Search Results (218)

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

The hemodialysis population has progressively aged over the past two decades; in several settings, adults aged ≥75 years represent one of the fastest-growing populations receiving dialysis. Frailty, characterized by reduced physiological reserve and heightened vulnerability to stressors, has emerged as a critical determinant of outcomes and is commonly assessed using validated instruments such as the Fried Frailty Phenotype or the Clinical Frailty Scale (CFS). Reported frailty prevalence in hemodialysis varies widely (approximately 20% to >80%), largely depending on the assessment instrument and the population studied, with consistently higher prevalence in older cohorts. It is consistently associated with older age, female sex, diabetes, lower serum albumin, cardiovascular disease, longer dialysis vintage, and lower physical activity. Compared with non-frail patients, frail hemodialysis patients have a substantially higher risk of death (approximately two-fold in pooled analyses). Seminal trials and large observational programs that shaped hemodialysis targets underrepresented very old, frail, and highly comorbid patients, limiting generalizability. In frail older adults with limited life expectancy and substantial comorbidity burden, standard thrice-weekly schedules, higher ultrafiltration intensity, and a uniform ‘fistula-first’ approach may increase treatment burden without clear proportional gains in patient-centered outcomes. This review examines evidence supporting individualized hemodialysis strategies in frail older adults. As the dialysis population continues to age, proficiency in goal-concordant, personalized prescribing is increasingly important for nephrologists and dialysis teams. Full article

Cystic fibrosis (CF) is an autosomal recessive disorder caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and primarily affects the respiratory, digestive, and reproductive systems. Globally, CF is most prevalent among European ancestry, with an incidence rate of approximately 1/2500 to 1/3500. In China, the incidence is about 1/128,000. However, CF is not extremely rare in the Chinese population; rather, its prevalence is significantly underestimated. The CFTR mutation spectrum in China is highly unique, characterized by an extremely low frequency of p.Phe508del. Instead, region-specific mutations such as p.Gly970Asp, p.Ile1023Arg, and p.Arg553Ter predominate, alongside a high proportion of splicing variants and complex rearrangements. A significant proportion of Chinese CF patients primarily present with CF-like phenotypes within the CF-related disease spectrum (such as congenital bilateral absence of the vas deferens and pseudo-Bartter syndrome), exhibiting overlapping features with classic CF but lacking typical respiratory-dominant symptoms. This review examines how these atypical symptoms deviate from the diagnostic pathways established in Western countries. Establishing localised data and functional platforms is a prerequisite for achieving precision medicine. Achieving a transition from symptom-focused care to defect-correcting therapy will require coordinated multicenter collaboration and sustained infrastructure development. Full article

The article presents a clinical case involving a patient with presumptive coexistence of two hereditary disorders, confirmed by molecular genetic analyses. Clinical evaluation of the proband, a 9-year-old girl, revealed features characteristic of Kabuki syndrome, including a typical “Kabuki makeup” facial phenotype, short stature, intracranial hypertension, and diffuse muscular hypotonia. Additional clinical findings included chronic right-sided otitis media, conjunctivitis, recurrent pneumonia, bilateral conductive hearing loss, astigmatism, and primary adenitis. Clinical assessment and molecular genetic testing were performed. High-throughput sequencing identified a previously reported pathogenic heterozygous variant in the KMT2D gene, NM_003482.4:c.15142C>T p.Arg5048Cys, and two known heterozygous variants in the CFTR gene: NM_000492.4:c.1521_1523delCTT p.Phe508del and c.3454G>C p.Asp1152His, classified as pathogenic and of variable clinical significance, respectively. Segregation analysis demonstrated that the KMT2D variant most likely arose in the proband de novo, whereas the CFTR variants were inherited from each of the parents. Notably, the proband’s clinically unaffected elder sister carried the same CFTR genotype. Based on the clinical presentation and molecular genetic findings, the diagnosis of Kabuki syndrome type 1 was conclusively established in the patient. Functional assessment of CFTR demonstrated its preserved function, which did not support a diagnosis of CF or CFTR-related disorders. Full article

Colletotrichum fructicola is the predominant pathogenic agent responsible for anthracnose in Camellia oleifera. RGS2 is a GTPase-activating protein that negatively regulates G-protein signaling by inactivating Gα subunits. In this study, we characterized the ortholog of CfRGS2 in C. fructicola to explore its pathogenic roles. Seven canonical RGS genes were identified through BLASTp and keyword searches. Conserved domains and subcellular localizations were predicted bioinformatically. A CfRGS2 knockout mutant was generated via overlap-PCR and PEG-mediated transformation, verified by PCR, and complemented by reintroducing the wild-type gene. Phenotypic characterization showed that the growth rates of mutants ΔCfrgs2-1 and ΔCfrgs2-2 were significantly reduced compared with those of the wild-type and complemented strains. On both PDA and minimal medium, the mutant strains exhibited significantly smaller colony diameters of 3.3 cm and 3.1 cm, respectively, relative to the control strains. Moreover, conidiation in the mutants was only 4% of that in the wild-type and complemented strains, and appressorium formation was reduced to 6%, with statistical analyses confirming high significance. Under cell wall stress induced by 400 μg/mL Congo red, the growth inhibition rates of ΔCfrgs2-1 and ΔCfrgs2-2 were 44% and 48%, respectively, significantly higher than those of the control strains. Pathogenicity assays demonstrated that the mutants failed to induce lesions on unwounded leaves and caused 47% and 30% smaller lesion areas on wounded apple fruits, respectively. In summary, C. fructicola possesses seven canonical RGS proteins that regulate G-protein signaling, among which CfRgs2 is implicated in growth, conidiation, the stress response to cell wall perturbation, and virulence. Full article

Background: Kidney transplantation is the optimal treatment for end-stage renal disease; however, acute rejection remains a major determinant of long-term graft dysfunction and failure. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a minimally invasive biomarker reflecting allograft injury, with growing evidence supporting diagnostic and prognostic utility. Objectives: This structured narrative review aimed to synthesize contemporary evidence (2020–2025) on the diagnostic and prognostic utility of plasma dd-cfDNA and its integration into kidney transplant rejection surveillance. Methods: A narrative literature review was conducted using PubMed to identify studies published or available online ahead of print, between January 2020 and September 2025, evaluating plasma dd-cfDNA in adult kidney transplant recipients. Manual screening of reference lists supplemented the search. Original clinical studies reporting diagnostic or prognostic outcomes were included, and the results were synthesized narratively due to methodological heterogeneity. Results: Across prospective and retrospective cohorts, elevated dd-cfDNA discriminated rejection from non-rejection biopsies, with strongest performance in antibody-mediated and microvascular rejection phenotypes. Longitudinal studies demonstrated that dd-cfDNA elevations often preceded histologically confirmed rejection and predicted adverse graft outcomes, while low levels were associated with immunologic quiescence. Assay variability limited cross-study comparability, whereas integration with donor-specific antibodies, gene expression profiling, or algorithm-based approaches improved diagnostic and prognostic discrimination. Conclusions: Dd-cfDNA is a clinically meaningful biomarker for kidney transplant rejection monitoring, providing diagnostic and prognostic information beyond conventional functional markers. When interpreted longitudinally and in clinical context, dd-cfDNA supports risk stratification and surveillance, with evidence supporting its expanding role in risk-adapted transplant care. Full article

Fate-mapping studies have challenged the longstanding view of the adult mammalian heart as a post-mitotic organ, suggesting limited cardiomyocyte renewal. This has spurred efforts to determine whether selected cardiac stromal cells have regenerative potential; however, their contribution to cardiac regeneration has been found to be minimal compared with that of cardiomyocyte proliferation. Despite this, transplantation of some cardiac stromal cell populations has shown therapeutic potential through paracrine signalling. The identity of the paracrine-active stromal cell populations remains unclear due to overlapping characteristics with other cardiac stromal cell populations, such as fibroblasts, mesenchymal cells, and pericytes. This study sought to clarify the transcriptional identity and heterogeneity of adult mouse cardiac stromal cells by developing a cardiac collagenase–trypsin protocol and comparing it to the established method for isolating cardiosphere-derived cells (CDCs). This novel protocol resulted in a higher cell yield and shorter expansion time, and the resulting cells showed superior survival under serum starvation compared to commercially acquired cardiac fibroblasts (CFs). Single-cell qRT-PCR analysis revealed that collagenase–trypsin cells (CTs) and CDCs share similar gene expression profiles, distinct from those of CFs. Notably, CTs exhibited higher expression of Tcf21 and lower expression of Tbx5, suggesting an epicardial-derived fibroblast phenotype, whereas Tbx5 was enriched in CDCs and CFs, reflecting heterogeneity within the cardiac fibroblast compartment. This study offers insights into the complex identity of cardiac stromal cells and concludes that CTs closely resemble CDCs but can be generated more rapidly, making them a robust and efficient source of paracrine-active cardiac stromal cells. Full article