Search Results (1,859)

Background: Joubert syndrome (JS) is a genetically heterogeneous ciliopathy wherein non-canonical splice-site (NCSS) variants are frequently reported as variants of uncertain significance (VUS), complicating prenatal counseling. We aimed to clarify the clinical significance of an NCSS in CC2D2A through functional validation. Methods: Trio-WES was performed on a 13-year-old female proband with clinically diagnosed JS. Candidate variants were validated by Sanger sequencing and familial segregation. An in vitro minigene assay and RT-PCR on patient peripheral blood RNA were used to assess the splicing effect of c.439-5T>G. Variant classification followed the ACMG/AMP guidelines using the ClinGen quantitative Bayesian framework. Results: Compound heterozygous CC2D2A variants were identified: c.439-5T>G (maternal) and c.4732G>A (p.(Val1578Met), paternal); both were initially classified as VUS. Minigene analysis showed that c.439-5T>G caused aberrant splicing, retaining the intronic nucleotides c.439-4_439-1 (ATAG) at the exon 6–7 junction (r.438_439insauag) and introducing a frameshift and premature termination (p.(Pro147IlefsTer14)). Patient RNA confirmed this pattern. c.439-5T>G was reclassified as likely pathogenic (PVS1_VeryStrong + PM2_Supporting). c.4732G>A remained a VUS (PM3 + PM2_Supporting + PP3) on an independent allele basis; its trans configuration with the likely pathogenic allele supported a family-specific biallelic explanation but did not establish the pathogenicity of the missense allele. The fetus in a subsequent pregnancy was confirmed to carry both variants, establishing the compound heterozygous state. Conclusions: Minigene-based validation provided evidence to reclassify a CC2D2A NCSS from VUS to likely pathogenic, enabling variant-directed prenatal testing and informed reproductive counseling in this JS family. The paternal missense variant c.4732G>A (p.(Val1578Met)) remains a VUS; its trans configuration with the likely pathogenic allele supports, but does not establish, a biallelic explanation. This study illustrates how functional assays can clarify splicing variants that in silico predictions alone cannot reliably interpret. Full article

Litchi (Litchi chinensis Sonn.), an important fruit in south China, rapidly loses commercial value within 3–4 days at ambient temperatures due to poor storability. Previous studies have shown that 5 mg L⁻¹ CPPU (N-(2-chloro-4-pyridyl)-N′-phenylurea) application can improve postharvest storage of litchi fruit. In this study, we investigated the improved storability of litchi fruit by CPPU application from the perspectives of fruit maturity and seed vigor. Litchi fruit on the tree were treated with CPPU 2 weeks before commercial maturation. Fourteen days after CPPU application, the treated fruit exhibited 61% higher pericarp chlorophyll, 22% thicker pericarp and 76% lower anthocyanin concentrations than untreated controls, which indicates delayed on-tree fruit maturation. CPPU also remodeled the endogenous hormone profiles in the pericarp and seeds, elevating pericarp IAA and DHZR by 47% and 90%, representing active auxin and cytokinin forms, respectively. During the 12 days of ambient storage of the treated preharvest fruit, CPPU-treated fruit showed reduced pericarp browning, disease incidence, and electrolyte leakage, while maintaining a 72% marketable fruit rate against the control’s 25% and higher antioxidant enzyme (APX) activity, indicating an increase in fruit storability when compared to the control. Moreover, CPPU suppressed the upregulation of eight senescence-related genes, including LcLOX1.5-1, LcLOX1.5-2, and LcRNase3. Notably, seed vigor of the litchi fruit decreased with the progress of storage, while the CPPU treatment maintained higher seed vigor compared to the control. These results suggest that the enhanced litchi fruit storability by preharvest CPPU application may be linked to recalcitrant seed vigor maintenance, hormone profile modulation, and pericarp senescence delay. Full article

Subtropical bamboo forests are important carbon sinks, yet long-term regional assessments of their net ecosystem production (NEP) and associated factor contributions remain scarce. Here, using approximately 646 km² of mapped Moso bamboo (Phyllostachys pubescens) in Anji County, China, we generated a monthly NEP reconstruction on a 500 m output grid for 2003–2022 by integrating eddy covariance observations, meteorological data, and multi-source remote sensing products within an automated machine learning framework. Bamboo NEP showed weak overall spatial heterogeneity but followed a clear unimodal elevational pattern, with the highest carbon sequestration at mid-elevations (342–550 m). Regional carbon uptake peaked in summer and reached a minimum in winter, consistent with bamboo phenology. Annual mean NEP was 0.43 Tg C yr⁻¹ and increased significantly over the study period (3.35 Gg C yr⁻², p < 0.001), with 95.8% of bamboo pixels exhibiting upward trends. Negative modeled anomalies coincided with drought years, whereas the biennial growth cycle of Moso bamboo had little effect on annual NEP at the regional scale. SHapley Additive exPlanations (SHAP) shows that long-term NEP enhancement was dominated by canopy vegetation indices and exhibited a descriptive transition around 2013, when the leading control changed from solar radiation to vegetation conditions. Structural equation modeling (SEM) further showed statistical pathways in which meteorological variables were associated with modeled NEP partly through vegetation indicators. These findings reveal a sustained strengthening of the regional bamboo carbon sink and identify shifting controls on its long-term variability, providing a scientific basis for carbon sink management in subtropical bamboo forests under climate change. Full article

Background/Objectives: Neural infiltration closely correlates with the progression and poor prognosis of gastrointestinal tumors. The vagus nerve regulates tumor cell proliferation and invasion through acetylcholine (ACh). Combining targeted neurotherapy with chemotherapy has recently emerged as a promising anticancer strategy. Methods: In this study, we designed a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) that co-delivers 5-fluorouracil (5-FU) and atropine (a vagal nerve blocker) for local gastric cancer chemotherapy. A key feature of this 5-FU + atropine/PLEL hydrogel system is its sol–gel phase transition in response to physiological temperature, enabling sustained drug release in vivo. Results: After intraperitoneal injection, this dual-drug-loaded hydrogel significantly reduced tumor growth in gastric cancer models, outperforming single-drug-loaded hydrogels and free 5-FU plus atropine combinations. This delivery system also reduced side effects. Conclusions: Therefore, this innovative dual-drug-loaded hydrogel shows strong potential for intratumoral gastric cancer chemotherapy and offers a clinically valuable option for postoperative management. Full article

Offshore wind power substations serve as fixed bases for unmanned aerial vehicle logistics distribution. In the mixed-fleet scheduling of multiple unmanned aerial vehicle types, parking spot allocation, configuration decisions, and transfer timing are deeply coupled, rendering traditional scheduling algorithms ineffective for efficient solution. To address this, this paper takes the context of substations performing material delivery and inspection missions to surrounding wind turbines, maintenance vessels, and other offshore facilities. An optimization model is constructed that comprehensively considers group priority, aircraft type differentiation, and configuration transition factors, with objectives of minimizing total transfer time, number of configuration changes, and workload variance among transfer crews. An event-driven configurable greedy initial solution generation strategy is introduced, and an adaptive large neighborhood search algorithm is designed, incorporating domain-knowledge-driven destruction and repair operators, an adaptive weight mechanism, and a simulated annealing acceptance criterion. Experimental results demonstrate that the proposed algorithm achieves the optimal mean objective values across all six test cases, outperforming the conventional adaptive large neighborhood search algorithm by 7.0–7.9% and the genetic algorithm by 14.4–22.1%, while maintaining the lowest standard deviation. The algorithm exhibits robust stability and practical applicability, providing effective decision support for unmanned aerial vehicle logistics distribution scheduling at offshore wind power substations. Full article

The U-box proteins (PUBs), as a prominent family of E3 ubiquitin ligases, have been reported to participate in diverse physiological processes, such as plant development, growth regulation, and adaptation to abiotic and biotic stresses. Nevertheless, a comprehensive genome-wide survey and functional investigation of the U-box family in melon remain limited. In this study, a total of 50 CmPUB genes harboring the U-box domain were identified and distributed across the 12 melon chromosomes. Phylogenetic analysis among melon, cucumber, tomato and Arabidopsis divided the 50 CmPUBs into six subfamilies. CmPUB37/48/49 are orthologous to salt stress-responsive AtPUB18/19 in Arabidopsis. Intraspecies collinearity analyses detected 11 homologous gene pairs within the CmPUB family and 15 to 67 collinear genes among five other species, respectively, based on the interspecies collinearity analyses. Promoter analysis revealed that CmPUBs had diverse and abundant cis-acting regulatory elements involved in light signal transduction, phytohormone regulation, and stress responses, as well as plant development. Transcriptome analysis of the CmPUBs in melon under salt stress revealed that most CmPUBs exhibited temporally differentiated expression patterns, with some genes being rapidly induced at the early stage of stress and continuously upregulated at the late stage. Physiological measurements under salt stress indicated that leaves were the primary tissue responding to salt-induced oxidative damage, and that the salt-tolerant line M4-116 alleviated this damage by maintaining higher superoxide dismutase (SOD) and catalase (CAT) activities and lower malondialdehyde (MDA) accumulation than the salt-sensitive line M4-75. Quantitative real-time PCR (qRT-PCR) was conducted using leaf tissues harvested at multiple time intervals. The expression patterns were compared between salt-tolerant and salt-sensitive cultivars, revealing that transcript levels were markedly elevated in the salt-tolerant cultivar under salt stress conditions. In conclusion, this study provides a foundation for further functional studies of U-box genes and offers new insights into stress responses in melon. Full article

Background: Plasmalogens (PLS) are a distinctive class of glycerophospholipids with reported neuroprotective properties; however, the mechanisms underlying their potential benefits for age-related cognitive decline remain incompletely understood. Methods: A D-galactose-induced mouse model of aging was used to evaluate the effects of PLS on cognitive performance. Hippocampal synaptic remodeling was assessed by examining the expression of synaptic proteins and receptors. An in vitro BBB model was used to evaluate the transport of PE-PLS 18:0/20:4. Molecular interaction analyses were conducted to investigate the potential binding of PE-PLS 18:0/20:4 to the brain-derived neurotrophic factor (BDNF) and its association with BDNF/TrkB signaling activation. Results: High-dose PLS supplementation significantly improved spatial memory and novel object recognition in D-galactose-treated mice. Molecular interaction analysis indicated that PE-PLS 18:0/20:4 could interact with BDNF through multiple hydrogen bonds. This interaction was associated with activation of the BDNF/TrkB signaling pathway, increased synaptic protein expression, and neuroprotective effects. Conclusions: PLS may mitigate age-related cognitive dysfunction by promoting hippocampal synaptic remodeling. PE-PLS 18:0/20:4 may contribute to these effects through BBB transport and modulation of BDNF/TrkB signaling, supporting the potential of plasmalogens as a nutritional strategy for promoting healthy brain aging. Full article

Fish gonad development is a central process in reproductive regulation, and elucidating its molecular mechanisms is highly important for developing aquatic genetic resources. However, the involvement of circular RNAs (circRNAs) in the gonad development of freshwater fish is unknown. In this study, a dynamic expression profile of circRNA during the development of red crucian carp testes was systematically constructed via whole-transcriptome sequencing. Notably, the circular characteristics and high testis-specific expression of the key circRNA circdmrt1, formed through the reverse splicing of the fourth exon of the dmrt1 gene, have been experimentally validated. The overexpression of circdmrt1 promoted cell proliferation and inhibited the expression of apoptosis-related genes. Furthermore, in the hybrid offspring of red crucian carp and white crucian carp, circdmrt1 expression exhibited a pronounced paternal-line-biased pattern. Our data reveal that circdmrt1 may act as a ceRNA by sequestering miR-122-5p and thereby modulating DHRSX expression, leading to the activation of HEK-293T cell proliferation. This study reveals for the first time the regulatory features of testicular circRNAs in crucian carp, providing support evidence into the mechanisms of gonadal development in teleosts. Full article

Aiming to improve short-term power load forecasting under nonlinear and nonstationary load characteristics, this paper develops an Improved Snow Ablation Optimizer (ISAO) and applies it to the hyperparameter optimization of a Variational Mode Decomposition (VMD)- Bidirectional Temporal Convolutional Network (BiTCN) forecasting framework. First, VMD is used to decompose the original load sequence into multiple intrinsic mode function (IMF) components in order to reduce the non-stationarity of the signal. Second, to address the limitations of the Snow Ablation Optimizer (SAO), four strategies—quantum-chaotic hybrid initialization, elite-pool-guided dual-population updating, the quantum tunneling effect, and dynamic lens opposition-based learning—are introduced to form the ISAO algorithm. Finally, ISAO is used to independently optimize the BiTCN hyperparameters of each IMF component, and the prediction results of all components are superimposed and reconstructed to obtain the final forecast. CEC2022 benchmark function tests and experiments on actual load data show that the ISAO algorithm achieves superior optimization performance; compared with the SAO-VMD-BiTCN model, the RMSE of the proposed model decreases from 2342.23 MW to 2202.14 MW, a reduction of 5.98% and the proposed model outperforms comparison models such as VMD-BiTCN and PSO-VMD-BiTCN across the RMSE, MAE, MAPE, and R² metrics. Furthermore, Diebold–Mariano (DM) test results provide additional statistical evidence for the favorable forecasting performance of the proposed framework across multiple random initializations. Full article

Background: Hepatocellular carcinoma (HCC) heterogeneity, particularly the presence of tumor cells co-expressing hepatocytic and cholangiocytic markers, contributes to therapeutic resistance and poor prognosis, yet its molecular correlates remain incompletely understood. This study aimed to characterize dual-phenotype HCC (DPHCC) and investigate the association and functional relevance of SPINT2 in tumor progression. Methods: We integrated multiplex immunofluorescence, CyTOF mass cytometry, single-cell RNA sequencing, and functional assays across clinical cohorts and cell lines. Results: Multiplex staining identified DPHCC in 22.89% of patients, correlating significantly with younger age, elevated AFP, and inferior recurrence-free and overall survival compared to non-DPHCC cases. Parallel scRNA-seq and CyTOF analyses showed that DPHCC-associated cells were enriched for stemness- and EMT-related features, with SPINT2 emerging as a top candidate gene in the transcriptomic analysis. Immunohistochemistry showed higher SPINT2 expression in DPHCC tissues, and high SPINT2 expression was associated with shorter overall survival in univariate Kaplan–Meier analysis and frequently co-localized with CK19. Functionally, SPINT2 modulation produced context-dependent changes in invasion, proliferation-related CCK-8 readouts, wound closure, sphere formation, and xenograft tumor growth in MHCC-97H and MHCC-LM3 cells. Collectively, these findings characterize DPHCC as a clinically relevant dual-lineage phenotypic state associated with aggressive tumor features and identify SPINT2 as a candidate molecule associated with this phenotype. Conclusions: SPINT2 is associated with the DPHCC-related state and aggressive tumor-cell phenotypes, but its mechanistic and clinical significance requires further validation. Full article

Aging is a major risk factor for chronic diseases, driving an urgent need for effective geroprotectors. Repurposing psychotropic agents offers an efficient strategy to accelerate anti-aging therapeutics development. In this study, we investigated the effects of pimozide (a diphenylbutylpiperidine-class antipsychotic) on aging in Caenorhabditis elegans and elucidated the underlying mechanisms. The results demonstrated that 0.1 μM pimozide significantly extends nematode lifespan, increasing mean, median, and maximum lifespans by 44.3%, 50.0%, and 39.8%, respectively. Furthermore, pimozide improves healthspan, as evidenced by reduced age-related lipofuscin accumulation, preserved locomotor function, and decreased paralysis incidence. Moreover, pimozide-treated nematodes showed enhanced resistance to heat, ultraviolet and oxidative stress, concomitant with reduced endogenous reactive oxygen species levels. Transcriptomic profiling and biochemical validation reveal that pimozide markedly upregulates collagen gene expression and increases hydroxyproline content, indicating enhanced collagen synthesis. Mechanistically, pimozide promotes the nuclear localization of SKN-1, and its beneficial effects on lifespan extension and collagen synthesis are SKN-1-dependent, as these effects are abolished in skn-1 mutants. Collectively, our findings demonstrate that pimozide promotes longevity and healthspan by activating skn-1, which is accompanied by enhanced collagen synthesis, providing a preclinical proof of concept for its potential repurposing as a geroprotector. Full article

Harmful cyanobacterial blooms require control strategies that suppress bloom-forming taxa while limiting effects on non-target primary producers and toxin-related risks. We developed a cationic polyquaternium (P126)-engineered local red-soil composite and evaluated its electrokinetic properties, taxon-dependent photophysiological effects, activity against colonial Microcystis, robustness to water chemistry, short-term Danio rerio responses, and field-scale performance. P126 modification reversed soil surface charge to the range of +20 to +33 mV across a pH range of 6.0–10.0, generating a strong electrostatic contrast with negatively charged cyanobacteria. At 10 mg L⁻¹, the composite suppressed maximum photosystem II quantum yield (F_v/F_m) in Microcystis aeruginosa and Dolichospermum sp., with no statistically detectable effects on the four tested chlorophyte and diatom strains. For Microcystis colonies ≥ 500 μm, 20 mg L⁻¹ of composite achieved >95% MTT-based inhibition within 24 h, versus < 15% for CuSO₄. Suppression persisted across the tested pH and nutrient ranges but was attenuated by high humate concentrations. The maximum unfractionated-sample ELISA microcystin-equivalent signal was approximately 25% lower than with CuSO₄; however, dissolved and particulate fractions were not resolved. No statistically detectable treatment-related differences in zebrafish hatching or larval length were observed up to 10.5 mg L⁻¹. In a physically isolated sub-lake, composite application preceded a decline of more than three orders of magnitude in algal/cyanobacterial density and an increase in Secchi depth from approximately 0.25 to 1.2 m; Vallisneria natans was planted subsequently. These results provide laboratory evidence and field case-study observations consistent with electrostatically favored, selective bloom suppression, while residual-polymer fate, sediment effects, chronic toxicity, and multi-trophic responses require further evaluation. Full article

Porcine endometritis, primarily resulting from mixed bacterial infections, adversely impacts sow reproductive performance and leads to substantial economic losses in the pig farming sector. Traditional antibiotic treatment is limited due to bacterial resistance and drug residue issues. Curcumin (Cur) possesses inherent antibacterial and anti-inflammatory properties; however, its use is restricted due to limited water solubility and low bioavailability. In this work, dominant pathogens were isolated and identified from vaginal swabs collected from 48 sows with clinical endometritis via 16S rRNA sequencing, followed by antibiotic susceptibility assessment. Cur-loaded ZIF-8 nanoparticles (Cur@ZIF-8) were synthesized for non-antibiotic therapeutic exploration against porcine endometritis. Physicochemical characterizations revealed that Cur@ZIF-8 possessed a hydrodynamic particle size of 106.2 nm, a curcumin loading efficiency of 10.8%, and an encapsulation efficiency of 86.4%. The nanoparticles exhibited uniform morphology, favorable dispersibility, and showed a moderate increase in curcumin release under acidic conditions. Hemolysis assays and mouse toxicity tests confirmed the favorable biocompatibility of Cur@ZIF-8 without obvious toxic effects. In vitro antibacterial evaluations demonstrated that Cur@ZIF-8 exerted potent bactericidal effects, with the minimum inhibitory concentration (MIC) against Proteus mirabilis determined to be 12.5 μg/mL. Consistent with clinical findings, Proteus mirabilis, Staphylococcus aureus, and Escherichia coli were confirmed as the major causative agents of porcine endometritis, which frequently occurred as mixed infections, and these clinical isolates exhibited prominent multi-drug resistance to common antibiotics. Using the isolated dominant clinical strains, we established mouse endometritis models and performed in vivo therapeutic evaluations via uterine bacterial load enumeration, histopathological observation, and immunofluorescence detection of macrophage polarization. The results demonstrated that Cur@ZIF-8 markedly mitigated uterine pathological injury, reduced intrauterine bacterial burden, and alleviated inflammatory infiltration. A decreased semi-quantitative histopathological inflammation score was observed in uterine tissues after Cur@ZIF-8 intervention. Mechanistically, Cur@ZIF-8 remodels the uterine inflammatory microenvironment through the modulation of macrophage polarization, achieving combined antibacterial and anti-inflammatory functions. Collectively, in vivo experiments in mouse endometritis models verified that the Cur@ZIF-8 nanoplatform produces antibacterial and anti-inflammatory effects and exhibits excellent biosafety and biocompatibility. This preclinical study offers a promising non-antibiotic nanotherapeutic candidate and provides an alternative strategy to reduce antibiotic consumption and combat antimicrobial resistance in livestock production; nevertheless, further systematic validation in sow models is still needed to support its practical clinical application for porcine endometritis control. Full article

The greenstone belt of the North China Craton (NCC) records the crustal evolution from the Neoarchean to the post-Archean period, offering critical insights into the ancient tectonic background. This study focuses on the late Paleoproterozoic granitoids in the Daxigou area, located within the greenstone belt of the Qianhuai Block along the northern margin of the NCC. Zircon U–Pb dating indicates that two representative samples (H1 and HZK97-2) were emplaced at 1849 ± 2.1 Ma and 1852 ± 2.0 Ma, respectively (ca. 1.85 Ga). Both samples are characterized by high K₂O (3.99–6.55 wt%) and Na₂O + K₂O contents (4.12–7.92 wt%), high 10,000 × Ga/Al ratios, zircon saturation temperatures (>800 °C), and seagull-type REE patterns, and are identified as A2-type granitic rocks. The Daxigou granitoids show LREE enrichment, negative Eu anomalies (δEu = 0.45–0.63), LILE enrichment, and Nb–Ta–Ti depletion, defining the arc-like trace-element signatures. Integrated with their low Mg# (0.15–0.20), Cr (12–21 ppm), and Ni (0.8–2.5 ppm) contents, negative zircon εHf(t) values (−4.25 to −0.17), Neoarchean Hf model ages (2.5–2.7 Ga), near-chondritic to slightly subchondritic Nb/Ta ratios (15.4–18.3), and high Zr/Hf ratios (41.2–44.1), these features indicate an inheritance from warm subduction-generated Neoarchean TTG protoliths. We propose that the arc-like signatures of the Daxigou granitoids reflect the source inheritance from Neoarchean TTG protoliths. At ca. 1.85 Ga, under an extensional setting, the ancient lower crust (TTG) underwent decompression melting, producing A2-type granitic rocks. They record a transition of the tectonic setting from Neoarchean warm subduction to late Paleoproterozoic post-orogenic extension. Full article

Precise orbit information is generally unavailable to users of noncooperative low Earth orbit (LEO) communication satellites such as Iridium NEXT, making publicly available two-line element (TLE) data the primary source of orbital states. However, TLE-derived orbital-state errors degrade Doppler positioning performance. This paper proposes an adaptively weighted multi-station Doppler orbit determination method. Using TLE-derived states as the orbit prior, the method formulates an orbital-dynamics-constrained batch least-squares (BLS) model. A priori weights are constructed from satellite elevation angles, and multi-station, multi-epoch Doppler measurements are adaptively reweighted by minimizing the uncertainty of the estimated satellite velocity projected onto the line of sight (LOS) from the ground station network centroid to the satellite. A Levenberg–Marquardt (LM)-type damping mechanism with diagonal scaling constrains the state correction vector to improve iterative stability. Experiments using real measurements show that the estimated orbital states yield a user-station two-dimensional root-mean-square error (2D RMSE) of 41.30 m, which is 16.06% lower than that obtained with the a priori weighted solution, 24.64% lower than that obtained with the equally weighted solution, and 64.25% lower than that obtained with the TLE-derived orbit. These results indicate that the proposed method improves the utility of the estimated orbital states for positioning with Iridium NEXT signals of opportunity. Full article