways under the present analytical framework. Joint analysis of ionomic and transcriptomic data highlighted ferric-chelate reductase oxidase (FRO) and zinc-regulated transporter/iron-regulated transporter-like protein (IRT/ZIP) family members as genes associated with Fe reduction, divalent metal uptake, and Fe–Mn balance based on differential expression and orthology with functionally characterized Arabidopsis homologs. Comparative genomics showed that FRO and ZIP families have expanded in potato, with conserved domain architectures but divergent gene structures and promoter architectures, consistent with potential functional diversification related to metal transport. In conclusion, under Fe deficiency, genotype-dependent transcriptional divergence was most pronounced in stems, whereas under Fe excess it was more evident in roots, jointly maintaining systemic Fe–Mn homeostasis in potato. Full article

The clinical translation of nucleic acids is severely hindered by multiple delivery barriers, such as enzymatic degradation, poor cellular uptake, endosomal entrapment, and rapid systemic clearance. Despite the remarkable therapeutic potential of these agents, conventional delivery systems often fail to address these challenges. Lipid nanoparticles (LNPs) have emerged as a versatile platform to overcome these obstacles, offering tunable physicochemical properties, high encapsulation efficiency, and pH-responsive endosomal escape. This review summarizes recent advances in LNP-based respiratory and gastrointestinal mucosal delivery of nucleic acids, with emphasis on formulation strategies for overcoming mucus and epithelial barriers. To overcome mucosal barriers, LNP studies have shown that keeping particle size below the local mucus mesh size (~100 nm), tuning surface charge toward near-neutrality via pH-responsive ionizable lipids, and maintaining a neutral, deformable, moderately PEGylated surface during the mucin transport stage can increase transmucosal diffusivity several-fold over conventional cationic LNPs. We further discuss current limitations and propose future directions, emphasizing the need for the integration of the pathological and physiological characteristics of specific mucosa with artificial intelligence (AI) platforms to develop intelligent and personalized delivery platforms with “spatiotemporal adaptive” capabilities. Full article

Resveratrol (RES) is a natural polyphenolic compound characterized by poor aqueous solubility and significant first-pass metabolism, resulting in extremely low oral bioavailability. Although resveratrol-loaded nanostructured lipid carriers (RES-NLCs) have shown potential in enhancing oral absorption, direct experimental evidence for their intestinal lymphatic transport mechanism remains limited, and existing explanations is largely based on indirect inference. RES-NLCs were prepared, and their pharmacokinetics and lymphatic transport characteristics were evaluated using a laboratory-established mesenteric lymph duct–jugular vein assisted reflux model in rats. Simultaneously, a 28-day repeated-dose toxicity study was conducted in ICR mice. Pharmacokinetic results showed that compared with RES-Sol, RES-NLCs increased Cmax by approximately 2.3-fold, improved relative bioavailability by 7-fold, and achieved an absolute bioavailability of 176%. The lymphatic transport model confirmed that RES-NLCs are absorbed via the intestinal lymphatic pathway. In the 28-day repeated-dose toxicity study, no mortality or obvious clinical symptoms were observed at a dose of 10 mg/kg. The RES-NLCs group exhibited increased liver coefficient and decreased spleen coefficient. Hematological analysis showed a mild increase in red blood cell count, along with decreases in mean corpuscular volume and red blood cell distribution width coefficient of variation. Serum biochemistry revealed significant elevations in aspartate aminotransferase and alanine aminotransferase (p = 9 × 10⁻⁵ and p = 4.02 × 10⁻⁷, respectively). However, no significant differences were observed in the organ coefficients of the heart, lungs, kidneys, or brain. Body composition and magnetic resonance imaging showed no abnormalities, and histopathological examination of major organs including the liver, stomach, and intestines revealed no structural damage. These findings provide direct evidence that RES-NLCs enhance the oral bioavailability by promoting intestinal lymphatic uptake, suggesting that this system may serve as an effective delivery platform for poorly soluble hydrophobic drugs. Full article

Background/Objectives: Phenotypic drug tolerance, distinct from genetic resistance, allows Mycobacterium tuberculosis (Mtb) to survive prolonged antibiotic exposure and contributes to treatment failure and relapse. The trehalose recycling pathway, mediated by the LpqY-SugABC transporter, has been implicated as a metabolic “escape” mechanism that sustains Mtb viability under antibiotic and nutrient-limiting stress, making it an attractive target for adjunctive, tolerance-breaking therapeutics. Methods and Results: Here, we conducted a high-throughput phenotypic screen of 50,000 compounds from chemically diverse libraries, using a carbon source-restricted assay that forces Mtb to rely on trehalose uptake for growth, to identify small-molecule inhibitors of this pathway. This approach yielded 23 confirmed hits in Mtb, spanning several chemical scaffolds, including thioureas, propanamides, benzamides, and carboxamides. Using an isogenic set of Mtb wild-type, LpqY-SugABC transposon knockout, and complemented strains, we confirmed that the genetic loss of transporter loss reproduces accelerated killing by isoniazid, rifampicin, and bedaquiline, but not moxifloxacin, and that loss of trehalose recycling sensitizes mycobacteria to oxidative stress. Using orthogonal functional assays, fluorescent trehalose probe (FITC-tre) uptake inhibition and H₂O₂ hypersensitization, thiourea-containing compounds emerged as the candidates most consistent with transporter-specific activity, phenocopying the effects of genetic LpqY-SugABC loss, while biochemical assays against recombinant trehalase (Rv2402) excluded downstream enzymatic inhibition as their mechanism of action. In addition, several hits potentiated rifampicin-mediated killing of intracellular Mtb in THP-1 macrophages, in some cases reducing bacterial burden below levels achieved by monotherapy. Conclusions: These findings indicate that the trehalose recycling pathway is functionally druggable by small molecules identified through unbiased phenotypic screening and nominate thiourea- and propanamide-based scaffolds as priority candidates for further mechanistic characterization, including direct target-engagement studies, and optimization as adjunctive anti-tuberculosis agents targeting drug-tolerant Mtb populations. Full article

Respiratory diseases impose a substantial global burden; however, early diagnosis, disease-activity monitoring, and the clinical translation of nucleic acid therapeutics are constrained by the lack of robust biomarkers and efficient delivery systems. This narrative review focuses on four classes of RNA—messenger RNA (mRNA), circular RNA (circRNA), small interfering RNA (siRNA), and microRNA (miRNA)—using exosomes as a representative subtype of extracellular vesicles (EVs) to discuss EV biogenesis, transport, uptake, and engineered cargo loading. We summarize the diagnostic and therapeutic applications of EV-associated nucleic acids in chronic or non-severe respiratory diseases, including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis, as well as in severe acute conditions such as acute respiratory distress syndrome and severe pneumonia. Biofluid-derived EV-associated RNAs can reflect inflammation, immune dysregulation, epithelial injury, infection, and fibrosis, supporting their potential use in disease classification, monitoring, and prognostic assessment. Natural EVs may modulate inflammation and tissue repair through their endogenous cargo, while engineered EVs can deliver therapeutic nucleic acids to exert anti-inflammatory, anti-infective, antifibrotic, and barrier-restorative effects. However, clinical translation is limited by non-standardized isolation and characterization methods, product heterogeneity, variable cargo loading, and insufficient stability and quality-control frameworks. Continued advances in EV isolation, characterization, nucleic acid loading, potency assessment, and manufacturing control are required to realize the diagnostic and therapeutic potential of EV-associated nucleic acids in respiratory diseases. Full article

The increasing use of cerium oxide nanoparticles (CeO₂-NPs) has raised concerns regarding their environmental fate and biological effects in soil–plant systems. This review uses cerium oxide nanoparticles (CeO₂-NPs) as a mechanistically well-characterized case study to examine relationships among dose, chemical speciation, and plant responses, with emphasis on Ce³⁺/Ce⁴⁺ redox cycling and condition-dependent, nanozyme-like activity. We discuss how particle size, surface charge, Ce³⁺/Ce⁴⁺ ratio, and coating interact with rhizosphere processes, including organic acid complexation, phosphate-mediated CePO₄ immobilization, and potentially microbially mediated transformation, to influence effective root-surface exposure. The resulting particulate, ionic, and secondary transformation-product pools affect root uptake, vascular transport, redox homeostasis, metabolism, and hormone-associated signaling. Major limitations include weak causal links between rhizosphere speciation and bioavailability, insufficient separation of particulate and ionic contributions, limited integration of multi-omics with speciation data, and uncertain extrapolation from hydroponic to soil systems. Standardized exposure protocols, integrated XANES, spICP-MS, and imaging workflows, and long-term soil studies are therefore required. Other rare-earth nanomaterials are discussed only briefly to define the material-specific boundaries of the CeO₂-centered framework. Full article

Oxidative stress is a central driver of atherosclerosis progression, promoting lipid peroxidation, vascular inflammation, and hepatic metabolic dysfunction. Forchlorfenuron (KT-30), a cytokinin-like plant growth regulator widely used on fruits such as kiwifruit, grapes, and watermelon, has been reported to elevate serum cholesterol levels, suggesting potential atherogenic effects. However, whether KT-30 induces oxidative stress and accelerates atherosclerosis remains unknown. Here, apolipoprotein E-deficient (apoE^−/−) mice were orally administered KT-30 (5 mg/kg/day) for four weeks. KT-30 significantly accelerated atherosclerotic lesion formation, elevated plasma cholesterol levels, upregulated scavenger receptors SR-A and CD36, and downregulated ABCA1 and LXRα, indicating impaired reverse cholesterol transport and enhanced foam cell formation. KT-30 also increased pro-inflammatory cytokines (IL-1β, IL-6, MIP-2) and aortic expression of F4/80 and VCAM-1. Critically, KT-30 exposure was associated with elevated oxidative stress markers, as evidenced by elevated plasma MDA levels, increased aortic 4-HNE immunostaining, and upregulation of NOX-1/4. In the liver, KT-30 induced lipid accumulation, characterized by elevated cholesterol and free fatty acids, accompanied by SREBP-1/2-driven de novo lipogenesis and impaired lipoprotein uptake. Proteomic analysis revealed significant alterations in mitochondrial oxidative phosphorylation- and sirtuin signaling-related protein expression. Taken together, KT-30-associated oxidative stress, accompanied by upregulation of NOX-1/4 and alterations in mitochondrial pathway-related protein expression, may represent an important mechanistic link between lipid homeostasis disruption and accelerated atherosclerosis in apoE^−/− mice, highlighting the potential pro-atherogenic effects of KT-30 in a susceptible experimental model and providing mechanistic evidence that warrants further investigation of its possible cardiovascular implications. Full article

The HAK/KUP/KT family represents a major group of plant potassium transporters involved in K⁺ uptake, ion homeostasis and stress responses. However, the accession-level diversity of HAK/KUP/KT genes in Brassica napus remains insufficiently characterized. In this study, we performed a pan-family analysis of HAK/KUP/KT genes across eight B. napus accessions. A total of 269 annotated HAK/KUP/KT family members were identified and classified into core, soft-core, dispensable and private orthogroups based on their representation across the analyzed genome annotations. Phylogenetic analysis grouped these proteins into four major clades together with reference HAK/KUP/KT members from Arabidopsis thaliana and rice. Ka/Ks analysis indicated that HAK/KUP/KT orthogroups were predominantly under purifying selection, while accession-variable orthogroups showed greater variation in sequence conservation. Gene structure, conserved domain, motif and predicted promoter cis-element analyses revealed conserved transporter-related protein features together with orthogroup-level structural and sequence variation. Expression profiling using the ZS11 BnIR dataset further revealed tissue-, hormone- and stress-responsive expression patterns among ZS11 HAK/KUP/KT genes. By integrating expression features, predicted promoter information, evolutionary characteristics, published salt GWAS context and BnVIR haplotype–phenotype information, BnaA08T0085800ZS was prioritized as a candidate locus located near salt-associated variation. This study provides a pan-genome perspective on HAK/KUP/KT family diversity in B. napus and establishes a framework for prioritizing candidate genes for future functional investigation. Full article

Imperatorin (IPT) is a naturally occurring coumarin with recognized antioxidant and anti-aging properties; unfortunately, its poor water solubility and low oral bioavailability severely limit its practical use. To get around these issues, we formulated IPT-loaded NLCs using grape seed oil and glyceryl monostearate—both food-grade excipients—with the goal of enhancing oral absorption. Optimized IPT@NLCs were prepared by high-pressure homogenization, featuring uniform spherical morphology, an average particle size of 186.63 ± 1.65 nm, a PDI of 0.188 ± 0.008, an encapsulation efficiency of 99.54 ± 0.10%, and a drug loading capacity of 9.08 ± 0.23%. IPT@NLCs remained stable in SGF, while their cumulative in vitro release over 48 h reached 90.56 ± 3.12% in SIF. We established a Caco-2/HT29-MTX-E12 co-culture monolayer to examine mucus penetration, cellular uptake, and transcellular transport routes. In parallel, oxidative stress experiments using 3T3-L1 cells, along with in vivo pharmacokinetic and gastrointestinal safety evaluations, were conducted to provide complementary evidence. Our results indicate that NLC encapsulation significantly improves both the dissolution and intestinal uptake of IPT, primarily by shifting the absorption mechanism from passive diffusion to energy-dependent active transport. In addition, IPT@NLCs effectively reduce intracellular oxidative damage through modulation of endogenous antioxidant enzyme activities. Animal studies further reveal an approximately 9-fold increase in relative oral bioavailability, with no notable irritation to gastrointestinal tissues. Overall, GSO-based NLCs offer safe and efficient oral delivery, enhancing IPT bioavailability and antioxidant activity, providing a strategy for developing natural-product-based formulations. Full article