bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

Bone 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

This 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

Bacteria 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

Congenital 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

As 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.
CETP expression in females increases body metabolism under both cold exposure and thermoneutrality contributing to a leaner phenotype
Authors: Castelli Júlia Z. , Raposo Helena F. , Navarro Claudia D. C. , Lazaro Carolina M. , Sartori Marina R. , Dalla Costa Ana Paula , Nogueira Pedro A. S. , Velloso Lício A. , Vercesi Anibal E. , Oliveira Helena C. F.
Published: February 2025

Susceptibility to obesity differs depending on the genetic background and housing temperatures. We have recently reported that CETP expressing female mice are leaner due to increased lipolysis, brown adipose tissue (BAT) activity, and body energy expenditure compared to nontransgenic (NTg) littermates under standard housing temperature (22°C). The aim of this study is to evaluate how CETP expression affects body temperature, composition, and metabolism during cold exposure (4°C) and thermoneutrality (30°C). When submitted to cold, CETP mice maintained rectal temperature, body weight, and food intake similarly to NTg mice along acute or chronic exposure to 4°C. The body oxygen consumption in response to an isoproterenol challenge was 21% higher at 22°C, and 41% higher after 7 days of cold exposure in CETP than in NTg mice. In addition, BAT biopsies from CETP mice showed reduced lipid content and increased basal oxygen consumption rates. Under thermoneutrality (30°C), when BAT activity is inhibited, CETP mice showed higher rectal and tail temperatures, increased food intake, and increased energy expenditure. Lean mass was elevated and fat mass reduced in CETP mice kept at 30°C. In this thermoneutral condition, soleus muscle, but not gastrocnemius or liver of CETP mice, showed increased mitochondrial respiration rates. These data indicate that CETP expression confers a greater capacity of elevating body metabolic rates at both cold exposure, through BAT activity, and at thermoneutrality, through increased muscle metabolism. Thus, the CETP expression levels in females should be considered as a new influence in the contexts of obesity and metabolic disorders propensity.
Age-Related Changes and Spinal Sagittal Alignment in Asymptomatic Community Dwelling Adults Over 50
Authors: Wang Wei , Wang Zheng , Wang Dongfang , Liu Chengxin , Kong Chao , Zhu Weiguo , Pan Fumin , Li Xiangyu , Chen Xiaolong , Lu Shibao
Published: February 2025

Study Design.

Monocentric, retrospective, cross-sectional study

Objective.

To investigate the age-related normative values of sagittal parameters and establish their relationships in asymptomatic community-dwelling adults aged over 50.

Background context.

Degenerative changes in the spine with aging alter the sagittal balance, causing spine pathologies. However, there was a lack of comprehensive study on age-related normative values of sagittal alignment and their relationship during degenerative evolution.

Methods.

Among a total of 1,370 volunteers, 701 asymptomatic volunteers were recruited. Participants underwent a lateral X-ray, and sagittal parameters were assessed using a customized computer application.

Results.

Age showed a stronger correlation with upper arc of thoracic kyphosis (Upper_TK) (r=0.39) compared to sagittal vertical axis (SVA) (r=0.28) and T1_slope (r=0.29). Lumbar lordosis (LL) did not exhibit a significant decrease with age. The geometrical relationship revealed a significant correlation between TK and LL (r=0.52), and LL and pelvic incidence (PI) (r=0.63), as per the equations: TK=Upper_TK+Lower arc of TK (Lower_TK), LL=Upper arc of LL (Upper_arc)+sacral slope (SS), Lower_TK≈Upper_arc, and PI=SS+pelvic tilt (PT). However, after removing intermediate control variables of Lower_TK (Upper_arc) and SS, the correlation between TK, LL, and PI was statistically weak, due to the little to no correlation between Lower_TK (Upper_arc), SS, and PT. Upper_arc (Lower_TK) was a relatively stable parameter with an age-independent value of 15.93±5.61° in elderly adults. For adults aged 60, Upper_TK significantly increased with age, while individuals over 75 exhibited a significant increase in PT and a decrease in SS and LL.

Conclusions.

Our study provided a normative age-related value of spinal sagittal parameters. To assess the spinal sagittal alignment, it was suggested that LL and TK be divided into two tangential arches based on the location of the lordotic or kyphotic apex. This study offered insights for spine surgeons in preparing for surgical corrections.
Telerehabilitation Resources for Educators in Physical Therapy
Authors: Davies Luke M. , Lee Alan C. , Davenport Todd E. , Russell Trevor G.
Published: February 2025

Research conducted during the COVID-19 pandemic has demonstrated the use of telehealth in physical therapy is not only necessary, but clinically effective in delivering physical therapy care that expands patient access and choice when it comes to personalized care. Recently, the telehealth literature includes an international clinical practice guideline with 7 recommendations for practitioners and students, 7 educational competencies with telehealth concepts for physical therapy educators, and 7 domains of core quality framework for videoconferencing for physical therapist training. Based on current evidence, the authors present these telerehabilitation resources for physical therapy educators to support education, research, and practice in telehealth.
Charting New Paths
Authors: O'Brien Callie A. , Brain Jessie M. , Jehle Jonathan , McGuire Hilary Carroll , O'Shea Lauren K. , Sciacca Kate
Published: February 2025

Palliative care has expanded beyond its traditional focus on the oncology population to meet the growing needs of patients with diverse diagnoses. A model of specialty-aligned palliative care has emerged as a means of integrating palliative care into various clinical specialties. Equipped with expert clinical skills, a holistic approach to patient care, and an emphasis on interprofessional collaboration, nurse practitioners are uniquely positioned to lead these teams. This article examines the role nurse practitioners play as leaders of 4 specialty-aligned palliative care teams at a major metropolitan academic medical center. It highlights key contributions to the successful integration of palliative care into oncology, cardiac, renal, and medical-surgical specialties. Although there are clear benefits of nurse practitioner–led specialty-aligned teams, further research and advocacy is needed to strengthen this model and increase access to quality palliative care.
Sexual dimorphism during LPS-induced systemic inflammation
Authors: Jansen Aron , Bruse Niklas , Waalders Nicole , van Lier Dirk , Leijte Guus , Gerretsen Jelle , Adriaansen Bas , van Herwaarden Teun , Pickkers Peter , Kox Matthijs
Published: February 2025

Incidence and outcomes of systemic inflammatory diseases, such as sepsis, differ between men and women, but the underlying mechanisms remain unclear. We examined systemic inflammatory responses in 56 male and 54 female healthy volunteers challenged with 1 ng/kg bacterial lipopolysaccharide (LPS) twice, with an interval of one week. Sex hormones, inflammatory markers, and monocyte RNA expression were determined. Women exhibited higher levels of several proinflammatory mediators than men during the first LPS challenge (TNF +45%, p=0.002; IL-6 +43%, p=0.0009; IP-10 +58%, p<0.0001; G-CSF +60%, p=0.02). Among women, use of hormonal contraceptives was associated with a more pronounced pro-inflammatory response (TNF +60%, p=0.001; IL-8 +30%, p=0.008; IP-10 +37%, p<0.0001). Endogenous concentrations of estrogens and testosterone inversely correlated with the extent of cytokine responses in women, while estrone positively correlated with these responses among men. The magnitude of endotoxin tolerance, exemplified by a significantly blunted cytokine response upon the second LPS challenge, was similar between the sexes, as were monocyte RNA expression patterns. In conclusion, our data indicate that there is considerable sexual dimorphism in systemic inflammation and implicate an important role for sex hormones in regulating immunity.
The influence of different sugars and sugar alcohol, and cultivars in the osmotically dehydrated peach fruit. Analysis of mass transfer parameters and the variation in the organoleptic properties, bioactive and nutritive compounds, and pro-health properties in dried peaches
Authors: Salvañal Lara , Gabilondo Julieta , Corbino Graciela , Budde Claudio O. , Lara María Valeria
Published: February 2025

Peach is a great-taste fruit, source of nutrients and bioactive compounds. It is a seasonal fruit that cannot be stored for prolonged periods of time. To increase its consumption over the year, promote its intake as a snack, utilize it in the industry, process the overproduced peach and to add value to the fruit, osmotic dehydration (OD) followed by hot-air drying (OD+D) is a suitable process. Here, we compared the use of three different osmolytes (glucose, sorbitol or sucrose) and four peach cultivars (Flordaking, Goldprince, Elegant Lady and Dixiland) exposed to OD+D to study the effects on organoleptic, nutritional and nutraceutical properties of the peach. OD+D slices were compared against fresh fruit exclusively exposed to hot-air treatment (D). A moisture content of 17.5% was obtained in OD+D and D peaches. Moisture content, water loss, solute gain and colour depended on the cultivar. Higher metabolite and antioxidant capacity retention was observed for OD+D peach slices compared to D peaches, minimizing adverse changes such as carotenoid decrease typical of D and even enhancing some features such as tannin content. Moreover, OD+D improved the inhibition of protease, α-amylase and α-amyloglucosidase, key enzymes involved in inflammatory processes and hyperglycemia management. The dehydration processes modified the antimicrobial capacity of peach slices, with responses varying depending on the cultivar and obtaining better inhibitions than in D. Finally, although mineral composition was altered in OD+D due to leaking to the solution, the addition of calcium in the hyperosmotic solution resulted in calcium enriched dried peaches. Collectively, the results obtained reveal the influence of the cultivar on the properties of the dried fruit and highlight the benefits of the osmotic pretreatments prior to conventional drying.
Pan-Cancer Biomarker Analysis from the Cancer Dependency Map: A Blueprint for Precision Oncology
Authors: Gong Dennis
Published: February 2025

The diversity of therapeutic modalities and targets continue to grow, and the number of cancer patients eligible for targeted therapy has expanded accordingly. Despite advances, response rates to individual targeted therapy drugs remain variable, rarely achieving uniform tumor shrinkage across patients. Biomarkers are crucial for identifying patients likely to respond to therapy while sparing non-responders from toxicity and guiding them toward alternative treatments. We conducted a multi-omic analysis of biomarker-dependency relationships across 1,150 cancer molecular profiles to identify novel biomarkers for patient stratification. We first validated the Cancer Dependency Map’s sensitivity and specificity in predicting therapeutic windows for targeted therapies. Next, we identified predictive biomarkers for single- and multi-gene dependencies, assessing their selectivity within biomarker-defined populations. Protein abundance analysis revealed potential immunohistochemistry (IHC) biomarkers for clinically deployed therapeutic compounds. We performed an analysis of lineage-enriched dependencies, highlighting new opportunities for target validation and drug development. Finally, we screen for associations between hotspot mutations, damaging mutations, and protein abundance, providing insights for developing heterobifunctional small molecules for induced proximity and protein degradation. These findings advance our understanding of cancer dependencies and inform biomarker-driven strategies to optimize therapeutic outcomes.
PROBind: A Web Server for Prediction, Analysis and Visualization of Protein-Protein and Protein-Nucleic Acid Binding Residues
Authors: Wu Chaojin , Zhang Fuhao , Jia Pengzhen , Zhu Jiuxiang , Zeng Min , Hu Gang , Wang Kui , Kurgan Lukasz , Li Min
Published: February 2025

Protein–protein and protein–nucleic acids interactions are fundamental to numerous cellular functions, yet only a small fraction have been experimentally characterized. Although modern computational methods have been developed for predicting interacting residues in proteins, they are challenging to use due to individual installation and execution requirements, lack of a standardized input or output format, and absence of support for result analysis. Moreover, methods trained using structures of complexes or intrinsically disordered regions, may not perform well on other types. To overcome these challenges, we develop PROBind, a web server for predicting, analyzing, and interactively visualizing protein, DNA and RNA binding residues from both protein sequences and structures. PROBind integrates 12 predictors trained on structural or disordered proteins, and supports the upload of results from external predictors. By normalizing and averaging predictions from multiple predictors targeting the same ligand type, PROBind generates meta-predictions that balance discrepancies among different methods. Furthermore, it provides interactive graphical tools for result analysis and contextualization. Overall, PROBind accommodates diverse ligand types and supports predictions and analysis based on both structure and sequence data, overcoming the limitations of existing tools. PROBind is freely accessible athttps://www.csuligroup.com/PROBind.
Investigating the factors influencing antibiotic use practices and their association with antimicrobial resistance awareness among poultry farmers in Enugu State, Nigeria
Authors: Ejikeugwu Chika P. , Nwakaeze Emmanuel A. , Aniekwe Chikaodi W. , Onu Euslar N. , Adikwu Michael U. , Eze Peter M.
Published: February 2025

Background

The irrational use of antibiotics in poultry production has far-reaching consequences and continues to impact the fight against antimicrobial resistance (AMR) in Africa. In Nigeria, antibiotics are available over-the-counter and are widely used in food animal production for various reasons, including prophylaxis and growth promotion. While this practice may support animal production, it also drives the spread of AMR, posing serious health challenges due to close human-livestock interactions and the country’s high disease burden. This study examined poultry farmers’ knowledge, attitudes, and practices (KAP) regarding antibiotic use and AMR, aiming to highlight the public health risks and challenges in combating AMR in Nigeria.

Methods

A cross-sectional survey of 200 poultry farms in Enugu State, Southeast Nigeria, was conducted to evaluate farmers’ KAP towards antibiotic usage and AMR. Using a validated, standardized, and self-administered questionnaire, data were collected from farmers responsible for key farm decisions, including input and feed management. The questionnaire comprised three sections: socio-demographic data, knowledge of AMR, and knowledge and practices regarding antibiotic use. Ethical approval was obtained, and participants gave oral consent based on their professional capacity.

Results

The evaluation of poultry’s farmers KAP regarding antibiotic usage and AMR revealed that the majority of farmers (90.5%) reported using antibiotics, primarily for treating infections (80.5%) or for feed enhancement, growth promotion, and prophylaxis (61%). Ampicillin (75%), ciprofloxacin (71.5%), and doxycycline (71%) were the most commonly administered antibiotics. Monthly administration was the most common (48%), and 89% of respondents believed that antibiotics promote poultry growth. Interestingly, a substantial proportion of respondents (65%) were unaware of AMR, highlighting a significant knowledge gap, with only 16% recognizing the risk of AMR infections.

Conclusion

Our study revealed that the surveyed poultry farmers heavily rely on antibiotics, primarily for treating infections and, to a significant extent, for growth promotion, despite their limited awareness of AMR. Ampicillin was identified as the most commonly used antibiotic, raising concerns due to its potential link to beta-lactamase selection amid the country’s carbapenem resistance issues. These findings underscore the urgent need for targeted education to address the AMR knowledge gap and reduce the misuse of antibiotics in poultry farming settings in Nigeria.
Single-cell and spatially resolved atlas of pancreatic cancer reveals immunophenotypes associated with clinical outcome
Authors: Pozo de Mattos P. Gabriel F. , Lins Marvin Paulo , Fontoura Julia , Osvaldt Alessandro Bersch , dos Santos Machado Simone Marcia , Filippi-Chiela Eduardo Cremonese , Bonorino Cristina
Published: February 2025

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of pancreatic neoplasms, is characterized by its poor prognosis, with a 5-year survival rate of only 12%. Most patients are diagnosed with metastatic or locally advanced disease, leaving only 15% eligible for curative resection. PDAC exhibits resistance to chemotherapy, targeted therapies, and immunotherapy, largely due to its highly heterogeneous tumor microenvironment (TME). In this study, we performed an integrative analysis of publicly available scRNA, spatial transcriptomics, and bulk RNA sequencing datasets to investigate the influence of TME composition and tumor architecture on PDAC progression, treatment response, and clinical outcomes. We identified TME subtypes with distinct cellular compositions, functional signatures, and immunomodulatory cell-cell interactions. Spatially distinct cellular niches and gene modules revealed heterogeneity across primary tumors and metastatic lesions. Deconvolution of these spatial niches in a large cohort of bulk RNA samples uncovered unique clusters associated with patient survival, providing novel insights into TME biology and its clinical implications. These findings underscore the importance of integrating multi-omics approaches to unravel the complexity of the PDAC TME and highlight its potential to inform therapeutic strategies and improve patient outcomes.
Inducible re-epithelialization of cancer cells increases autophagy and DNA damage: implications for breast cancer dormancy
Authors: Drago Garcia Diana , Giri Suvendu , Chattaerjee Rishita , Simoni Nieves Arturo , Abedrabbo Maha , Genna Alessandro , Uribe Rios Mary Luz , Lindzen Moshit , Sekar Arunachalam , Gupta Nitin , Aharoni Noa , Bhandari Tithi , Mayalagu Agalyan , Schwarzmüller Luisa , Tarade Nooraldeen , Zhu Rong , Mohan-Raju Harsha-Raj , Karatekin Feride , Roncato Francesco , Eyal-Lubling Yaniv , Keidar Tal , Nof Yam , Belugali Nataraj Nishanth , Bernshtein Karin Shira , Wagner Bettina , Ulhas Nair Nishanth , Sanghvi Neel , Alon Ronen , Seger Rony , Pikarsky Eli , Donzelli Sara , Blandino Giovanni , Wiemann Stefan , Lev Sima , Prywes Ron , Barkan Dalit , Rueda Oscar , Caldas Carlos , Ruppin Eytan , Shiloh Yosef , Dahlhoff Maik , Yarden Yosef
Published: February 2025

Epithelial lineage differentiation is pivotal to mammary gland development and it can pause metastasis of breast cancer (BC) by inducing tumor dormancy. To simulate this, we expressed epithelial genes in mesenchymal BC cells. Inducible expression of the epithelialOVOLgenes in metastatic BC cells suppressed proliferation and migration. We found thatC1ORF116, an OVOL’s target, is susceptible to genetic and epigenetic aberrations in BC. It is regulated by steroids and functions as a putative autophagy receptor that inhibits antioxidants like thioredoxin. Accordingly, boosting epithelialization lowered glutathione, elevated reactive oxygen species and increased both DNA oxidation and double strand breaks. Epithelialization also associated with redistribution of NRF2 and an altered interplay among p38, ATM, and the other kinases regulating the DNA damage response. Hence, hormonal regulation of OVOLs and chronic stress might permit epithelial differentiation and retard exit from dormancy, while altering redox homeostasis and permitting DNA damage accumulation, which may awaken dormant tumors.
Hi-C sequencing data from cortex of laboratory rats
Authors: Kim Panjun , Ward Rachel R. , Sharp Burt M. , Williams Robert W. , Chen Hao
Published: February 2025

The three-dimensional conformation and packaging of chromosomes modulates the spatial organization of the nucleus, orchestrating DNA replication and repair, maintaining genome stability and integrity, and regulating gene expression. Hi-C methods provide high-resolution data on chromatin-to-chromatin interactions both within and among chromosomes at a genome-wide scale. Hi-C resolves topologically-associated domains (TADs) and chromatin loops that are linked to cell-specific transcriptional control. We present a comprehensive Hi-C dataset generated from the frontal cortex of laboratory rats, encompassing a diverse group of inbred strains (SHR/OlaIpcv, BN-Lx/Cub, BXH6/Cub, HXB2/Ipcv, HXB10/Ipcv, HXB23/Ipcv, HXB31/Ipcv, LE/Stm, F344/Stm) and an F1 hybrid (SHR/Olalpcv x BN/NHsdMcwi). This dataset serves as a valuable resource for studying the mechanisms by which three-dimensional chromatin architecture governs gene expression in the brain. Strain-specific variations in genome organization can illuminate the influence of chromatin structure on gene expression, neuronal functionality, and the predisposition to neurological and behavioral disorders.
Hydrophobic tuning with non-canonical amino acids in a copper metalloenzyme
Authors: Fischer Sandro , Natter Perdiguero Anton , Lau Kelvin , Deliz Liang Alexandria
Published: February 2025

Hydrophobicity controls many aspects of protein and enzyme function. Although hydrophobic tuning can be achieved to a limited extent with canonical amino acids, the incorporation of non-canonical amino acids (ncAAs) further extends this ability to enable new and improved functionality. Herein, we engineer an aminoacyl-tRNA synthetase/tRNA pair for the site-specific genetic encoding of a set of bulky, hydrophobic amino acids, namely cyclopentylalanine, cyclohexylalanine, and cycloheptylalanine. With the resulting orthogonal translations systems, we demonstrate the utility of ncAA-based hydrophobic tuning to engineer a bacterial laccase, which is both a classical metalloenzyme and a high-value catalyst for industrial processes. The resulting mutations conveyed significant improvements in catalytic activity, particularlykcatand total turnover number. The redox potential and structure-function relationships were examined to elucidate the source of this improved functionality. We envision that these tools for hydrophobic tuning will be highly valuable for general enzyme engineering and also in other fields, including peptide chemistry.
Impact of Aging on Theta-Phase Gamma-Amplitude Coupling During Learning: A Multivariate Analysis
Authors: Strzelczyk Dawid , Peylo Charline , Langer Nicolas
Published: February 2025

Aging is associated with cognitive decline and memory impairment, but the underlying neural mechanisms remain unclear. Phase-amplitude coupling (PAC) between mid-frontal theta (5 Hz) and occipital gamma (>30 Hz) oscillations is a proposed marker for parallel storage of multiple items in working memory. However, research has mainly focused on young individuals and epilepsy patients, with only a few studies on aging populations. Moreover, these studies have relied on univariate PAC methods, which can be flawed by potential spurious or biased PAC estimates due to non-stationarity of EEG signals. Additionally, these methods typically assess PAC at the level of individual electrodes, potentially overlooking the broader functional significance of theta-gamma coupling in coordinating neural activity across distant brain regions.

To address these gaps, we employed multivariate PAC (mPAC) through generalized eigendecomposition (GED) analysis, which avoids the pitfalls of non-sinusoidal oscillations. 113 young and 117 older healthy participants engaged in a sequence learning paradigm (6423 sequence repetitions, 55’944 stimuli), in which they learned a fixed sequence of visual stimuli over repeated observations, allowing us to track the mPAC during the incremental process of learning.

Behavioral results revealed that younger participants learned significantly faster than older participants. Neurophysiological data showed that mPAC increased over the course of learning in both age groups and could identify fast and slow learners. However, older participants exhibited lower mPAC compared to younger counterparts, which suggest compromised parallel storage of items in working memory in older age. Finally, stratification analysis revealed that mPAC effects persist across performance groups with similar mid-frontal theta levels, suggesting that theta alone does not account for these effects. These findings shed light on the age-related differences in memory formation processes and may guide interventions to enhance memory performance in older adults and slow learners.
Non-invasive peripheral delivery of CDNF fragment protects neurons in models of Parkinson’s and ALS
Authors: Yu Li Ying , Viljakainen Tuulikki , Beckett Liam , Nam Jinhan , Hyysalo Anu , Lüningschrör Patrick , Albert Katrina , Koppinen Tapani , Hyvärinen Tanja , Tossavainen Helena , Hellman Maarit , Airavaara Mikko , Sendtner Michael , Permi Perttu , Lindholm Päivi , Saarma Mart , Voutilainen Merja H.
Published: February 2025

Non-invasive delivery of brain therapeutics is a key challenge for treating neurodegenerative diseases. Here, we discovered a novel carboxy (C)-terminal fragment of cerebral dopamine neurotrophic factor (C-CDNF) that protects dopamine (DA) and motoneurons (MNs) in rodent models of Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). C-CDNF retains the same structure as CDNF and similarly to CDNF regulates cell stress pathways but unorthodoxly enters cultured neurons and passes through the blood-brain barrier.In vivo, intracranially or peripherally delivered C-CDNF improves motor deficits, protects DA neurons, and restores motor behavior in a rat model of PD. Subcutaneous C-CDNF also protects MNs and reduces microglial activation in an ALS model. Based on our findings, beginning C-CDNF treatment soon after diagnosis is anticipated to delay progression of PD and ALS, thereby improving treatment outcome. Thus, systemic delivery of C-CDNF should simplify the administration of protein-based therapeutics to patients while reducing treatment risk and financial burden for patients and families.
Validation of ten federated learning strategies for multi-contrast image-to-image MRI data synthesis from heterogeneous sources
Authors: Fiszer Jan , Ciupek Dominika , Malawski Maciej , Pieciak Tomasz
Published: February 2025

Deep learning (DL)-based image synthesis has recently gained enormous interest in medical imaging, allowing for generating multi-contrast data and therefore, the recovery of missing samples from interrupted or artefact-distorted acquisitions. However, the accuracy of DL models heavily relies on the representativeness of the training datasets naturally characterized by their distributions, experimental setups or preprocessing schemes. These complicate generalizing DL models across multi-site heterogeneous data sets while maintaining the confidentiality of the data. One of the possible solutions is to employ federated learning (FL), which enables the collaborative training of a DL model in a decentralized manner, demanding the involved sites to share only the characteristics of the models without transferring their sensitive medical data. The paper presents a DL-based magnetic resonance (MR) data translation in a FL way. We introduce a new aggregation strategy called FedBAdam that couples two state-of-the-art methods with complementary strengths by incorporating momentum in the aggregation scheme and skipping the batch normalization layers. The work comprehensively validates 10 FL-based strategies for an image-to-image multi-contrast MR translation, considering healthy and tumorous brain scans from five different institutions. Our study has revealed that the FedBAdam shows superior results in terms of mean squared error and structural similarity index over personalized methods, like the FedMRI, and standard FL-based aggregation techniques, such as the FedAvg or FedProx, considering multi-site multi-vendor heterogeneous environment. The FedBAdam has prevented the overfitting of the model and gradually reached the optimal model parameters, exhibiting no oscillations.
A vertical stacking approach to rapid generation cycling for indoor growth of tall annual crops - the case ofVicia faba
Authors: Pazos-Navarro Maria , Bennett Richard G , Munday Christine , Creasy Robert , Catt Samuel C , Lichtenzveig Judith , Ribalta Federico , Croser Janine
Published: February 2025

Accelerating breeding cycles through rapid generation turnover is a critical strategy to improve genetic gain in crops. This study presents a vertically stacked accelerated single-seed descent (aSSD) protocol for faba bean (Vicia fabaL.), aimed at reducing generation time while ensuring robust plant development and seed viability. Alongside photoperiod extension to truncate time to flowering, we present innovations including flurprimidol application to control plant height and enable vertically stacked growth, and optimisation of immature seed desiccation for precocious seed germination. Under controlled environment conditions, the protocol achieved 4.1 to 5.7 generations per year across phenologically diverse germplasm. Plant height was successfully reduced by up to 50% with flurprimidol without compromising flowering or seed yield. The methodology was validated within the University of Adelaide led Australian PBA faba bean breeding program (FBA), advancing 14 recombinant inbred line populations over three years. Beyond faba bean, this scalable, genotype-independent platform offers potential applications for other tall annual species in breeding and vertical farming systems, enabling year-round crop production and genetic improvement. Moreover, the protocol’s adaptability to closed-environment agriculture presents unique opportunities for plant-based life-support systems in extreme environments, including space missions. This integrated approach to speed breeding and vertical farming represents a significant advancement in agricultural innovation, with implications for food security and space exploration.
Ultrahigh Resolution Structure of the Heat-stable Form-IAq RuBisCO from the Thermophilic Purple Sulfur Bacterium Thermochromatium tepidum
Authors: Chen Jing-Hua , Chang Shenghai , Wang Weiwei , Madigan Michael T. , Yu Long-Jiang , Gao Haichun , Wang-Otomo Zheng-Yu , Zhang Xing
Published: February 2025

Ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) catalyzes the initial carbon fixation reaction in the Calvin-Benson-Bassham cycle in plants and most microbial autotrophs. Among the many forms of RuBisCOs, form-I, a protein complex containing 8 large and 8 small subunits, is the most common, representing over 90% of all known RuBisCOs. Although many form-I RuBisCO structures have been determined, no structure has been reported for a form-IAq RuBisCO. Here, and at ultrahigh (1.55 angstrom) resolution, we detail the structure of the heat-stable form-IAq RuBisCO from the thermophilic and anaerobic purple bacterium Thermochromatium (Tch.) tepidum. The overall structure of the Tch. tepidum form-IAq RuBisCO resembles both a form-IAc RuBisCO from a chemolithotrophic sulfur bacterium and a synthetic form-I RuBisCO reconstructed from ancestral sequences. However, despite significant structural and sequence similarities with other form-I RuBisCOs, the Tch. tepidum form-IAq RuBisCO shows significantly greater interactions between adjacent small subunits through their extended N-terminal domains that contain a characteristic six-residue insertion unique to form-IAq RuBisCOs. Structural differences of Tch. tepidum RuBisCO from its mesophilic relative Allochromatium vinosum suggests the mechanisms of its enhanced thermostability. In addition to small subunit interactions, key substitutions on the hydrophilic surface of the small subunits likely contribute to its thermostability as well. It has been proposed that form-I RuBisCOs first appeared in anaerobic thermophiles. Our structure of the Tch. tepidum RuBisCO represents the first such structure of a form-IAq enzyme, providing fresh clues for unraveling the evolutionary history of RuBisCO and new details for how this key enzyme remains active at elevated temperatures.
GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice
Authors: Huot Joshua R. , Jamnick Nicholas A. , Pin Fabrizio , Livingston Patrick D. , Callaway Chandler S. , Bonetto Andrea
Published: February 2025

Introduction

The survival rate for children and adolescents has increased to over 85%. However, there is limited understanding of the impact of pediatric cancers on muscle development and physiology. Given that brain tumors alone account for 26% of all pediatric cancers, this study aimed to investigate the skeletal muscle consequences of tumor growth in young mice.

Methods

C2C12 myotubes were co-cultured with GL261 murine glioblastoma cells to assess myotube size. GL261 cells were then injected subcutaneously into 4-week-old male C57BL/6J mice. Animals were euthanized 28 days post-GL261 implantation. Muscle function was testedin vivoandex vivo. Muscle protein synthesis was measured via the SUnSET method, and gene/protein expression levels were assessed via Western blotting and qPCR.

Results

In vitro, the C2C12 cultures exposed to GL261 exhibited myotube atrophy, consistent with a disrupted anabolic/catabolic balance.In vivo, carcass, heart, and fat mass were significantly reduced in the tumor-bearing mice. Skeletal muscle growth was impeded in the GL261 hosts, along with smaller muscle CSA. Bothin vivomuscle torque and theex vivoEDL muscle force were unchanged. At molecular level, the tumor hosts displayed reduced muscle protein synthesis and increased muscle protein ubiquitination, in disagreement with decreased muscle ubiquitin ligase mRNA expression.

Conclusions

Overall, we showed that GL261 tumors impact the growth of pediatric mice by stunting skeletal muscle development, decreasing muscle mass, reducing muscle fiber size, diminishing muscle protein synthesis, and altering protein catabolism signaling.