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PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗

PubMed2026

Comprehensive multi-post-translational modifications profiling reveals age-associated remodeling in skeletal muscle.

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, is a major hallmark of aging. Post-translational modifications (PTMs) play essential roles in regulating protein activity and cellular homeostasis; however, how multiple PTMs are remodeled during skeletal muscle aging remains incompletely characterized. Here, we performed comprehensive multi-layered proteomic profiling of skeletal muscle from young (3-month-old) and aged (24-month-old) mice, systematically quantifying the global proteome together with five major PTMs: acetylation, phosphorylation, N-glycosylation, O-glycosylation, and ubiquitination. In total, we identified 5 337 proteins and mapped thousands of PTM sites, generating an integrated atlas of age-associated proteomic and PTM remodeling in skeletal muscle. Pathway enrichment analyses revealed distinct modification-specific patterns: acetylation and phosphorylation were predominantly associated with metabolic and mitochondrial-related pathways; N-glycosylation was enriched in immune- and secretory pathway-related processes; O-glycosylation was associated with muscle contraction-related pathways; and ubiquitination was preferentially linked to cytoskeletal organization in muscle cells. Correlation analyses further uncovered diverse association patterns among different PTMs across protein- and modification-level datasets. Phosphorylation and ubiquitination exhibited consistent positive associations, whereas acetylation and ubiquitination showed both inverse and concordant co-variation patterns across subsets of proteins. Phosphorylation and O-glycosylation displayed heterogeneous association patterns across different proteins, and acetylation and phosphorylation demonstrated positive correlations with distinct age-associated directional changes across protein subsets. Together, these results provide a comprehensive, multi-dimensional view of age-associated remodeling of the skeletal muscle proteome and multiple PTM layers, offering a valuable resource for understanding molecular alterations accompanying muscle aging and sarcopenia.

Animals↗

PubMed2026

Exploratory proteomic and metabolomic profiling of pleural effusions identifies histone H4 and alanine as promising complementary markers for pleural tuberculosis.

The diagnosis of pleural tuberculosis (Pl-TB) remains challenging. Histopathological analysis and pathogen detection in pleural biopsies are informative but limited. We investigated differentially expressed proteins and metabolites in pleural effusions from patients with Pl-TB, malignancies, and other pathologies. A proteomic analysis of pooled pleural effusions identified 45 proteins exclusively detected or upregulated in Pl-TB samples, many linked to infectious processes. Conversely, 18 proteins were uniquely found or upregulated in malignant pleural effusions, mainly associated with detoxification and hemostasis. To validate these findings, we employed targeted proteomics in individual samples. Eight proteins were validated: S100-A9, histone H4, insulin-like growth factor-binding protein 2, fibrinogen beta chain, ficolin-3, immunoglobulin heavy constant alpha 1, sulfhydryl oxidase 1, and histidine-rich glycoprotein. Additionally, NMR-based metabolomics identified 13 metabolites with differential abundance between Pl-TB and non-TB samples. Notably, N-acetyl-glycoprotein and the branched-chain amino acids, alanine and lysine differed between groups. Proteomic and metabolomic analyses revealed distinct molecular profiles between Pl-TB and non-TB patients, despite intra-group variability. To address this, we applied classification models. Histone H4 and alanine consistently emerged as discriminative features. Overall, this study provides novel insights into the molecular landscape of Pl-TB. The combined quantification of proteins and metabolites may improve differential diagnosis, although should be further validated in larger, independent cohorts before clinical application.

Humans↗

PubMed2026

A profile of firearm-related fatalities admitted to the Diepkloof Forensic Pathology Service Soweto medico-legal mortuary during the COVID-19 and post COVID-19 periods.

This retrospective descriptive study examined firearm-related fatalities during (April-December 2020; n = 241) and after (April-December 2023; n = 299) COVID-19 lockdowns using 540 cases from the Diepkloof Forensic Pathology Service, Soweto, South Africa. Data was obtained from autopsy reports, forensic records, police statements, and death scene documentation. Firearm violence affected young adult Black males (22-43 years), with only minor demographic shifts post-pandemic. The overall burden and core patterns of violence remained stable, with criminal activity - primarily robbery and interpersonal violence - persisting as the leading contexts, and homicide the dominant manner of death. Post-COVID-19 findings demonstrated contextual shifts, including increased incidents in public and social environments, reflecting greater mobility and resumption of social activity. A significant rise in mean blood alcohol concentration (0.09 g/100 mL vs 0.14 g/100 mL; p < 0.0001) suggests increased alcohol involvement following easing of restrictions. Unfortunately, persistent information gaps, noted particularly in circumstantial history, incident location, firearm type, highlighting the need for improved data provision and capture systems. While the epidemiology of firearm-related fatalities remained unchanged, the post-COVID-19 period was characterised by increased alcohol involvement, shifts toward public-space violence, and fewer gunshot wounds per victim, suggesting changes in situational and behavioural dynamics rather than underlying drivers of violence.

Humans↗

PubMed2026

A validated sensitive LC-MS/MS method and its application in elucidating the unique ocular pharmacokinetic profile of 0.01% atropine underpinning its clinical utility for myopia.

A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify atropine in ten rabbit ocular tissues enabling systematic characterization of the ocular pharmacokinetic profile of 0.01% atropine sulfate eye drops after a single topical administration. The method demonstrated excellent linearity (coefficient of determination, R2 ≥ 0.9908) across all matrices, with lower limits of quantification (LLOQ) of 0.05 ng/mL for most tissues and 0.10 ng/mL for retina and lens; intra- and inter-day accuracy, precision, matrix effects, extraction recoveries, and stability all met the acceptance criteria. Following a single bilateral topical dose (50 μL/eye) in New Zealand White rabbits, atropine distributed rapidly into all 12 ocular compartments (the sclera further divided into three anatomical regions) with marked heterogeneity-the highest exposures were found in conjunctiva and cornea, a distinct anterior-to-posterior concentration gradient was observed in the sclera, sustained retention was noted in the retina (mean residence time from zero to the last measurable time point, MRT0-t 3.30 h), while aqueous and vitreous humor eliminated rapidly (elimination half-life, t₁/₂ < 0.7 h), and all tissues except aqueous humor followed a two-compartment model. This validated method and the comprehensive pharmacokinetic data reveal that topically applied 0.01% atropine achieves sustained exposure in key myopia-regulating tissues (retina, choroid, posterior sclera) with low exposure in side-effect target tissues (iris, ciliary body, lens).

Animals↗

PubMed2026

Efficacy and Safety Profile of a Triple Single-Pill Combination of Valsartan/Amlodipine/Chlorthalidone in Patients with Uncontrolled Hypertension.

PURPOSE: This randomized, double-blind, multicenter Phase III study evaluated the efficacy and safety profile of a single-pill triple combination of valsartan/amlodipine/chlorthalidone (KDF1901, Valdipine Plus) compared with a dual combination of valsartan/amlodipine (KDF1901-R) in patients with essential hypertension. METHODS: Patients (n = 294) with inadequately controlled hypertension after a 4-week run-in phase with valsartan/amlodipine (80/5 mg) were randomized to receive KDF1901 (valsartan/amlodipine/chlorthalidone 160/10/25 mg, n = 147) or KDF1901-R (valsartan/amlodipine 160/10 mg, n = 147) for 8 weeks. The primary efficacy endpoint was the change in mean sitting systolic blood pressure (MSSBP) from baseline to week 8. Secondary endpoints included changes in mean sitting diastolic blood pressure (MSDBP), BP normalization rates, and response rates. Safety profile outcomes assessed treatment-emergent adverse events (TEAEs), laboratory parameters, and serious adverse events. FINDINGS: At week 8, the KDF1901 group exhibited a significantly greater reduction in MSSBP (-22.8 ± 1.0 mmHg) compared with the dual therapy group (-16.7 ± 1.0 mmHg, P < 0.0001). Similarly, the mean MSDBP reduction was significantly greater with KDF1901 (P = 0.0006). BP normalization rates (75.9% vs 54.5%, P < .0001) and response rates (73.8% vs 51.7%, P < 0.0001) were significantly higher in the triple combination group. Overall, the incidence of TEAEs was similar between groups (24.7% vs 21.5%, P = 0.5783), with mild cases of dizziness were most commonly reported. Exploratory ad hoc analyses showed statistically greater changes in sodium, potassium, and uric acid levels with triple therapy, but clinically meaningful extreme electrolyte abnormalities were rare in both groups, and the overall laboratory profile remained acceptable. IMPLICATIONS: This trial reported that the single-pill triple combination KDF1901 significantly improved BP control compared with dual therapy without compromising tolerability. GOV IDENTIFIER: NCT07116863.

Humans↗

PubMed2026

ChIP-seq profiling identifies diapause-regulated H3K27me3 targets in the fat body of Culex pipiens.

Culex pipiens, a principal vector of significant arboviruses, survives winter through diapause, a hormonally controlled inactive phase that enhances endurance under severe cold circumstances. Recent data suggests that epigenetic processes, namely histone post-translational modifications (hPTMs), play a crucial role in regulating seasonal dormancy. Prior studies from our laboratory indicated a decrease in the methylation of Histone 3 (H3K27me3) in diapausing fat body tissue, associated with elevated expression of the histone demethylase UTX. Nonetheless, the precise genomic areas impacted by these chromatin alterations remained unidentified. We used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) to delineate the genome-wide distribution of H3K27me3 across fat body chromatin in diapausing (D) and non-diapausing (ND) female Cx. pipiens. Notably, the higher signal at transcription start sites (TSSs) reflects localized redistribution rather than a global decrease, as diapausing fat bodies retain less H3K27me3 overall but concentrate it at promoters. To investigate the functional significance of these chromatin alterations, we confirmed a number of target loci via ChIP-qPCR and assessed gene expression with qRT-PCR. We identified many critical genes that were markedly increased in diapausing mosquitoes, exhibiting an inverse relation to H3K27me3 enrichment. Our data demonstrates different H3K27me3 chromatin landscapes between diapausing and non-diapausing Cx. pipiens, corroborating a hypothesis of selective, locus-specific repression in the non-diapause state and its targeted removal during diapause to permit activation of dormancy-associated genes. These results suggest that chromatin remodeling is a core driver of the diapause switch.

Animals↗

PubMed2026

Mitigating pH-induced instability in deruxtecan-based ADCs: an onboard-mixing icIEF approach for robust charge heterogeneity characterization.

Accurate charge variant analysis of antibody-drug conjugates (ADCs) is essential for understanding product heterogeneity and ensuring quality control. However, Deruxtecan (DXd)-based ADCs present a unique analytical challenge due to the intrinsic instability of the payload, where the lactone ring readily undergoes hydrolysis under alkaline conditions, resulting in time-dependent shifts in charge distribution during imaged capillary isoelectric focusing (icIEF). In this study, we describe the development of an onboard-mixing icIEF method designed to minimize pH-induced degradation during sample preparation. By separating ADC samples from carrier ampholytes (CAs) prior to injection and enabling real-time mixing within the instrument, this approach effectively suppresses premature lactone ring opening and stabilizes charge variant profiles. Comparative studies between conventional premixing and onboard-mixing approach demonstrated that the latter significantly enhances reproducibility, particularly for acidic variants that are highly sensitive to structural conversion. Comprehensive method validation confirmed excellent precision, linearity, and sensitivity, with consistent performance across run-to-run and intra-day analyses. The results underscore the importance of controlling microenvironmental pH exposure in the analysis of chemically instable ADCs. The proposed onboard-mixing strategy provides a robust and efficient solution for icIEF-based characterization, reducing analytical artifacts while simplifying method development. This approach is broadly applicable to ADCs and other biotherapeutics containing pH-sensitive functional groups.

Hydrogen-Ion Concentration↗

PubMed2026

Probiotic supplementation improves body composition, lipid profiles, and fatty acid metabolism in combat sports athletes during the weight reduction phase.

PURPOSE: Pre-competition weight control for combat sports athletes may alter body composition and fatty acid metabolism. Probiotics have shown potential to regulate overall metabolism; however, their specific effects on fatty acid metabolism during weight control in athletes remain unclear. METHODS: Thirty-two combat sports athletes participating in the 4-week weight reduction period were assigned to either the probiotic group (Group E) or the placebo group (Group C). Body composition, lipid profiles, and fatty acid metabolism were measured before and after the 4-week weight reduction phase. RESULTS: All the athletes experienced a decrease in body weight, body mass index (BMI), body fat percentage, and muscle mass following the 4-week weight loss intervention. Notably, a more significant reduction in body fat percentage (p < 0.05) was observed, along with lower levels of triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), specifically in Group E. Weight loss intervention resulted in increased levels of short-chain fatty acids (SCFAs), specifically acetic acid, propionic acid, and butyric acid. Notably, Group E exhibited higher mean values for SCFAs compared to Group C (p < 0.05). Additionally, the serum levels of γ-linolenic acid and 8,11,14-eicosatrienoic acid were significantly reduced in Group E (p < 0.05). In contrast, the majority of free fatty acids (FFAs) showed significant increases, with greater magnitudes of change observed in Group C (p < 0.05). CONCLUSION: Probiotic supplementation can improve body composition, enhance SCFAs levels, and decrease circulating FFAs in combat sports athletes, suggesting that probiotics may have a beneficial impact on pre-competition weight management. TRIAL REGISTRATION NUMBER: chiCTR2400079908 (Reg Date:2024-01-16).

Humans↗

PubMed2026

Low-salinity stress alters growth, histology, physiology, and transcriptomic profiles of the gills and antennal glands in Macrobrachium rosenbergii.

Salinity is a major abiotic constraint in freshwater aquaculture of the giant freshwater prawn Macrobrachium rosenbergii, yet the coordinated roles of the gills and antennal glands, the two primary osmoregulatory organs in decapod crustaceans, under low-salinity stress remain poorly characterized. Here, we integrated histological, physiological, and transcriptomic analyses to characterize the adaptive responses of M. rosenbergii to acute (96 h) and chronic (8 weeks) exposure to salinity 5. Chronic low-salinity stress significantly impaired growth performance and decreased the survival rate. Acute stress induced thinning of the gill filaments, partial disorganization of pillar cells, and dilation of the intermicrovillar space in the antennal glands, whereas chronic stress caused gill vacuolization, cuticle thinning, and adaptive folding of antennal gland microvilli. In parallel, acute exposure significantly decreased hemolymph sodium and potassium ion concentrations but increased magnesium ion concentration, whereas chronic exposure increased hemolymph sodium and potassium ion concentrations, upregulated gill Na+/K+-ATPase activity, and enhanced hepatopancreatic antioxidant capacity. Transcriptomic analyses revealed distinct tissue-specific responses. Under acute stress, the gills preferentially activated pathways associated with cytoskeletal remodeling, motor proteins, and tight junctions, whereas chronic acclimation shifted the transcriptional response toward the renin-angiotensin system and glutathione metabolism. In the antennal glands, acute stress rapidly activated the renin secretion pathway, whereas chronic exposure promoted membrane remodeling by enriching pathways related to lipid and glycan metabolism. These findings reveal tissue-specific functional differentiation and synergistic coordination between the gills and antennal glands that underpin M. rosenbergii's adaptive response to low-salinity stress.

Animals↗

PubMed2026

Altered reproductive hormone profiles in systemic lupus erythematosus - A systematic review and meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) shows a marked female predominance during reproductive years, possibly suggesting hormonal factors in its pathogenesis. However, evidence regarding reproductive hormone alterations in SLE remains inconsistent. OBJECTIVES: To systematically review studies assessing reproductive hormone levels in adult SLE patients compared with healthy controls and across disease activity states. METHODS: Following PRISMA guidelines and a pre-registered protocol (PROSPERO CRD42024544730), PubMed and Scopus were searched (May 2024). Eligible observational studies reported estradiol, testosterone, progesterone, prolactin, FSH, LH, DHEA-S, DHEA or androstenedione in SLE patients versus controls or by disease activity. Random-effects meta-analyses were conducted. RESULTS: Eighty-three studies were included (5389 individuals for SLE vs. controls; 2067 for active vs. inactive SLE). Prolactin was consistently higher in SLE (MD 8.07 ng/mL; 95% CI 4.69-11.45; p < 0.001) and even more during flare (MD 5.83 ng/mL; 95% CI 3.88-7.78; p < 0.001). Estradiol showed non-significant overall elevations but was significantly higher in women with active disease (MD 8.55 pg/mL; 95% CI 1.37-15.73; p = 0.03). DHEA-S was found to be significantly lower in SLE (MD -1.00 μg/mL; 95% CI -1.5 to -0.50; p = 0.002) but too few studies evaluated its dynamics during flares. FSH and LH were significantly higher in men with SLE. Other hormones were inconsistent. Only three small heterogeneous studies evaluated hormonal changes during flares. CONCLUSIONS: Prolactin excess and androgen deficiency are consistent features of SLE, particularly in women, while elevated gonadotropins are mainly seen in men. Estradiol is higher during active disease but other data are inconsistent. Longitudinal studies are limited, with prolactin the only hormone consistently linked to disease activity and full hormonal profiles during flares are largely unstudied.

Humans↗

PubMed2026

Comparing Clinical and Cytokine Profiling of Genital Inflammation as Predictors of HIV Acquisition in Women.

BACKGROUND: Inflammation in the female genital tract is a key risk factor for HIV acquisition, but it remains unclear whether clinical or immunological measures best predict risk. We aimed to compare HIV acquisition among women with clinically and/or immunologically defined inflammation. SETTING: HIV-uninfected women enrolled in the CAPRISA 004 tenofovir gel randomized controlled trial in South Africa were followed for up to 34 months. METHODS: We analyzed data from 889 women, with cytokine measurements available for 774 participants. Clinical genital abnormalities were assessed at scheduled visits, and 9 cytokines were measured in cervicovaginal lavage samples. HIV incidence was compared across categories of clinical and immunological inflammation using time varying Cox proportional hazards models, adjusting for relevant covariates. RESULTS: Immunological inflammation, defined as ≥9 elevated cytokines, was present in 18% (140/774) of women. Among specific clinical signs, abnormal genital discharge (adjusted hazard ratio: 2.67, 95% confidence interval [CI]: 1.14 to 6.23, P = 0.024) and cervicitis (adjusted hazard ratio: 10.34, 95% CI: 2.46 to 43.65, P = 0.001) were significantly associated with increased HIV acquisition. Women with both clinical and immunological inflammation had the highest risk of HIV acquisition, with adjusted hazard ratios of 2.08 (95% CI: 1.10 to 3.91, P = 0.022) and 2.46 (95% CI: 1.21 to 5.03, P = 0.013), respectively. CONCLUSIONS: Clinical and immunological definitions of inflammation were each independently associated with increased HIV acquisition risk and combined, they reflected greater susceptibility. These findings highlight the important role of genital inflammation in women's HIV susceptibility, suggesting that clinical signs may provide practical early indicators of risk even as cytokine profiles provide more sensitive measures of underlying inflammation.

Humans↗

PubMed2026

Plasma proteome profiling identifies XPNPEP3 as a novel biomarker associated with metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus.

OBJECTIVE: To identify plasma protein differences between type 2 diabetes mellitus (T2DM) patients with and without metabolic dysfunction-associated steatotic liver disease (MASLD), and to evaluate the diagnostic potential of X-prolyl aminopeptidase 3 (XPNPEP3) for identifying MASLD in T2DM patients. METHODS: Twenty T2DM inpatients were categorized into groups with and without MASLD and their plasma samples were analyzed using data-independent acquisition mass spectrometry, followed by bioinformatics analysis to identify differentially expressed proteins. The cohort was then expanded to 84 patients, and plasma XPNPEP3 levels were validated by enzyme-linked immunosorbent assay. Correlation between XPNPEP3 and clinical indicators were evaluated, and diagnostic performance was determined via receiver operating characteristic (ROC) analysis. Immunohistochemistry was employed to compare hepatic XPNPEP3 expression between the two groups. RESULTS: Proteomic analysis identified 176 differentially expressed proteins, with XPNPEP3 exhibiting the most significant down-regulation by fold change. In the validation cohort, plasma XPNPEP3 was significantly lower in T2DM+MASLD versus T2DM alone. XPNPEP3 levels were negatively correlated with diabetes duration, liver function markers, and triglyceride levels, and was identified as an independent factor inversely associated with MASLD in T2DM.ROC analysis demonstrated strong diagnostic performance for XPNPEP3, further enhanced when combined with BMI and diabetes duration.  Immunohistochemistry confirmed reduced hepatic XPNPEP3 expression in T2DM+MASLD patients. CONCLUSIONS: Lower plasma XPNPEP3 is independently associated with MASLD in T2DM patients and demonstrates strong diagnostic potential, positioning XPNPEP3 as a promising biomarker for diagnosing MASLD in T2DM patients and a novel target for non-invasive diagnostic tool development.

Humans↗

PubMed2026

Microbial signal profiles and organism-level concordance between plasma metagenomic sequencing and blood culture in suspected bloodstream infection.

Plasma metagenomic next-generation sequencing (mNGS) and blood culture detect different components of the microbial signal and frequently produce discordant organism reports. We characterized microbial signal class, report-derived burden, organism-level concordance, and independent clinical attribution in a retrospective, single-center, episode-level cohort. Among 329 episodes with evaluable plasma mNGS reports, 315 had blood culture performed; 232 were mNGS positive/culture negative and 53 were positive by both methods. In the 232 discordant episodes, the recorded routine-care diagnosis classified 124 as bloodstream infection (BSI) and 108 as non-BSI. Nonviral signals were present in 78.2% and 42.6%, respectively (P < 0.001), and median maximum report-derived sequence counts were 98.5 and 11.5 (P < 0.001). Two laboratory physicians then independently reviewed source records using structured criteria while masked to the recorded BSI label and mNGS organism and sequence-count information. Initial agreement for the five-category BSI assessment was 97.6% (Cohen's kappa, 0.960). Within the mNGS-positive/culture-negative subgroup, adjudicated BSI likelihood showed a modest ordinal association with report burden (Spearman rho = 0.190; P = 0.004), while mNGS organisms were considered supported in 1 episode, plausible in 158, unlikely or contaminant in 72, and unresolved in 1. Among 53 dual-positive episodes, 33 (62.3%) shared at least one species, but only 5 (9.4%) had complete species-set concordance. Plasma mNGS and blood culture therefore frequently generated non-equivalent organism sets. Signal class and report burden contributed graded contextual evidence, but organism-level attribution required clinical review and orthogonal microbiology rather than binary positivity alone.

Humans↗

PubMed2026

Effects of 12 weeks of resistance and concurrent training with graded protein intakes on lipid profile, kidney and liver biomarkers in middle-aged to older women.

PURPOSE: To examine secondary lipid, kidney-related, and liver-enzyme responses to three protein intakes during resistance training (RT) alone or the same RT plus cycling (CT) in middle-aged to older women. METHODS: In this randomized 2×3 factorial trial, 108 women aged 40-77 years were assigned to RT or CT and 0.8, 1.6, or 2.2 g kg-1 d-1 protein for 12 weeks. This complete-case secondary analysis included 83 participants. Linear mixed-effects models tested Time × Training, Time × Protein, and Time × Training × Protein effects, with false-discovery-rate-adjusted omnibus tests and Holm-adjusted contrasts. RESULTS: Triglycerides, total cholesterol, LDL-C, and apolipoprotein B decreased and HDL-C increased in all conditions. Lipid changes differed by protein condition, and several were more favorable with CT; however, CT comprised RT plus additional cycling and greater exercise exposure. Urea, blood urea nitrogen, creatinine, the blood urea nitrogen-to-creatinine ratio, and cystatin C increased, whereas three eGFR estimates decreased. Responses differed mainly between 0.8 and the two higher protein conditions, with little evidence of differences between 1.6 and 2.2 g kg-1 d-1. ALT, AST, and GGT differed by protein condition; AST and GGT also showed training-dependent responses. CONCLUSIONS: The dietary and exercise interventions modified lipid and clinical-chemistry responses. Because energy and food composition were not fully matched and CT added cycling to RT, the findings do not isolate protein dose or exercise modality. Changes in eGFR estimates and liver enzymes do not establish organ injury or long-term safety.

Humans↗

PubMed2026

Storm and Stress 2.0? A Dual-Factor, Person-Centered Analysis of Adolescent Well-being Across Two Year 7 Cohorts and Gender.

PURPOSE: Concerns about the mental health and well-being of younger generations is a recurring theme across countries and time. Adolescence is debated as a period of volatility ("storm and stress") or growth. Recent trends have reignited worries about youth mental health and well-being, particularly for females, and revived a deficit-based view of adolescence. To advance understanding, this study adopts a dual-factor approach that incorporates both negative and positive well-being domains. Mental health trends were compared across two grade-matched Australian adolescent cohorts assessed 5 years apart. METHODS: Data were drawn from cross-sectional cohorts of year 7 students (12-13 years) in one Australian jurisdiction: 2,085 in 2018 and 2,378 in 2023. Positive affect, happiness, resilience, depression, and anxiety were assessed using latent profile analysis to identify mental health profiles, which were then compared between cohorts and gender. RESULTS: Four profiles were identified: complete mental health, symptomatic but positive, resilient but disaffected, and troubled. Approximately 80% of students were classified in profiles reflecting some positive mental health. Between 2018 and 2023, the proportion with complete mental health declined by 7.93%, while those categorized as troubled increased by 4.76%. Declines were most pronounced among female students. DISCUSSION: Findings highlight both resilience and vulnerability in adolescent mental health. While most students continue to show positive well-being, the decline among females signals an urgent need for gender-sensitive approaches. At the same time, the results add nuance to accounts of a youth mental health 'crisis' to some degree, by highlighting positive domains of well-being which are often overlooked.

Humans↗

PubMed2026

Proteomic and phosphoproteomic profiles of time-dependent dynamic changes in LPS-induced macrophage polarization.

The temporal proteomic and phosphoproteomic reprogramming during early M1 macrophage polarization (0-6 h) remains poorly understood. We performed time-resolved proteomic and phosphoproteomic analyses of LPS-stimulated RAW264.7 macrophages at seven time points within 6 h. Time-clustering of differentially expressed molecules revealed two patterns: initial change with partial recovery, and sustained dysregulation. Upregulated proteins and phosphorylation sites were enriched in the Rho GTPase signaling pathway, T-cell receptor signaling pathway, NF-κB cascade, osteoclast differentiation pathway, and antiviral immune pathway. Downregulated pathways were associated with cell cycle regulation, chromatin remodeling, RNA metabolism, and mRNA processing, indicating resource reallocation to prioritize acute inflammatory responses. Kinase-substrate network analysis confirmed the mitogen-activated protein kinase (MAPK), cyclin-dependent kinase (CDK), protein kinase B (AKT), and ribosomal S6 kinase (RSK) families as core upstream phosphorylation regulators. Integrated analysis revealed synergistic and antagonistic relationships between proteomic and phosphoproteomic changes. This study provides a temporal molecular atlas of M1 polarization, delineating inflammatory signaling dynamics and offering a basis for therapeutic target discovery in inflammatory diseases. SIGNIFICANCE: Macrophage M1 polarization is a central event in innate immune defense against pathogenic invasion, yet its dysregulation is a pivotal driver of the onset and progression of a broad spectrum of inflammation-associated disorders, spanning autoimmune diseases, infectious conditions and inflammatory bone diseases, making the dissection of its molecular regulatory mechanisms an urgent research priority in immunology and translational medicine. Dynamic molecular events within 0-6 h after LPS stimulation are critical for initiating and shaping M1 inflammatory activation, yet systematic time-resolved proteomic and phosphoproteomic profiling remains insufficient.In this study, we comprehensively characterized temporal proteome and phosphoproteome changes at seven consecutive time points during macrophage polarization, clarified two distinct dynamic molecular patterns, identified core signaling pathways and key kinase regulators involved in inflammatory reprogramming, and uncovered the leading role of post-translational phosphorylation modifications in initiating polarization. This work delineates the time-series molecular atlas of early macrophage activation, provides novel insights into the temporal regulatory mechanism of inflammatory signaling networks, and lays a solid experimental foundation for exploring new intervention targets and regulatory nodes in clinical translational research.

Lipopolysaccharides↗

PubMed2026

Multiparametric flow cytometry immune profiling of pulmonary and extra-pulmonary tuberculosis reveals distinct blood-based biomarker signatures.

This study investigated immune cell distributions, cell-specific immune markers, and selected biomarker targets in pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) using multiparametric flow cytometry (MFC). Whole blood was collected from 45 individuals, including healthy controls (HC), EPTB, and PTB patients (n = 15/group). Peripheral blood leukocytes were analysed by MFC to characterize CD4+ and CD8+ T cells, natural killer (NK), invariant NKT (iNKT) and NKT cells, classical (CM), intermediate (IM) and non-classical monocytes (NCM), and activated monocytes (AM). Expression of GBP1, CALCOCO2, IFIT3, SNX10, ARG1, PD-1, and PD-L1 was assessed across these immune subsets. Increased frequencies of NK, NKT, and monocytes were observed in PTB and EPTB compared with HC, while CD4+, CD8+, iNKT, and AM were reduced. Monocyte-to-lymphocyte ratios were incrementally elevated in EPTB and PTB compared with HC. Despite variability of expression within groups, median biomarker fold-change expression changes were found between HC, EPTB and PTB groups; (i) (>2.0FC) for ARG1 in CD4, CD8, CM and AM, for CALCOCO2 in AM, GBP1 in CD8 and NCM, PD-1 in CD4, CD8, NK, IM and AM, PD-L1 in CD4, CD8, iNKT and NKT, NK, IM and AM and SNX10 in CD4, CD8, NCM, IM and AM (ii) (<2.0FC) in TB vs HC for CALCOCO2 in iNKT and NKT, IFIT3 in NCM, PD-1 in NK and NCM, PD-L1 in NCM, IM and AM and SNX10 in AM. Statistical significance was achieved for ARG1 (P = 0.017) in CD4 cells. Our findings highlight distinct immune cell and biomarker signatures in PTB and EPTB.

Humans↗