bluuebunny/crossref_metadata_2025_split huggingface dataset:
Occupational health topics series on the effects of chemicals: epidemiological and toxicological risk assessments of ortho-toluidine for bladder cancer
Authors: Nakano Makiko , Gi Min , Toyooka Tatsushi , Suzuki Shugo , Wanibuchi Hideki , Takebayashi Toru 
Published: February 2025

Abstract

Objectives
Our aim was to report integrative evidence for the health risk assessment of ortho-toluidine (OT) in bladder cancer in a mini-review of the recent studies of humans, experimental animals, and OT skin permeability.

Methods
Bladder cancer cases were identified in workers in Japan who were occupationally exposed in 2014-2017 to aromatic amines, primarily to the human carcinogen OT.

Results
A key epidemiological study of 98 aromatic amine–exposed workers in Japan showed a clear OT exposure–response relationship with a standardized incidence ratio. A rat model experimental study also indicated that OT and acetoaceto-o-toluidine are potent bladder carcinogens. Multiple mechanisms of OT-related bladder cancer have been proposed: metabolic activation to reactive metabolites that bind DNA and proteins, mutagenicity, oxidative DNA damage, chromosomal damage, and cytotoxicity by OT. Recent comprehensive analyses of DNA adducts in rats identified a number of common oxidative DNA adducts, including 8-OHdG, in the rat urothelium and indicated that oxidative stress may play a crucial role in the development of urinary cancer caused by OT. The skin permeability of 6 aromatic amines (o-toluidine, aniline, p-toluidine, o-anisidine, 2,4-dimethylaniline, and o-chloroaniline) was examined with the use of a 3-dimensional (3D) reconstructed human skin model; ~70%-80% of the 6 aromatic amines had permeated through the 3D skin within 8 hours. Genotoxic potency testing in a human urothelial cell line using γ-H2AX, a marker of DNA damage, suggested that OT exhibited strong γ-H2AX generation.

Conclusions
Prolonged dermal exposure to OT along with other genotoxic aromatic amines over many years may contribute to the development of bladder cancer.
A tale of too many trees: a conundrum for phylogenetic regression
Authors: Adams Richard , Roa Lozano Jenniffer , Duncan Mataya , Green Jack , Assis Raquel , DeGiorgio Michael 
Published: February 2025

Abstract
Just exactly which tree(s) should we assume when testing evolutionary hypotheses? This question has plagued comparative biologists for decades. Though all phylogenetic comparative methods require input trees, we seldom know with certainty whether even a perfectly estimated tree (if this is possible in practice) is appropriate for our studied traits. Yet, we also know that phylogenetic conflict is ubiquitous in modern comparative biology, and we are still learning about its dangers when testing evolutionary hypotheses. Here we investigate the consequences of tree-trait mismatch for phylogenetic regression in the presence of gene tree-species tree conflict. Our simulation experiments reveal excessively high false positive rates for mismatched models with both small and large trees, simple and complex traits, and known and estimated phylogenies. In some cases, we find evidence of a directionality of error: assuming a species tree for traits that evolved according to a gene tree sometimes fares worse than the opposite. We also explored the impacts of tree choice using an expansive, cross-species gene expression dataset as an arguably “best-case” scenario in which one may have a better chance of matching tree with trait. Offering a potential path forward, we found promise in the application of a robust estimator as a potential, albeit imperfect, solution to some issues raised by tree mismatch. Collectively, our results emphasize the importance of careful study design for comparative methods, highlighting the need to fully appreciate the role of accurate and thoughtful phylogenetic modeling.
Coding Genes Helped the Origination and Diversification of Intragenic MicroRNAs
Authors: Liu Chengzhang , Zhang Xiaojun , Yuan Jianbo , Xiang Jianhai , Li Fuhua 
Published: February 2025

Abstract
Noncoding microRNAs tend to evolve within introns of coding genes that provide them with transcriptional opportunity. As an outcome of natural selection, the intragenic position of microRNAs is crucial for their expression, evolution, and functional cooperation with the host gene. Therefore, understanding the evolution of intragenic microRNA structures may bring novel insights into genetic and phenotypic evolution. However, it remains largely unexplored. Here, by analyzing microRNA genomics in 34 metazoan species, we found that the majority (630/1,154) of microRNA families originated from introns of coding genes that provided them with initial transcriptional capacity. The most rapid expansion of intragenic microRNAs happened at the advent of vertebrates when 21 microRNA families emerged from introns of neural genes and reorganized the gene regulatory network, leading to the rise of vertebrate-specific neural crest cells, which transformed the invertebrate head and enabled the ecological shift from filter feeding to active predation. Intragenic microRNAs gradually gain independence from their host genes, which is accelerated by whole-genome duplications. After a whole-genome duplication, the purging of redundant host genes often set an orphaned microRNA “free” to diversify with the transcriptional elements inherited from the host. Whole-genome duplications facilitated a dramatic microRNA diversification during the initial divergence of vertebrates, as the intragenic status of 12 neural crest-regulating microRNAs was retained in jawed vertebrates but was lost in jawless cyclostomes, which diverged their neural crest development. We propose that coding genes not only facilitate the origination of new microRNAs, but also “sacrifice” themselves to help microRNA diversification.
Metamorphic evolution of kyanite-bearing garnet pyroxenites from the Variscan orogenic root: Gföhl Unit, Moldanubian Zone, Austria
Authors: Asenbaum Rene , Zelinková Tereza , Racek Martin , Janoušek Vojtěch , Hauzenberger Christoph , Abart Rainer 
Published: February 2025

Abstract
Kyanite-bearing garnet pyroxenites occurring in centimetre to several hundred metres sized lenses of (ultra-)mafic lithologies embedded in felsic granulites of the Gföhl Unit in the south-eastern part of the Moldanubian Zone recorded a polyphase metamorphic evolution. An early high-pressure–high-temperature (HP–HT) stage at temperatures of 900 °C to 1000 °C and pressures in excess of 2 GPa is represented by the assemblage garnet–kyanite–omphacitic clinopyroxene–rutile (± quartz). Subsequent re-crystallisation under medium-pressure–high-temperature (MP–HT) conditions of about 1.0–1.3 GPa and 900–1000 °C is documented by the replacement of omphacitic clinopyroxene by symplectic intergrowth of diopsidic clinopyroxene and plagioclase, formation of sapphirine-bearing symplectites after kyanite, and a pronounced secondary compositional zoning of pre-existing garnet. Systematic compositional variations in the garnet cores over mm- to cm-sized mineralogically and microstructurally distinct domains indicate that equilibration volumes were small during the early HP–HT stage. In contrast, the compositions of the minerals that formed, or re-crystallised, during the MP–HT overprint are uniform throughout the samples, indicating substantially larger equilibration volumes during that stage. The metamorphic evolution is discussed in the light of deep subduction and relamination of felsic metaigneous crust, which subsequently experienced buoyancy-driven exhumation to mid-crustal levels and incorporated slivers of mafic and ultramafic material from the lithospheric mantle and lower crust en route.
Engineering of anti-cancer human IgA equipped with albumin for enhanced plasma half-life
Authors: Mester Simone , Chan Chilam , Lustig Marta , Foss Stian , Jansen J H Marco , Leangen Herigstad Marie , Evers Mitchell , Nilsen Jeannette , Reiding Karli R , Damen J Mirjam A , Burger Renate , Grevys Algirdas , Dalhus Bjørn , Valerius Thomas , Sandlie Inger , Leusen Jeanette H W , Andersen Jan Terje 
Published: February 2025

Abstract
Most therapeutic antibodies are based on immunoglobulin G (IgG) due to their potent effector functions and long plasma half-life. However, also monomeric IgA has emerged as an attractive candidate for cancer treatment as, upon specific binding to tumor cells, it can activate myeloid cells, like polymorphonuclear leukocytes and macrophages, to kill the tumor cells by engaging the Fc α receptor I (FcαRI). Despite this favorable property, human IgA has a short plasma half-life in both mice and humans, which is clearly limiting preclinical studies in a translational perspective. Here, we report on albumin-equipped designs of human IgA antibodies that are long-acting due to tailored binding to the human form of neonatal Fc receptor (FcRn), which is a natural plasma half-life regulator of albumin. Importantly, this was achieved without compromising the ability of IgA to engage and activate FcαRI-expressing effector cells for tumor cell killing in vitro and in vivo in a new mouse model transgenic for the human forms of FcRn and FcαRI. We further show that the potency of the engineered long-acting human IgA against tumor cells with intermediate target antigen expression levels could be enhanced by myeloid checkpoint inhibitors targeting the signal regulatory protein α - CD47 axis.
Longitudinal risk of serious infections in patients with inflammatory arthritis on immunomodulating therapy compared to controls
Authors: Christensen Ingrid Egeland , Lillegraven Siri , Sexton Joseph , Kvien Tore K , Uhlig Till , Provan Sella Aarrestad 
Published: February 2025

Abstract

Objectives
To compare the risk of serious infection across time-cohorts in patients with inflammatory arthritis (IA) initiating their first biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD), to that of the general population. Secondarily, to compare the development in infection risk during treatment across diagnoses and examine risk dynamics during the course of b/tsDMARD treatment.

Methods
Patients with IA starting their first b/tsDMARD were included from the prospective NOR-DMARD study. Controls were randomly drawn from the general population. Cox-regressions were used to compare the 12-month risk of serious infections across three time-cohorts following initiation (2009–2011, 2012–2014, 2015–2018), and risk during the course of treatment at 6-months intervals up to 24 months.

Results
4309 patients (rheumatoid arthritis (RA)=1581, psoriatic arthritis (PsA)=1032 and spondyloarthritis (SpA) =1696) and 86 640 controls were included. From 2009 through 2018, 51 serious infections occurred during the first year of b/tsDMARD treatment in RA patients, HR 2.42 (95% CI 1.83, 3.21) compared with controls, 52 serious infections were observed in patients with PsA/SpA, HR 1.91 (1.44, 2.52). There were no significant differences in 12-month risk of serious infections during b/tsDMARD exposure between time-cohorts. PsA/SpA patients had a consistently lower risk of serious infection compared with RA patients. The risk of serious infections did not change during treatment course.

Conclusion
Patients with IA starting their first b/tsDMARD between 2009–2018 had a consistently higher 12-month risk of serious infection compared with controls. No change in the risk of serious infection across time-cohorts of b/tsDMARD initiation was observed, nor during treatment course.
Bank Competition and Bargaining over Refinancing
Authors: Emiris Marina , Koulischer François , Spaenjers Christophe 
Published: February 2025

Abstract
We model mortgage refinancing as a bargaining game involving the borrowing household, the incumbent lender, and outside banks. We show that bargaining can provide a competitive advantage to the incumbent bank. In equilibrium, the borrower’s ability to refinance depends on the incumbent bank’s cost (dis)advantage relative to locally present competing banks and on the average creditworthiness of borrowers in the relevant market. It is also driven by borrower impatience and switching costs. We find empirical support for the key predictions of our model in an administrative data set covering the universe of mortgages in Belgium. (JEL G11, G21, G51)
Prodomain processing controls BMP‐10 bioactivity and targeting to fibrillin‐1 in latent conformation
Authors: Spanou Chara E. S. , Yang Chengeng , Godwin Alan R. F. , Morosky Stefanie , Anbalagan Arulselvi , Lütke Steffen , Mörgelin Matthias , Marcous Fady , Aziz Ubair , Wohl Alexander P. , Jabeen Ishrat , Koch Manuel , Jowitt Thomas A. , Roman Beth L. , Tarakanova Anna , Baldock Clair , Sengle Gerhard 
Published: February 2025

AbstractBone morphogenetic protein 10 (BMP‐10) is crucial for endothelial cell signaling via activin receptor‐like kinase 1 (ALK1), a pathway central to vascular homeostasis and angiogenesis. Dysregulated BMP‐10 signaling contributes to cardiovascular diseases and cancer, highlighting the need to control ALK1‐mediated endothelial responses to BMP‐10 for therapeutic development. BMP‐10 biosynthesis involves processing by proprotein convertases (PPCs) resulting in a non‐covalently associated prodomain–growth factor (PD–GF) complex (CPLX), similar to other TGF‐β superfamily ligands. However, the molecular requirements for BMP‐10 bioactivity remain unclear. We investigated how PPC processing impacts BMP‐10 structure, bioactivity, and its interaction with the extracellular matrix (ECM) protein fibrillin‐1. Molecular dynamics simulations post‐in silico cleavage of the BMP‐10 dimer model as well as negative staining and transmission electron microscopy (TEM) revealed that PD processing increases BMP‐10 flexibility converting it from a latent wide‐angle conformation to a bioactive CPLX which can adopt a V‐shape with tighter angle. Only processed BMP‐10 demonstrated high potency in HUVEC and C2C12 cells and robust binding to immobilized BMP receptors. Circular dichroism and interaction studies revealed that the N‐terminal region of the BMP‐10 PD is rich in alpha‐helical content, which is essential for efficient complexation with the BMP‐10 GF. Binding studies and TEM analyses showed that only the processed BMP‐10 CPLX interacts with the N‐terminal region of fibrillin‐1, causing a conformational change that renders it into a closed ring‐shaped conformation. These findings suggest that PD processing induces specific folding events at the PD–GF interface, which is critical for BMP‐10 bioactivity and its targeting to the ECM.
Novel role of the SOX4/CSNK2A1 axis in regulating TOP2A phosphorylation in breast cancer progression
Authors: Zou Jiaqiong , Geng Ruiman , Zhang Zhengkun , Ji Xuxu , Yin Zhaoru , Wang Dingxue , Guo Rong , Chen Lihong , Liu Ji 
Published: February 2025

AbstractThis study examines the critical role of DNA topoisomerase II alpha (TOP2A) phosphorylation in breast cancer progression, regulated by the SRY‐box transcription factor 4 (SOX4)/Casein kinase II subunit alpha 1 (CSNK2A1) axis. Using integrated transcriptomic and proteomic analyses, data were sourced from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) databases. To explore the dataset, differential analysis, kinase‐substrate enrichment analysis (KSEA), and weighted gene co‐expression network analysis (WGCNA) were performed. Immune profiling, combined with survival analysis, revealed the prognosis linked to different immune profiles in breast cancer patients. In vitro experiments assessed the effect of SOX4 on CSNK2A1 promoter activity through real‐time quantitative polymerase chain reaction (RT‐qPCR), Western blot, dual‐luciferase reporter assays, and chromatin immunoprecipitation (ChIP). The phosphorylation level of TOP2A was also measured. Cell proliferation, migration, and invasion were evaluated using cell counting kit‐8 (CCK‐8), colony formation, and Transwell assays. In vivo studies extended to mouse models, where the effect of SOX4 on CSNK2A1‐TOP2A phosphorylation was analyzed about tumor growth and metastasis. The results showed that upregulation of SOX4 increases CSNK2A1 transcription, which in turn promotes TOP2A phosphorylation and accelerates breast cancer progression. The clinical analysis identified three immune profiles, with the intermediate profile associated with a poorer prognosis, possibly due to enhanced TOP2A phosphorylation mediated by SOX4/CSNK2A1. Silencing SOX4 significantly reduced cell proliferation, migration, invasion, and tumor growth in vivo by lowering CSNK2A1‐TOP2A phosphorylation. These findings highlight the therapeutic potential of targeting the SOX4/CSNK2A1 axis in breast cancer and provide insight into its mechanism through TOP2A phosphorylation.
Exploring a novel risk model based on core disulfidptosis‐related genes in periodontitis: Bioinformatics analyses and experimental validation
Authors: Yang Yiqiang , Liu Qi , Lu Xun , Wang Yuran , Tian Xue , Yang Jiahui , Chen Jia 
Published: February 2025

AbstractBacteria in dental plaque invade periodontal tissues, causing chronic inflammation known as periodontitis. Despite advancements in understanding periodontitis, its molecular pathogenesis remains incompletely elucidated. In this study, a total of 247 samples were retrieved from the Gene Expression Omnibus (GEO) database, comprising 183 from individuals with periodontitis and 64 from healthy controls. Differentially expressed DRGs (DE‐DRGs) were identified, and their expression correlations were analyzed. Immune cell infiltration and its association with DE‐DRGs were assessed. Gene Set Variation Analysis (GSVA) was performed to determine key functions and pathways related to DE‐DRGs. Characteristic DE‐DRGs (CDE‐DRGs) were identified using the Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and a risk model and personalized nomogram were constructed. Model performance was validated through calibration and decision curve analysis (DCA). External experiments, including qRT‐PCR and Western blot, confirmed the differential expression of DE‐DRGs. Fourteen DE‐DRGs were identified. Expression analysis revealed a strong synergistic correlation between MYH9 and ACTB (coefficient = 0.86) and an antagonistic correlation between NCKAP1 and FLNA (coefficient = −0.52). Immune profiling showed significant differences in the proportions of 22 immune cell types between groups, with 14 DE‐DRGs correlated with immune infiltration levels. Cluster analysis of periodontitis samples revealed distinct patterns of DE‐DRGs expression and immune cell infiltration across two clusters. A risk model incorporating four CDE‐DRGs (DSTN, SLC7A11, SLC3A2, and RPN1) was developed, alongside a personalized nomogram for predicting periodontitis risk. qRT‐PCR and Western blot analyses demonstrated downregulation of DSTN, SLC3A2, IQGAP1, CD2AP, and NCKAP1 and upregulation of SLC7A11, RPN1, FLNA, MYH9, TLN1, ACTB, MYH10, CAPZB, and PDLIM1 in periodontitis tissues. This study identified key DRGs in periodontitis, developed a predictive risk model and nomogram, and detailed the immune infiltration profile and its association with DRGs. These findings provide insights into the molecular pathogenesis of periodontitis and suggest potential strategies for personalized risk assessment, early diagnosis, and targeted therapy.
Mesenchymal retinoic acid signaling is required for normal diaphragm development in mice
Authors: Garcia Rivas Juan F. , Applin Nicole H. M. , Albrechtsen Jaida F. P. , Ghazanfari Adibehalsadat , Doschak Michael , Clugston Robin D. 
Published: February 2025

AbstractCongenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm, causing herniation of the abdominal organs and subsequent lung hypoplasia; however, the etiology of CDH is poorly understood. The Retinoid Hypothesis posits that abnormal retinoic acid signaling leads to the formation of diaphragmatic hernias. Our goal is to better understand diaphragm development and the etiology of CDH. To achieve this goal, we first performed single‐cell RNA sequencing analysis of the developing diaphragm, then generated a conditional retinoic acid receptor dominant negative knock‐in to inhibit retinoic acid signaling in the mesenchyme of the developing diaphragm. Our single‐cell RNA sequencing analysis revealed 10 distinct cell populations in the developing diaphragm, with mesenchymal cells being the primary expresser of CDH and retinoic acid signaling‐related genes. Transgenic inhibition of mesenchymal retinoic acid signaling in the developing diaphragm caused hernias in 100% of embryos, recapitulating the hallmarks of CDH. Overall, our studies show that retinoic acid signaling in the mesenchymal component of the diaphragm is required for normal diaphragm development.
Marein alleviates the development of atherosclerosis through targeting miR‐126/lipoprotein‐associated phospholipase A2 axis
Authors: Zhao Lisha , Xing Jie , Wang Yunfei , Xin Ling , Cheng Xiaorong , Chen Yanying , Wang Panpan , Zhang Lanlan , Zhao Weiguo 
Published: February 2025

AbstractAs a classical precious medicine, Coreopsis tinctoria Nutt. (C. tinctoria) is widely utilized for treatment of cardiometabolic diseases, while the important compound of C. tinctoria, marein exhibits multiple beneficial biological effects that related to the pathophysiological processes underlying atherogenesis. Thus, the purpose of present study is to investigate the role of marein on the development of atherosclerosis. In the current study, we observed that marein exhibited anti‐inflammatory response function verified by reduced mRNA and protein levels of classical M1 but enhanced alternative M2 macrophage genes. Moreover, marein dramatically attenuated macrophage‐induced foam cell formation with up‐regulated cholesterol efflux but down‐regulated cholesterol influx‐related genes expression in bone marrow‐derived macrophage (BMDMs) administrated with oxidized low‐density lipoprotein (Ox‐LDL), observed by staining with Oil‐Red O, RT‐PCR, or western blot analysis. Treatment of ApoE knockout mice (ApoE−/−) with marein at indicated time which consistently fed with high‐fat diet for 12 weeks was utilized to explore the function of marein on atherogenesis in vivo. We revealed that marein‐treated group alleviated atherosclerotic plaques in the entire aorta and aortic root and inhibited plaque vulnerability characterized by decreased necrotic core, reduced macrophage, and lipid accumulation, whereas increased fibrous cap, enhanced smooth muscle cell, and collagen deposition. Importantly, we noticed that miR‐126 could target to lipoprotein‐associated phospholipase A2 (Lp‐PLA2), and enhanced miR‐126 but reduced Lp‐PLA2 expression was responsible for the alleviated function of marein on macrophage dysfunction. Collectively, we identified that marein could be a promising drug for prevention of the development of atherosclerosis by protecting against macrophage‐mediated foam cell formation and inflammation, partially through miR‐126/Lp‐PLA2 dependent mechanism.