Search Results (25,841)

Background: Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal-recessive combined immunodeficiency marked by severe cutaneous viral infections, atopy with elevated IgE, malignancy, and early mortality without hematopoietic stem-cell transplantation (HSCT). Foundational syntheses predate the current transplant era and biologic therapy. Objective: It aims to provide an updated individual-patient-data (IPD) synthesis of DOCK8 deficiency cases reported from 2017 to 2026. Methods: Following PRISMA 2020 and PRISMA-IPD guidance, we searched PubMed/MEDLINE (with full Boolean strings provided for Embase, Scopus, Web of Science and Cochrane CENTRAL) for reports with extractable individual data on confirmed DOCK8 deficiency. Two-stage screening, Murad-2018 risk-of-bias assessment, random-effects Freeman–Tukey pooled proportions (with a random-intercept logistic model as a sensitivity analysis), and reconstructed Kaplan–Meier analyses were performed. Results: Of 360 records, 56 full texts were assessed, and 41 studies were included; 29 provided individual data for 64 patients from 22 countries, and 12 contributed aggregate data. Sixty-three potentially eligible reports were paywalled and could not be retrieved, and non-English reports were excluded, introducing possible retrieval and language bias. Consanguinity was reported in 40/43 (93%); the genotype spectrum was dominated by large deletions and splice/intronic variants. Eczema (72%), cutaneous viral infection (80%) and bacterial infection (64%) predominated. The pooled proportion alive at last reported follow-up was 87.3% (95% CI 81.1–92.6); this is a cross-sectional proportion over variable follow-up and is not a long-term survival estimate, as reconstructed age-specific Kaplan–Meier survival fell to approximately 53% by age 20 (exploratory analysis). Pooled malignancy prevalence was 10.6% (95% CI 3.4–20.7; I² = 66%), and pooled post-HSCT survival was 86.3% (95% CI 79.0–92.5). Conclusions: Contemporary reports reaffirm the severe infectious and malignant burden of DOCK8 deficiency and support HSCT as definitive therapy, alongside emerging biologic (dupilumab, siltuximab) and gene-directed strategies. Findings are constrained by reporting, retrieval and language bias and by reconstructed IPD; completion of the planned multi-database searches and independent second-reviewer verification are ongoing to finalise the evidence base. Full article

Object detection in UAV aerial images remains fundamentally constrained by extremely small object scales, strong background interference, and progressive structural information degradation along the feature extraction pipeline. Current small-object detection methods suffer from two fundamental deficiencies rooted in their convolutional feature extraction pipelines: the smoothing effect of strided convolutions in early layers, which attenuates fine-grained details before backbone processing, and the feature overwriting phenomenon, where sequential transformations progressively erase structural information from earlier layers. We propose PFE-Det (Progressive Feature Evolution Detector), built upon the DEIM framework and constructing a continuous optimization pathway across three stages. A Feature Adaptive Enhancement Network (FAENet) is adopted as a front-end preprocessor to decouple high- and low-frequency components via a Laplacian pyramid at the input stage, mitigating early-layer smoothing at the input. A Multi-Receptive-Field Adaptive Fusion Module (MFAM) is designed to reorganize single-path features into structure-retaining and progressive enhancement paths and is further coupled with hierarchical receptive-field modeling, suppressing feature overwriting through multi-scale context modeling. A Multi-Path Gated State Space Modeling Block (MG-SSM Block) couples HSM-SSD-based long-range dependency extraction with Convolutional Gated Linear Units (CGLU) for adaptive feature selection in the encoder. Experiments on VisDrone2019 demonstrate an AP of 0.225 and an ${\mathrm{AP}}_s$ of 0.134, yielding a 13.5% relative improvement in small-object precision over the baseline. Cross-dataset evaluations on DIOR and UAVVaste, each under independent training and testing, further support the effectiveness of progressive feature evolution for UAV small-object detection. Full article

At the same structural position within the northern part of Block K, the coalbed methane (CBM) wells in the 3^# and 15^# coal seams exhibit marked productivity disparities. This study integrates a correlation analysis of engineering parameters with dynamic diagnosis of production indicator curves to examine two dimensions: static engineering compatibility and dynamic seepage interference. The results show that the degree of matching between engineering parameters and geological conditions is a key factor controlling the productivity variation. The 3^# coal seam has favorable engineering performance, and boosting fracturing scale and drainage rate both help promote gas output. Compared with the 3^# coal seam, the 15^# coal seam has a notable deficiency in engineering compatibility: its effective horizontal section length and coal encounter rate decrease by 8.4% and 5%, respectively, while sidetracking frequency increases approximately fivefold; moreover, enlarging fracturing scale does not bring better gas results. Production indicator curves were established based on the relationship between cumulative water production per unit effective horizontal length and production pressure difference and were classified into upward-convex and downward-concave types. The resulting chart for exogenous water interference enables quantitative characterization of key metrics, including theoretical ultimate gas production, interference level, and gas production efficiency. The theoretical ultimate gas production of the 3^# coal seam reaches 69.454 m³/(d·m), over ten times that of the 15^# coal seam, but the critical interference threshold of the 3^# seam is lower than that of the 15^# seam. Most 3^# wells are stably located in the non-interference zone, indicating high production capacity and strong sensitivity to exogenous water interference. For the 15^# seam, the production indicator curves of most wells deviate toward the interference zone at an early production stage, reflecting strong exogenous water leakage recharge. Therefore, for this block, CBM development must shift from the traditional approach of blindly enlarging stimulation scale to geological compatibility and recognition of exogenous water interference. Full article

Wetlands have been noted to provide us with a wide range of ecosystem services—climate, water quality, flood regulation, and habitat benefits among others. The evidence that supports these service benefits is fairly well documented in the literature. However, it is often scattered across studies, metrics, and valuation methods, making it difficult for planners and landscape architects to use in physical projects and plans. The empirical result of this difficulty is that wetlands are often overlooked and under-utilized as part of broader ecosystem and land based planning solution sets. This paper addresses this usability deficiency using an ecosystem accounting framework that translates wetland science into spatially specific design and planning metrics. The framework follows the System of Environmental-Economic Accounting-Ecosystem Accounting (SEEA EA), an international statistical framework adopted by the UN to measure the environment’s contribution to the economy and human well-being. In our study, wetland extents in the state of Illinois are mapped on a statewide 30 m × 30 m grid. Individual wetland system conditions are estimated from floristic quality using a generalized additive model trained on 244 wetland sites that are part of the long-term Critical Trends Assessment Program (CTAP) at the Illinois Department of Natural Resources (IDNR). A floristic condition scalar, $w\left(x\right)$, provides a screening-level measure of ecological condition. It is applied only to a nonmonetary habitat-condition account and is not used to scale the monetary service accounts. Climate regulation, water purification, and flood regulation are quantified through service-specific physical models and reported as carbon-price and replacement-cost proxies. Under the central scenarios, these three monetary proxy accounts produce a combined subtotal of USD 1408.6 million per year. The annualized surface-storage replacement-cost scenario accounts for USD 1048.5 million, load-gated nitrogen-removal replacement cost for USD 338.0 million, and the climate-regulation carbon-price proxy for USD 22.1 million. These estimates are planning proxies rather than observed market benefits or realized avoided damages. The separate habitat-condition account totals 198,280 condition-weighted hectares, with a statewide mean $w\left(x\right)$ of 0.502, and is not added to the monetary subtotal. Climate performance varies across wetland types: methane emissions cause some emergent wetland categories to function as net greenhouse-gas sources under the central assumptions, while other categories remain net sinks. A protection-gap analysis shows that Tier 4 wetlands contain 70.1% of the classified vegetated-wetland area and 67.0% of the condition-weighted habitat area within the classified domain. Broadly, the framework demonstrates how ecosystem accounting can translate fragmented wetland evidence into consistent spatial metrics for planning. The resulting layers support statewide screening, comparison among wetland categories, conservation and restoration screening, and protection-gap analysis while preserving the distinction between monetary service proxies and nonmonetary ecological condition. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in screening, surgical techniques, systemic therapies, and multidisciplinary care. The increasing implementation of precision oncology has fundamentally transformed CRC management by enabling molecularly guided therapeutic strategies based on tumor-specific genetic alterations. In recent years, the molecular landscape of CRC has expanded considerably beyond traditional histopathological classification, incorporating a growing number of clinically actionable biomarkers with prognostic, predictive, and therapeutic significance. This review provides a comprehensive and up-to-date overview of the genetic landscape of CRC, focusing on established biomarkers currently integrated into clinical practice, including microsatellite instability/mismatch repair deficiency (MSI/dMMR), KRAS, NRAS, BRAF, HER2, and NTRK alterations. In addition, emerging biomarkers such as tumor mutational burden (TMB), POLE/POLD1 mutations, circulating tumor DNA (ctDNA), DNA damage repair (DDR) alterations, transcriptomic signatures, and artificial intelligence-based molecular prediction models are critically discussed. Particular emphasis is placed on their biological significance, diagnostic methodologies, prognostic and predictive value, and potential role in treatment selection. A structured, database-informed narrative review identified 140 relevant publications, primarily published between January 2020 and June 2026, supplemented by earlier seminal studies and major clinical guidelines. Based on the available evidence, we propose a Clinical Actionability Framework for CRC, categorizing biomarkers into three hierarchical tiers according to their level of clinical validation and therapeutic relevance: established standard-of-care biomarkers, emerging clinical biomarkers, and future precision oncology biomarkers. Collectively, current evidence supports a progressive transition from single-gene testing toward integrated multi-omics precision medicine. Advances in comprehensive genomic profiling, liquid biopsy technologies, transcriptomics, radiogenomics, and artificial intelligence are expected to further refine patient stratification, optimize therapeutic decision-making, and facilitate the development of adaptive precision oncology models. Understanding the evolving genetic landscape of CRC is therefore essential for maximizing treatment efficacy and improving patient outcomes in the era of personalized cancer care. Full article

Selenium (Se) is an essential trace element in animals and humans, usually acquired via nutrition and thus often dependent on the Se content of the soil from where the food crops originate. The uneven distribution of Se in soils may therefore result in regional Se deficiencies, often further exacerbated due to climate change and its subsequent effects on Se speciation (i.e., the chemical forms in which Se occurs) and the element’s mobility. In recent years, biofortification has emerged as a promising approach to address this issue. This review provides an overview of how climate-driven changes in Se cycling influence soil Se availability and discusses the resulting implications for plant resilience, crop biofortification and dietary Se supply. Although plants do not require Se per se, an increased Se content of plants may improve their yields, antioxidant defences, and tolerance to various—climate (change)-related—stresses such as drought, salinity, and oxidative stress at low concentrations. So far, selenite (SeO₃²⁻) and selenate (SeO₄²⁻) are the most commonly employed Se species in agriculture, often via foliar and soil applications, and due to their excellent solubility in water are subject to leaching or other weather-related limitations. Alternative Se compounds, such as Se nanoparticles (SeNPs) and selenium sulfide (SeS₂) present promising approaches that may enable a more controlled Se release in soils. Nonetheless, their long-term agronomic performance and environmental behaviour require further investigations. Full article

Phosphorus (P) deficiency severely limits soybean (Glycine max L.) productivity. This study proposed a three-stage screening framework to identify reliable traits and P-efficient genotypes. In Experiment I, percent tolerance to phosphorus deficiency (PTPD) was calculated for ten growth parameters across 98 genotypes under P-deficient and control conditions. Principal component analysis and comprehensive evaluation identified six key indicators in Experiment I, which were subsequently refined to five indicators through further analysis: SPAD at V3 and R1, photosynthetic rate at R1, shoot dry weight at R8, and seed number per plant at R8. Experiment II re-evaluated these traits using 12 contrasting genotypes under three P levels, identifying CN 15 as the most P-efficient and SN 22 as the most P-inefficient. Experiment III further revealed that CN 15 maintained superior PSII performance and exhibited a 26.2% increase in grain P-utilization efficiency under 0 µM KH₂PO₄ treatment. This integrated framework offers a preliminary reference for screening P-efficient soybean genotypes under controlled conditions, pending field evaluation. Full article

Background/Objectives: Branchio-oto syndrome (BOS) is an autosomal dominant disorder primarily associated with pathogenic variants in EYA1, mainly characterized by branchial anomalies, auricular abnormalities, and hearing loss. However, the co-occurrence of inner ear malformations in BOS remains understudied, especially severe malformations. This study aimed to investigate the clinical and genetic characteristics of patients with EYA1-associated BOS, with emphasis on cochlear nerve deficiency (CND). Methods: From January 2020 to April 2026, patients diagnosed with EYA1-associated BOS at an otology outpatient clinic in a tertiary hospital were included. Clinical manifestations, audiological assessments, imaging and genetic findings were analyzed. Results: Thirteen patients (six females and seven males) from eight unrelated families aged 0.3–58.3 years were enrolled. Branchial cleft fistulas and preauricular pits were each observed in 76.9% (10/13) of patients. The mean pure-tone average was 74.3 ± 20.7 dB HL. Eight EYA1 variants (four truncating, two large deletions, and two splicing) were identified. Among these, five were novel (c.320_329del, c.518del, c.1307dupT, c.1475+1G>A, and exon 12–18 deletion). CND was detected in 38.5% (5/13) of patients and 26.9% (7/26) of ears. Patients with CND carried either truncating variants (n = 3) or large deletions (n = 2) of EYA1. No CND was observed in patients with splicing variants. Conclusions: This study identifies five novel EYA1 pathogenic variants and suggests that CND may be a relatively common radiologic feature in EYA1-associated BOS, particularly among patients with truncating variants or large deletions, although larger studies are needed to confirm this association. Full article

Background: Nitrogen (N) availability is an important factor affecting soybean growth, photosynthetic capacity, and seed development. Identification of genomic regions associated with N-responsive traits may enable the development of cultivars with enhanced performance under reduced fertilizer inputs. Methods: A soybean diversity panel consisting of 193 accessions was evaluated under N-deficient (N−) and N-sufficient (N+) conditions during the 2024 and 2025 growing seasons. Best linear unbiased predictors were estimated for SPAD area under the curve (SPAD AUC) and 1000-seed weight (SW) under N− and N+ conditions and used for genome-wide association analysis with 37,429 single-nucleotide polymorphism (SNP) markers. Results: Six loci associated with SPAD AUC under N−, four with SW under N−, and 10 with SW under N+ exceeded the Bonferroni-corrected significance threshold, whereas no significant loci were detected for SPAD AUC under N+. Candidate genes near significant loci encoded proteins including receptor-like kinases, WRKY transcription factors, peroxidases, and protein kinases, which are involved in signal transduction, transcriptional regulation, oxidative stress responses, carbohydrate metabolism, and developmental processes. Allelic effect analyses revealed significant phenotypic differences between favorable and unfavorable alleles at representative loci, supporting the biological relevance of the identified associations. Conclusions: These findings provide insight into the genetic architecture of chlorophyll accumulation and seed weight under contrasting N environments and identify candidate loci that may facilitate the improvement of nitrogen-use efficiency and agronomic performance in soybean. Full article

Hypophosphatasia (HPP) is a rare inherited disorder caused by deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity and classically characterized by impaired mineralization processes, although growing evidence suggests broader systemic involvement beyond bone. This cross-sectional study aimed to characterize circulating levels of osteoglycin and sclerostin in patients with HPP and to explore their relationships with TNSALP activity and systemic clinical–biochemical profiles. This cross-sectional study included 25 genetically confirmed HPP patients and 25 age- and sex-matched controls without cardiovascular disease. Circulating osteoglycin and sclerostin were measured by ELISA, and clinical, metabolic, renal, inflammatory, cardiovascular, and bone-related variables were assessed. HPP patients showed lower osteoglycin and higher sclerostin levels compared with controls. Osteoglycin was mainly associated with ALP activity and mineral-related variables, while sclerostin showed broader associations involving glycemic, inflammatory, renal, and cardiovascular domains. In multivariable analyses, osteoglycin was linked to ALP, renal and inflammatory markers, whereas sclerostin was associated with glycemic, mineral, inflammation, and circulatory markers. Overall, osteoglycin variability appeared mainly driven by mineral-related factors, while sclerostin was more influenced by metabolic and inflammatory domains. In conclusion, HPP is associated with an imbalance in circulating bone-derived proteins, characterized by reduced osteoglycin and increased sclerostin, suggesting systemic alterations in bone-related signaling beyond impaired mineralization. Full article

Introduction: Asthma is the most common chronic inflammatory disease in childhood, with complex pathogenesis and heterogeneous clinical manifestations. Current efforts are focused on achieving remission through phenotyping and personalized therapy. Micronutrient deficiency is commonly observed in both children and adults, and current evidence points to their role in the pathogenesis of numerous acute and chronic conditions. Method: In this narrative review, we analyzed current information regarding the influence of micronutrient deficiencies on asthma control. The aim was to clarify the extent to which current knowledge provides evidence for implementing specific dietary measures in children with asthma to achieve disease control. We conducted a review of the literature covering the past 20 years to assess the impact of iron, vitamin D, and folic acid deficiency on asthma control. The research was performed in PubMed, Web of Science, Cochrane Library and Embase. Results: Vitamin D deficiency is associated with the frequency of asthma exacerbations in children. However, data regarding the severity of exacerbations, hospitalizations, or emergency department visits are not consistent across different studies. Vitamin D supplementation has controversial effects on disease control. Iron deficiency may contribute to the development of asthma, but there is no clear evidence. Observational studies have reported associations between iron deficiency, poorer asthma control, frequent exacerbations, and impaired lung function. An association between low folate levels and increased asthma risk and poorer asthma control was also reported. Conclusions: Assessing micronutrient status in children with asthma and the effect of correcting deficiencies as part of a personalized treatment plan to achieve symptom control remains a topic that requires further research. Full article

Toxoplasmosis, caused by Toxoplasma gondii, remains an important zoonotic disease affecting both human and animal health, particularly in immunocompromised individuals and during pregnancy. Current treatments are unable to eliminate latent tissue cysts and are further limited by adverse effects and prolonged treatment regimens, highlighting the need for effective vaccines. In this study, we evaluated the virulence attenuation and protective efficacy of a CRISPR–Cas9-generated rhoptry protein 64 knockout strain (RHΔrop64) as a live attenuated vaccine candidate in Kunming mice. RHΔrop64 exhibited markedly reduced virulence, and mice tolerated doses of up to 1 × 10² tachyzoites without obvious clinical signs. Immunization provided substantial protection against acute challenge with the parental RHΔku80 and ToxoDB#9 (PYS) strains at 30 days post-vaccination and partial protection against type II (Pru) tachyzoites. In addition, all immunized mice survived following oral challenge with 10 or 40 Pru cysts and exhibited reduced brain cyst burdens among surviving mice. Vaccination also induced measurable humoral and cytokine responses, characterized by increased levels of T. gondii-specific IgG and cytokines that were maintained for at least 75 days post-vaccination. These results suggest that RHΔrop64 has the potential to serve as a live attenuated vaccine candidate, providing substantial, although incomplete, protection against acute challenge with the three T. gondii strains tested and being associated with reduced brain cyst burdens among surviving mice following chronic challenge. Further evaluation is required to determine its safety and applicability as a vaccine candidate for food-producing animals and cats. Full article

A previously healthy 19-month-old female presented after her family found her upon awakening to be sleepy, uninterested in eating, and lethargic. On arrival, blood gas showed profound metabolic acidosis with normal lactate that did not improve with normalization of glucose and sodium. Her acidosis continued to worsen, so a broad workup was initiated, considering ingestions, DKA, and inborn errors of metabolism. In collecting further history, the patient’s nutrition history included a combination of breastfeeding and a vegan diet followed by her family. Her B12 level returned undetectably low. She improved dramatically over the next several hours after receiving an injection of cyanocobalamin. Ultimately, she was confirmed to have methylmalonic acidemia secondary to severe Vitamin B12 deficiency. Full article

Accurately identifying organic-rich shale intervals remains a major challenge in lacustrine shale oil exploration, particularly in continental rift basins characterized by rapid environmental change and pronounced vertical heterogeneity. This study investigates the upper Jiufotang Formation in the Ludong Sag, Kailu Basin, NE China, using total organic carbon (TOC), vitrinite reflectance, multi-stage programmed rock pyrolysis, and major and trace element geochemistry to constrain the processes governing organic matter enrichment and hydrocarbon occurrence. The studied shales contain abundant organic matter, with TOC values ranging from 1.91% to 7.55% and averaging 4.22%. Type II₂ kerogen and vitrinite reflectance values of 0.60–0.94% indicate oil-prone organic matter at low-mature to mature stages within the oil generation window. Multi-stage pyrolysis shows that the hydrocarbon assemblage is dominated by bound oil and residual kerogen-derived fractions, whereas the low-temperature movable oil fraction is limited. TOC is more strongly associated with the high-temperature pyrolysis fractions than with the light free-oil fraction, indicating that organic matter abundance primarily controls residual hydrocarbon generation potential but does not directly determine present-day movable oil content. Multiple elemental proxies are collectively consistent with deposition in a hydrologically restricted, variably brackish–saline lacustrine system with water-mass differentiation. Redox-sensitive indicators, including V/(V + Ni) and Mo, suggest persistent weakly reducing to reducing bottom-water conditions. After correction for carbonate- and phosphate-associated Ca, CIA values fall within a narrow range of approximately 67–70, indicating moderate and relatively stable source area chemical weathering. Organic matter enrichment was governed by the coupled effects of organic matter supply, preservation under stratified oxygen-deficient waters, and sedimentary dilution. We therefore propose a two-stage process framework in which depositional productivity–preservation coupling first promoted organic matter accumulation, whereas subsequent thermal maturation, hydrocarbon expulsion, retention, and adsorption reshaped the present hydrocarbon occurrence state. The results demonstrate that high organic matter abundance and residual generation potential do not necessarily translate into high movable oil content and provide a well-scale geochemical basis for source rock evaluation and future multi-well assessment in continental rift lake systems. Full article

P4-ATPases maintain transbilayer lipid asymmetry, yet their functional roles in legume crops remain poorly understood. In the present study, GmALA1-a plasma membrane-localized P4-ATPase in soybean, was identified and characterized. Its physical interaction with the β-subunit GmALIS2 at the plasma membrane via biomolecular fluorescence complementation was confirmed. Heterologous expression in the P4-ATPase-deficient yeast strain ZHY709 demonstrated that GmALA1 fully complemented the cold-sensitive growth phenotype, while co-expression with GmALIS2 only partially restored growth, suggesting GmALIS2 may modulate rather than simply stimulate GmALA1 activity, though the mechanism remains unresolved. GmALA1 suppresses triacylglycerol accumulation while elevating lysophosphatidylethanolamine and lysophosphatidylcholine content in both wild-type and mutant yeast. These findings were consistent with GmALA1-driven remodeling of membrane lipid flux. In yeast and transgenic soybean hairy roots, GmALA1 alone or in combination with GmALIS2 differentially altered the internalization and tissue-specific distribution of multiple phospholipid classes, with the pattern of NBD-lipid accumulation differing depending on GmALIS2 co-expression and cellular context. GmALA1 expression was also associated with altered yeast sensitivity to divalent cations including Ca²⁺, Co²⁺, and Zn²⁺. Also, cellular cation accumulation in the P4-ATPase-deficient background was enhanced. However, whether this reflects a direct interaction between GmALA1 and cation homeostasis machinery remains to be established. These findings establish GmALA1 as a functionally active phospholipid flippase that coordinates transmembrane lipid redistribution in concert with GmALIS2. These findings advance our understanding of P4-ATPase biology in soybean and legume crops. Full article