bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning-guided deconvolution of plasma protein levels
Authors: Pietzner Maik , Beuchel Carl , Demircan Kamil , Hoffman Anton Julian , Zeng Wenhuan , Römisch-Margl Werner , Yasmeen Summaira , Uluvar Burulça , Zoodsma Martijn , Koprulu Mine , Kastenmüller Gabi , Carrasco-Zanini Julia , Langenberg Claudia
Published: January 2025

Proteomic techniques now measure thousands of circulating proteins at population scale, driving a surge in biomarker studies and biological clocks. However, their potential impact, generalisability, and biological relevance is hard to assess without understanding the origins and role of the thousands of proteins implicated in these studies. Here, we provide a data-driven identification of the foundations of protein variation that underly their links to ageing and diseases, differ between sexes and ancestries, and help guide protein biomarker and drug target discovery. We use machine learning to systematically identify and quantify the foundations of plasma levels of ∼3,000 protein targets among 43,240 participants of the UK Biobank. Out of >1,700 participant and sample characteristics, we identify a median of 19 factors (range: 1-36) that jointly explained an average of 23.7% (max. 79.9%) of the variance in plasma levels across protein targets. Proteins segregated into distinct clusters according to their explanatory factors, with modifiable characteristics explaining more variance compared to genetic variation (13.3% vs 9.8%). We identify proteins for which the factors underlying their variation differed by sex (n=1414 proteins) or across ancestries (n=86 proteins). We establish a knowledge graph that integrates our findings with genetic studies and drug characteristics to guide identification of potential markers of target engagement. We demonstrate the value of our resource 1) by identifying disease-specific biomarkers, like matrix metalloproteinase 12 for abdominal aortic aneurysm, and 2) by developing a framework for phenotype enrichment of protein signatures from independent studies to identify underlying sources of variation. All results are explorable via an interactive web portal (https://omicscience.org/apps/prot_foundation) and can be readily integrated into ongoing studies using an associatedRpackage.
Direct Health Care Costs Associated with Asthma Hospitalizations Before and During the Covid-19 Pandemic in the United States: A Nationwide Inpatient Sample Analysis
Authors: Solanki N. , Fakhry B. F. , Zhang P. , Attaway A. , Zein J. , Tsuang W.
Published: January 2025

Background

Asthma, a chronic inflammatory airway disorder, can increase the risk of hospitalizations in individuals with viral infections such as COVID-19. The impact of the COVID-19 pandemic on asthma-related hospitalizations in the United States remains unknown.

Objective

We hypothesized that the COVID-19 pandemic led to an increase in economic burden to society and a decrease in hospitalization rates for asthma.

Methods

We analyzed weighted data from National Inpatient Sample (NIS) between January 1, 2018, and December 31, 2020. The outcomes were asthma hospitalization rates, length of stay (LOS), in-hospital mortality rates, and hospital admission costs.

Results

More people were admitted with a primary diagnosis of asthma in 2018 and 2019 compared to 2020 (hospitalization rate per 100,000: 2018: 38.6 versus (vs) 2019:37.0 vs 2020: 21.4; P <0.001). Hospital costs increased (2018: median [IQR] 5,251 [ 3,426, 8,278]; 2019:5,677 [3,725, 8.969]; 2020: 5,881 [3,920-9,216]; P <0.001). Additionally, in-patient mortality rates slightly increased in 2020, rising to 0.44%, compared to 0.20% in 2018 and 0.30% in 2019 (P <0.001). When comparing geographic divisions, the mid-Atlantic division had the highest hospitalization rates, and the Pacific division had the highest hospitalization costs from 2018-2020 (P <0.05).

Conclusion

Asthma hospitalizations decreased in 2020 compared to previous years. Those admitted during the pandemic had slightly higher mortality and significantly increased hospital costs. This investigation provides valuable insights for policy makers about shifts in healthcare utilization during the pandemic.
UFMylation promotes orthoflavivirus infectious particle production
Authors: Schmidt Hannah M. , Sorensen Grace C. , Lanahan Matthew R. , Grabowski Jenna , Park Moonhee , Horner Stacy M.
Published: January 2025

Post-translational modifications play crucial roles in viral infections, yet many potential modifications remain unexplored in orthoflavivirus biology. Here we demonstrate that the UFMylation system, a post-translational modification system that catalyzes the transfer of UFM1 onto proteins, promotes infection by multiple orthoflaviviruses including dengue virus, Zika virus, West Nile virus, and yellow fever virus. We found that depletion of the UFMylation E3 ligase complex proteins UFL1 and UFBP1, as well as other UFMylation machinery components (UBA5, UFC1, and UFM1), significantly reduces infectious virion production for orthoflaviviruses but not the hepacivirus, hepatitis C. Mechanistically, UFMylation does not regulate viral RNA translation or RNA replication but instead affects a later stage of the viral lifecycle. We identified novel interactions between UFL1, and several viral proteins involved in orthoflavivirus virion assembly, including NS2A, NS2B-NS3, and Capsid. These findings establish UFMylation as a previously unrecognized post-translational modification system that promotes orthoflavivirus infection, likely through modulation of viral assembly. This work expands our understanding of the post-translational modifications that control orthoflavivirus infection and identifies new potential therapeutic targets.
A Mean Field Theory for Pulse-Coupled Oscillators based on the Spike Time Response Curve
Authors: Canavier Carmen C
Published: January 2025

A mean field method for pulse-coupled oscillators with delays used a self-connected oscillator to represent a synchronous cluster of N-1 oscillators and a single oscillator assumed to be perturbed from the cluster. A periodic train of biexponential conductance input was divided into a tonic and a phasic component representing the mean field input. A single cycle of the phasic conductance from the cluster was applied to the single oscillator embedded in the tonic component at different phases to measure the change in the cycle length which the perturbation was initiated, that is, the first order phase response curve (PRC), and the second order PRC in the following cycle. A homogeneous network of 100 biophysically calibrated inhibitory interneurons with either shunting or hyperpolarizing inhibition tested the predictive power of the method. A self-consistency criterion predicted the oscillation frequency of the network from the PRCs as a function of the synaptic delay. The major determinant of the stability of synchrony was the sign of the slope of the first order PRC of the single oscillator in response to an input from the self-connected cluster at a phase corresponding to the delay value. For most short delays, first order PRCs correctly predicted the frequency and stability of simulated network activity. However, considering the second order PRC improved the frequency prediction and resolved an incorrect prediction of stability of global synchrony at delays close to the free running period of single neurons in which a discontinuity in the PRC precluded existence of 1:1 self-locking.
CONSERVED NUCLEAR MORPHOLOGY IDENTIFIES FUNCTIONAL RADIAL GLIA NEURAL PROGENITORS
Authors: Soriano J.P. , Borau C. , Sortino R. , Garma L. , Ortega J.A. , Asín J. , Alcántara S.
Published: January 2025

Radial glia (RG) progenitor cells are the principal neural progenitors of the embryonic brain, giving rise to neurons and glial cells. RG apical-basal polarity and anchorage are crucial for maintaining their integrity and function. By using a biomimetic substrate that reproduces RG surface properties and mechanical anisotropy, we previously described the dedifferentiation of cultured astrocytes into functional RG, although the underlying mechanotransducive components remain largely unknown. Here we analyzed the role of nuclear morphology in mechanically driven RG induction, as nuclear deformation is critical for driving gene expression and cell fate changes in response to mechanical signals. A multivariate logistic regression model developed for fitting RG probability revealed the existence of intrinsic nuclear constraints, allowing a precise range of permitted RG nuclear morphologies, which are associated with calcium dynamics and conservedin vivo,in vitroand through evolution. Moreover, nuclear deformation predicts astrocyte or RG fate acquisition in response to mechanical signals.
The RING Finger E3 Ligase RNF25 Protects DNA Replication Forks Independently of its Canonical Roles in Ubiquitin Signaling
Authors: Chiou Lilly F. , Jayaprakash Deepika , Droby Gaith N. , Zhang Xingyuan , Yang Yang , Mills C. Allie , Webb Thomas S. , Barker Natalie K. , Wu Di , Herring Laura E. , Bowser Jessica , Vaziri Cyrus
Published: January 2025

The DNA damage response (DDR) mechanisms that allow cells to tolerate DNA replication stress are critically important for genome stability and cell viability. Using an unbiased genetic screen we identify a role for the RING finger E3 ubiquitin ligase RNF25 in promoting DNA replication stress tolerance. In response to DNA replication stress, RNF25-deficient cells generate aberrantly high levels of single-stranded DNA (ssDNA), accumulate in S-phase and show reduced mitotic entry. Using single-molecule DNA fiber analysis, we show that RNF25 protects reversed DNA replication forks generated by the fork remodeler HLTF from nucleolytic degradation by MRE11 and CtIP. Mechanistically, RNF25 interacts with the replication fork protection factor REV7 and recruits REV7 to nascent DNA after replication stress. The role of RNF25 in protecting replication forks is fully separable from its canonical functions in ubiquitin conjugation. This work reveals the RNF25-REV7 signaling axis as an important protective mechanism in cells experiencing replication stress.
Leading and lagging strand abasic sites differentially affect vertebrate replisome progression but involve analogous bypass mechanisms
Authors: Cranford Matthew T. , Dahmen Steven N , Cortez David , Dewar James M.
Published: January 2025

Abasic sites are one of the most frequent forms of DNA damage that interfere with DNA replication. However, abasic sites exhibit complex effects because they can be processed into other types of DNA damage. Thus, it remains poorly understood how abasic sites affect replisome progression, which replication-coupled repair pathways they elicit, and whether this is affected by the template strand that is damaged. UsingXenopusegg extracts, we developed an approach to analyze replication of DNA containing a site-specific, stable abasic site on the leading or lagging strand template. We show that abasic sites robustly stall synthesis of nascent DNA strands but exert different effects when encountered on the leading or lagging strand template. At a leading strand AP site, replisomes stall ∼100 bp from the lesion until it is bypassed or a converging fork triggers termination. At a lagging strand abasic site, replisome progression is unaffected and lagging strands are reprimed downstream, generating a post-replicative gap, which is then bypassed. Despite different effects on replisome progression, both leading and lagging strand abasic sites rely on translesion DNA synthesis for bypass. Our results detail similarities and differences between how leading and lagging strand AP sites affect vertebrate DNA replication.
Nucleolar Stress-inducing Compounds Influence rDNA occupancy of RNA Polymerase I Transcription Machinery
Authors: Yglesias Matthew V. , DeRose Victoria J.
Published: January 2025

Transcription of ribosomal RNA (rRNA) by RNA Polymerase I (Pol I) is often upregulated in cancer to facilitate rapid cell growth and proliferation, and has emerged as a potential target for chemotherapeutic agents. BMH-21 and Pt(II) chemotherapeutic agent oxaliplatin are well documented as inhibitors of Pol I activity, however the underlying mechanisms for this inhibition are not completely understood. Here, we applied chromatin immunoprecipitation sequencing (ChIP-seq) techniques and immunofluorescence imaging to probe the influence of oxaliplatin and BMH-21 on Pol I machinery. We demonstrate oxaliplatin and BMH-21 induce early nucleolar stress leading to the formation of “nucleolar caps” containing Pol I and upstream binding factor (UBF) which corresponds with broad reductions in ribosomal DNA (rDNA) occupancy of Pol I. Distinct occupancy patterns for the two compounds are revealed in ChIP-seq experiments. Taken together, our findings suggest that in vivo, oxaliplatin does not induce Pol I inhibition via interrupting a specific step in Pol I transcription, while treatment with BMH-21 induced unique polymerase stalling at the promoter and terminator regions of the human ribosomal RNA gene.
Rigorous process for isolation of gut-derived extracellular vesicles and the effect on latent HIV
Authors: Anyanwu Nneoma C.J. , Premadasa Lakmini S. , Naushad Wasifa , Okeoma Bryson C. , Mahesh Mohan , Okeoma Chioma M.
Published: January 2025

Aim

Extracellular particles (EPs) are produced/secreted by cells from all domains of life and are present in all body fluids, brain, and gut. EPs consist of extracellular vesicles (EVs) made up of exosomes, microvesicles, and other membranous vesicles; and extracellular condensates (ECs) that are non-membranous carriers of lipid-protein-nucleic acid aggregates. The purity of EVs|ECs, which ultimately depends on the isolation method used to obtain them is critical, particularly EVs|ECs from the gastrointestinal (GI) tract that is colonized by a huge number of enteric bacteria. Therefore, identifying GI derived EVs|ECs of bacterial and host origin may serve as a window into the pathogenesis of diseases and as a potential therapeutic target.

Methods

Here, we describe the use of high-resolution particle purification liquid chromatography (PPLC) gradient-bead-column integrated with polyvinylpolypyrrolidone (PVPP)-mediated extraction of impurities to isolate GI-derived EPs.

Results and Conclusion

PVPP facilitates isolation of pure and functionally active, non-toxic EVs ColEVs from colonic contents. ColEVs are internalized by cells and they activate HIV LTR promoter. In the absence of PVPP, ColEVs have a direct reductive potential of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) absorbance in a cell-free system. Assessment of the origin of ColEVs reveals that they are composed of both bacteria and host particles. This protocol requires ∼12 hours (5 hours preprocessing, 7 hours isolation) to complete and should be used to purify EVs from sources contaminated with microbial agents to improve rigor. Additionally, this protocol provides a robust tool for researchers and clinicians investigating GI-derived EVs and the translational use of GI-derived EVs for diagnostic and therapeutic use.

Highlight

ColEVs but not ColECs are present in colonic content (GI tract) and can be isolated with gradient or single bead PPLC column.

ColEVs isolated without PVPP are toxic to cells and they have a direct reductive potential of MTT. Addition of PVPP treatment in the isolation protocol results in clean and non-toxic ColEVs that transactivate the HIV LTR promoter.
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

Background

Vascular 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.

Methods

Primary 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.

Results

METTL3 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.

Conclusions

METTL3-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

Background

Stroke 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.

Methods

We 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.

Results

We 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.

Conclusion

Despite 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

Lung 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

Background

Lung 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 Methods

344 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.

Results

Immune 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.

Conclusions

Combining immune monitoring with CT scan data is an effective approach to improving sensitivity and specificity of Lung cancer screening even in symptomatic patients.

Highlights

Combining 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

The 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.

This 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

Exacerbations 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.

A 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

Alterations 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

Background and Objectives

In 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.

Methods

60 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.

Results

PRLs 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.

Conclusion

Our 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

Escherichia 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

N-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.

NMDA 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.
Timescale and genetic linkage explain the variable impact of defense systems on horizontal gene transfer
Authors: Liu Yang , Botelho João , Iranzo Jaime
Published: January 2025

Prokaryotes have evolved a wide repertoire of defense systems to prevent invasion by mobile genetic elements (MGEs). However, because MGEs are vehicles for the exchange of beneficial accessory genes, defense systems could consequently impede rapid adaptation in microbial populations. Here, we study how defense systems impact horizontal gene transfer (HGT) in the short term and long term. By combining comparative genomics and phylogeny-aware statistical methods, we quantify the association between the presence of seven widespread defense systems and the abundance of MGEs in the genomes of 196 bacterial and one archaeal species. We also calculate the differences in the rates of gene gain and loss between lineages that possess and lack each defense system. Our results show that the impact of defense systems on HGT is highly taxon and system dependent and, in most cases, not statistically significant. Timescale analysis reveals that defense systems must persist in a lineage for a relatively long time to exert an appreciable negative impact on HGT. In contrast, for shorter evolutionary timescales, frequent coacquisition of MGEs and defense systems results in a net positive association of the latter with HGT. Given the high turnover rates experienced by defense systems, we propose that the inhibitory effect of most defense systems on HGT is masked by their strong linkage with MGEs. These findings help explain the contradictory conclusions of previous research by pointing at mobility and within-host retention times as key factors that determine the impact of defense systems on genome plasticity.
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

Purpose

The 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/approach

This 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.

Findings

Diverse 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 implications

Environmental 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/value

This 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.
How manufacturers make decision of digital service collaboration in ecosystem: a niche selection perspective
Authors: Zhang Yaqi , Geng Danfeng , Wang Jing , Chen Juhong
Published: January 2025

Purpose

The purpose of this study is to investigate how manufacturers make collaborative decisions in the ecosystem in the context of digital servitization.

Design/methodology/approach

Constructing an inframarginal analysis mathematical model to transform the ideal ecological niche choice of firms into solving the problem of maximizing the utility of firms, exploring the service boundary conditions of digital service business under the ideal ecological niche choice and focusing on the effects of niche factor, digital technology input and transaction efficiency on the boundary decision.

Findings

The boundaries of digital services business are in dynamic change, and changes are influenced by a combination of niche factor, digital technology input and transaction efficiency. Businesses focusing on a single niche and fully collaborative business delivery models are more in line with the trends under the digital service transformation.

Originality/value

Analyzing ecosystem participants’ cooperative decision-making on digital services from the perspective of ecological niche strategy selection. The study enriches the research on firm niche theory as well as service boundary decision theory in servitization transformation and provides theoretical guidance and management suggestions for firms to construct appropriate service boundaries to achieve synergistic and stable development of service ecosystems in the process of digital servitization transformation.
Café or art exhibition? Which experience is more effective in luxury fashion flagships?
Authors: Jeong Jin , Lee Ha Kyung , Lee Yuri
Published: January 2025

Purpose

The purpose of this study is to investigate the effect of brand experiences through cafés or art spaces in luxury fashion flagships on consumers’ buying behavior toward authorized shopping channels.

Design/methodology/approach

Online questionnaires are used by adapting measurements from prior research. We test whether positive relationships exist between multi-faceted (i.e. sensory, emotional, intellectual, and relational) experiences, consumer’s revisiting intention toward the experiential spaces, and the purchase intention of luxury fashion goods from authorized channels, especially focusing on the mediation effect of the intention to revisit. We also include the experiential space type (cafés vs. art exhibitions) as moderator.

Findings

The results confirm that sensory, emotional, intellectual, and relational experiences in cafés or art exhibitions of luxury fashion flagships have a positive impact on the intention to revisit. This revisit intention to experience space has a significant effect on purchase intention from authorized shopping channels. Specifically, sensory experiences in an art space could lead to a positive revisit intention for consumers. Furthermore, relational experiences in cafés could create positive revisit intention in consumers.

Originality/value

This is the first study to compare consumers' perceptions by categorizing extended brand spaces and assessing experiential marketing for authorized shopping channels.
Social media’s role in enhancing psychological well-being of Generation Z expatriates
Authors: Duong Hoai Lan , Vo Thi Kim Oanh , Tran Minh Tung , Tran Thi Kim Cuc
Published: January 2025

Purpose

The purpose of this research is to investigate the role of social media in supporting the psychological well-being of young expatriates.

Design/methodology/approach

The study adopts a qualitative research design based on semi-structured interviews with Gen Z expatriates who are active social media users.

Findings

This study reveals social media’s pivotal role in enhancing Gen Z expatriates’ psychological well-being. It fosters virtual connections to their home country, validating their distinctive international experiences, facilitating integration into the host culture and challenging stereotypes. By developing bonding and bridging social capital, social media mitigates cultural distance, strengthens social support and ultimately contributes to positive expatriate well-being.

Originality/value

This research responds to the growing call for studies on the intersection of digitalization and expatriation, offering insights into how digital tools can enhance the well-being of expatriates. By developing a conceptual model grounded in social media and expatriate support literature, this research highlights the specific mechanisms through which social media impacts the psychological well-being of Gen Z expatriates, a previously under-researched area. While physical support is limited by geographical proximity and shared experiences, digital support can transcend these boundaries, providing access to a wider range of resources and perspectives. By focusing on Gen Z, a generation known for its digital fluency and reliance on social media, we provide insights that can inform targeted interventions and support strategies specifically tailored to this demographic.
Aspects of Radical Gay Liberation Theory in West Germany's Tuntenstreit, 1973–1975
Authors: Branding Hauke
Published: January 2025

This article examines in depth the theoretical positions of the Tuntenstreit – a major theoretical dispute within the radical West German gay liberation movement in the 1970s. By working through archival material as well as the dispute's fundamental texts, it renders visible its often‐neglected underlying theoretical motifs and, consequently, its idiosyncratic contribution to a ‘gay theory’. Subsequently, it shows how questions of publicity and appearance – exemplified in the figure of the Tunte – were integrated into the revolutionary politics of the movement. This critical examination seeks to inform understandings and genealogies of West German gay liberation and its theory production.
Insurance gaps at age‐19 and age‐26 health insurance eligibility thresholds by childhood‐onset condition severity, Colorado 2014–2018
Authors: McMahon Mercedes V. , Okumura Megumi J. , Toomey Sara L. , Chan Christina H. , D'Ambrosi Gabrielle R. , Gray Kathryn P. , Landrum Mary Beth , Meara Ellen , Chien Alyna T.
Published: January 2025

Objective

To characterize health insurance gap patterns related to age‐19 Medicaid and age‐26 commercial age‐eligibility cutoffs.

Study Setting and Design

This descriptive analysis spans 2014–2018, after Affordable Care Act implementation, but before COVID‐19 emergency provisions. We defined insurance gaps as ≥3 consecutive months without observed enrollment, preceded and followed by ≥1 month of enrollment and stratified results by insurance source and clinical severity (e.g., with chronic, complex, or disabling conditions or not).

Data Sources and Analytic Sample

The Colorado all‐payer claims database provided data for enrollees aged 10–29, 52% (649,346) of whom were initially Medicaid insured, whereas 47% (576,596) were commercially insured.

Principal Findings

The percent of enrollees with insurance gaps peaks within six months of turning age‐19 and age‐26—at 8.9% Medicaid and 8.7% commercial, respectively. The percentage point difference between ages 27–28 and 11–18 was 3.3 percentage points higher for prior Medicaid recipients (p < 0.001) and 2.2 percentage points greater for prior commercial enrollees (p < 0.001). Relative to the other clinical severity groups, young adults with disabling health conditions who were initially Medicaid insured had the lowest peak gap rate, 5.7%, compared with 10.5% among the previously commercially insured; this latter finding was sensitive to gap specification.

Conclusions

Young adults would likely benefit from greater attention to age‐19 and age‐26 health insurance “unwinding.”