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Ribosomes modulate transcriptome abundance via generalized frameshift and out-of-frame mRNA decay
Get PDFCells need to adapt their transcriptome to quickly match cellular needs in changing environments. mRNA abundance can be controlled by altering both its synthesis and decay. Here, we show how, in response to poor nutritional conditions, the bulk of the S. cerevisiae transcriptome undergoes −1 ribosome frameshifts and experiences an accelerated out-of-frame co-translational mRNA decay. Using RNA metabolic labeling, we demonstrate that in poor nutritional conditions, nonsense-mediated mRNA decay (NMD)-dependent degradation represents at least one-third of the total mRNA decay. We further characterize this mechanism and identify low codon optimality as a key factor for ribosomes to induce out-of-frame mRNA decay. Finally, we show that this phenomenon is conserved from bacteria to humans. Our work provides evidence for a direct regulatory feedback mechanism coupling protein demand with the control of mRNA abundance to limit cellular growth and broadens the functional landscape of mRNA quality control
Toward a domain-overarching metadata schema for making health research studies FAIR (findable, accessible, interoperable, and reusable): development of the NFDI4Health Metadata Schema
Get PDFBACKGROUND: Despite wide acceptance in medical research, implementation of the FAIR (findability, accessibility, interoperability, and reusability) principles in certain health domains and interoperability across data sources remain a challenge. While clinical trial registries collect metadata about clinical studies, numerous epidemiological and public health studies remain unregistered or lack detailed information about relevant study documents. Making valuable data from these studies available to the research community could improve our understanding of various diseases and their risk factors. The National Research Data Infrastructure for Personal Health Data (NFDI4Health) seeks to optimize data sharing among the clinical, epidemiological, and public health research communities while preserving privacy and ethical regulations. OBJECTIVE: We aimed to develop a tailored metadata schema (MDS) to support the standardized publication of health studies' metadata in NFDI4Health services and beyond. This study describes the development, structure, and implementation of this MDS designed to improve the FAIRness of metadata from clinical, epidemiological, and public health research while maintaining compatibility with metadata models of other resources to ease interoperability. METHODS: Based on the models of DataCite, ClinicalTrials.gov, and other data models and international standards, the first MDS version was developed by the NFDI4Health Task Force COVID-19. It was later extended in a modular fashion, combining generic and NFDI4Health use case-specific metadata items relevant to domains of nutritional epidemiology, chronic diseases, and record linkage. Mappings to schemas of clinical trial registries and international and local initiatives were performed to enable interfacing with external resources. The MDS is represented in Microsoft Excel spreadsheets. A transformation into an improved and interactive machine-readable format was completed using the ART-DECOR (Advanced Requirement Tooling-Data Elements, Codes, OIDs, and Rules) tool to facilitate editing, maintenance, and versioning. RESULTS: The MDS is implemented in NFDI4Health services (eg, the German Central Health Study Hub and the Local Data Hub) to structure and exchange study-related metadata. Its current version (3.3) comprises 220 metadata items in 5 modules. The core and design modules cover generic metadata, including bibliographic information, study design details, and data access information. Domain-specific metadata are included in use case-specific modules, currently comprising nutritional epidemiology, chronic diseases, and record linkage. All modules incorporate mandatory, optional, and conditional items. Mappings to the schemas of clinical trial registries and other resources enable integrating their study metadata in the NFDI4Health services. The current MDS version is available in both Excel and ART-DECOR formats. CONCLUSIONS: With its implementation in the German Central Health Study Hub and the Local Data Hub, the MDS improves the FAIRness of data from clinical, epidemiological, and public health research. Due to its generic nature and interoperability through mappings to other schemas, it is transferable to services from adjacent domains, making it useful for a broader user community
What can we learn from an intersectionality-informed description of study participants? Results from the German National Cohort
Get PDFBACKGROUND: Intersectionality has contributed to novel insights in epidemiology. However, participants of epidemiological studies have rarely been characterised from an intersectional perspective. We aimed to show the gained insights of an intersectionality-informed approach to describing a study population by comparing it to a conventional approach. METHODS: We used data of the German National Cohort (NAKO), which recruited 205,415 participants between 2014 and 2019. In the conventional approach, marginal proportions of educational level, cohabitation status, and country of birth were compared between the study populations of the NAKO and the German census survey (MZ) of 2014. In the intersectionality-informed approach, so-called intersectional population strata were constructed by cross-classifying educational level, cohabitation status, and country of birth. Proportions of these strata were also compared between NAKO and MZ. All analyses were stratified by sex and age group. RESULTS: The conventional approach showed that the proportion of people with low education was lower in the NAKO compared to the MZ in all sex and age strata. Similarly, proportions of all intersectional population strata with low education were lower in the NAKO. Concerning cohabitation, the conventional approach showed that the proportion of those living without a partner was lower in the NAKO than in the MZ for women under 60 and men. The intersectionality-informed approach revealed that the proportions of some subgroups of those living without a partner were higher in the NAKO than in the MZ. These were intersectional population strata who lived without a partner, had a high level of education and were born in Germany. The intersectionality-informed approach revealed similar within-group heterogeneity for country of birth, showing that not all proportions of foreign-born people were lower in the NAKO compared to the MZ. Proportions of foreign-born with high education who lived with a partner were higher. CONCLUSIONS: Our results showed that heterogeneity within social categories can be revealed by applying the concept of intersectionality when comparing study participants with an external population. This way, an intersectionality-informed approach contributes to describing social complexity among study participants more precisely. Furthermore, results can be used to reduce participation barriers in a more targeted way
Advancing research on regulatory autoantibodies targeting GPCRs: insights from the 5th international symposium
Get PDFThe 5th International Symposium on Regulatory Autoantibodies Targeting GPCR (RAB-GPCRs) advanced the understanding of the significant role played by autoantibodies targeting G-protein-coupled receptors (GPCRs) in various human diseases. Once considered passive markers, RAB-GPCRs are now recognized as active modulators of cellular signaling, immune regulation, and inflammation. The symposium highlighted their involvement in multiple prominent pathologies, including autoimmune diseases, cardio- and cerebrovascular diseases, and neuroimmunologic disorders such as myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 syndrome (ME/CFS/PCS), as well as solid organ and hematopoietic stem cell transplantation (SOT/HSCT). Experts from rheumatology, immunology, and neurology presented interdisciplinary discussions on the potential of RAB-GPCRs as biomarkers and therapeutic targets. Advances in screening methods, biomarker identification, and therapeutic strategies were shared, emphasizing their diagnostic potential and application in novel therapeutic interventions. This report summarizes key insights from the symposium, particularly focusing on the modulatory properties of RAB-GPCRs and their relevance in both immune-mediated diseases and other pathologies (e.g., vascular, degenerative) that are traditionally not considered primarily immune-mediated. Ongoing research is expected to further establish these autoantibodies as crucial components in disease modulation and systems biology contexts, offering new opportunities for precision medicine and improved clinical outcomes in immune-related disorders
The relation of multiple sclerosis to family history, lifestyle, and health factors in childhood and adolescence: findings of a case-control study nested within the German National Cohort (NAKO) study
No full textBACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disease of presumed autoimmune origin. A combination of genetic susceptibility and exposure to certain environmental and lifestyle factors might trigger the onset of MS. The currently known risk factors include a genetic predisposition, infection with the Epstein–Barr virus (EBV), smoking, and an increased body mass index. METHODS: In 2021–22, we carried out a case–control study nested within the German National Cohort (NAKO) to investigate associations of potential risk factors with MS. RESULTS: The subjects included 576 persons with MS (cases) and 895 without MS (controls). Beyond the known risk factors, we observed associations between MS and the cumulative number of common childhood infections (odds ratio (OR) 1.14 per additional infection, 95% confidence interval (CI): [1.03; 1.25]), major stressful life events (SLE) (OR 1.25 per additional event, [1.06; 1.48]), being the firstborn child of a mother aged 30 or older (OR 2.11, [1.08; 4.13]); higher amounts of physical activity in the teenage years were associated with a lower risk of MS (OR 0.82 per unit increase in activity level, [0.71; 0.95]). CONCLUSION: We confirmed known risk factors for MS and found associations with a number of new ones, e.g., the cumulative number of common childhood infections. These findings may shed light on the etiology of MS and merit further study
The postbiotic ReFerm versus standard nutritional support in advanced alcohol-related liver disease (GALA-POSTBIO): a randomized controlled phase 2 trial
Get PDFImpaired gut barrier function may lead to progression of liver fibrosis in people with alcohol-related liver disease. The postbiotic ReFerm® can lower gut barrier permeability and may thereby reduce fibrosis formation. Here, we report the results from an open-labelled, single centre randomized controlled trial where 56 patients with advanced, compensated, alcohol-related liver disease were assigned 1:1 to receive either ReFerm® (n = 28) or standard nutritional support (Fresubin®, n = 28) for 24 weeks. The primary outcome was a ≥ 10% reduction of the fibrosis formation marker alpha-smooth muscle actin in liver biopsies, assessed by a blinded pathologist using automated digital imaging analysis. Paired liver biopsies meeting quality criteria for the primary outcome were available for 40 participants (ReFerm®, n = 21 and Fresubin®, n = 19). This reduction was observed in 29% of patients receiving ReFerm®, compared to 14% with Fresubin® (OR = 2.40; 95% CI 0.63 to 9.16; p = 0.200). No treatment-related serious adverse events occurred. Our findings suggest that ReFerm® may reduce liver fibrosis by enhancing gut barrier function, potentially preventing the progression of alcohol-related liver disease
Diurnal urinary aldosterone excretion and potassium intake during pregnancy are associated with high normal blood pressure in early childhood
Get PDFBACKGROUND: Offspring blood pressure (OBP) may be programmed during pregnancy. Accordingly, maternal third-trimester 24-hour urine aldosterone levels are associated with fetoplacental trophic effects. Furthermore, high potassium and low sodium intakes are generally recommended in adults with normal renal function. We hypothesized that maternal 24-hour urine aldosterone levels were positively associated with OBP, and maternal intake of potassium and sodium may influence the association. The study aimed to investigate associations between maternal third-trimester 24-hour urine aldosterone, potassium and sodium intake, and OBP. METHODS: In the prospective OCC (Odense Child Cohort), 475 mother-child dyads had 24-hour urine aldosterone from gestational week 29 and OBP (systolic and diastolic), at ages 3 and 18 months and 3 and 5 years. Maternal potassium and sodium intakes were calculated from 24-hour urine potassium and urine sodium excretions. RESULTS: Increased maternal 24-hour urine aldosterone associated with higher systolic blood pressure in offspring at ages 3 months (β=0.54 mm Hg [95% CI, 0.29; 0.79]) and 18 months (β=0.24 mm Hg [95% CI, 0.03; 0.44]). One thousand mg/d increase in maternal potassium intake was associated with an average increase in offspring systolic blood pressure of 0.68 mm Hg (95% CI, 0.02-1.34) up to age 5 years (pooled), with significant associations only in girls (β=1.14 mm Hg [95% CI, 0.21-2.08]). No significant association was seen between maternal sodium intake and OBP. CONCLUSIONS: Elevated maternal 24-hour urine aldosterone and higher dietary potassium intake were associated with higher OBP but within normal range in young children, and girls were more susceptible to maternal potassium intake. REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: ID NCT02183558
Design and characterization of G-quadruplex RNA aptamers reveal RNA-binding by KDM5 lysine demethylases
Get PDFHere, we show that the histone lysine demethylases KDM5A and KDM5B can bind to RNA through interaction with G-quadruplexes, despite neither being categorized as RNA- nor G-quadruplex binding proteins across numerous experimental large-scale and computational studies. In addition to characterizing the KDM5 G-quadruplex interaction we show that RNA is directly involved in the formation of KDM5-containing protein complexes. Computational predictions and comparisons to other ARID domain containing proteins suggest that the ARID domain is directly interacting with both DNA and RNA across several proteins. Our work highlights that the RNA-binding by KDM5 lysine demethylases is dependent on recognizing G-quadruplex structures and that RNA mediates the formation of alternative KDM5-containing protein complexes
(23)Na MRI quantification of sodium content in porcine eyes after immersion in saltwater and freshwater en route to time in water estimation
Get PDFBACKGROUND: Differentiation between saltwater and freshwater immersion as well as estimating the corpse's time in water can be challenging. We aimed to establish and examine the feasibility of a novel approach based on sodium magnetic resonance imaging ((23)Na MRI) of the eye to facilitate noninvasive sodium quantification. METHODS: Enucleated porcine eyes were immersed in NaCl 0.9%, NaCl 3.0%, NaCl 5.85%, distilled water (DW) or lake water (LW) at different time intervals, followed by (23)Na 7-T MRI sodium quantification. RESULTS: After 6 h of immersion, a significant difference in vitreous body (VB) sodium concentration was found for NaCl 5.85% versus DW or LW (p ≤ 0.019). After 24 and 48 h of immersion, a significant difference in VB sodium concentration was found for NaCl 5.85% versus DW, LW, NaCl 3.0% or NaCl 0.9%, as well as for NaCl 3.0% versus DW, LW or NaCl 0.9% (p ≤ 0.001). After 24 h of immersion, lens sodium concentration showed a significant difference for NaCl 5.85% versus DW, LW, NaCl 3.0% or NaCl 0.9% (p ≤ 0.009); after 48 h of immersion, for NaCl 5.85% versus DW, LW, NaCl 3.0% or NaCl 0.9% (p ≤ 0.001), as well as for NaCl 3.0% versus DW, LW or NaCl 0.9% (p ≤ 0.007). For VB, sodium concentration changes over immersion time, and exponential curves were fitted to the data. CONCLUSION: Using (23)Na MRI in ex vivo porcine eyes with different immersion times in various saltwater concentrations and freshwater equivalents allowed noninvasive quantification of VB and lens sodium concentrations. RELEVANCE STATEMENT: Although not a substitute for autopsy, (23)Na MRI assessment of VB and lens sodium concentrations may provide biochemical support in suspected drowning, especially in cases where an internal examination of the body is not authorized or where objections to autopsy are upheld. KEY POINTS: Postmortem porcine eyes with different immersion times in saltwater and freshwater. Noninvasive quantification of vitreous body and lens sodium concentrations with (23)Na MRI. Exponential time course of vitreous body sodium concentration in saltwater and freshwater
Insights into therapeutic discovery through the Kelch domain structure of Keap1 at ambient temperature
Get PDFBACKGROUND/AIM: The Kelch-like-ECH associated protein 1 (Keap1) is an integral component of the E3-ubiquitin ligase complex, which binds to Nuclear factor erythroid 2-related factor 2 (Nrf2) and facilitates its degradation by the 26S proteasome. The Kelch domain of Keap1, composed of six repeated structural motifs, plays a key role in this interaction. This study aims to investigate the dimeric structure of the Keap1 Kelch domain at ambient temperature and to examine its implications for conformational dynamics, particularly in relation to the DMF and Nrf2 binding sites. MATERIALS AND METHODS: The dimeric crystal structure of the Keap1 Kelch domain was determined at 3.0 Å resolution using data collected at the Turkish Light Source ‘Turkish DeLight.’ To analyze structural dynamics, Gaussian Network Model (GNM) analysis was applied, and molecular docking studies were performed using the ambient temperature structure to evaluate the binding of compounds acting as inhibitors of the Keap1/Nrf2 complex. RESULTS: The study reveals significant potential conformational changes in Keap1 residues, especially at the DMF and Nrf2 binding sites, driven by temperature-induced shifts. GNM analysis suggests that the allosteric behavior of DMF binding residues is fully realized in the ambient temperature structure. Molecular docking of various compounds, including CNN (a hybrid of L-carnosine and L-histidyl hydrazide), ZINC 12433145, and ZINC 105508677, demonstrated favorable binding interactions with key Keap1 residues, highlighting their potential as inhibitors. CONCLUSION: Our in silico and crystallo results suggest that CNN is a promising lead compound for Keap1 inhibition. Understanding the dimeric form of the Keap1 Kelch domain and its conformational changes at ambient temperature is crucial for elucidating the dynamics of the Keap1-Nrf2 interaction