bluuebunny/crossref_metadata_2025_split huggingface dataset:
Competition effects regulating the composition of the microRNA pool
Authors: Raak Sofia B. , Hanley Jonathan G. , O’Donnell Cian 
Published: May 2024

AbstractMicroRNAS (miRNAs) are short non-coding RNAs that can repress mRNA translation to regulate protein synthesis. During their maturation, multiple types of pre-miRNAs compete for a shared pool of the enzyme Dicer. It is unknown how this competition for a shared resource influences the relative expression of mature miRNAs. We study this process in a computational model of pre-miRNA maturation, fitted toin vitroDrosophila S2 cell data. We find that those pre-miRNAs which efficiently interact with Dicer outcompete other pre-miRNAs, when Dicer is scarce. To test our model predictions, we re-analysed previously publishedex vivomouse striatum data with reducedDicer1expression. We calculated a proxy measure for pre-miRNA affinity to TRBP (a protein which loads pre-miRNAs to Dicer). This measure well-predicted mature miRNA levels in the data, validating our assumptions. We used this as a basis to test the the model’s predictions through further analysis of the data. We found that pre-miRNAs with strong TRBP association are over-represented in competition conditions, consistent with the modelling. Finally using further simulations, we discovered that pre-miRNAs with low maturation rates can affect the mature miRNA pool via competition among pre-miRNAs. Overall, this work presents evidence of pre-miRNA competition regulating the composition of mature miRNAs.
Bayes Factor for Linear Mixed Model in Genetic Association Studies
Authors: Guan Yongtao , Levy Daniel 
Published: May 2024

AbstractMotivationBayes factor has advantages over p-value as test statistics for association, particularly when comparing multiple alternative models. A software package to compute Bayes factor for linear mixed model is lacking.ResultsWe transformed the standard linear mixed model as Bayesian linear regression, substituting the random effect by fixed effects with eigenvectors as covariates whose prior effect sizes are proportional to their corresponding eigenvalues. Using conjugate normal inverse gamma priors on regression parameters, Bayes factors can be computed in a closed form. We then showed that the transformed Bayesian linear regression produced identical estimates to those of the best linear unbiased prediction (BLUP), providing a new derivation to a known connection between BLUP and Bayesian estimates.Availability and implementationMethods described in this note are implemented in the software IDUL as two new functionalities: computing Bayes factors and residuals for the linear mixed model. IDUL and its source code are freely available athttps://github.com/haplotype/idul.
The epithelial adherens junction component PLEKHA7 regulates ECM remodeling and cell behavior through miRNA-mediated regulation of MMP1 and LOX
Authors: Daulagala Amanda C. , Cetin Metin , Nair-Menon Joyce , Jimenez Douglas W. , Bridges Mary Catherine , Bradshaw Amy D. , Sahin Ozgur , Kourtidis Antonis 
Published: May 2024

AbstractEpithelial adherens junctions (AJs) are cell-cell adhesion complexes that are influenced by tissue mechanics, such as those emanating from the extracellular matrix (ECM). Here, we introduce a mechanism whereby epithelial AJs can also regulate the ECM. We show that the AJ component PLEKHA7 regulates levels and activity of the key ECM remodeling components MMP1 and LOX in well-differentiated colon epithelial cells, through the miR-24 and miR-30c miRNAs. PLEKHA7 depletion in epithelial cells results in LOX-dependent ECM remodeling in culture and in the colonic mucosal lamina propria in mice. Furthermore, PLEKHA7-depleted cells exhibit increased migration and invasion rates that are MMP1- and LOX-dependent, and form colonies in 3D cultures that are larger in size and acquire aberrant morphologies in stiffer matrices. These results reveal an AJ-mediated mechanism, through which epithelial cells drive ECM remodeling to modulate their behavior, including acquisition of phenotypes that are hallmarks of conditions such as fibrosis and tumorigenesis.TeaserEpithelial cells instruct ECM remodeling to modulate their behavior, as a result of adherens junction and miRNA disruption.
Protective effect of P2Y receptors antagonism on stress-induced retinal degeneration
Authors: Bao Yi , Bond Kyle , Sarraf Pauline , Esterberg Robert , Serpa Megan , Twarog Michael , Xu YongYao , MacLeod Heather , Huang Qian , Saint-Geniez Magali 
Published: May 2024

AbstractThe death of retinal pigment epithelial (RPE) cells and photoreceptors (PR) is a hallmark of the progression of several degenerative ocular disorders. The precise molecular driver(s) behind RPE and PR cell death, however, remains unknown. Recent studies have suggested the involvement of ATP and purinergic signaling in the progression of age-related macular degeneration (AMD) and retinal degeneration. We have discovered that RPE cells release ATP when subjected to stress, which in turn exacerbates stress-related signaling via purinergic receptors that ultimately results in degeneration. Our findings demonstrate that blocking P2Y purinergic receptors using suramin can effectively prevent toxin-induced RPE cell death and dysfunctionin vitro. Furthermore, we show efficacy of suramin in preventing photoreceptor degenerationin vivousing the RHO-P23H zebrafish model. This study reinforces the involvement of ATP and purinergic signaling in maintaining retinal health, and highlights the potential of purinergic receptor antagonism as a therapeutic strategy for retinal degeneration.
FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPRERand ER-phagy
Authors: Lacy Shannon M. , Taubitz Rebecca J. , Urban Nicholas D. , Turowski Samantha N. , Smith Eric D. , Helms Adam S. , Michele Daniel E. , Truttmann Matthias C. 
Published: May 2024

AbstractCardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. Here, we find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis, and that FICD knockout mice maintain normal cardiac function after cardiac pressure overload. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response (UPRER) and impairs BiP interaction with FAM134B, an ER-phagy receptor, thus limiting ER-phagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent UPRERinduction and ER-phagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.
Gram-positive bacteria are primed for surviving lethal doses of antibiotics and chemical stress
Authors: Guha Manisha , Singh Abhyudai , Butzin Nicholas C. 
Published: May 2024

AbstractAntibiotic resistance kills millions worldwide yearly. However, a major contributor to recurrent infections lies in a small fraction of bacterial cells, known as persisters. These cells are not inherently antibiotic-resistant, yet they lead to increased antibiotic usage, raising the risk of developing resistant progenies. In a bacterial population, individual cells exhibit considerable fluctuations in their gene expression levels despite being cultivated under identical, stable conditions. This variability in cell-to-cell characteristics (phenotypic diversity) within an isogenic population enables persister cells to withstand antibiotic exposure by entering a non-dividing state. We recently showed the existence of “primed cells” inE. coli. Primed cells are dividing cells prepared for antibiotic stress before encountering it and are more prone to form persisters. They also pass their “prepared state” down for several generations through epigenetic memory. Here, we show that primed cells are common among distant bacterial lineages, allowing for survival against antibiotics and other chemical stress, and form in different growth phases. They are also responsible for increased persister levels in transition and stationary phases compared to the log phase. We tested and showed that the Gram-positive bacteriumBacillus megaterium, evolutionarily very distant from E. coli, forms primed cells and has a transient epigenetic memory that is maintained for 7 generations or more. We showed this using ciprofloxacin and the non-antibiotic chemical stress fluoride. It is well established that persister levels are higher in the stationary phase than in the log phase, and B. megaterium persisters levels are nearly identical from the early to late-log phase but are ∼2-fold and ∼4-fold higher in the transition and stationary phase, respectively. It was previously proposed that there are two distinct types of persisters: Type II forms in the log phase, while Type I forms in the stationary phase. However, we show that primed cells lead to increased persisters in the transition and stationary phase and found no evidence of Type I or II persisters with distant phenotypes. Overall, we have provided substantial evidence of the importance of primed cells and their transitory epigenetic memories to surviving stress.
Transcriptomic signatures and network-based methods uncover new Senescent Cell Anti-Apoptotic Pathways and Senolytics
Authors: Olascoaga Samael , Konigsberg Mina , Espinal-Enríquez Jesús , Tovar Hugo , Matadamas-Martínez Félix , Pérez-Villanueva Jaime , López-Diazguerrero Norma Edith 
Published: May 2024

AbstractCellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age-related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and anti-apoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network-based methods, we identified various genes that could represent new senescence-related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multi-target mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescence-associated survival and anti-apoptotic resistance pathways. The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAPs development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new anti-apoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.Graphical Abstract
Continuous quality improvement with a two-step strategy effective for large-scale SARS-CoV-2 screening at the Tokyo 2020 Olympic and Paralympic Games
Authors: Miyachi Hayato , Asai Satomi , Kuroki Rika , Omi Kazuya , Ikenoue Chiaki , Shimada Satoshi 
Published: May 2024

AbstractThe Tokyo 2020 Olympic Games (Games) were held during the height of the coronavirus disease 2019 (COVID-19) pandemic. In order to detect the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) early enough to contain the spread as well as to facilitate the timely arrival of athletes at their game venues, all participating athletes up to 14,000 staying in the Olympic Village were screened daily for the infection. Toward this aim, a two-step strategy was adopted comprising screening of self-collected saliva samples using a chemiluminescence enzyme immunoassay followed by confirmatory testing using polymerase chain reaction. The testing system was integrated with an information management system covering all steps. To ensure the accuracy of testing results, rigorous quality assurance measures and monitoring of performance/specimen quality were implemented. The chronological chart analysis was implemented to monitor the holistic process and to give feedback to improve the sampling. Nearly all test results for 418506 saliva samples were reported within 12 hours of sample collection, achieving the target mean turnaround time of 150 minutes for confirmatory testing. As a result, athlete activity and performance for the Games were ensured. The chronological chart confirmed that no athletes were retired due to a false-positive result and no infection clusters among athletes were identified. In conclusion, continuous quality improvement in the two-step strategy for the large-scale screening of COVID-19 contributed to the success of the Games during the pandemic. The quality practice, systems, and workflows described here may offer a model for future mass-gathering sporting events during similar major infectious disease epidemics.
Baseline immunotypes and immune entropy are indicators of multiple vaccine responsiveness
Authors: Cevirgel Alper , van der Heiden Marieke , Shetty Sudarshan A. , Viljanen Markus , Vos Martijn , Bijvank Elske , van Sleen Yannick , Imhof Celine , Rolwes Joeri A.J. , Samson Leonard Daniël , Beckers Lisa , Rots Nynke , van Beek Josine , Buisman Anne-Marie , van Baarle Debbie 
Published: May 2024

ABSTRACTImmune aging is associated with decreased vaccine responses, but biomarkers for vaccine responsiveness remain unidentified. We analyzed immunotypes describing baseline immune cell profiles and their associations with triple vaccine responsiveness to influenza, pneumococcal, and SARS-CoV-2 vaccines in adults aged 25-78 years. Additionally, we developed an innovative measure, immune entropy, to quantify cumulative perturbations in the immune cell subset network. Specific immunotypes associated with either weak or robust triple vaccine responsiveness. In addition, immune entropy was inversely related to vaccine responsiveness regardless of age. In a validation cohort of older adults, higher immune entropy was also associated with a lower antibody response to the BNT162b2 vaccine. A separate cohort of kidney transplant recipients, typically exhibiting diminished vaccine responses, demonstrated significantly increased immune entropy compared to healthy counterparts. Our findings suggest immunotypes and immune entropy as potential indicators to identify individuals at risk for suboptimal vaccine responses, potentially guiding personalized vaccination strategies.
No evidence of interaction betweenFADS2genotype and breastfeeding on cognitive or other traits in the UK Biobank
Authors: Centorame Giulio , Warrington Nicole M. , Hemani Gibran , Wang Geng , Davey Smith George , Evans David M. 
Published: May 2024

AbstractBackgroundBreastfeeding is hypothesised to benefit child health and cognitive functioning by providing long-chain polyunsaturated fatty acids (LC-PUFA), which are essential for brain development. In 2007, Caspiet al.found evidence in two cohorts for an interaction between genetic variation in theFADS2gene (a gene involved in fatty acid metabolism) and breast feeding on IQ. However, subsequent studies have provided mixed evidence for the existence of an interaction.ObjectiveTo investigate the relationship between genetic variation in theFADS2region, breastfeeding, and their interaction on traits putatively affected by their interplay in a large, population-based cohort with appropriate control for confounders in genetic associations.MethodsWe tested for the interaction in up to 335,650 individuals from the UK Biobank, over a range of cognitive functioning tests, as well as educational attainment and other traits thought to be influenced by breastfeeding, including cardiometabolic traits, reproductive success, and atopic allergy.ResultsFADS2alleles associated with an increase in docosahexaenoic acid (DHA) in blood serum (the C allele of rs174575) were associated with decreased verbal-numerical reasoning (p=2.28× 10−5) and triglycerides (p=1. 40× 10−41), increased reproductive success (p=3. 40× 10−5), total cholesterol (p=5. 28× 10−36), HDL (p=1. 42× 10− 51), and LDL cholesterol (p=1. 46× 10− 21). We observed no evidence of an interaction in any of the traits, regardless of the modelling strategy.ConclusionsWe failed to replicate any breastfeeding by genotype interactions on any cognitive or non-cognitive traits. We postulate that the previous positive findings are likely to be spurious, perhaps due to lack of appropriate control for latent population structure.
Methylome-wide studies of six metabolic traits
Authors: Smith Hannah M. , Ng Hong Kiat , Moodie Joanna E. , Gadd Danni A. , McCartney Daniel L. , Bernabeu Elena , Campbell Archie , Redmond Paul , Taylor Adele , Page Danielle , Corley Janie , Harris Sarah E. , Tay Darwin , Deary Ian J. , Evans Kathryn L. , Robinson Matthew R. , Chambers John C. , Loh Marie , Cox Simon R. , Marioni Riccardo E. , Hillary Robert F. 
Published: May 2024

AbstractExploring the molecular correlates of metabolic health measures may identify the shared and unique biological processes and pathways that they track. Here, we performed epigenome-wide association studies (EWASs) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio (WHR), and blood-based measures of glucose, high-density lipoprotein (HDL) cholesterol, and total cholesterol. We considered blood-based DNA methylation (DNAm) from >750,000 CpG sites in over 17,000 volunteers from the Generation Scotland (GS) cohort. Linear regression analyses identified between 304 and 11,815 significant CpGs per trait at P<3.6×10-8, with 37 significant CpG sites across all six traits. Further, we performed a Bayesian EWAS that jointly models all CpGs simultaneously and conditionally on each other, as opposed to the marginal linear regression analyses. This identified between 3 and 27 CpGs with a posterior inclusion probability ≥ 0.95 across the six traits. Next, we used elastic net penalised regression to train epigenetic scores (EpiScores) of each trait in GS, which were then tested in the Lothian Birth Cohort 1936 (LBC1936; European ancestry) and Health for Life in Singapore (HELIOS; Indian-, Malay- and Chinese-ancestries). A maximum of 27.1% of the variance in BMI was explained by the BMI EpiScore in the subset of Malay-ancestry Singaporeans. Four metabolic EpiScores were associated with general cognitive function in LBC1936 in models adjusted for vascular risk factors (Standardised βrange: 0.08 – 0.12, PFDR< 0.05). EpiScores of metabolic health are applicable across ancestries and can reflect differences in brain health.
Risk Prediction In Long Term Kidney Transplant Recipients – Model Development Using Apelinergic Markers And Machine Learning Tools
Authors: Batko Krzysztof , Sączek Anna , Banaszkiewicz Małgorzata , Małyszko Jolanta , Koc-Żórawska Ewa , Żórawski Marcin , Niezabitowska Karolina , Siek Katarzyna , Bętkowska-Prokop Alina , Krzanowski Marcin , Krzanowska Katarzyna 
Published: May 2024

AbstractIntroductionLimited tools exist for predicting kidney function in long-term kidney transplant recipients (KTRs). Elabela and apelin are APJ receptor agonists that constitute the apelinergic axis, which is a recently discovered system regulating vascular and cardiac tissue, in opposition to renin-angiotensin-aldosterone.MethodsLongitudinal, observational cohort of 102 KTRs who maintained graft function ≥24 months, with no acute rejection history or current active or chronic infection. Serum apelin, elabela, fibroblast growth factor 23 (FGF-23) and α-Klotho were tested using enzyme-linked immunoassay and compared with a control group of 32 healthy volunteers.ResultsMedian (IQR) follow-up time was 83 (42, 85) months. Higher serum FGF-23 and elabela, but lower α Klotho concentrations were observed in KTRs. Most KTRs had stable trajectories of renal function. All candidate markers were significantly associated with mean two-year eGFR over follow-up, which itself was validated respective to ‘death with functioning graft’ censored dialysis requirement. Using a cross-validation approach, we demonstrated eGFR at initial visit as the most salient predictor of future renal function. Machine learning models incorporating both clinical and biochemical (candidate markers) assessments were estimated to explain 15% of variance in future eGFR when considering eGFR-independent predictions.ConclusionsUtilization of machine learning tools that incorporate clinical information and biochemical assessments, including serum amrkers of the apelinergic axis, may help stratify risk and aid decision making in the care of long term KTRs.