Search Results (329)

Background: X-linked immunodeficiency with magnesium defect, Epstein–Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1, leading to impaired N-linked glycosylation. Although chronic EBV viremia is a hallmark of XMEN disease, the mechanisms underlying its marked clinical heterogeneity remain poorly understood. Methods: We performed an in-depth clinical, immunological, and genetic characterization of two siblings carrying a pathogenic MAGT1 variant (c.369_370insCC; p.Gly124fs), validated and deposited in ClinVar (SCV007293792). Assessments included whole-exome sequencing, multiparametric flow cytometry focusing on NKG2D expression, and longitudinal clinical follow-up. Results: Despite shared absence of NKG2D expression, the siblings exhibited strikingly divergent phenotypes. One sibling developed progressive neurodegeneration with central nervous system atrophy. The other presented with a complex immuno-hematologic phenotype, including EBV-positive Hodgkin lymphoma, recurrent autoimmune cytopenias, and lymphoma-associated thrombotic microangiopathy, representing a novel clinical association in XMEN disease. Comparative immunophenotyping revealed shared defects in B-cell maturation but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a descriptive, hypothesis-generating three-category conceptual classification comprising early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the nervous system. Conclusions: These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect. Full article

Background: CrossFit^® has gained widespread popularity as a high-intensity training modality, yet evidence describing neuromuscular performance characteristics in this population remains limited. This study aimed to evaluate isometric and ballistic strength profiles in trained CrossFit^® athletes and to identify sex-based differences in absolute and relative neuromuscular performance. Methods: Seventy-two athletes participated (41 males and 31 females) participated in the study, completing two maximal isometric mid-thigh pull (IMTP) tests and three countermovement jump (CMJ) tests within a single testing session. Assessments were conducted using a dual force plate system (Hawkin Dynamics, Westbrook, ME, USA). Results: In the IMTP, males exhibited substantially higher absolute isometric force outputs, including peak force (3059 ± 576 vs. 1899 ± 324 N; p < 0.001) and relative peak force (36.34 ± 6.74 vs. 30.99 ± 4.41 N/kg; p < 0.001). Rates of force development were also greater in males for both early (0–50 ms: 7665 ± 5420 vs. 4001 ± 3021 N/s; p < 0.001) and late phases (0–250 ms: 5350 ± 1832 vs. 3035 ± 886 N/s; p < 0.001). However, no significant sex differences were detected in time to peak force (2.31 ± 1.27 vs. 1.94 ± 1.04 s) or dynamic strength index (0.72 ± 0.12 vs. 0.73 ± 0.12 a.u.). In ballistic performance using CMJ, males achieved higher jump height (0.33 ± 0.07 vs. 0.23 ± 0.05 m; p < 0.001), jump momentum (215 ± 27.9 vs. 131 ± 19.1 kg·m/s; p < 0.001), and modified reactive strength index (0.46 ± 0.11 vs. 0.32 ± 0.08 a.u.; p < 0.001). Relative propulsive and braking forces were also moderately greater in males. Notably, sex differences were reduced when variables were normalized to body mass or peak force, indicating comparable relative neuromuscular function across sexes. Conclusions: These findings provide descriptive neuromuscular performance data for CrossFit^® athletes and show that sex-based differences primarily reflect disparities in absolute force-production capacity rather than intrinsic neuromuscular efficiency. Such insights may support more precise, evidence-informed, and sex-specific training prescriptions to optimize performance. Full article

Objectives: This study compares linear sprint force–velocity (F–v) mechanical variables between elite Under-19 (U19) academy players and senior professional players. Methods: Thirty-eight senior players (SP; mean age 24.5 ± 4.3 y) and 214 U19 academy players (YP; mean age 17.4 ± 0.5 y) from 14 first-division club academies were tested during October 2023 using a motorized resistance device (1080 Motion). The following F–v variables were assessed: maximal theoretical force (F₀, N·kg⁻¹), maximal theoretical velocity (v₀, m·s⁻¹), maximal ratio of horizontal-to-resultant force (RF_max, %), and decrease in the ratio of forces (DRF, %). Between-group comparisons were performed using the t-test, and Cohen’s d effect sizes were reported. Results: Senior players outperformed U19 players across all F–v variables. F₀ exhibited a mean difference = 0.220 N·kg⁻¹, with a 95% confidence interval (CI) [0.056, 0.384], p = 0.0166, and d = 0.46. v₀ exhibited a mean difference = 0.560 m·s⁻¹, with a 95% CI [0.410, 0.710], p < 0.0001, and d = 1.07. RF_max exhibited a mean difference = 1.470%, with 95% CI [0.830, 2.110], p = 0.0003, and d = 0.69. DRF exhibited a mean difference = 0.260%, with a 95% CI [0.103, 0.417], p = 0.0013, and d = 0.53. Conclusions: U19 players demonstrated lower F₀, lower v₀, and reduced mechanical effectiveness compared with senior players. Regular monitoring of F–v profiles and individualized training interventions (force- or velocity-targeted) may be useful for training and monitoring strategies aimed at supporting physical preparation during the transition to senior soccer. Full article

Background: Non-classical MHC class I molecules MICA and MICB are stress-inducible NKG2D ligands that contribute to immune surveillance, non-HLA antibody formation, and alloreactivity in solid organ and hematopoietic stem cell transplantation; population-level data for Southern Europe remain limited. Methods: High-resolution MICA and MICB genotyping was performed in 1364 unrelated individuals from southern Portugal using a hybrid-capture next-generation sequencing workflow, and allele calls were analyzed with standard population-genetic metrics (allele and genotype frequencies, heterozygosity, Hardy–Weinsberg equilibrium, and LD-like D, D′, r²) and multilocus allele presence/absence encodings explored by k-means clustering, spectral clustering, principal component analysis, t-distributed stochastic neighbor embedding, and uniform manifold approximation and projection. Results: Forty-two MICA and twenty-two MICB alleles were identified; MICA*002:01, MICA*004:01, MICA*008:01, MICA*008:04 and MICB*002:01, MICB*004:01, MICB*005:02, MICB*008:01 were most frequent, and most individuals carried at least two distinct MICA and two distinct MICB allotypes. Co-occurrence and LD-like analyses revealed conserved MICA–MICB combinations, including a strong association between MICA*009:02 and MICB*005:06, while unsupervised analyses identified partially overlapping multilocus genotype backgrounds and recurrent four-allele constellations. Conclusions: These findings provide a detailed non-classical MHC reference for southern Portugal and a multilocus framework to support interpretation of non-HLA antibodies and MICA/MICB-aware donor evaluation in selected clinical scenarios, as well as the development of machine learning-based immunologic risk models. Full article

Background: Upper-limb performance in handball depends on accurate shoulder sensorimotor control under high loads and fatigue. This study examined between-cohort differences associated with concentric versus eccentric exercise-induced fatigue in shoulder proprioception, kinesthesia, functional stability, and isometric force output in professional male handball players. Methods: This was a retrospective, quasi-experimental (non-randomized) between-cohort comparison of two previously collected cohorts who completed either a concentric (n = 46) or eccentric (n = 33) fatigue protocol, with pre- and post-fatigue assessments of joint repositioning sense (absolute angular error, AAE), threshold to detection of passive movement (TTDPM), Y Balance Test Upper Quarter (YBT-UQ), and the Athletic Shoulder (ASH) test. Results: Fatigue significantly increased AAE across all tested angles (Time: all p < 0.001), with a contraction-specific effect at end-range internal rotation (IR45°), where AAE increased more after concentric than eccentric fatigue (Time × Fatigue Type: p = 0.017; Δ = +1.34° (+61.8%) vs. +0.20° (+7.4%)). TTDPM increased after fatigue (p = 0.001) with no interaction (p = 0.968). YBT-UQ performance decreased after fatigue for all dominant-limb outcomes and for non-dominant inferolateral, superolateral, and composite scores (all p ≤ 0.018), but not for non-dominant anteromedial reach (p = 0.986); no Time × Fatigue Type interactions were detected for YBT-UQ outcomes (all p > 0.05). ASH force output decreased across all positions and both limbs (all p ≤ 0.002), with the dominant-limb Y position showing a greater decline following eccentric fatigue (Time × Fatigue Type: p = 0.030; e.g., ASH Y dominant Δ = −0.49 (−4.6%) vs. −1.43 N·kg⁻¹ (−13.3%)). Conclusions: Exercise-induced fatigue impairs shoulder sensorimotor function and upper-limb performance in handball. Contraction-mode differences were small and task-specific in this between-cohort comparison, emerging primarily at end-range proprioception and selected isometric strength positions. These findings may inform the design of training programs that emphasize fatigue-resistant sensorimotor control and end-range strength, while causal inferences regarding contraction mode are not warranted given the non-randomized design. Full article

Hepatocellular carcinoma (HCC) exhibits a striking male predominance, particularly in Hepatitis B Virus (HBV) endemic regions. While lifestyle factors and estrogen protection are traditional explanations, they fail to fully account for this disparity. This review elucidates the molecular mechanisms driving this gender gap, focusing on the interplay between the Androgen Receptor (AR), viral replication, and the suppression of NKG2D-mediated immune surveillance. We synthesized experimental and clinical findings linking AR signaling, the viral protein HBx, and the regulation of NKG2D ligands (MICA/MICB). Current evidence identifies a positive feedback loop where AR enhances HBV replication, while HBx amplifies AR activity. Crucially, this axis systematically dismantles innate immunity: AR signaling represses MICA/B transcription via miRNA networks and upregulates ADAM metalloproteases, leading to ligand shedding and the release of soluble MICA (sMICA), effectively blinding Natural Killer (NK) cells. We propose that historical failures of anti-androgen monotherapy likely stemmed from ignoring this immune modulation. Consequently, targeting the AR-NKG2D axis represents a promising strategy to sensitize tumors to immunotherapy, suggesting that future therapeutic approaches should combine AR modulation with immune checkpoint inhibitors or shedding-blockade. Full article

Background: Previous research suggests that resistance training in hypoxia can cause physiological and muscle adaptations. However, this method may not be efficient for individuals who are training to optimize maximal strength and power. Objective: This study aimed to investigate the effects of 8 weeks of high-intensity resistance circuit in normobaric hypoxic conditions on maximal and explosive measures of muscle strength in upper and lower limbs. Methods: A total of 28 subjects were randomly assigned to either hypoxia (fraction of inspired oxygen [F_IO₂] = 15%; HRC_hyp: n = 15; age: 24.6 ± 6.8 years; height: 177.4 ± 5.9 cm; weight: 74.9 ± 11.5 kg) or normoxia [F_IO₂] = 20.9%; HRC_norm: n = 13; age: 23.2 ± 5.2 years; height: 173.4 ± 6.2 cm; weight: 69.4 ± 7.4 kg) groups. Training sessions consisted of two blocks of three exercises and the training intensity was fixed performed at six repetition maximum. Participants exercised twice weekly for 8 weeks, and upper and lower body power tests were performed before and after the training program. The statistical analysis applied was a two-way analysis of variance with repeated measures and Bonferroni post hoc. Results: No significant differences were observed between groups. However, the hypoxia group showed higher intra-group differences in absolute (N) (F = 7.97; Δ7.3%; p < 0.05; ES = 0.49) and relative (N/Kg) (F = 8.34; Δ7.2%; p < 0.05; ES = 0.49) maximum push-up force after the training period. Conclusions: Hypoxic circuit training may improve a specific upper body performance outcome, but no clear advantage over normoxia was observed. Full article

Natural Killer (NK) cell-based immunotherapy relies on CD16-mediated Antibody-Dependent Cellular Cytotoxicity (ADCC), yet the ovarian tumor microenvironment (TME) severely compromises this function via Transforming Growth Factor-beta (TGF-β). This study investigated the molecular mechanisms driving this suppression and evaluated a bi-specific Chimeric Antigen Receptor (CAR) strategy to overcome this hurdle. Primary PBNK cells exposed to TGF-β showed sustained canonical SMAD2 phosphorylation, accompanied by a marked reduction in activating receptors such as CD16 and NKG2D and an increase in exhaustion markers such as PD-1. Functionally, these phenotypic alterations led to failed infiltration and cytotoxicity in vitro and within ovarian cancer-derived spheroids. To overcome this limitation, we engineered NK-92 cells with a bi-specific CAR-targeting Folate Receptor Alpha (FRα) and CD16. While TGF-β typically impairs NK cell function, our armed CAR-NK cells successfully infiltrated tumoroids and synergized with Trastuzumab to induce potent ADCC-mediated lysis. Our findings define the TGF-β/SMAD2 axis as a central driver of NK cell dysfunction in ovarian cancer and demonstrate that bi-specific CAR-NK platforms offer a robust therapeutic solution to bypass TME-induced suppression and restore antibody-mediated tumor suppression. Full article

Natural Killer (NK) cells contribute to airway inflammation in severe eosinophilic asthma (SEA). IL-33, elevated in SEA, may modulate NK cell function, but its effects are unclear. We analyzed peripheral blood NK cell subsets from five SEA patients and five healthy controls using flow cytometry, assessing CD56/CD16-defined subsets and markers, CD57, NKG2A, CD62L, and ICAM-1, at baseline and after 72 h IL-33 stimulation. SEA patients showed reduced mature cytotoxic NK cells and altered expression of adhesion and regulatory molecules. IL-33 selectively increased ICAM-1 and NKG2A in mature NK cells, while decreasing these markers in immature subsets. These findings indicate that IL-33 differentially regulates NK-cell phenotype and function, highlighting NK cells as dynamic mediators of inflammation in SEA. Full article

Breast cancer (BC) is a global health problem. BC is a biologically heterogeneous disease in which novel immunotherapeutic strategies are needed, particularly in the metastatic setting. The NKG2D/NKG2D ligand (NKG2DL) axis is a key component of innate antitumor immunity and represents a potential therapeutic target, but its relevance in BC has not been fully characterized. We performed an in silico analysis of NKG2DL expression in BC cell lines, healthy breast tissue, and tumor samples using publicly available transcriptomic databases (DSMZCellDive, ShinyTHOR, GTEx, TCGA, Human Protein Atlas), complemented by survival analyses from TCGA and KMPlot and a narrative review of the literature. NKG2DL transcripts were consistently expressed in BC cell lines and tumor tissues, with higher expression observed in ductal histology, higher tumor stage, and basal molecular subtype. Survival analyses showed heterogeneous and generally weak associations between individual NKG2DLs and clinical outcomes. In silico proteomics data are scarce, but the narrative review showed that NKG2DLs are expressed by immunohistochemistry in tumor tissues but absent in surrounding healthy tissues. The literature review also revealed concomitant dysfunction of NKG2D+ effector cells due to multiple resistance mechanisms (including ligand shedding). We also review potential therapeutic approaches. Full article

Background: Lung cancer and chronic obstructive pulmonary disease (COPD) are morbid and mortal conditions arising from noxious endothelial stress. Soluble Major Histocompatibility Complex I Chain Related A (sMICA) is an activating ligand for the NKG2C receptor, and the soluble form indicates endothelial stress and is a mechanism for evading immune surveillance in lung cancer. We provide independent associations between sMICA*008 levels and the prevalence of lung cancer, lung cancer histologies, COPD, and risk factors for both diseases. Methods: We describe statistical associations between sMICA and demographic and clinical variables. Multivariate linear regression determined the independent associations between sMICA levels and lung cancer histology, between those with and without primary lung cancer, and prevalent COPD in participants without lung cancer. Point estimates and 95% confidence intervals are reported; p < 0.05 is considered statistically significant. Results: The cohort (n = 586 patients) included 24% female and 48% current or former smokers. Mean sMICA were 5.20 pg/mL ×10², and FEV1%-predicted of 62. sMICA levels were higher in those who smoked vs. those who did not. In Multivariate regression, non-small cell lung cancer (NSCLC) was associated with 14.2 pg/mL ×10² (95% CI 3.57 to 24.9 pg/mL ×10²) higher sMICA levels compared to those without cancer. No other histology was independently associated with higher sMICA. Primary lung cancer [12.5 pg/mL ×10² (2.85 to 22.2 pg/mL ×10²)] and COPD in those without cancer [4.38 pg/mL ×10² (0.38 to 8.39 pg/mL ×10²)] were associated with higher sMICA. Conclusions: sMICA*008 is independently associated with NSCLC, primary lung cancer, and COPD, respectively, in a cohort of current, former, and never smokers with and without lung cancer. sMICA levels were also higher in smokers. This study provides a foundation for future studies on sMICA activity in lung cancer and COPD, and assessment of sMICA as a biomarker for lung cancer cell type and risk of lung function loss in COPD. Full article

As an early cradle of China’s plastics industry and a typical megacity, Shanghai’s urban rivers face increasingly severe microplastic pollution. This study selected the Suzhou River, known as Shanghai’s “mother river,” as its research subject. It systematically investigated the pollution characteristics of microplastics in the water and sediments, as well as the heavy metals carried on their surfaces. The abundance, shape, particle size, color, and polymer composition of microplastics were analyzed. SEM–EDS was employed for semiquantitative analysis of surface-bound heavy metals on microplastics. Results: The average microplastic abundance in the Suzhou River water was 2.18 ± 0.76 n·L⁻¹, whereas the average microplastic abundance in the sediments was 939.29 ± 401.26 n·kg⁻¹, indicating a relatively high pollution level in the sediments. Microplastics predominantly comprise fragments, fibers, and films, with polypropylene (PP), polyethylene (PE), and polyethylene terephthalate (PET) as the primary polymer types. EDS analysis detected 11 heavy metals on microplastic surfaces: Ti, Cr, Fe, Zn, Ga, As, Cd, In, Sn, Hg, and Pb. Critically, fragmented MPs were the primary carriers of multiple heavy metals, containing up to 7 different elements in sediments, including toxic Pb and Hg. Compared to water bodies, the metal spectrum loaded in sediments is more complex. It highlights their role as long-term reservoirs for co-pollutants. These findings demonstrate that MPs, especially fragments accumulated in sediments, may serve as significant vectors for the persistent storage and potential bioaccessible transfer of toxic heavy metals in urban aquatic ecosystems, posing a distinct long-term ecological risk that complicates sediment remediation efforts. Full article

Neoadjuvant systemic therapy (NST) is standard for locally advanced breast cancer (BC), yet predictors of pathological complete response (pCR) remain elusive. While Natural Killer (NK) cells are vital for anti-tumor response, their specific receptor dynamics during NST are poorly defined. This study provides a high-dimensional characterization of the peripheral NK cell landscape and immune signatures associated with therapeutic success. This prospective cohort study included 34 BC patients and 35 healthy donors (HD). Clinical characteristics were collected, and peripheral blood NK cell subsets were evaluated. We utilized high-parameter flow cytometry and unsupervised clustering (UMAP) to longitudinally track NK cell phenotypes (NKG2D, DNAM-1, PD-1, TIGIT) pre- and post-NST. NK cell cytotoxicity was evaluated, and serum levels of related IL-17A (interleukin), IL-2, IL-4, IL-10, IL-6, TNF-α (tumor necrosis factor-alpha), Fas, sFasL, IFN-γ (interferon-gamma), and Granzyme A were analyzed. Patients exhibited distinct NK cell profiles according to the pathological response. Only 12 BC patients achieved pCR. These patients showed improved NK cell cytotoxicity and higher concentrations of IL-2, TNF-α, sFASL, and Granzyme B after treatment compared with Non-pCR patients. In contrast, in Non-pCR patients, the percentages of CD56^bright NK cells increased after neoadjuvant therapy, whereas the more cytotoxic CD56^dim NK cell population decreased. Additionally, NK cells from Non-pCR patients exhibited higher co-expression of inhibitory checkpoints (TIGIT and PD-1), indicating reduced NK cell function. Otherwise, pCR patients displayed a more favorable balance of activating receptors (NKG2D and DNAM-1), and a favorable shift in the TIGIT/DNAM-1 activating-to-inhibitory axis. This study highlights the potential role of NK cells in determining the response to neoadjuvant therapy in BC patients. Those who achieved pCR showed enhanced NK cell activity and higher expression of activating receptors. Moreover, NK cells from Non-pCR patients showed lower cytotoxicity and higher expression of inhibitory receptors. These results suggest that NK cell phenotype evaluation could serve as a biomarker of treatment response in patients with BC. They also showed that the TIGIT/DNAM-1 axis can be a critical determinant of pCR. Full article

Major histocompatibility complex class I chain-related gene A (MICA) is a non-classical MHC-I molecule essential for immune surveillance, yet its intracellular maturation remains poorly understood. We show that MICA is predominantly retained intracellularly in melanoma cells and colocalizes with the endoplasmic reticulum chaperone calreticulin (CRT). Notably, MICA also colocalizes with CRT in healthy skin. Immunoprecipitation assays reveal that CRT preferentially associates with a low-molecular-weight form of MICA. Recombinant protein assays and in silico analyses support direct interaction between CRT and non-glycosylated MICA, but not with fully glycosylated eukaryotic MICA. These findings identify CRT-dependent retention of MICA as a physiological checkpoint that may be dysregulated in melanoma to promote immune evasion. Full article

Background: Sitting and standing with conventional hip–knee–ankle–foot (HKAF) prostheses are demanding tasks for hip disarticulation (HD) amputees due to the passive nature of current prosthetic hip joints that cannot assist with moment generation. This study developed a sitting and standing control strategy for a motorized hip joint and evaluated whether providing active assistance reduces the intact side demand of these activities. Methods: A dedicated control strategy was developed and implemented for a motorized hip prosthesis (Power Hip) compatible with existing prosthetic knees, feet, and sockets. One HD participant was trained to perform sitting and standing tasks using the Power Hip. Its performance was compared with the participant’s prescribed passive HKAF prosthesis through measurements of ground reaction forces (GRFs), joint moments, and activity durations. GRFs were collected using force plates, kinematics were captured via Theia3D markerless motion capture, and joint moments were computed in Visual3D. Results: The Power Hip enabled more symmetric limb loading and faster stand-to-sit transitions (1.22 ± 0.08 s vs. 2.62 ± 0.41 s), while slightly prolonging sit-to-stand (1.69 ± 0.49 s vs. 1.22 ± 0.40 s) compared to the passive HKAF. The participant exhibited reduced intact-side loading impulses during stand-to-sit (4.97 ± 0.78 N∙s/kg vs. 15.06 ± 2.90 N∙s/kg) and decreased reliance on upper-limb support. Hip moment asymmetries between the intact and prosthetic sides were also reduced during both sit-to-stand (−0.18 ± 0.09 N/kg vs. −0.69 ± 0.67 N/kg) and stand-to-sit transitions (0.77 ± 0.20 N/kg vs. 2.03 ± 0.58 N/kg). Conclusions: The prototype and control strategy demonstrated promising improvements in sitting and standing performance compared to conventional passive prostheses, reducing the physical demand on the intact limb and upper body. Full article