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Association between serum carotenoid concentrations and risk of all-cause and cause-specific mortality in individuals with osteoarthritis
No full textOBJECTIVE: Osteoarthritis (OA) has been a major public health challenge. The role of non-negligible dietary factors in the development of OA and in mortality risk among OA patients is unclear. This study aims to investigate the associations of serum carotenoid levels with mortality in OA patients. METHODS: We analyzed data from 2051 OA patients in NHANES III. Mortality through December 31, 2019, was determined via the National Death Index. We assessed associations between carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, lycopene) and mortality using cubic splines and Cox regression. Sensitivity and stratified analyses were performed. RESULTS: Overall, 942 deaths occurred during a median 12.58-year follow-up. Higher quartiles of all carotenoids (except lutein/zeaxanthin) were associated with lower all-cause mortality (hazard ratios and 95% confidence intervals: 0.53 [0.41, 0.67], 0.74 [0.59, 0.95], 0.75 [0.59, 0.96], and 0.66 [0.51, 0.86] for α-carotene, β-carotene, β-cryptoxanthin, and lycopene). BMI modified the relationship between β-carotene and mortality, showing a protective effect with BMI < 30 kg/m. CONCLUSION: Higher serum carotenoid levels are linked to reduced mortality. While suggesting potential benefits, carotenoid supplement use remains questionable due to possible antioxidant interactions and synergistic effects
Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models
No full textAutosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients’ quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ∼30% of wildtype transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases
Cefiderocol resistance genes identified in environmental samples using functional metagenomics
Full text linkAntibiotic resistance poses a global public health threat, which can originate from the transfer of environmental antibiotic resistance genes to pathogenic bacteria, as highlighted by the “One Health” framework. Cefiderocol is a siderophore cephalosporin recently introduced in clinical practice which displays a “Trojan Horse” mechanism, utilizing bacterial iron transportation systems for cell entry. Although it is only used as a last-line antibiotic, resistance has already been observed in clinical isolates. Yet, cefiderocol resistance genes are difficult to monitor as resistance mechanisms remain mostly undescribed in antibiotic resistance gene databases and therefore uncharacterized in the environment. To address this critical gap, we applied functional metagenomics to diverse environmental samples (wastewater, freshwater, and soil) from France, Germany, Sweden, and Pakistan. Four antibiotic resistant genes were identified as responsible for increased cefiderocol minimum inhibitory concentrations to clinically-relevant levels (ranging from 1 to 4 mg/l), including ꞵ-lactamases (VEB-3, OXA-372 homolog, and YbxI homolog) and a partial penicillin-binding protein homolog. None of these genes had been previously reported as a cefiderocol resistance gene. Three out of four had their closest homologs in pathogenic bacteria. The bla(VEB-3) gene was associated with a mobile genetic element and distributed across all wastewater metagenomes analyzed in this study. We therefore highlight the critical need for functional metagenomics, to characterize previously uncharacterized last-line antibiotic resistance mechanisms which will be used to enrich antibiotic resistance gene databases and thereby improving antibiotic resistance surveillance in all One Health compartments
Extrachromosomal DNA micronucleation constrains tumour fitness and improves patient survival
Full text linkExtrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification, intratumoural heterogeneity and rapid genetic change. Micronuclei (MN) are frequently observed in chromosomally unstable cancers, yet their origins and relevance in ecDNA-driven tumours remain incompletely understood. Here, we investigate the relationship between ecDNA segregation errors and MN formation. We find that ecDNA frequently localizes to MN and represents a prominent source of MN content in ecDNA-positive cancer cells. Mitotic clustering of oncogene-bearing ecDNAs is associated with asymmetric inheritance and mis-segregation into MN. Transfer of oncogenes from ecDNA into MN is accompanied by reduced transcriptional output. Single-MN sequencing shows that individual MN are enriched for ecDNA to a degree that exceeds expectations from stochastic mis-segregation and that in MN oncogenes originating from multiple distinct ecDNAs coalesce. Using live-cell imaging, we observe that cells inheriting ecDNA-positive MN show limited proliferative capacity and an increased likelihood of cell death. In neuroblastoma patients with MYCN-amplified ecDNA, higher frequencies of ecDNA-positive MN at diagnosis are associated with improved event-free and overall survival. Together, these findings link ecDNA mis-segregation to MN formation and reduced cellular fitness, suggesting that ecDNA-positive MN may reflect a state of impaired oncogenic ecDNA function with potential relevance for clinical outcome
Magnesium depletion, metabolic impairment, and cardiac alterations: the NAKO-MRI study with mendelian randomization
No full textCONTEXT: Magnesium deficiency may contribute to subclinical cardiac changes, particularly metabolic diastolic cardiomyopathy. OBJECTIVE: To investigate the association between magnesium depletion, metabolic syndrome (MetS), and magnetic resonance imaging (MRI)-derived cardiac alterations in a population-based sample. METHODS: We cross-sectionally analyzed participants (N = 9568) from the baseline examination of the German National Cohort who underwent whole-body MRI. Associations of serum magnesium and magnesium depletion score (MDS) with MetS and cardiac alterations were assessed using multivariable logistic and linear regression, respectively. Two-sample Mendelian Randomization was performed to evaluate the potential causal relationship between serum magnesium and MRI-derived cardiac parameters. RESULTS: Our analysis revealed no correlation between serum magnesium and MDS (Spearman's rho = 0.065; P < .001). A 1-SD increase in serum magnesium was associated with lower MetS prevalence (odds ratio, 0.93 [95% CI, 0.88-0.99]) and reduced left and right ventricular systolic and diastolic volumes. Higher MDS, indicating magnesium deficiency, was linked to increased MetS prevalence (OR per 1 unit, 1.32 [95% CI, 1.23-1.41]) and its individual components. Furthermore, higher MDS was associated with increased left ventricular remodeling index (estimate, 0.012 g/mL [95% CI, 0.008-0.017]) and decreased left ventricular end-diastolic volume (estimate, −1.132 mL/m(2) [95% CI, −1.538 to −0.727]), indicating concentric hypertrophy. Two-sample Mendelian Randomization suggested no causal relationship between serum magnesium and MRI-derived cardiac markers. CONCLUSION: Magnesium depletion may serve as an early indicator of cardiac impairment. However, Mendelian Randomization results do not support a causal role of serum magnesium on cardiac structure and morphology
An integrated view of the structure and function of the human 4D nucleome
Full text linkThe dynamic three-dimensional (3D) organization of the human genome (the 4D nucleome) is linked to genome function. Here we describe efforts by the 4D Nucleome Project1 to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function
HFpEF and MASLD: converging mechanisms and clinical implications
No full textHeart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly prevalent, interrelated conditions driven by the global rise in obesity and metabolic syndrome. Once viewed in isolation, HFpEF and MASLD are now recognized as organ-specific manifestations of shared systemic metabolic dysfunction. Evidence from the past decade highlights not only overlapping risk factors but also a dynamic, bidirectional inter-organ crosstalk between the liver and the heart that shapes their natural history. In this Review, we explore the epidemiological and mechanistic basis of the MASLD–HFpEF connection, focusing on shared metabolic drivers such as lipotoxicity, meta-inflammation and oxidative stress. We also discuss emerging liver-derived mediators, including hepatokines, metabolites and extracellular vesicles, that influence cardiac structure and function. Finally, we highlight diagnostic and therapeutic strategies relevant to both conditions and propose a multiorgan framework to improve their clinical recognition and management. Understanding the liver–heart axis is key to rethinking cardiometabolic disease beyond organ silos and towards more integrated, mechanism-based approaches
Novel deiodinase 2-selective inhibitors — possible reference substances for regulatory in vitro tests for endocrine disruptors and drugs targeting T3-dependent processes
No full textBACKGROUND: Thyroid hormone (TH) homeostasis depends on the coordination of several key events to maintain proper local TH signaling, including iodide uptake, hormone synthesis, metabolism, and elimination. Three selenoprotein isoenzymes, deiodinases 1–3 (DIO1–3), are essential components of TH metabolism, and their activities have been identified as relevant endpoints regarding the screening of compounds influencing the TH system. Given the importance of DIO2 as the key enzyme for local activation of the prohormone T4 to the active T3 in various tissues, and limited data on selective biochemical DIO2 inhibition, there is a clear need to identify potent and selective DIO2-inhibiting compounds.
METHODS: Human-recombinant DIO2 enzyme pools were prepared from HEK293 cells overexpressing DIO2 and used as a robust enzyme source for the development, optimization, and semiautomated miniaturization of a nonradioactive DIO2 high-throughput screening (HTS) enzyme assay for the identification of DIO2-selective small molecule inhibitors. LT4 was used as substrate, and enzymatic release of iodide was colorimetrically quantified by the iodide-catalyzed Sandell–Kolthoff reaction. Eight comprehensive small molecule libraries were screened, covering ∼1/5 of the synthetic chemicals currently registered, natural products, as well as FDA-approved drugs. A total of 59,928 compounds were first screened at a single 10 µM concentration, followed by a validation screen to confirm the primary hits. Subsequently, DIO isoenzyme selectivity and cytotoxicity were evaluated.
RESULTS: Utilizing this highly reproducible and robust HTS test system with a determined median Z′-factor of 0.70 identified 356 primary inhibitory hits. Concentration-response experiments verified 17 potent inhibitors, further characterized regarding their DIO isoenzyme selectivity and cytotoxicity. Six potent DIO2-selective inhibitors, including two FDA-approved drugs and various novel pan-DIO inhibitors, for example, the fungicide fluazinam, were identified.
CONCLUSIONS: Specific DIO2 inhibitors, such as the FDA-approved drugs racecadotril and ibrutinib and the tyrosine kinase inhibitor rociletinib, might serve as a future toolbox for reversible pharmacological interference with the local provision of DIO2-generated T3 from T4 during development, tissue regeneration, and various DIO2-dependent metabolic processes. Furthermore, they can serve as reference compounds for the development and validation of regulatory in vitro tests. Identified FDA-approved drugs warrant a closer look at potential disturbances of local TH availability