bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Hormone and Bioactive Lipid Plasma Profile in Rodent Models of Polycystic Ovarian Syndrome Revealed by Targeted Mass Spectrometry
Authors: Scott Hannah C , Philpott Martin , Berridge Georgina , Yu Zhanru , O’Brien Darragh P , Becker Christian , Lindgren Cecilia , Oppermann Udo , Müller Jörg , Fritsch Martin , Pinto-Fernández Adán , Kessler Benedikt M 
Published: October 2024

AbstractPolycystic ovarian syndrome (PCOS) symptoms include excessive body or facial hair, irregular periods, reduced fertility, and reoccurring pregnancy loss. Hyperandrogenism and chronic inflammation are hallmarks of PCOS, which is diagnosed by analysing steroid hormones in the blood. Studies suggest that bioactive lipids are contributing to chronic inflammation. To research PCOS, animal models, such as letrozole- and dihydrotestosterone-treated rats, are used. They display similar ovarian and metabolic characteristics, although plasma lipid profiles have not been determined. Therefore, in order to validate the use of these models for PCOS, we have optimised a mass spectrometry based targeted lipidomics workflow which increases the sensitivity of measuring these lipids in rat plasma. Our analysis shows that letrozole caused a significant elevation of 5α-androstene-3,17-dione and testosterone. Dihydrotestosterone treatment resulted in increased dehydroepiandrosterone-sulphate and allopregnanolone but a reduction in testosterone, progesterone, pregnenolone, and D-sphingosine. In both models 25-hydroxycholesterol and leukotriene C4were significantly diminished and 4-cholesten-3-one was significantly increased, and these particular metabolites are not known to be changed in human PCOS. These results suggest that the plasma lipids of these rodent models have some changes akin to human PCOS and other changes that are not.
How the microbiome liberates iron from heme
Authors: Nath Arnab Kumar , da Silva Ronivaldo Rodrigues , Gauvin Colin C. , Akpoto Emmanuel , Adedoyin Victoria , Dlakić Mensur , Lawrence C. Martin , DuBois Jennifer L. 
Published: October 2024

AbstractThe microbiome is a hidden organ system with diverse metabolic roles. UsingBacteroides thetaiotaomicron(B theta) as a model, we asked how microbiome species process iron, the quintessential biometal supporting respiration and life as we know it, when iron is provided in complex with protoporphyrin IX (PPIX) asheme. An intestinal transporter for heme has not been unequivocally identified. Canonical pathways for reclaiming heme iron from host cells or the diet require O2, which is unavailable in the GI tract and many pathological microenvironments. HmuS, a homolog of cobalamine-(vitamin B12) and chlorophyll-building chelatases, is widespread in anaerobic microbial ecosystems. In this work, we provide direct physiological, biochemical, and structural evidence for the anaerobic removal of iron from heme by HmuS, a de-chelatase that deconstructs heme to PPIX and Fe(II). We show that heme can be used as a sole iron source byB theta, yielding PPIX, and thathmuSinactivation under these conditions is lethal. Iron removal from heme depends on theB thetamembrane fraction, NADH, and O2exclusion. Absorbance spectra indicate that heterologously expressed HmuS is isolated with a non-substrate heme bound and can accommodate multiple heme equivalents under saturating conditions. Solution of the cryoEM structure reveals heme and two cations at sites that are conserved across the HmuS family and the chelatase superfamily, respectively. The proposed structure-based mechanism for iron removal further links biosynthetic and biodegradative pathways for heme, chlorophyll, and vitamin B12, three ancient and biologically crucial metallocofactors.Significance StatementIron in its heme and non-heme forms is essential for nearly all life. This work defines a microbial mechanism for metabolizing heme that is widespread in gastrointestinal and other anaerobic ecosystems. To date, an intestinal cellular transporter for heme has not been unequivocally identified. However, heme, abundant in both red meat diets and animal cells, is converted by the bacterial HmuS enzyme into a non-heme form from which the iron can be repurposed. HmuS enzymes form a distinct de-chelatase subset of a superfamily of chelatases that catalyze metal insertion into chlorophyll and vitamin B12, indicating convergence of metabolic pathways for biosynthesis and degradation of three of life’s essential metallocofactors. Understanding HmuS function supports engineered approaches to directing microbiome-host metabolism and offsetting heme-associated pathologies including anemia, inflammation, and cancer.
Highly expressed cell wall genes contribute to robustness of sepal size
Authors: Hartasánchez Diego A. , Dumond Mathilde , Dubrulle Nelly , Monéger Françoise , Boudaoud Arezki 
Published: October 2024

AbstractReproducibility in organ size and shape is a fascinating trait of living organisms. The mechanisms underlying such robustness remain, however, to be elucidated. Taking the sepal of Arabidopsis as a model, we investigated whether variability of gene expression plays a role in variation of organ size and shape. Previous work from our team identified cell-wall related genes as being enriched among the genes whose expression is highly variable. We then hypothesized that the variation of measured morphological parameters in cell-wall related single knockout mutants could be correlated with the variation in gene expression of the corresponding gene (the knocked-out gene) in wild-type plants. We analyzed sepal size and shape from 16 cell-wall mutants and found that sepal size variability correlates positively, not with gene expression variation, but with mean gene expression of the corresponding gene in wild type. These findings support a contribution of cell-wall related genes to the robustness of sepal size.
An analysis of RNA quality metrics in human brain tissue
Authors: Tian Jiahe , Lam Tiffany G. , Ross Sophie K. , Ciener Benjamin , Leskinen Sandra , Sivakumar Sharanya , Bennett David A. , Menon Vilas , McKhann Guy M. , Runnels Alexi , Teich Andrew F. 
Published: October 2024

AbstractHuman brain tissue studies have historically used a range of metrics to assess RNA quality. However, few large-scale cross-comparisons of pre-sequencing quality metrics with RNA-seq quality have been published. Here, we analyze how well metrics gathered before RNA sequencing (post-mortem interval (PMI) and RNA integrity number RIN) relate to analyses of RNA quality after sequencing (Percent of counts in Top Ten genes (PTT), 5’ bias, and 3’ bias) as well as with individual gene counts across the transcriptome. We conduct this analysis across four different human cortical brain tissue collections sequenced with varying library preparation protocols. PMI and RIN have a low inverse correlation, and both PMI and RIN show consistent and opposing correlations with PTT. Unlike PMI, RIN shows strong consistent correlations with measurements of 3’ and 5’ bias, and RIN also correlates with 3,933 genes across datasets, in comparison to 138 genes for PMI. Neuronal and immune response genes correlate positively and negatively with RIN respectively, suggesting that different gene sets have divergent relationships with RIN in brain tissue. In summary, these analyses suggest that conventional metrics of RNA quality have varying degrees of value, and that PMI has an overall minimal but reproducible effect on RNA quality.
Sequential structure probing of cotranscriptional RNA folding intermediates
Authors: Szyjka Courtney E. , Kelly Skyler L. , Strobel Eric J. 
Published: October 2024

AbstractCotranscriptional RNA folding pathways typically involve the sequential formation of folding intermediates. Existing methods for cotranscriptional RNA structure probing map the structure of nascent RNA in the context of a terminally arrested transcription elongation complex. Consequently, the rearrangement of RNA structures as nucleotides are added to the transcript can be inferred but is not assessed directly. To address this limitation, we have developed linked-multipointTranscriptionElongationComplex RNA structureprobing (TECprobe-LM), which assesses the cotranscriptional rearrangement of RNA structures by sequentially positioningE. coliRNAP at two or more points within a DNA template so that nascent RNA can be chemically probed. We validated TECprobe-LM by measuring known folding events that occur within theE. colisignal recognition particle RNA,Clostridium beijerinckii pflZTP riboswitch, andBacillus cereus crcBfluoride riboswitch folding pathways. Our findings establish TECprobe-LM as a strategy for detecting cotranscriptional RNA folding events directly using chemical probing.
Apoptosis is increased in cortical neurons of female Marfan Syndrome mice
Authors: Esfandiarei Mitra , Anwar Faizan , Nuthi Manogna , Harrison Alisha , Barrameda Mary Eunice , Curry Tala , Pull Kasey , Currier Thomas Theresa , Jadavji Nafisa M. 
Published: October 2024

AbstractMarfan Syndrome (MFS) is an autosomal dominant genetic disorder that affects connective tissue throughout the body due to mutations in theFBN1gene. Individuals with MFS display symptoms in different organs, particularly in the vasculature, but the mechanisms of this multi-system dysfunction are still under investigation. There is still a gap in our understanding of the impact of monogenic connective tissue aberrations on the brain. This study aims to determine the impact of MFS on neurodegeneration, in cortical brain tissue of male and female MFS mice. Brain tissue of 6-month-old female and male mice with theFBN1C1041G/+mutation and wildtype litter mates was collected and stained for active caspase-3 (ac3), brain derived neurotrophic factor (BDNF), and neuronal nuclei (NeuN) or with TUNEL and DAPI. Data revealed increased levels of ac3 in neurons within the sensory and motor cortical areas of female MFS mice compared to sex- and age-matched controls. We confirm increased levels of apoptosis in MFS mice using TUNEL staining within the same brain areas. We also report increased levels of neuronal BDNF levels in cortical brain tissue of male and female MFS mice. These results indicate a heightened susceptibility for neurodegeneration in the mouse model of MFS.Significance StatementThe study revealed that female mice with aFBN1C1041G/+mutation have more apoptotic neurons in sensory and motor cortical brain tissue compared to wildtype litter mates.
A parasite-inclusive food web for the California rocky intertidal zone
Authors: Zilz Zoe L. , Hascall Emily , DiBartolo Athena , Flores Delén , Cameron Sophie , Orli Jaden E. , Kuris Armand M. 
Published: October 2024

AbstractWe present a highly resolved, species-rich food web, including parasitic interactions, for the California rocky intertidal zone. The food web is comprised of 1809 nodes, representing 1845 taxa, and 13,222 links representing trophic interactions between nodes. While only 670 links represent parasitic interactions, we have assembled possibly the most speciose parasite-inclusive food web ever published. The inclusion of all nodes and links are justified using multiple lines of evidence which are built into the dataset. In addition, metadata, including trophic strategy, taxonomic information, habitat, and other ecological attributes allow the data user to filter the food web to their specifications. The food web is a powerful and flexible tool for researchers with questions about large network properties, ecological dynamics of rocky shores, and the role of parasites in ecosystems. Our food web can be used to predict how complex ecosystems like the California rocky intertidal will respond to anthropogenic change and management strategies.
Tumors with mutations in chromatin regulators are associated with higher mutational burden and improved response to checkpoint immunotherapy
Authors: Kungulovski Goran , Gjorgjievska Marija , Mehandziska Sanja , Bukovec Djansel , Risteski Milan , Kungulovski Ivan , Mitrev Zan 
Published: October 2024

AbstractIn recent years, it has been demonstrated that many of the pervasive genetic defects throughout cancerogenesis occur in genes encoding chromatin regulators (CRs). We analyzed the distribution and characteristics of well-studied CRs across tens of thousands of tumor samples. Our analysis revealed that tumors with mutations in CRs are associated with high tumor mutational burden (TMB). The co-occurrence of mutations in multiple CRs was linked with a further increase in TMB. Given that TMB may predict the clinical response to immune checkpoint inhibitor (ICI) treatment, we investigated the relationship between mutations in CRs and ICI response. We found that patients harboring mutations in CRs exhibited improved responses to ICI treatment, comparable to those with deficiencies in canonical DNA repair pathways. Overall, this study uncovered significant relationships between mutations in chromatin regulators and critical features of cancer, underscoring the need for further functional and clinical studies.
Digital biomechanical biomarkers in the clinical assessment of patients with peripheral neuropathies
Authors: Tejada-Illa Clara , Pegueroles Jordi , Claramunt-Molet Mireia , Pi-Cervera Ariadna , Heras-Delgado Ainhoa , Gascón-Fontal Jesus , Idelsohn-Zielonka Sebastian , Rico Mari , Vidal Nuria , Martín-Aguilar Lorena , Caballero-Ávila Marta , Lleixà Cinta , Collet-Vidiella Roger , Llansó Laura , Carbayo Álvaro , Vesperinas Ana , Querol Luis , Pascual-Goñi Elba 
Published: October 2024

AbstractThe clinical status and treatment response of patients with peripheral neuropathies (PN) rely on subjective and inaccurate clinical scales. Wearable sensors have shown success in evaluating gait and balance in individuals with other neurological disorders. We aimed to explore the ability of biomechanical analysis via wearable technology to monitor disease activity in PN by conducting a single-center, longitudinal study to analyze gait parameters in PN patients and healthy controls using wearable sensors. First, we analyzed the sensor’s ability to detect changes in ataxia and steppage gait severity and found significant differences in spatiotemporal and angular variables. Second, we found correlations between biomechanical features and clinical scales linked to specific gait phenotypes. Finally, we demonstrated that this technology captures clinical changes in gait features over time. Our study provides proof-of-concept that wearable technology effectively detects and grades gait impairment, captures clinically relevant changes, and could enhance gait assessment in routine care and research for PN patients.
Mathematical Model of Disease Transmission and Control: Incorporating Age and Deprivation Decile
Authors: Oyedele Gbeminiyi J. , Idowu Oluwarimi J. , Tildesley Michael J. 
Published: October 2024

ABSTRACTThe epidemic of COVID-19 has opened a significant interest in developing mathematical models that could incorporate more complexities into the dynamics of disease transmission and control. This study aims to perform a rigorous mathematical analysis on incorporating the effects of age mixing and deprivation decile into an epidemic model of infectious diseases using deterministic models. We consider a mathematical model consisting of nine compartments: susceptible, exposed, asymptomatic, unreported and untested, tested and awaiting test results, positively tested symptomatic and hospitalised, recovered, and dead. The basic reproduction number was estimated using the next generation matrix approach. The analysis shows that the most deprived group in the population demonstrated disproportionately higher number of infections compared with the least deprived groups, and this was consistent across the deprivation spectrum. Our work suggests that in order to effectively control disease, support should be given to those individuals with higher levels of deprivation in order to improve uptake of intervention measures in those groups to reduce the burden of disease.
Investigating Sex Bias in Machine Learning Research: A Systematic Review in Rheumatoid Arthritis
Authors: Talwar Anahita , Turner Shruti , Maw Claudia , Quayle Georgina , Watt Thomas N , Gohil Sunir , Duckworth Emma , Ciurtin Coziana 
Published: October 2024

AbstractUnchecked sex bias in machine learning (ML) algorithms used in healthcare can exacerbate disparities in care and treatment. We aimed to assess the acknowledgment and mitigation of sex bias within studies using supervised ML for improving clinical outcomes in Rheumatoid Arthritis (RA). For this systematic review, we searched PUBMED and EMBASE for original, English language studies published between 2018 to November 2023. We scored papers on whether the authors reported, attempted to mitigate or successfully mitigated the following types of bias: training data bias, test data bias, input variable bias, output variable bias, analysis bias, and assessed the quality of ML research in all papers. This study is registered on PROSPERO with ID CRD42023431754. We identified 52 papers to include in our review. All but one had a female skew in their study participants, yet 42 papers did not acknowledge any potential sex bias. Three papers assessed bias in model performance by sex disaggregating their results. One paper acknowledged potential sex bias in input variables, and six papers in their output variables, predominantly disease activity scores. No paper attempted to mitigate for any type of sex bias. The findings demonstrate the requirement for increased promotion of inclusive and equitable ML practices in healthcare.
Post Intensive care outcomes and follow-up in Children: A Collaboration of Health care providers, researchers, and families Utilizing knowledge co-production
Authors: Dunphy Michelle , Yang Gaby , Marchand Jason , Retallack Jenny 
Published: October 2024

AbstractBackgroundMany children do not return to their pre-admission health status following admission to the paediatric intensive care unit (PICU), facing a range of physical, cognitive, emotional, and social challenges collectively known as Post-Intensive Care Syndrome in Paediatrics (PICS-p). The sequelae associated with PICS-p necessitate comprehensive follow-up care intending to address these multifaceted needs. ThePostIntensive care outcomes and follow-up inChildren:A Collaboration ofHealth care providers, researchers, and familiesUtilizing knowledge co-production (PICACHU) study aims to develop a shared care follow-up service for post-PICU patients and their families. It also seeks to facilitate outcomes research and identify quality improvement (QI) initiatives to mitigate the impact of PICS-p.MethodsThe study employs a pragmatic approach informed by the Medical Research Council (MRC) framework and co-design methodology. The research includes surveys and focus group discussions (FGDs) with purposively sampled post-PICU families, acute care pediatricians, community pediatricians, general practitioners (GPs), and primary care nurse practitioners (NPs). Data collection tools include adapted versions of existing surveys and semi-structured interview guides. The analysis will involve qualitative and quantitative methods, utilising SPSS for statistical analysis and NVivo for thematic analysis of FGDs.ConclusionThe PICACHU study is the first of its kind to use a co-design approach to create a post-PICU shared care follow-up service in British Columbia (BC), Canada. The findings will provide valuable insights for improving post-PICU care services in BC and potentially other jurisdictions.
Genome-wide association study for circulating metabolites in 619,372 individuals
Authors: Tambets Ralf , Kronberg Jaanika , Abner Erik , Võsa Urmo , Rahu Ida , Taba Nele , Kolde Anastassia ,   Estonian Biobank Research Team, Fischer Krista , Esko Tõnu , Alasoo Kaur , Palta Priit 
Published: October 2024

AbstractExamining the downstream molecular consequences of genetic variation significantly enhances our understanding of the heritable determinants of complex traits and disease predisposition. Metabolites serve as key indicators of various biological processes and disease states, playing a crucial role in this systematic mapping, also providing opportunities for the discovery of new biomarkers for disease diagnosis and prognosis. Here, we present a genome-wide association study for 249 circulating metabolite traits quantified by nuclear magnetic resonance spectroscopy across various genetic ancestry groups from the Estonian Biobank and the UK Biobank. We generated mixed model associations in the Estonian Biobank and six major genetic ancestry groups of the UK Biobank and performed two separate meta-analyses across the predominantly European genetic ancestry samples (n = 599,249) and across all samples (n = 619,372). In total, we identified 89,489 locus-metabolite pairs and 8,917 independent lead variants, out of which 4,184 appear to be novel associated loci. Moreover, 12.4% of the independent lead variants had a minor allele frequency of less than 1%, highlighting the importance of including low-frequency and rare variants in metabolic biomarker studies. Our publicly available results provide a valuable resource for future GWAS interpretation and drug target prioritisation studies.
Impact of anionic lipids on the energy landscape of conformational transition in anion exchanger 1 (AE1)
Authors: Chen Tianle , Vallese Francesca , Gil-Iturbe Eva , Kim Kookjoo , Quick Matthias , Clarke Oliver , Tajkhorshid Emad 
Published: October 2024

AbstractAnion Exchanger 1 (AE1) is an elevator-type membrane transporter that plays a key role in erythrocytes by mediating the exchange of chloride and bicarbonate ions across the membrane, thus participating in acid-base homeostasis. While previous studies have provided structural insights into AE1 and its substrate binding, the conformational transitions and the role of lipid interactions remain elusive. In this study, we utilized cryo-electron microscopy (cryo-EM) to resolve three high resolution structures of distinct conformational states of AE1: two inward-facing (IF1 and IF2) and one outward-facing (OF). Furthermore, uptake assay revealed the modulatory effect of phosphatidylinositol 4,5-bisphosphate (PIP2) lipids on AE1. Molecular dynamics (MD) simulations were conducted on these structures to capture anion binding and determine the anion binding sites in AE1. We then used a combination of advanced enhanced sampling techniques together with system-specific collective variables to study the OF⇔IF transition in AE1 and provided refined pathways for the process in three different systems:apo, HCO3−-bound, and an AE1 system in which cryo-EM-determined interfacial PIP2lipids had been removed. The refined pathways were then used to calculate the free energy of the OF⇔IF transition in AE1 under different conditions. The energies show how substrate binding reduces the transition barrier and, therefore, facilitates the transport. Furthermore, they clearly capture the inhibitory effect of PIP2lipids at the dimer interface. Furthermore, the simulation results provide a molecular mechanism for this inhibitory effect. These results provide a molecular-level understanding of the mechanistic basis for ion transport in AE1 and the regulatory role of PIP2on its function.