Search Results (224)

Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD⁺) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune–metabolic regulation. This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD⁺ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework. Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation. Full article

Liquid biopsy is now an established component of precision oncology, and its clinical implementation to date has been led by cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) assays. These assays report genomic alterations, yet they may be limited by low tumor fraction, reduced shedding in early disease, and incomplete representation of dynamic tumor biology. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and emerging small or poorly annotated RNA species, provide a complementary layer because they can reflect regulatory programs, tissue injury, immune modulation, metastatic communication, and therapeutic pressure. This review explores circulating and extracellular vesicle (EV)-associated ncRNAs as functional readouts in cancer liquid biopsy. We discuss their biological origin, carrier state, biofluid context, clinical applications, analytical technologies, artificial intelligence (AI)-assisted integration, standardization barriers, and regulatory requirements. The technology discussion considers sequencing, targeted amplification, and emerging direct or polymerase chain reaction (PCR)-free strategies as complementary translational routes for reliable ncRNA measurement. We propose that ncRNAs should not be viewed as alternatives to ctDNA, but as potential functional biomarkers that can link tumor genotype, regulatory state, and clinical phenotype within integrated multi-analyte precision oncology. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy. In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1–dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP). While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation. We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases. Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets. Full article

Background: Febrile seizures (FSs) are the most common neurological emergency in early childhood; however, the biological basis of disease heterogeneity remains poorly understood. Although growing evidence suggests that gut–brain axis dysregulation contributes to seizure susceptibility, it remains unclear whether gut microbiota-associated metabolic disturbances are linked to clinical phenotypes, particularly simple FS (SFS) and complex FS (CFS). Methods: An integrated multiomics study was conducted in clinically characterized pediatric cohorts, comprising 50 children with FS and 50 healthy controls, and their gut microbiota was profiled via 16S rRNA sequencing. As some pediatric serum specimens did not meet the minimum volume requirement of the analytical platform, serum amino acid profiling was performed in a subset of samples using an equal-volume pooling strategy. In brief, two individual serum samples from the same study group were combined into one composite sample, yielding 25 pooled samples in the FS group and 25 in the control group. Subsequently, untargeted fecal metabolomics was performed in an expanded cohort of 53 healthy controls, 50 children with SFS, and 42 children with CFS. Additionally, the central metabolic profiles of the CFS and SFS groups were compared using untargeted cerebrospinal fluid metabolomics. Given the variation in sample sizes across omics platforms, each dataset was analyzed within its corresponding eligible subset, and cross-omics integration was interpreted primarily at the pathway and phenotype levels. Results: Children with FS exhibited reduced gut microbial diversity and altered microbial composition, characterized by the enrichment of Streptococcus, Enterococcus, and Escherichia–Shigella, along with the depletion of beneficial taxa, including Faecalibacterium, Lachnoclostridium, and Parasutterella. Functional prediction indicated significant changes in amino acid-related pathways, especially arginine and proline metabolism, amino acid metabolism, and glutathione metabolism. Serum profiling showed elevated levels of phenylalanine, kynurenine, and γ-aminobutyric acid, along with reduced levels of tryptophan, threonine, lysine, glutamine, taurine, citrulline, 3-methylhistidine, α-aminobutyric acid, hydroxyproline, and phosphoethanolamine. Correlation analysis identified Lachnoclostridium and Parasutterella as key taxa associated with neuroactive metabolites. Additionally, fecal metabolomics revealed that both SFS and CFS samples exhibited significant metabolic divergence from the controls, with arginine biosynthesis emerging as a shared altered pathway and L-arginine reduced in both phenotypes. Notably, cerebrospinal fluid metabolomics demonstrated clear metabolic separation between CFS and SFS, signifying phenotype-specific central metabolic signatures. Conclusions: FS is related to gut microbiota dysbiosis, systemic amino acid remodeling, and phenotype-associated metabolic stratification. Arginine metabolism may represent a shared mechanistic hub across FS phenotypes, while central metabolic divergence may contribute to the biological distinction between SFS and CFS. These findings establish a multiomics framework for understanding FS pathogenesis and identifying potential biomarkers and therapeutic targets. Full article

Stenotrophomonas maltophilia is an emerging multidrug-resistant opportunistic pathogen in intensive care units (ICUs) and cystic fibrosis (CF), where biofilm formation may favor persistence, device-associated colonization/infection, and clonal dissemination. This study compared biofilm formation, clonal relatedness, biofilm phenotypes, and motility in 37 ICU-associated and 42 CF-associated S. maltophilia isolates. Biofilm formation on polystyrene was quantified by crystal violet assay and expressed both as absolute biomass and as a growth-normalized Biofilm Index, calculated to account for differences in planktonic growth. Genetic diversity was assessed by pulsed-field gel electrophoresis, while swimming and twitching motility were evaluated using agar-based assays. ICU isolates showed a higher prevalence of biofilm formation, greater biofilm biomass, and higher growth-normalized Biofilm Index values than CF isolates. They also displayed lower genetic diversity and more frequent cross-transmission, supporting the circulation of selected hospital-associated lineages. Conversely, CF isolates showed greater heterogeneity and a more complex biofilm pattern, consistent with adaptation to a distinct chronic airway environment. Motility was not associated with biofilm formation, suggesting that the enhanced biofilm phenotype of ICU isolates is not explained by swimming or twitching alone. Overall, these findings support a setting-specific model in which enhanced biofilm-forming capacity may contribute to S. maltophilia ICU persistence and clonal dissemination, highlighting the need for targeted surveillance and careful device management. Full article

Cystic fibrosis (CF) is an autosomal recessive disorder caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is increasingly understood through a genomics-informed framework linking variant architecture to phenotype, diagnosis, and therapeutic eligibility. This review summarizes current evidence on CFTR structure, variant interpretation, genotype-phenotype heterogeneity, diagnostic workflows, and modern management. We highlight how full-gene sequencing, curated disease-liability databases, functional testing, and organoid-informed theratyping refine diagnosis and treatment selection; how disrupted chloride and bicarbonate transport drives muco-obstructive airway disease and multisystem complications; and why modulator therapy must still be integrated with respiratory, nutritional, endocrine, hepatobiliary, reproductive, and psychosocial care. We also outline unresolved challenges in rare variants, residual organ damage, ancestry-related diagnostic gaps, and mutation-agnostic therapeutic development. Full article

Background: Frailty in older adults is linked to adverse cardiovascular outcomes, but its relationship with echocardiographic markers of diastolic function remains unclear. We examined associations between frailty measures and indices of diastolic function in community-dwelling older adults. Methods: This cross-sectional study included 537 adults aged ≥65 years from a multidisciplinary outpatient clinic. Frailty was assessed using the Fried phenotype, Clinical Frailty Scale (CFS), gait speed, and handgrip strength. Associations with diastolic indices were analyzed using multivariable regression with sequential adjustment. Sensitivity analysis was performed via matching. Results: According to the Fried phenotype, 30.8% of participants were robust, 59.7% pre-frail, and 9.5% frail. Indexed left atrial dimension (LAi) was consistently higher in frail individuals. Frailty was also associated with higher odds of elevated right ventricular systolic pressure (>35 mmHg) in unadjusted analyses. Using the CFS, individuals with a score higher than 3 had significantly higher NT-proBNP levels compared to those with a score of 1–2. Higher gait speed and handgrip strength were associated with more favorable cardiac structure, including smaller left heart chamber sizes, and lower natriuretic peptide levels. Conclusions: Frailty was independently associated with structural and functional markers of diastolic dysfunction in older adults, particularly left atrial enlargement (as captured in Fried) and NT-proBNP elevation (as captured in CFS), supporting the integration of frailty assessment into cardiovascular risk evaluation. Full article

Background: Currently, increasing attention is being paid to the role of genes other than CFTR and their variants as factors modifying the course of cystic fibrosis (CF). One such gene is SLC26A9, which encodes a protein involved in chloride and bicarbonate transport across the epithelial cell membrane. Variants of SLC26A9, such as c.229G>A (p.Gly77Ser) and c.1885C>T (p.Pro629Ser), have been described in patients with severe and rapidly progressive CF. The aim of this study was to identify SLC26A9 variants in a group of 20 patients with CF. Methods: DNA was isolated from blood samples and collected from all patients. Fragments of exons 3 and 17 of the SLC26A9 gene were amplified by PCR and sequenced using the Sanger method. Results: An SLC26A9 variant was identified in two siblings. These patients were diagnosed with CF in adulthood and presented with moderate pulmonary symptoms without exocrine pancreatic insufficiency. In both siblings carrying the CFTR variants p.Phe508del and c.3140-26A>G, the SLC26A9 variant c.1847C>T (p.Pro616Leu) was detected. This variant has not been widely described in the literature and has not previously been associated with CF. Conclusions: The c.1847C>T (p.Pro616Leu) variant is located near a domain that may affect the transport function of the SLC26A9 protein. However, patients in whom the variant was identified did not present a severe disease phenotype. Further studies on larger patient cohorts are required, and at present this variant should be considered of uncertain significance in CF. Full article

In vitro cultured plant calli, induced through dedifferentiation, are colonized by diverse endophytes. Most of these endophytes, being substantially inherited from the mother plant and highly dependent on the host’s internal ecological niche, are termed host-dependent endophytes (HDEs). Due to their close association with their hosts, HDEs exhibit heritable characteristics. However, our current understanding of plant HDEs and their effects on the host plant is limited. In this study, we characterized the composition and potential functions of the endophytic microbiota in grapevine calli derived from different varieties and organs corresponding to Cabernet Sauvignon berry flesh (CF), Rose Honey berry flesh (RF), and Rose Honey shoot tip (RS) using high-throughput sequencing and bioinformatics. Our results showed that the genotype and organotype of the explant did not affect the alpha diversity of endophytes in callus, but were associated with differences in beta diversity and community structure of the endophytic microbiota. Different types of grapevines calli inherited distinct endophytes from their mother plants, whereas sharing a conservative core endophytic microbiota consisting of a small number of amplicon sequence variants (ASVs) with high relative abundances (bacteria: 38 ASVs ranging from 79 to 92%; fungi: 9 ASVs ranging from 32 to 58). Prediction analyses using revealed conserved functional traits of the endophytic microbiota across callus types, including a core suite of bacterial adaptive phenotypes, stable central metabolism dominated by oxidative phosphorylation, and uniformly structured fungal communities dominated by saprotrophs and pathotrophs, while consistently containing yeast-form fungi. Although minor variations such as elevated trait abundance in the CF group were noted, no statistically significant functional divergence was observed, demonstrating that the endophytic microbiota of grapevine callus maintains a conserved functional profile across different types. Collectively, this study provides a methodological framework for investigating plant HDEs and offers new insights into host-endophyte interactions at the cellular level. Full article

Human endogenous retroviruses (HERVs) are potential driving forces of the pathophysiology of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linking post-infectious immune dysfunction to chronic inflammation and immune and neurocognitive dysfunction that are hallmark features of ME/CFS. Accumulating evidence from related autoimmune diseases and cancers has shown that reactivated HERVs can contribute to disease pathogenesis by amplifying immune activation through viral protein-mediated innate sensing, long terminal repeat (LTR)-driven transcription, and disrupting epigenetic silencing. HERV signatures are therefore promising biomarkers for diagnosis, patient stratification for drug-repurposing trials, and therapy monitoring. Accumulating evidence suggests a possible correlation between HERV expression and ME/CFS symptom severity, alterations in immune phenotypes, function and inflammatory gene networks. Importantly, locus-specific HERV profiling is a promising approach for distinguishing ME/CFS from overlapping or co-morbid conditions and healthy controls. Furthermore, HERV-targeted antibodies, immune modulators, epigenetic and antiviral interventions offer promise as concomitant therapeutic strategies for ME/CFS. Additional research incorporating viromics and other-omics validation, functional assays, and HERV-stratified clinical trials is now needed to realise this potential and to transform ME/CFS from a symptom-based syndrome into a mechanism-driven, treatable condition. Full article

Background/Objectives: Childhood non-cystic fibrosis (non-CF) bronchiectasis is clinically heterogeneous. We aimed to describe fractional exhaled nitric oxide (FeNO) levels in affected children and examine associations with etiology, spirometry, and CT-defined disease extent. Methods: This single-center prospective observational study included 100 clinically stable children aged 6–18 years with CT-confirmed non-CF bronchiectasis evaluated between September 2014 and December 2015. FeNO was measured before spirometry using an online single-breath electrochemical technique. Chest CT was reviewed at the lobar level, with the lingula counted separately, and disease extent was summarized by the number of involved lobar regions. Associations were assessed using Spearman correlation and non-parametric tests. Results: Mean age was 14.9 ± 2.0 years, 55% were male, and mean FeNO was 20.9 ± 14.0 ppb. FeNO correlated positively with FEV1 (% predicted), FVC (% predicted), and FEF25–75 (% predicted) (all p < 0.01). FeNO was higher in males and adolescents than in females and younger children, respectively. FeNO did not differ by CT-defined lobar extent. It was lower in primary ciliary dyskinesia than in asthma overlap. Overall, 82% of the cohort received an ICS-containing maintenance regimen and household tobacco smoke exposure was present in 58%. Conclusions: FeNO was associated with selected functional indices and etiologic subgroups, but not with CT-defined structural extent, suggesting a greater role in clinical phenotyping than in reflecting radiologic burden. Rather than reflecting overall disease severity, FeNO may be more relevant as a marker of T2-leaning airway inflammatory phenotype in selected children with non-CF bronchiectasis. These findings should be interpreted as exploratory and hypothesis-generating, particularly for etiologic subgroup comparisons and for FeNO interpretation in the setting of treatment and environmental confounding. Full article

Muco-obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis, are characterized by the accumulation of highly viscoelastic mucus that compromises mucociliary clearance and fosters infection and inflammation. Mucoactive therapy, encompassing both true mucolytics and non-cleaving agents, seeks to restore airway patency by altering mucus structure, hydration, and transport properties, yet its clinical impact remains variable. This narrative review provides a critical reappraisal of the pharmacological actions and therapeutic outcomes of the main mucolytic agents: N-acetylcysteine (NAC), erdosteine, carbocisteine, bromhexine, ambroxol, and dornase alfa. Beyond their classical role in reducing mucus viscosity, these drugs exhibit pleiotropic effects, including antioxidant, anti-inflammatory, and immunomodulatory activities. Specifically, for thiol-based compounds, the action consists of breaking the disulfide bonds that stabilize the mucin network; for carbocisteine, it lies in modulating mucin glycosylation and chloride transport. Ambroxol and bromhexine act by stimulating surfactant secretion and enhancing mucociliary clearance. Finally, dornase alfa exerts an enzymatic effect on extracellular DNA, a key contributor to the tenacity of mucus in cystic fibrosis. Clinical evidence indicates that NAC and erdosteine can reduce exacerbation rates in COPD, carbocisteine shows benefit with prolonged administration, and dornase alfa remains a cornerstone in CF management. However, therapeutic efficacy is constrained by heterogeneous mucus composition, pharmacokinetic limitations, and disease-specific variability. A key interpretative message is that clinical benefit appears greatest when the dominant biophysical determinant of mucus pathology is specifically targeted, supporting a transition from broad disease-label prescribing to mechanism-informed, phenotype-aware mucolytic therapy. Emerging strategies, such as agents targeting mucin–DNA interactions and advanced inhalation delivery systems, promise improved specificity and durability. By integrating mechanistic insights with clinical data, this review underscores the need for personalized mucolytic therapy and innovative approaches to overcome current challenges in managing muco-obstructive lung diseases. Full article

Bacterial persistence, a non-heritable high-antibiotic-tolerance phenotype, is a key driver of recurrent clinical infections and antibiotic treatment failure. The pheromone-responsive pCF10 plasmid in Enterococcus faecalis (E. faecalis) mediates antibiotic resistance gene dissemination, but its role in bacterial persister formation remains unclear. This study systematically investigated the regulatory role of pheromone cCF10 in the persister phenotype of pCF10-carrying E. faecalis and its underlying molecular mechanisms. We confirmed that cCF10 enhanced persistence against levofloxacin in OG1RF (pCF10), with the persister frequency increasing from 0.291% to 16.466% upon treatment. Transcriptomic analysis revealed that cCF10 activated the (p)ppGpp-mediated stringent response and downregulated the expression of genes associated with energy-intensive pathways, including those involved in DNA repair, protein folding, and respiration. Concurrently, cCF10 enhanced the expression of genes related to biofilm formation and cell lysis resistance and downregulated components of its own sensing and uptake systems. These findings demonstrate that cCF10 induces transcriptional reprogramming associated with increased persister formation in E. faecalis carrying the pCF10 plasmid and identify potential targets within the stringent response and associated metabolic pathways for the development of anti-persister strategies. Full article

Achromobacter spp. are opportunistic pathogens in people with cystic fibrosis (PwCF), yet the role of the upper airways in their persistence and adaptation remains poorly understood. We investigated whether the sinonasal compartment may act as reservoir and evolutionary niche for Achromobacter spp. during airway infection. Twenty-two isolates obtained from paired nasal lavage and sputum samples of seven PwCF were analysed by whole-genome sequencing. Within each PwCF, identical clone types were detected in both airway compartments, supporting bacterial exchange between upper and lower airways. Despite clonal relatedness, substantial genomic diversification was observed between paired isolates. Genomic signatures indicative of elevated mutation rates were detected in a high number of isolates (73%) and in both airway compartments, highlighting widespread genomic diversification across the respiratory tract. Mobilome analysis revealed compartment-specific variations in insertion sequences, prophages, and integrative elements, suggesting genome plasticity. Additionally, mutation in an aspartate kinase gene was consistently associated with loss of biofilm formation in vitro, highlighting a potential link between this pathway and biofilm phenotype. Overall, our findings indicate that upper and lower airways represent interconnected but partially independent ecological niches where Achromobacter populations can diverge during colonization, supporting the view that both compartments contribute to their persistence and evolution in CF airways. Full article

Exercise adaptation and training maladaptation arise from overlapping metabolic, redox, inflammatory, endocrine, and tissue-remodeling processes, so the translational question is not whether biomarkers change but when, where, and for which decision they become informative. This narrative review develops a decision-linked framework for minimally invasive biomarkers across the recovery–overload continuum and treats biomarker meaning as a molecule–matrix–time–decision relationship rather than as a stand-alone peak. The framework is organized around five coupled layers: stimulus architecture, signaling and release biology, sampling matrix and pre-analytics, bout-relative kinetics, and the monitoring decision to be supported. Current evidence indicates that no single biomarker reliably separates productive remodeling from delayed recovery, tissue strain, non-functional overreaching, or early maladaptation. Classical chemistry remains useful for bounded tasks, especially delayed tissue strain and stress reactivity; cfDNA appears promising for rapid load sensitivity; targeted metabolite panels are strongest for recovery phenotyping; and circulating RNAs and extracellular-vesicle cargo add mechanistic depth but remain constrained by pre-analytical fragility and incomplete standardization. The central practical implication is that overload is better interpreted as progressive loss of signal resolution than as threshold-crossing and that sparse temporally staggered panels are more likely to aid monitoring decisions than isolated markers or untimed high-dimensional profiles. Progress will depend on purpose-specific panels, transparent analytical standards, and prospective validation against symptoms, performance, and established measures across sex, hormonal, circadian, and training contexts. Full article