Search Results (354)

Oxidative stress plays an important role in systemic lupus erythematosus (SLE). To elucidate whether it is already present in early phases, we investigate oxidative stress-related genes in incomplete SLE (iSLE) and quiescent SLE (qSLE, inactive disease), as well as the effect of nuclear factor erythroid-derived 2-like 2 (NRF2) activators on NRF2-related genes in peripheral blood mononuclear cells (PBMCs) and HaCaT keratinocytes. In total, 28 qSLE patients, 29 iSLE patients and 21 age- and sex-matched healthy controls (HCs) were included. Serum free thiols, reactive oxygen species (ROS) levels and NRF2-related antioxidant gene expression were measured. Furthermore, PBMCs and HaCaT keratinocytes were treated with the NRF2 activators sulforaphane (SFN) and dimethyl fumarate (DMF) in vitro to assess expression of antioxidant genes. Finally, NRF2 and Heme oxygenase-1 (HMOX1) proteins in non-sun-exposed skin sections were assessed. Thiols were significantly lower in qSLE patients compared to HCs. In whole blood, Kelch-like ECH-associating protein 1 (KEAP1) and catalase (CAT) mRNA levels were significantly reduced in iSLE and qSLE. Treatment with SFN or DMF in PBMCs upregulated HMOX1 and NAD(P)H quinone dehydrogenase-1 (NQO1) mRNA expression and downregulated CAT expression. In HaCaT cells, mRNA expression of HMOX1, NQO1 and thioredoxin was upregulated. There were no differences in protein expression of NRF2 and HMOX1 in skin tissues. In conclusion, in qSLE patients, oxidative stress is elevated, while antioxidant capacity is decreased. A similar trend, although not significant, is seen in iSLE patients, which indicates that redox imbalances are already present in early phases, but not as obvious as in established SLE. NRF2 activators upregulate antioxidant gene expression in PBMCs and HaCaT cells, highlighting their potential role to modulate oxidative stress pathways in SLE. Full article

Ischaemic stroke constitutes a leading cause of global disability. Rapid extraction of the infarct core from multimodal computed tomography perfusion (CTP) imaging guides reperfusion therapy and clinical decision-making. Deep learning algorithms automate this delineation, yet hospital translation is hindered by high-dimensional data, inter-scanner variability, and the low contrast of early ischaemia. Architectural comparisons in the literature frequently carry methodological biases originating from disparate preprocessing protocols and data partitions. This study reduces these variables by evaluating three segmentation strategies under a shared preprocessing pipeline and an identical data partition using the ISLES 2024 dataset. Three models were trained on the same 133-patient partition using a shared preprocessing pipeline based on morphological skull-stripping and modality-specific clinical intensity ranges. The data, preprocessing, and partitions are held constant across models, while framework-dependent factors (optimiser, patch size, physical field of view, spatial resampling, augmentation policy, and model capacity) remain coupled to each architecture and are therefore treated as part of the compared strategy rather than as fully isolated variables. The first of these is a single-stage 5-channel nnU-Net, followed by a two-stage cascaded nnU-Net (2 and 7 channels) and a lightweight Transformer (SegFormer3D). Evaluation on a fixed 15-patient held-out test set isolated the architectural performance. The cascade model achieved the highest Dice Similarity Coefficient (0.224). The single-stage nnU-Net provided the most precise volumetric estimation, recording an Absolute Volume Difference (AVD) of 23.70 mL and a lesion-wise F1-score of 7.60%. On the other hand, SegFormer3D returned the lowest overall metrics (DSC 0.163, AVD 27.28 mL, F1 2.30%). In the small held-out cohort, paired statistical testing did not reveal significant differences between models, so the reported orderings describe the present dataset and experimental configuration rather than a general architectural law. Within these limits, the local inductive bias of the convolutional models retained an empirical advantage over the single Transformer evaluated when processing this moderately sized neuroimaging dataset, and complex cascade topologies offered only marginal gains compared with a well-calibrated single-stage network. Although the predictive segmentation of infarcted tissue at acute stages still demands computational improvements, these results suggest that preprocessing quality is at least as decisive for clinical impact as increasing the complexity of neural architectures. Full article

Ion-adsorption rare earth deposits (IADs) constitute the primary global source of medium-to-heavy rare earth elements. The sustainable exploitation of these resources hinges on the precise characterization of the weathered crust architecture and its hydrogeological properties. Conventional drilling often fails to resolve the complex vertical heterogeneity of regolith profiles, thereby limiting orebody delineation and the optimization of in situ leaching (ISL). To address this, this study integrates Electrical Resistivity Tomography (ERT) with Archie’s Law and the Kozeny–Carman equation. Focusing on the YZK1 and YZK2 survey lines in the Dabu mining area, southern Jiangxi, we derived 2D distributions of porosity and permeability from resistivity inversions. Our results delineate the weathered crust into four distinct vertical strata: a surface accumulation layer, a completely-to-highly weathered granite layer, a moderately-to-slightly weathered layer, and fresh bedrock. Quantitatively, the completely-to-highly weathered layer exhibits a “low resistivity (10–700 Ω·m)–high porosity (8.7%–17%)–high permeability (0.04–1.2 mD)” mode, serving as the primary leachable reservoir. In contrast, the surface and moderately weathered layers display “high resistivity (>800 Ω·m)–low porosity (3.4%–6.4%)–low permeability (0.01–0.04 mD)” characteristics. Crucially, although the fractured bedrock zones on both YZK1 and YZK2 profiles exhibit similar absolute permeability values (~0.016 mD), they represent two distinct hydraulic architectures. On the YZK1 profile, the fractured zone acts as a relatively homogeneous potential leakage pathway. Conversely, the YZK2 profile displays significant vertical segmentation: the upper and lower margins function as permeable pathways, while the central core, likely infilled with fault gouge, acts as a sealing zone that impedes fluid flow. Consequently, resistivity data alone are insufficient to accurately assess hydraulic conductivity; joint interpretation incorporating both permeability and porosity is essential to definitively determine whether a fault zone acts as a “conduit” or a “barrier.” By transitioning from qualitative imaging to quantitative parameter evaluation, this study provides a robust technical paradigm for fine-scale exploration and ISL optimization in IADs. Full article

This study addresses a significant feature of many early modern Reformed Lord’s Supper liturgies, the ‘Reformed sursum corda.’ This term refers to elaborations of the ancient liturgical phrase “Lift up your hearts” placed in the liturgy and used to teach a Reformed eucharistic piety. The article traces the development of this liturgical element throughout the sixteenth and early seventeenth centuries, beginning with its origin in the liturgies of Guillaume Farel and John Calvin and turning to two separate appropriations of Calvin’s Reformed sursum corda: one from the Stranger Churches in England to Germany, the Netherlands, and Poland; another from English and Scottish exiles in Frankfurt and Geneva to the British Isles. It makes three principal arguments: (1) that Farel’s liturgical innovation was dependent upon his reading of Oecolampadius, (2) that the principal later versions of the Reformed sursum corda were derived from John Calvin’s, and (3) that the Reformed sursum corda tradition impacted the interpretation of the English Book of Common Prayer. In so doing, this article deepens our understanding of the development of between early modern Reformed Lord’s Supper liturgies as well as the connection between eucharistic theology and eucharistic practice in the Reformed tradition. Full article

Background: Uveal melanoma (UM) represents the most prevalent primary intraocular malignancy in adults, yet patients harboring GNAQ/GNA11 mutations face particularly poor prognoses with median survival of merely 6–12 months following metastasis. Multi-targeted combination therapy offers a promising strategy to circumvent drug resistance. The present study investigated the synergistic anti-tumor efficacy and mechanistic basis of Isoliquiritigenin (ISL), Quercetin (Que) and Methylnissolin (Meth), three bioactive constituents from Astragalus membranaceus (Huangqi, a widely used traditional Chinese medicinal herb) against UM. Methods: Molecular docking and 100 ns molecular dynamics simulations assessed binding stability between the compounds and their respective targets (Gαq, MEK and YAP). Synergistic interactions were quantified using the Zero Interaction Potency (ZIP) model, a reference synergy model that compares observed combination effects to predicted non-interaction baselines across full dose–response matrices, based on CCK-8 assays. Cell cycle distribution, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry. Western blotting detected target proteins and apoptotic markers. A male BALB/c nude mouse xenograft model validated therapeutic efficacy and systemic safety. Results: Molecular docking revealed binding energies <−7.0 kcal·mol⁻¹ for all three drug–target pairs, with molecular dynamics trajectories confirming stable complex conformations (RMSD < 3 Å). In vitro, the ISL-Que-Meth (IQM) combination exhibited strong synergism (ZIP scores > 10), significantly increasing apoptotic rates, collapsing mitochondrial membrane potential and upregulating cleaved-caspase 9 expression compared with monotherapy, and a modest G2/M phase accumulation was also observed, although the magnitude was limited relative to apoptotic induction. In vivo, the triple combination achieved approximately 50% reduction in tumor growth compared with the control group, with effects comparable to or exceeding those of the clinical reference agent Trametinib, and reduced Ki67 proliferation indices while elevating cleaved-caspase 9 levels, without eliciting hepatorenal toxicity. While these data demonstrate therapeutic efficacy, they do not establish in vivo synergy, as single-agent and dual-combination arms were not included in the xenograft design. Conclusions: These findings demonstrate that IQM synergistically suppresses UM growth in association with coordinated modulation of Gαq/MEK/YAP axis components and caspase 9-dependent apoptosis via the intrinsic mitochondrial pathway, providing preclinical evidence for natural product-based multi-targeted therapy against UM. Full article

Hydraulic fracturing is a key stimulation technique for enhancing the permeability of tight sandstone-hosted uranium deposits. However, existing hydraulic fracture network evaluation methods are primarily applicable to stress regimes in which the vertical principal stress exceeds the horizontal principal stress, making them unsuitable for evaluating low-angle or subhorizontal hydraulic fractures formed under high-horizontal-stress and low-vertical-stress conditions. To address this limitation, this study develops a semi-quantitative method for evaluating hydraulic fracturing effectiveness under stress regimes characterized by high horizontal stress and low vertical stress. The proposed method introduces a Stoneley-wave attenuation index and combines it with Stoneley-wave chevron-apex responses to identify hydraulically fractured intervals. By further integrating conventional well-log data to reduce interference from borehole enlargement, lithological boundaries, and natural fractures, the method supports the identification of hydraulically induced fractures and provides a semi-quantitative assessment of their development. The method was applied to a hydraulic fracturing pilot test for in situ leaching uranium mining in the Bayingobi Basin, Alxa, China, where it supported the identification of hydraulically induced fractures and fractured intervals in both stimulation and monitoring wells. Field application results support the engineering applicability of the proposed method and provide preliminary validation of its effectiveness. The results indicate that this method provides an effective logging-based approach for evaluating hydraulic fracturing performance and investigating fracture propagation in tight sandstone-hosted uranium deposits. Full article

Avian influenza viruses (AIVs) are widely distributed and have a wide range of hosts. Recently, the number of cases of infection associated with the circulation of highly pathogenic avian influenza H5N1 2.3.4.4b has raised concerns about its high transmission capacity in birds and mammals. This study analyzed swabs from bird and mammal species from the coast of Paraná and the northwest region of São Paulo, Brazil, for the presence of AIV in animals that did not present clinical or histopathological lesions of infection that indicated the need for molecular characterization during monitoring. Of the 661 animals analyzed, three tested positive, two of which were birds (Sula leucogaster and Thalasseus acuflavidus) while one was a mammal (Otaria flavescens) (0.45%, CI 95%: 0.16–1.33). A complete genome sequence of H5N1 AIV was obtained from a brown booby (Sula leucogaster) from the Paraná coast (GISAID accession number: EPI_ISL_1897537). Our study reinforces the importance of continuous genomic surveillance, especially in AIV hosts that do not show signs of infection, to enhance the One-Health assessment approach. Full article

In situ leaching (ISL) is the most popular method for uranium mining worldwide, particularly in arid and semi-arid regions. Despite its economic benefits, ISL raises concerns about radioactive migration and groundwater contamination. This review assesses the environmental impacts of ISL uranium mining, focusing on radionuclide transport pathways and key information gaps. This review, focusing on groundwater contamination, radionuclide migration, soil and sediment contamination, atmospheric impacts, vegetation responses, and ecosystem disturbances, summarizes current understanding of the hydrogeochemical, radiological, and environmental impacts of uranium mining. The analysis indicates that groundwater is the environmental component most vulnerable to contamination during ISL operations due to the injection of acidic or alkaline leaching solutions that may mobilize uranium, radium, sulfates, selenium, arsenic, and other potentially hazardous elements. In addition to impacts on groundwater, there have also been reports of soil contamination, airborne dust, radioactive accumulation in flora, and impacts on aquatic and microbiological resources, particularly in arid and semi-arid regions. Although cleanup methods and natural attenuation can minimize contamination to some extent, residual contamination can persist for decades after mine closure. Overall, ISL uranium mining emphasizes the need for effective groundwater management, long-term environmental monitoring, and improved reclamation methods, balancing surface disturbance with long-term hydrogeochemical and environmental concerns. Full article

Multi-layer low Earth orbit constellations (ML-LEOs) have become a pivotal trend in the development of satellite network systems, where their layered orbital architecture improves system performance by strategically deploying satellites in distinct orbital layers. However, two critical issues remain open: how does the configuration of ML-LEO affect its performance, and how many layers are required to achieve optimal performance? This paper first investigates the impact of the number of layers L on the capacity of ML-LEOs. By analyzing the distribution of inter-layer inter-satellite links (ISLs) and the flow count on bottleneck links, we derive a closed-form mathematical expression for ML-LEO capacity under different values of L. In particular, we show that when each layer adopts an identical constellation topology and the number of satellites per orbit equals the number of orbits, the capacity of the ML-LEO is $\sqrt{L}$ times that of a single-layer low Earth orbit constellation (SL-LEO). Furthermore, we present the optimal parameter configuration for ML-LEOs: the number of orbits per layer should equal the number of satellites per orbit, the number of layers should be half the number of satellites per orbit, and the optimal number of inter-layer ISLs is twice the product of the number of orbits per layer and the number of layers. Finally, extensive simulations are carried out to thoroughly verify the accuracy of the analytical results. Our analysis reveals the performance benefits of multi-layer topology and establishes a theoretical framework for parameter optimization in ML-LEO. Full article

This study focuses on the Labrador Coastal Current (LCC), which is the coastal branch of the Labrador Current System (LCS). We characterize the LCS by combining existing Global Drifter Program (GDP) data with new surface drifters deployed by the Community-based Observations of Nunatsiavut Ocean Circulation (CONOC) project, specifically designed to fill the near-coast gap where the LCC lies. Autonomous ocean gliders are used to map hydrography and infer baroclinic and barotropic circulation components of the LCS. Tidal currents are generally weak across most of the shelf but are notably stronger in areas such as the Hudson Strait and the Strait of Belle Isle. The main Labrador Current (MLC), over the shelf break, exhibits strong currents (ca. 0.5 m/s) while the LCC, closer to the Labrador coast, shows moderate speeds of up to 0.25 m/s. Combining drifter- and glider-derived velocities, we find that the surface velocities in the LCC are predominantly barotropic (ca. 70%) while in the MLC they are predominantly baroclinic (ca. 70%). While volume transports in the MLC are several times larger than the LCC, their freshwater transports are comparable in magnitude. These observations provide crucial detail on the dynamics and watermass properties of the LCC. Full article

Shelter organisations take responsibility for the care, assessment and homing of large numbers of domestic cats from diverse backgrounds. However, not all cats that come under shelter care are suited to close human-cohabitation or to certain types of human-domestic lifestyles. Shelter stakeholders may undertake decision-making processes to determine how each cat should be managed and where they should go next. These processes may lead to different cat welfare experiences and long-term outcomes depending on how they occur, yet little is known about current approaches. The aim of this study was to characterise current approaches to cat and adopter assessments, behaviour management and homing decisions across the British Isles shelter sector, considering reported practices against sector minimum standards where applicable. A total of 393 quantitative and qualitative responses from employees and volunteers were received. Responses indicated that overall, stakeholders were consistently undertaking cat and prospective adopter assessments, with subsequent information used to support cat management, decision-making and homing. However, the degree of standardisation and objectivity associated with these processes was unclear, with considerable variation in approaches, including certain practices potentially associated with poor cat welfare outcomes identified. Examples include exposure to stressful handling and behavioural interventions and assessment ‘tests’, prolonged stays for harder-to-home cats and potentially suboptimal homing decisions for cats not suited to domestic ‘pet’ lifestyles. Identified opportunities to support welfare-friendly processes at the individual level include more consistent use of cats’ within-shelter behavioural presentations as grounds for ‘pet’-suitability assessments, and careful and consistent application of cat-labelling and terminology. It is also recommended that care is taken to ensure methods of cat assessments, behavioural interventions and homing decisions are pragmatic and optimised to positive cat welfare outcomes. Full article

Meeting the physiological and psychological needs of shelter cats through appropriate care is critical to reducing stress and disease risk, as well as enabling positive homing outcomes. Shelter organisations across the British Isles provide care for many cats; however, little is known about the types of housing and husbandry approaches applied. This study, therefore, aimed to quantify current approaches to cat housing, husbandry, and general care practices, in addition to providing information relevant to local site capacity, considering reported practices against sector minimum standards where applicable. Nine hundred and sixty-one shelter organisations and/or sites caring for cats were identified and invited to complete an online survey including predominantly multiple-choice questions. A total of 393 unique responses were collected from employees and volunteers, and quantitative data were summarised descriptively. In most cases, the results provided evidence of majority alignment with sector standards, although substantial variations in reported practices were also consistently captured. While most responses described approaches supportive of meeting cats’ basic physiological needs (e.g., access to veterinary care and basic resources), psychological needs were addressed less consistently (e.g., general housing and husbandry approaches), potentially leading to poor welfare outcomes. Identified opportunities to better meet cats’ needs include more cat-friendly, low-stress approaches to pen cleaning and cat handling; greater and more consistent provisioning of within-pen resources; and improved approaches to multi-cat housing and associated decision-making. Additional opportunities to enhance both cat and human wellbeing include more structured intake and assessment processes and capacity management to support optimal cat-to-staff ratios, staff working hours, cat lengths of stay and more consistent access to isolation and emergency intake facilities. Full article

Background: The relationship between neonatal DNA methylation (DNAm) and childhood atopy, particularly its temporal dynamics, remains inadequately characterized. Establishing this will provide insights into the epigenetic mechanisms underlying atopy development. Methods: Skin prick tests (SPT) for 11 common allergens were performed in the Isle of Wight third-generation birth cohort (IOWF2) at ages 1, 3, and 6 years. Atopy was defined as a positive response to one or more allergens on SPT. DNAm at birth at 294,265 CpGs from umbilical cords (n = 192) or Guthrie cards (n = 107) was screened (through R package ttscreening) for potential association with atopy. Pathway enrichment analysis of screened CpGs was performed using the missMethyl package in R. Associations between CpGs that passed screening and atopy status were assessed via logistic regressions with repeated measures, adjusting for age, sex, and birth weight. Age-specific associations were examined via DNAm × age interactions. CpGs showing age-specific association were further tested in the parental cohort (IOWBC (F1); n = 717). Multiple testing was controlled using FDR-adjusted p-values at 0.05. Results: In total, 601 CpGs passed screening. Pathway enrichment analysis identified enrichment of the cell activation pathway (GO:0001775; FDR-adjusted p-value = 0.017). DNAm at 502 CpGs in F2 showed age-specific associations with atopy. Among these, 102 CpGs showed consistent directions in F1, and 14 were statistically significant (p-value < 0.05). Except for cg01519508 (FOXF1), DNAm–atopy associations weakened over time at the remaining 13 CpGs. Conclusions: At certain CpGs, DNAm at birth is associated with childhood atopy in an age-dependent manner, and for CpGs showing association at an earlier age, such associations weaken at later ages. Full article

Low and Medium Earth Orbit (LEO/MEO) satellite constellations have emerged as a compelling architectural paradigm for delivering multipurpose services. In this study, we investigate the joint optimization of communication and positioning performance metrics in a multilayer LEO/MEO constellation equipped with inter-satellite links (ISLs). A genetic algorithm framework is employed to optimize key constellation design variables, including the number of satellites per orbital plane, the number of planes, and the inter-plane phase offsets across layers, to minimize end-to-end user latency and Geometric Dilution of Precision (GDOP), subject to coverage and total satellite count constraints. Numerical results highlight the trade-offs among different architectural options. Full article

Licorice is a traditional Chinese medicine; however, its bioactive constituents and specific molecular mechanisms responsible for protecting against radiation-induced brain injury remain poorly elucidated. Oxidative stress overactivation acts as the core pathological mechanism underlying radiation-triggered neuronal injury. This study aimed to investigate the neuroprotective effect and underlying mechanism of isoliquiritigenin (ISL), a major blood-absorbed component of licorice, against radiation-induced neural injury in C57BL/6J mice via the Keap1-Nrf2 signaling pathway. Molecular docking and MST analysis verified the strong binding affinity of ISL to Keap1. In vitro, ISL restored the viability of X-ray-irradiated PC12 cells; reduced LDH release and intracellular ROS accumulation; and enhanced SOD1 activity, GSH content, and T-AOC levels. Moreover, ISL upregulated the expression of antioxidant-related genes and induced Nrf2 nuclear translocation. In vivo, oral ISL administration ameliorated radiation-induced cognitive impairment, improved spatial learning and memory, alleviated hippocampal neuronal loss, and increased cerebral cortical Nrf2 expression in C57BL/6J mice. In conclusion, ISL alleviates radiation-induced neuronal injury by suppressing oxidative stress and activating the Keap1-Nrf2 signaling pathway, thus representing a promising therapeutic agent for the prevention and treatment of radiation brain injury. Full article