Search Results (185,557)

Brain aging is characterized by heterogeneous microglial states and altered mitochondrial, metabolic, and lysosomal homeostasis. Mitophagy is central to mitochondrial quality control, but its contribution to age-associated microglial dysfunction remains incompletely understood. This review examines how microglial mitophagy interacts with mitochondrial and lysosomal quality control, immunometabolic adaptation, and inflammatory signaling during brain aging, while distinguishing direct microglial evidence from findings derived from other experimental systems. Aging remodels microglial mitochondrial, metabolic, and lysosomal functions in a state- and context-dependent manner, including reactive, disease-associated, lipid-associated, and senescence-like states. Mitophagy may preserve mitochondrial quality control by limiting the accumulation of damaged mitochondria and associated oxidative and danger signals. However, static mitophagy-associated markers do not establish completed mitophagic flux, which requires mitochondrial delivery to lysosomes and subsequent degradation within them. Human postmortem studies reveal age- and disease-associated alterations in mitochondrial quality control and mitophagy-related pathways, but direct measurements of mitophagic flux in defined human microglial populations remain limited. Age-related changes in lysosomal capacity, acidification, metabolic stress, mitochondrial dynamics, and coordination between mitochondrial clearance and biogenesis may collectively influence microglial resilience. Whether phagocytic and mitophagic cargo directly compete for lysosomal capacity remains unproven. We therefore propose a Microglial Mitophagy Threshold Model as a conceptual, testable framework in which mitochondrial damage, mitophagic clearance, lysosomal capacity, mitochondrial renewal, and microglial state collectively determine mitochondrial homeostasis or persistent inflammatory dysfunction. Microglial mitophagy should be viewed as part of an interconnected mitochondrial–lysosomal quality control network. Direct assessment of mitophagic flux alongside microglial state, mitochondrial dynamics and function, bioenergetics, and lysosomal capacity will be essential to validate this framework. Full article

Understanding seed longevity in genebanks is fundamental for effective long-term conservation of plant genetic resources. Although storage environment, species biology, seed age, and oxygen exposure are known to influence viability, substantial variation in germination among accessions stored under identical conditions suggests the presence of additional genetic determinants. Here, we analysed 947 barley seed lots (686 hulled and 261 hulless) across nine harvest years (1975–2017) to assess the relationship between seed viability and a broad range of phenotypic traits, including plant phenology, inflorescence and seed morphology, and seed macronutrient composition. Each harvest year represented a distinct set of genebank accessions cultivated under uniform field conditions and stored for equal durations. Hulled barley consistently exhibited higher viability than hulless barley, and grain protein content was negatively associated with germination in five of the seven years studied. Additionally, year-specific but statistically significant associations were detected for ear emergence timing and lemma pigmentation. These results underscore the value of comprehensive genebank descriptors and phenotypic metadata for improving predictions of seed longevity and supporting strategic germplasm conservation. Full article

Extracellular vesicles (EVs) mediate endocrine and metabolic signalling. EV responses to shifts in substrate utilisation, from euketonaemia to hypoketonaemia, remain poorly understood. Chronic hyperinsulinaemia suppresses ketogenesis, causing hypoketonaemia; however, its impact on EV profiles in metabolically healthy individuals has not been characterised. We investigated the effects of hypoketonaemia on EV profiles in the KetoSAge cohort, examining associations between EV concentration, mean size, and modal size and metabolic–endocrine biomarkers. Ten lean (BMI, 20.52 ± 1.39 kg/m²), healthy premenopausal women (mean age, 32.30 ± 8.97 years) maintaining euketonaemia (mean 3.9 ± 2.3 years) completed a three-phase crossover trial, comprising 21 days each of: euketonaemia (baseline), induced-hypoketonaemia, and return-to-euketonaemia. No statistically significant phase-level differences in EV concentration or size parameters were detected. Linear mixed-effects analyses identified nominally significant associations between EV concentration and adiponectin, free T3, bilirubin, luteinising hormone, and epidermal growth factor, between EV mean size and HDL-cholesterol and between EV modal size and insulin, HOMA-IR, beta-hydroxybutyrate, GKI, thyroid hormones, ALT, AST, IL-6 and oestrogen (all unadjusted p < 0.05). However, none of these associations remained statistically significant after false discovery rate correction (FDR < 0.10). Hypoketonaemia via insulin-compensated euglycaemia revealed coordinated EV–biomarker relationships across metabolic–endocrine, hepatic and inflammatory pathways. Although exploratory, these findings suggest that EV profiles may reflect an insulin-responsive signalling network linked to the systemic bioenergetic state, highlighting their potential as early indicators of metabolic–endocrine adaptation. Full article

SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors constitute a plant-specific family defined by a conserved SBP DNA-binding domain. They recognize cis-elements containing the core GTAC motif and cooperate with various co-regulators to govern downstream gene expression, thereby participating in leaf morphogenesis, phase transition, fruit development, anthocyanin accumulation and abiotic stress adaptation. Notably, the abbreviation SPL is also used for the unrelated SPOROCYTELESS/NOZZLE (SPL/NZZ) protein, which belongs to a separate family lacking the SBP-box domain; these two families should not be confused. Flower development, a central reproductive program in angiosperms, encompasses the acquisition of flowering competence, the vegetative-to-reproductive transition, floral meristem specification, organ patterning, and gametophyte formation. This review summarizes structural characteristics and classification of SPL proteins, distinguishes miR156/miR157-targeted paralogs from non-targeted ones, and synthesizes current understanding of their molecular functions across successive floral stages. Acting as signaling hubs, SPLs integrate photoperiod, gibberellin-DELLA, age-dependent miR156/miR157, temperature, sugar and cytokinin signals to fine-tune flowering time. They drive the reproductive transition via direct activation of LFY, FUL and AP1, and later remodel inflorescence architecture and floral organ size by balancing cell proliferation and expansion. In addition, they maintain fertility by modulating gametogenesis. Based largely on findings from Arabidopsis thaliana, we construct an updated regulatory framework for SPL-dependent floral development, compare conserved and lineage-divergent functions across herbaceous and woody species, identify unresolved questions, and discuss potential applications for crop improvement. Full article

Background: Schizophrenia is frequently underdiagnosed or diagnosed late due to the lack of objective diagnostic markers. This study aimed to develop and validate a machine learning model using routine hematological parameters for the auxiliary diagnosis of schizophrenia. Methods: A total of 150 first-episode drug-naïve schizophrenia patients and 150 healthy controls were enrolled. Study parameters included routine hematological parameters and its derived inflammatory markers. Feature selection was performed using Elastic Net regression, followed by the construction of an L2-regularized logistic regression model. Model discriminative performance, calibration, and clinical utility were assessed through internal validation, area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. An independent cohort of 50 schizophrenia patients and 50 patients with major depressive disorder (MDD) was used for exploratory differential diagnostic evaluation. Results: The final model incorporated 12 features: neutrophil count (NEUT), eosinophil count (EO), mean platelet volume (MPV), hematocrit (HCT), hemoglobin (HGB), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-platelet ratio (NPR), along with age and sex. The model achieved an AUC of 0.859 (95% CI: 0.780–0.937) on the test set, with an accuracy of 0.767, sensitivity of 0.711, and specificity of 0.822. Calibration curves confirmed good calibration, and decision curve analysis further verified its clinical utility. In the exploratory differential diagnostic analysis, the model showed limited performance in distinguishing schizophrenia from MDD. Conclusions: The model based on routine hematological parameters and L2-regularized logistic regression can effectively differentiate first-episode drug-naïve schizophrenia patients from healthy controls, providing a low-cost and easily accessible auxiliary diagnostic tool for clinical practice. Full article

Background: Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, reflecting the quantity of the remaining follicular pool. While chronological age is the primary determinant of AMH concentrations, emerging evidence suggests that vitamin D, vitamin B12, folate, and iron metabolism parameters may also influence ovarian function through mechanisms involving steroidogenesis, DNA synthesis, and oxidative stress regulation. However, clinical findings regarding these associations remain inconsistent. Objective: The aim of this study was to evaluate the relationships between serum AMH concentrations and biomarkers of vitamin D status, vitamin B12, folate, ferritin, and lipid profile in women of reproductive age, and to compare the strength of these associations with that of chronological age. Methods: This retrospective, observational, cross-sectional study included 264 women who underwent AMH testing at Atlas University Hospital. Demographic and laboratory data including AMH, age, vitamin D, vitamin B12, folic acid, ferritin, and lipid parameters were extracted from electronic medical records. Bivariate correlations were assessed using Pearson’s and Spearman’s coefficients on both untransformed and Box–Cox power-transformed data, and were repeated as first-order partial correlations conditioning on chronological age. Statistical significance was set at p < 0.05. Results: The mean age was 34.61 ± 5.75 years, and median AMH was 0.96 ng/mL (Q1–Q3: 0.34–2.34). Age showed a moderate-to-strong, significant inverse correlation with AMH (Pearson’s r = −0.508, Spearman’s rho = −0.547; p < 0.001), and the linear component of this association strengthened after Box–Cox transformation (Pearson’s r = −0.553; p < 0.001). In contrast, vitamin D, vitamin B12, folic acid, ferritin, and lipid parameters (triglycerides, HDL, LDL, total cholesterol) showed no statistically significant and no clinically meaningful correlation with AMH, with all coefficients remaining below 0.20 regardless of transformation (all p > 0.05). After adjustment for age, every coefficient attenuated further towards the null (all |r_partial| < 0.10; all p ≥ 0.127), the largest being that of 25-hydroxyvitamin D (r_partial = 0.094, 95% CI −0.027 to 0.213). A sensitivity power analysis confirmed 80% power to detect an age-adjusted partial correlation of |r| = 0.172 and 91% power at |r| = 0.200. Conclusions: Age remains the principal determinant of ovarian reserve, while vitamin D, vitamin B12, folic acid, ferritin, and lipid parameters show no statistically significant or clinically meaningful association with AMH. These findings suggest that any biological influence of these micronutrients on ovarian reserve, if present, is markedly overshadowed by age-dependent follicular decline. Prospective studies incorporating longitudinal AMH measurements and standardized nutritional assessment are needed to further clarify these relationships. Full article

The increasing demand for sustainable construction materials has intensified interest in alternative fine aggregates for shotcrete production. Crushed glass aggregate (CGA) offers environmental and economic benefits by diverting waste glass from landfills and reducing reliance on natural sand; however, its influence on the fresh-state rheological behaviour of wet-mix shotcrete remains poorly understood. This study investigated the effects of replacing natural sand with a commercially processed angular CGA (particle size approximately 0.1–2.0 mm) at levels of 5–100% by volume on flowability and early-age rheological behaviour using mixtures with constant water content and optimised superplasticiser dosage. Flow table testing was combined with steady-shear and oscillatory rheological measurements to characterise viscosity, shear stress, and viscoelastic transitions relevant to flow initiation. Moderate CGA replacement levels (10–20%) exhibited the most favourable rheological performance, characterised by reduced low-shear viscosity, lower resistance to flow initiation, and earlier viscoelastic transition compared to the control mix. By contrast, high CGA replacement levels (≥75%) exhibited increased low-shear viscosity, stronger elastic behaviour, and delayed or absent viscoelastic transition despite achieving target flow values through admixture adjustment. These results demonstrate that empirical flow tests alone cannot fully capture shear-dependent flow behaviour. Moderate CGA replacement therefore represents a viable pathway for improving shotcrete sustainability while maintaining favourable fresh-state rheological performance. Full article

Background: In the 1960s and 1970s, several authors reported that manipulation of diet by excluding certain additives and natural chemical substances led to apparent clinical benefit for patients with adverse food reactions involving the skin, gastrointestinal tract, respiratory tract, and central nervous system. Methods: Over the past 48 years, patients of all ages presenting to the Royal Prince Alfred Hospital Allergy Unit with adverse food reactions were offered an elimination diet low in natural salicylates, biogenic amines, and glutamate, and free of additives such as preservatives and colors, for two to six weeks. Those who became asymptomatic were offered testing with a “N-of-1” double-blind, placebo-controlled (DBPC) challenge protocol. Results: There were 14,119 patients who elected to undertake either the strict elimination diet (10,074) (71.4%), the moderate approach (2760) (19.5%), or the simple approach (1285) (9.1%). Of these, 6645 (47.1%) became asymptomatic within two to six weeks; 628 (4.4%) reported no improvement; and 6846 (48.5%) were lost to follow-up. Of those who improved, 4963 (35.2%) returned for interpretation of their challenges, and 2429 had undertaken open food challenges; 3326 had completed the DBPC capsule challenge protocol, and 1830 completed both DBPC capsule and food challenges. Although individual reactivity was idiosyncratic, a highly reproducible pattern was evident across the entire group. The proportion reacting to each of the active chemical challenges versus placebo was highly significant (p < 0.001). Conclusions: In many patients with food intolerance, idiosyncratic dietary triggers can be reliably identified with a standardized elimination diet and DBPC challenge protocol. Long-term symptom control can be achieved by appropriate dietary modification. Full article

Chronic low back pain (cLBP) compromises daily function, but associated balance deficits remain difficult to quantify using traditional scales. We recruited 50 participants with CLBP (age: 65.68 ± 11.84) and 50 age-matched controls (age: 65.26 ± 10.73) wearing multiple inertial measurement units (IMUs) to evaluate kinematics: average absolute angular velocity ($J\omega$) and linear acceleration ($J\alpha$) across static (single-leg stance), perturbed (balance board), locomotor (walking, tandem gait), and transitional (five times sit-to-stand) tasks. Group differences were assessed using multivariate analysis of variance and Bonferroni-adjusted univariate tests. During the balance board test, $J\omega$ was significantly higher at the chest ($p$ = 0.027) and hip ($p$ = 0.003) in the CLBP group. Conversely, during the sit-to-stand tests, the CLBP group showed significantly lower $J\alpha$ and $J\omega$ (p < 0.0001) at the hip. The CLBP group exhibited globally lower $J\omega$ ($p$ < 0.01) during normal walking, while the ${Amp}_{PR}$ ($p$ = 0.001) was exclusively reduced during tandem gait. These results suggest that multi-sensor IMU-based assessments provide a sensitive tool for detecting subtle, task-specific balance deficits in CLBP, indicating that rehabilitation should target rotational mobility and reactive control rather than core stiffening alone. Larger-scale and longitudinal research is still required to determine their clinical utility. Full article

Background: Trans-resveratrol (3,5,4′-trihydroxystilbene) is a natural polyphenolic antioxidant widely used in anti-aging dermocosmetics for its strong radical-scavenging capacity and its activation of cell-protective pathways such as sirtuin 1 (SIRT1). However, its poor aqueous solubility, photochemical lability, and low bioavailability limit its incorporation into topical formulations and its delivery into the skin. Objective: In this study, ethosomal nanocarriers were designed as a phospholipid–ethanol vesicular system to solubilize, stabilize, and control the release of trans-resveratrol for dermocosmetic applications. Microfluidization is not a commonly used method; however, circulating the formulation through the interaction chamber under optimized pressure can produce ethosomes with desirable colloidal stability by this simple process. Methods: Resveratrol-loaded ethosomes were prepared with synthetic phosphatidylcholine (Lipoid P75), ethanol, and vitamin E. Microfluidization was optimized by varying the number of high-pressure homogenization cycles and the applied pressure. Vesicle size, size distribution and distribution uniformity, zeta potential, pH, conductivity, density, and long-term stability were monitored for up to 180 days; morphology was examined by cryogenic scanning electron microscopy (cryo-SEM) and molecular compatibility by Fourier-transform infrared (FTIR) spectroscopy. A trans-resveratrol high-performance liquid chromatography (HPLC) assay was developed and validated according to International Council for Harmonisation (ICH) Q2 guidelines for quantitative analysis. Encapsulation efficiency was determined by HPLC after ultracentrifugation, cytotoxicity was assessed in human keratinocytes (HaCaT), and in vitro release was evaluated using Franz diffusion cells with two different membranes. Results: All ethosome formulations yielded a nanoscale size distribution (median diameter around 190 nm for loaded and around 90 nm for unloaded) and good colloidal stability, with absolute zeta potentials above the 30 mV threshold at early time points and a skin-compatible pH (around 6.5). The optimized formulation (T16; 1.5% w/w trans-resveratrol, 5% w/w phosphatidylcholine (Lipoid P75), 0.3% w/w vitamin E and 30% w/w ethanol, processed with seven microfluidization cycles) achieved a high encapsulation efficiency (EE) of 95.5% on day 1. 84.2% EE was retained after 180 days, consistent with strong partitioning of the lipophilic active into the ethanol–phospholipid bilayer. FTIR confirmed preservation of the phospholipid bilayer and indicated non-covalent loading, with the resveratrol bands largely masked by the dominant lipid signals. Cryogenic Scanning Electron Microscopy (Cryo-SEM) confirmed near-spherical vesicles with narrow size distribution. In vitro release showed a sustained, controlled release profile relative to a 1.5% w/w resveratrol solution. Slower diffusion across the skin-mimicking Strat-M membrane was observed compared to cellulose acetate membrane. Conclusions: Optimized trans-resveratrol-loaded ethosomes represent a stable, efficient vesicular system enabling formulation stability and controlled topical release. The antioxidant and photoprotective efficacy of the loaded system was not assessed in this study and is identified as a topic for future work. Full article

Complex and semi-refractory gold–silver ores pose significant challenges for efficient metal recovery using conventional cyanidation methods. This study investigates the effect of roasting thermal pretreatment on the leaching performance and mineralogical structure of a polymetallic gold–silver ore from northeastern Türkiye. The samples were roasted at 220 °C, 420 °C, and 620 °C prior to cyanidation to evaluate roasting-induced mineralogical transformations and their effects on metal recovery. High-temperature roasting markedly improved both gold and silver recovery. Gold recovery increased from 75% for the untreated ore to 95.84%, while silver recovery increased from 69.72% to 86.12% after roasting at 620 °C. XRD analysis indicated the transformation of pyrite to hematite, while the characteristic reflections of kaolinite and sphalerite were no longer detected at 620 °C. Moreover, the lowest cyanide consumption (6.5 kg NaCN/t ore) was observed after roasting at 620 °C, coinciding with the highest Au and Ag recovery. These results indicate that roasting-induced mineralogical transformations enhance the accessibility of precious-metal-bearing phases during subsequent cyanidation. Overall, controlled high-temperature roasting shows potential for improving Au and Ag recovery while reducing cyanide consumption in complex semi-refractory ores. Full article

Objective: We aimed to evaluate the association between pre-pregnancy excess weight and the adequacy of the ω-6/ω-3 ratio using a directed acyclic graph (DAG) to guide the selection of potential confounders. Methods: We conducted a cross-sectional study with 89 lactating women visiting a breast milk bank in Rio de Janeiro, Brazil. Pre-pregnancy excess weight was assessed using the body mass index according to World Health Organization criteria. ω-6 and ω-3 levels were determined by gas chromatography, and their ratios were calculated and categorized, with a ratio of greater than 10 being considered inadequate in accordance with dietary intake recommendations for these fatty acids. A DAG was constructed to identify a minimally sufficient set of confounders, including maternal age, socioeconomic status, parity, interbirth interval and food consumption patterns. Prevalence ratios were estimated using Poisson regression with robust variance. Results: The mean ω-6/ω-3 ratio was 10.8. Prevalence of inadequate ω-6/ω-3 ratio was higher in women with pre-pregnancy excess weight compared to women with normal pre-pregnancy weight. After adjusting for the confounders identified by the DAG, prevalence of inadequate ω-6/ω-3 ratio was higher among women with pre-pregnancy excess weight (PR = 1.35; 95% CI: 1.02–1.78). Conclusions: Pre-pregnancy excess weight is associated with an unfavorable breast milk lipid profile characterized by an imbalance in the ω-3 to ω-6 essential fatty acid ratio. The use of a DAG-based approach enables parsimonious and theoretically grounded adjustment for potential confounders, contributing to greater robustness of the findings. Our results underscore the importance of nutritional care strategies during the preconception period to promote maternal and child health. Full article

Background/Objectives: This study aimed to characterize the cell-mediated immune (CMI) profile—peripheral lymphocyte subsets, a 14-cytokine panel, and intracellular granzyme B/perforin expression—in children with acute IM compared with age- and sex-matched healthy controls, and to describe its dynamics at symptom resolution in an exploratory paired subset. This is a descriptive, hypothesis-generating study. Methods: We enrolled 40 patients and 50 healthy controls, analyzing peripheral blood T cell subsets, intracellular granzyme B and perforin expression, and serum cytokines. Cross-sectional comparisons were made between the IM group and the healthy control group at diagnosis; in addition, paired samples obtained at clinical symptom resolution were available for a subset of 7 patients and were analyzed as an exploratory longitudinal comparison. Results: Patients showed significantly elevated leukocytes, lymphocytes, and monocytes compared to healthy controls. Immunophenotyping revealed a higher total T cell count, with a lower CD4+ frequency but higher absolute count, and markedly increased CD8+ frequency and count. The B cell frequency was lower, while the NK cell frequency was lower but its absolute count was higher. A broad elevation in measured cytokines was observed, with significantly higher levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17A, IL-17F, IL-22, TNF-α, TNF-β, and IFN-γ. A cytotoxic phenotype was also more pronounced, with increased proportions of granzyme B- and perforin-expressing cells among CD3+ T cells, CD3+CD8+ T cells, and CD3-CD16/56+ NK cells. Conclusions: In conclusion, pediatric IM is characterized by profound changes in immune cell numbers and proportions, serum cytokine levels, and the expression of cytotoxic-effector molecules. These descriptive findings largely confirm the expected acute anti-EBV response and, in particular, reveal a pronounced coordinated CD8+/NK cytotoxic-effector signature. They warrant prospective, controlled study—ideally including a non-IM febrile/viral comparator—to determine whether such CMI parameters can support diagnosis or grade disease activity. Full article

Exclusive breastfeeding (EBF) for the first six months of life is recommended by the World Health Organization, but its association with executive function (EF) in early childhood remains uncertain. This study examined whether EBF during the first six months of life and breastfeeding duration were associated with EF in early childhood and explored relevant child and family characteristics. We conducted an analytical cross-sectional study among 316 children aged 24–35 months attending the Well-Child Clinic, Health Promotion Hospital, Regional Health Promotion Center 7 Khon Kaen, Thailand. EF was assessed using the Minnesota Executive Function Scale (MEFS). The continuous MEFS Standard Score was used as the primary outcome and analyzed using multivariable linear regression. Post hoc exploratory analysis using the 55th percentile threshold and sensitivity analysis using the normative 50th percentile were also conducted. In the primary analysis, EBF was not statistically significantly associated with the MEFS Standard Score (adjusted β = −0.96, 95% CI: −2.13 to 0.21; p = 0.108). Child age was inversely associated with the MEFS Standard Score (adjusted β per 1-month increase = −0.29, 95% CI: −0.46 to −0.11; p = 0.002), whereas maternal education at the bachelor’s degree level or above was positively associated with EF (adjusted β = 2.44, 95% CI: 1.18 to 3.71; p < 0.001). Family functioning was not statistically significantly associated with EF in the primary continuous-score analysis (overall p = 0.319). The absence of a statistically significant association between EBF and EF was consistent across the alternative categorical outcome definitions. In contrast, the association with family functioning was only observed in the post hoc 55th percentile analysis and was not robust across outcome definitions. Breastfeeding duration as a continuous measure was not statistically significantly correlated with the MEFS Standard Score. In the post hoc exploratory analysis using the 55th percentile threshold, breastfeeding for >0 to 6 months was associated with higher odds of higher EF performance compared with no breastfeeding, whereas breastfeeding for >6 months was not. This pattern did not indicate a consistent dose–response association. These findings provide no statistically significant evidence of an association between EBF and EF in this sample, while maternal education was associated with EF performance. The findings regarding family functioning should be regarded as exploratory and hypothesis-generating. Full article