bluuebunny/crossref_metadata_2025_split huggingface dataset:
METTL3 Aggravates Intimal Hyperplasia by Facilitating the m6A-YTHDC1-dependent SGK1 Gene Transcription
Authors: Huang Jiaqi , Feng Qianqian , Dong Zhigang , Li Zhuofan , Liu Yihan , Xu Ran , Liu Zhujiang , Ding Qianhui , Yang Xueyuan , Yu Fang , Jia Yiting , Zhou Yuan , Kong Wei , Tang Hao , Fu Yi 
Published: January 2025

AbstractBackgroundVascular smooth muscle cell (VSMC) migration and proliferation substantially contribute to neointimal hyperplasia related to in-stent restenosis. N6-methyladenosine (m6A) catalyzed by the methyltransferase-like 3 (METTL3)-involved methyltransferase complex is the most abundant RNA epigenetic modification in eukaryotes, but the role of m6A RNA methylation in VSMC migration and proliferation as well as neointima formation remains highly controversial.MethodsPrimary human and rat VSMCs were utilized forin vitroexperiments. VSMC-specific METTL3 knockout mice (Mettl3flox/floxMyh11-CreERT2) were generated to explore wire injury in carotid arteriesin vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was performed to screen for target genes by METTL3-catalyzed m6A RNA methylation. Methylation site mapping, MeRIP-quantitative PCR (MeRIP-qPCR), chromatin immunoprecipitation-qPCR (ChIP‒qPCR) and reporter gene assays were applied to explore how METTL3 modulates its target gene expression.ResultsMETTL3 was consistently upregulated in the neointima from mice subjected to carotid wire injury and patients undergoing carotid endarterectomy. VSMC-specific METTL3 deficiency significantly attenuated neointima formation in carotid arteries following wire injury in mice. Accordingly, METTL3 ablation markedly repressed VSMC proliferation bothin vitroandin vivo. Mechanistically, METTL3 directly catalyzed m6A methylation on serum/glucocorticoid regulated kinase 1 (SGK1) mRNA and subsequently facilitated its transcription, which relies on the established association between the SGK1 transcript and SGK1 promoter DNA by recruiting the m6A reader YTHDC1. Conversely, SGK1 overexpression abolished METTL3 deficiency-mediated suppression of VSMC proliferation and postinjury neointima formation.ConclusionsMETTL3-catalyzed m6A RNA methylation promoted VSMC proliferation and aggravated postinjury neointima formation by facilitating YTHDC1-dependent SGK1 gene transcription. Targeting the METTL3-YTHDC1-SGK1 axis to modulate VSMC proliferation may be a potential strategy for in-stent restenosis therapy.
Characterisation of the axon initial segment and intrinsic excitability in the sub-acute phase post-ischemic stroke
Authors: King Emily S , Beros Jamie L , Fujiyama Hakuei , Reynolds John N.J , Tang Alexander D 
Published: January 2025

AbstractBackgroundStroke is a leading cause of disability and stroke-induced changes in cortical excitability are thought to impede functional recovery. Identifying cellular targets that contribute to maladaptive excitability holds great potential for the development of therapeutic interventions to improve stroke outcomes. One potential target is the axon initial segment (AIS), the specialised cellular domain where action potentials are initiated. In the acute phase post stroke, neurons in the peri-infarct zone display abnormal AIS structural properties which is assumed to contribute to altered neuronal excitability. However, whether this continues into the sub-acute phase post stroke, a period with heightened plasticity and when physical rehabilitation typically begins is unknown.MethodsWe induced a photothrombotic ischemic stroke to the right motor cortex of 13-week-old mice alongside adeno-associated virus labelling of layer 2/3 and layer 5 pyramidal neurons in the peri-infarct zone and contralesional motor cortex. Immunofluorescence staining for Ankyrin-G and whole-cell patch clamp electrophysiology measures were made at 28-days post stroke to assess changes in AIS structure and function. Additionally, we investigated potential hemispheric-, cortical layer-, and sex-dependent differences in AIS and intrinsic excitability properties.ResultsWe found that normal AIS structure and function are preserved in the sub-acute phase post ischemic stroke. However, we found evidence of reduced input resistance across both hemispheres and reduced evoked spike firing frequency in the peri-infarct zone in both sexes. In addition, we found stroke reduced the evoked spike firing frequencies in the contralesional hemisphere, but only in males.ConclusionDespite the preservation of normal AIS structure and function in the sub-acute phase post ischemic stroke, cortical pyramidal neuron excitability is reduced through other intrinsic membrane mechanisms. Additionally, we show that changes to neuronal excitability spread to the contralesional hemisphere in males. These findings provide novel insight into the maladaptive changes to neural excitability in the sub-acute phase of ischemic stroke and further highlight the need to develop sex-specific stroke treatments.
Interpreting Lung Cancer Health Disparity at Transcriptome Level
Authors: Sobhan Masrur , Islam Md Mezbahul , Mondal Ananda Mohan 
Published: January 2025

AbstractLung cancer is a leading cause of cancer-related mortality, with disparities in incidence and outcomes observed across different racial and sex groups. Understanding the genetic factors of these disparities is critical for developing targeted treatment therapies. This study aims to identify both patient-specific and cohort-specific biomarker genes that contribute to lung cancer health disparities among African American males (AAMs), European American males (EAMs), African American females (AAFs), and European American females (EAFs). The real-world data is highly imbalanced with respect to race, and the lung cancer dataset is no exception. So, classification with race labels will generate highly biased results toward the larger cohort. We developed a computational framework by designing the classification problems with disease conditions instead of races and leveraging the local interpretability of explainable AI, SHAP (SHapley Additive exPlanations). This study used three disease conditions of lung cancer, including Lung Adenocarcinoma (LUAD), Lung Squamous Cell Carcinoma (LUSC), and Healthy samples (HEALTHY) to design four classification tasks: one 3-class problem (LUAD-LUSC-HEALTHY) and three 2-class problems (LUAD-LUSC, LUAD-HEALTHY, and LUSC-HEALTHY). This multiple-classification approach allows a LUAD patient to be interrogated via three classification problems, namely LUAD-LUSC-HEALTHY, LUAD-LUSC, and LUAD-HEALTHY, thus providing a robust approach of retrieving disparity information for individual patients through the local interpretation of SHAP.The proposed method successfully discovered the sets of genes and pathways related to health disparities in lung cancer between two cohorts, including AAMs vs. EAMs, AAFs vs. EAFs, AAMs vs. AAFs, and EAMs vs. EAFs. The discovered list of genes and pathways provide a short list for biological scientists to conduct wet lab experiment.
Fusing Data from CT Deep Learning, CT Radiomics and Peripheral Blood Immune profiles to Diagnose Lung Cancer in Symptomatic Patients
Authors: Mustapha Rami , Ganeshan Balaji , Ellis Sam , Dolcetti Luigi , Tharmakulasingam Mukunthan , DeSouza Karen , Jiang Xiaolan , Savage Courtney , Lim Sheena , Chan Emily , Thornton Andrew , Hoy Luke , Endozo Raymond , Shortman Rob , Walls Darren , Chen Shih-hsin , Groves Ashley M , Schnabel Julia A , Win Thida , Barber Paul R , Ng Tony 
Published: January 2025

AbstractBackgroundLung cancer is the leading cause of cancer-related deaths. Diagnosis at late stages is common due to the largely non-specific nature of presenting symptoms contributing to high mortality. There is a lack of specific, minimally invasive low-cost tests to screen patients ahead of the diagnostic biopsy.Patients and Methods344 symptomatic patients from the lung clinic of Lister hospital suspected of lung cancer were recruited. Predictive covariates were successfully generated on 170 patients from Computed Tomography (CT) scans using CT Texture Analysis (CTTA) and Deep Learning Autoencoders (DLA) as well as from peripheral blood data for immunity using high depth flow-cytometry and for exosome protein components. Predictive signatures were formed by combining covariates using Bayesian regression on a randomly chosen 128-patient training set and validated on a 42-patient held-out set. Final signatures were generated by fusing the data sources at different levels.ResultsImmune and DLA were the best single modality signatures with test set AUCs of 0.76 (95% CI: 0.61 – 0.91) and 0.75 (95% CI: 0.60 - 0.90) respectively. The final combined signature had a ROC AUC of 0.86 (95% CI: 0.73 - 0.99) on the withheld test set. The overall sensitivity and specificity were 0.722 and 0.901 respectively.ConclusionsCombining immune monitoring with CT scan data is an effective approach to improving sensitivity and specificity of Lung cancer screening even in symptomatic patients.HighlightsCombining immune monitoring in peripheral blood with CT scan data improves lung cancer screening sensitivity and specificity.Elevated levels of KIR3DL1+ CD8 T cells may be indicative of cancer.A cancer biomarker that combines a deep learning autoencoder with peripheral immune profiling achieved a 0.86 ORC AUC.
Wnt/LRP6 signaling imbalance impairs ciliogenesis in human retina epithelial cells
Authors: Yuan Cheng , Branushali Ayushi , Simons Matias , Acebrón Sergio P. , Pereira Gislene 
Published: January 2025

AbstractThe primary cilium is a microtubule-based organelle essential for various cellular functions, particularly signal transduction. While the role of cilia in regulating signaling pathways has been extensively studied, the impact of signaling pathways on cilia formation remains less well understood. Wnt signals are critical modulators of cell fate. In this study, we investigate how modulating Wnt signaling affects cilia formation in human retinal epithelial cells. Our findings show that enhancement of Wnt/LRP6 signaling before serum starvation impairs ciliogenesis. Cells with high baseline Wnt activity exhibited defective distal appendage formation, failure to remove CP110/CEP97 from mother centrioles, and reduced Rab8-vesicular docking, which are critical events for cilia membrane establishment and axoneme extension. Additionally, these cells displayed reduced autophagic flux, increased mTOR kinase activity, and elevated OFD1 levels at centriolar satellites. Importantly, mTOR inhibition rescued ciliogenesis in cells with elevated Wnt activity, underscoring the interplay between these signaling pathways. Our data also indicate that insufficient Wnt signaling activation disrupts ciliogenesis, emphasizing the need for precisely regulated Wnt levels.SummaryThis study investigates how modulating Wnt signaling affects ciliogenesis in human retinal epithelial cells, revealing that both excessive and insufficient Wnt activity disrupt cilia formation and highlighting the interplay between Wnt and mTOR signaling in this process.
Convergent validity of a person-dependent definition of a low back pain flare
Authors: Suri Pradeep , Korpak Anna , Timmons Andrew , Tanus Adrienne D. , Brubeck Hannah , Costa Nathalia , Staab Carina A. , Hodges Paul , Daniels Clinton J. , Heagerty Patrick J. , Jensen Mark P. 
Published: January 2025

ABSTRACTExacerbations of existing low back pain (LBP) or new LBP episodes are colloquially referred to as “flares”. Although the experience of flares is common to many people with LBP, few validated measures enable people to self-report if they are experiencing a flare. This study examined the convergent validity of a person-dependent definition of flares (“a worsening of your low back pain that lasts from hours to weeks”) as compared to (1) LBP intensity, (2) LBP-related pain interference, and (3) analgesic use, in a large, prospective research study of Veterans with LBP. Veterans seeking care for LBP (n=465) were followed prospectively for up to 1 year. Participants completed up to 36 scheduled surveys and additional patient-initiated surveys (triggered by the onset of new flares) over follow-up. Each survey inquired about current flare status, pain intensity measured on a 0 to 10 numeric rating scale (NRS), LBP-related pain interference, and analgesic use. Linear mixed-effects models estimated the association between current flare status and pain intensity, with and without adjustment for potential confounding factors; secondary analyses examined associations with pain interference and analgesic use. In longitudinal analyses of 11,817 surveys, flare status was significantly associated with a 2.8-NRS-point greater pain intensity (p<0.0001), with and without adjustment for other factors. Statistically significant associations were found between flare status and LBP-related pain interference and analgesic use. New flare periods were associated with impacts on coping, functional limitations, and mood/emotions. These findings support the convergent validity of a person-dependent flare definition.SUMMARYA person-dependent definition of “flare” among individuals with low back pain has convergent validity as shown by its associations with pain intensity and pain interference.
Kynurenine Metabolism is Associated with Antidepressant Response to Selective Serotonin Reuptake Inhibitors
Authors: Rampersaud Ryan , Suneson Klara , Wu Gwyneth W. Y. , Reus Victor I , Lindqvist Daniel , Ho Tiffany C. , Meyerhoff Dieter J. , Irwin Michael R. , Wolkowitz Owen M. , Mellon Synthia H. , Brundin Lena 
Published: January 2025

AbstractAlterations in the kynurenine pathway, and in particular the balance of neuroprotective and neurotoxic metabolites, have been implicated in the pathophysiology of Major Depressive Disorder (MDD) and antidepressant treatment response. In this study, we examined the relationship between changes in kynurenine pathway activity (Kynurenine/Tryptophan ratio), focusing on the balance of neuroprotective-to neurotoxic metabolites (Kynurenic Acid/Quinolinic Acid and Kynurenic Acid/3-Hydroxykynurenine ratios), and response to 8 weeks of selective serotonin reuptake inhibitor (SSRI) treatment, including early changes four weeks after SSRI initiation. Additionally, we examined relationships between kynurenine metabolite ratios and three promising biomarkers of depression and antidepressant response: amygdala/hippocampal volume, and glutamate metabolites in the anterior cingulate cortex. Responders showed an increase in the Kynurenic Acid/3-Hydroxykynurenine ratio by week 8 (F(1,46)= 11.92, p = .001) and early increases in the Kynurenine/Tryptophan ratios at week 4 (F(2,58)= 5.224, p = .008), while Non-Responders did not. Pre-treatment Kynurenic Acid/Quinolinic Acid and Kynurenic Acid/3-Hydroxykynurenine ratios were positively associated with right amygdala volume (β = . 247 p = .032 and β = .245 p = .028, respectively). Lastly, in a subset of participants, pre-treatment Kynurenic Acid/3-Hydroxykynurenine ratio showed a positive, small effect size association with glutamate metabolites (Glx) in the anterior cingulate cortex (β = .307 p = .079), which became significant post-treatment with a large effect size (β = .652 p = .021). These results suggest that response to SSRIs may arise from shifting the balance from neurotoxic to neuroprotective kynurenine metabolites.
The Presence of a Paramagnetic Phase Rim is Linked to Lesion Age in Multiple Sclerosis
Authors: Klistorner Samuel , Usnich Tatiana , Clarke Margareta A. , Pareto Deborah , Rovira Àlex , Paul Friedemann , Barnett Michael , Klistorner Alexander 
Published: January 2025

AbstractBackground and ObjectivesIn relapsing-remitting multiple sclerosis (RRMS), smouldering inflammation at the rims of chronic active lesions has emerged as a crucial contributor to disease progression. Paramagnetic rim lesions (PRLs), has been proposed as the most pathologically validated marker for chronic active lesions. However, the strength of the association between PRLs and clinical or radiological measures of disease progression remains unclear, and the relationship between PRL presence and lesion-specific characteristics, such as lesion size and age, is not well understood. The objective of this study is to investigate the effect of PRL presence on clinical and radiological markers of disease progression, and its association with lesion characteristics such as size and age.Methods60 RRMS patients, each with at least five years of previous structural MRI data were investigated using SWAN protocols. Lesions exceeding a volume of 100 mm³ were included in analysis.ResultsPRLs were present in 48% of patients, comprising 13% (80 out of 607) of the total lesion count. Patients with PRLs were significantly younger than those without (p<0.001). Furthermore, PRLs were significantly larger (p<0.0001) and exhibited more severe structural damage compared to non-PRLs (p<0.0001). These characteristics were consistent both within and between patients. PRL count and volume were significantly correlated with radiological measures of disease progression, including central and total brain atrophy (p<0.001 and <0.05 for PRL count and volume, respectively).Crucially, our results showed that all 32 lesions appearing within five years preceding SWAN imaging displayed a paramagnetic rim. This finding was validated in two independent international cohorts, reinforcing the link between PRLs and lesion age. Moreover, the proportion of rim-positive lesions decreased as lesion age increased. In a sub-set of patients with longitudinal susceptibility data the paramagnetic rim tended to diminish or disappear over time.ConclusionOur findings indicate that the presence of a paramagnetic rim in MS lesions is a characteristic feature of all newly formed lesions that exceed a specific size threshold, and that this rim gradually diminishes as lesions age. As such, this study enhances the understanding of lesion formation and may also have significant implications for using PRLs as a biomarker of lesion activity.
Escobase and AcR:Escherichia colidatabases of genomes and acid resistance genes from isolates from cattle farms
Authors: Lucile Martin , Philippe Ruiz , Sabine Leroy , Panagiotis Sapountzis 
Published: January 2025

AbstractEscherichia coliis a gram-negative bacterium commonly found in mammals and birds’ intestinal microbiota. It can be easily isolated and has been studied for more than nine decades, making it an ideal model organism. It is mainly commensal but occasionally pathogenic, expressing virulence factors, antibiotic-resistance and acid-resistance genes, which contribute to its ability to persist and colonize diverse environments. Its multi-resistance, combined with the virulence of certain pathotypes (e.g. STEC), poses a recurring threat to public health, as treatment for clinical infections is not always straightforward. The remarkable propensity ofE. colifor diversification and genomic variability is often referred to as an open pangenome.This project’s objective was to create the ‘Escobase’ database (Escherichiacoli database), which is comprised exclusively ofEscherichia coliisolates from cattle farms, allowing us to generate a reference set of genomes that can be used for comparative genomics on samples from cattle and cattle farms. Using the annotatedE. coligenomes, we further built a catalog of predicted proteins that helpE. colisurvive in low pH environments, often encountered when the bacteria traverse through the intestine. We believe these two databases will be of great help to the community, and we plan to keep improving them and publish updated versions in the future.
A GluN2B disease-associated variant promotes degradation of NMDA receptors via autophagy
Authors: Benske Taylor M. , Williams Marnie P. , Zhang Pei-Pei , Palumbo Adrian J. , Mu Ting-Wei 
Published: January 2025

AbstractN-methyl-D-aspartate receptors (NMDARs) are essential for excitatory neurotransmission and their pathogenic variants can lead to proteostasis defects and thus neurological diseases. However, how the proteostasis network degrades pathogenic variants is not well understood. Here, we demonstrated that the R519Q GluN2B variant is retained in the endoplasmic reticulum (ER) and fails to traffic to the surface to form functional NMDARs. Pharmacological and genetic inhibition of autophagy results in the accumulation of this variant, indicating that it is degraded by the autophagy-lysosomal proteolysis pathway. Since GluN2B has a cytosolic LIR motif, which can interact with cytosolic autophagy machinery, we demonstrated that disrupting this LIR motif impairs the autophagic clearance of this variant. Additionally, the R519Q variant is recognized by ER-phagy receptors, including CCPG1 and RTN3L. Our result provides the molecular mechanism for the degradation of NMDAR variants and identifies a pathway for targeted therapeutic intervention for neurological disorders with dysfunctional NMDARs.SummaryNMDA receptors are essential for excitatory neurotransmission and their proteostasis defects lead to neurological diseases. Benske et al. report that pathogenic R519Q variants predispose GluN2B subunits to degradation and clearance by the autophagy-lysosomal pathway.
How stakeholders respond to airline sustainability signaling – a social media analysis
Authors: Setälä Kaarle , Aarikka-Stenroos Leena , Wright Stephen J. , Grundström Mika 
Published: January 2025

PurposeThe purpose of this study is to explore stakeholder responses to an airline’s sustainability signaling act. Responding stakeholders, their interpretations and feedback to the signal are studied in light of signaling theory and corporate social responsibility (CSR).Design/methodology/approachThis study was conducted using the social media analytics approach. A total of 7,002 publications in the public domain were collected from the internet’s news services, blogs and major social media websites. These posts were subjected to content, sentiment and reach analyses.FindingsDiverse stakeholder groups, ranging from industry professionals to societal influencers, responded via social media to a CSR-related press release, the main types being general influencers of society and those working in the aviation or tourism industry. The themes of responses ranged from sustainability, technical development and the future of transport to green transition policies. Hence, the press release as a signal was linked to other discussions prevalent in society. Sentiments of the publications were mainly neutral or positive, with very few negative responses from stakeholders. Many responses were supportive, and the critical responses did not contain accusations of greenwashing.Practical implicationsEnvironmental CSR communications are strategically important to companies operating in carbon-intensive industries. The public may view breakthroughs in technology as an efficient way of emissions reductions cascaded with improvements in processes and practices. Utilizing new technology also affects several stakeholders and creates new opportunities for them. Knowledge on the subject may influence the tone of discussion.Originality/valueThis study views a press release as sustainability-related signaling and examines stakeholder responses in social media, contributing to CSR and signaling research in the context of the airline industry by observing the signaling process over time along with the behavior of the actors involved.