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Smouldering disease in paediatric-onset multiple sclerosis. 小儿发病多发性硬化症中的闷烧病。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-11 DOI: 10.1016/j.ebiom.2025.105921
Massimo Filippi, Monica Margoni, Brenda Banwell, Tanuja Chitnis, Russell Dale, Giulia Fadda, Yael Hacohen, Lauren B Krupp, Paolo Preziosa, E Ann Yeh, Emmanuelle Waubant, Maria A Rocca
{"title":"Smouldering disease in paediatric-onset multiple sclerosis.","authors":"Massimo Filippi, Monica Margoni, Brenda Banwell, Tanuja Chitnis, Russell Dale, Giulia Fadda, Yael Hacohen, Lauren B Krupp, Paolo Preziosa, E Ann Yeh, Emmanuelle Waubant, Maria A Rocca","doi":"10.1016/j.ebiom.2025.105921","DOIUrl":"10.1016/j.ebiom.2025.105921","url":null,"abstract":"<p><p>Smouldering disease in multiple sclerosis (MS) refers to chronic central nervous system processes that occur beyond acute inflammation, driving long-term disability. Although current therapies effectively reduce relapse rates and MRI lesions, many individuals experience progression independent of relapse activity. While clinical progression is uncommon during childhood or adolescence, growing evidence suggests that subclinical progressive disease biology is already active even in this young age group, warranting early intervention to preserve function. Conventional MRI, while critical for diagnosis, lacks sensitivity for subtle damage. Advanced MRI techniques, including detection of chronic active lesions, global and focal brain damage, hold promise for early identification. Fluid biomarkers, such as neurofilament light chain and glial fibrillary acidic protein, provide non-invasive measures of neuroaxonal injury and ongoing chronic inflammation. This review summarises the role of MRI and fluid biomarkers in detecting smouldering disease in paediatric-onset MS and their application in supporting therapeutic decision-making.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105921"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease. 一种新型线粒体复合物I抑制剂在阿尔茨海默病的体内和体外模型中的治疗评估。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-15 DOI: 10.1016/j.ebiom.2025.105924
Sergey Trushin, Thi Kim Oanh Nguyen, Andrea Stojakovic, Mark Ostroot, J Trey Deason, Su-Youne Chang, Liang Zhang, Slobodan I Macura, Toshihiko Nambara, Wenyan Lu, Takahisa Kanekiyo, Eugenia Trushina
{"title":"Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease.","authors":"Sergey Trushin, Thi Kim Oanh Nguyen, Andrea Stojakovic, Mark Ostroot, J Trey Deason, Su-Youne Chang, Liang Zhang, Slobodan I Macura, Toshihiko Nambara, Wenyan Lu, Takahisa Kanekiyo, Eugenia Trushina","doi":"10.1016/j.ebiom.2025.105924","DOIUrl":"10.1016/j.ebiom.2025.105924","url":null,"abstract":"<p><strong>Background: </strong>Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed.</p><p><strong>Methods: </strong>We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signalling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design and structure‒activity relationship studies yielded mtCI inhibitors profiled in a drug discovery funnel designed to address safety, selectivity, and efficacy.</p><p><strong>Findings: </strong>The lead compound C458 is highly protective against Aβ toxicity, has favourable pharmacokinetics, and minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted using functional tests, metabolic assessment, in vivo<sup>31</sup>P-NMR spectroscopy, blood cytokine panels, ex vivo electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signalling, and cellular energetics. Efficacy against Aβ and p-Tau was confirmed in human organoids.</p><p><strong>Interpretation: </strong>These studies provide further evidence that the restoration of mitochondrial function in response to mild energetic stress represents a promising disease-modifying strategy for AD.</p><p><strong>Funding: </strong>This research was supported by grants from NIH AG 5549-06, NS1 07265, AG 062135, UG3/UH3 NS 113776, and ADDF 291204 (all to ET); U19 AG069701 (to TK); the Alzheimer's Association Research Fellowship grant 23AARF-1027342 (to TKON).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105924"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
DNA demethylation mediated endogenous retroviruses transcription promotes aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway. DNA去甲基化介导的内源性逆转录病毒转录通过rig - 1途径促进系统性红斑狼疮中T细胞的异常分化。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-23 DOI: 10.1016/j.ebiom.2025.105934
Xiaoli Min, Yaqin Yu, Zhi Hu, Lianlian Ouyang, Yueqi Qiu, Hongjun Zhao, Jiali Wu, Chun Zou, Meiling Zheng, Shuang Yang, Sujie Jia, Di Yu, Qianjin Lu, Ming Zhao
{"title":"DNA demethylation mediated endogenous retroviruses transcription promotes aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway.","authors":"Xiaoli Min, Yaqin Yu, Zhi Hu, Lianlian Ouyang, Yueqi Qiu, Hongjun Zhao, Jiali Wu, Chun Zou, Meiling Zheng, Shuang Yang, Sujie Jia, Di Yu, Qianjin Lu, Ming Zhao","doi":"10.1016/j.ebiom.2025.105934","DOIUrl":"10.1016/j.ebiom.2025.105934","url":null,"abstract":"<p><strong>Background: </strong>Systemic lupus erythematosus (SLE) displays quantitative and/or qualitative deficiencies of regulatory T cells (Treg) and expansion and hyperfunction of pathogenic T cells. However, the underlying mechanism of dysregulated T lymphocyte differentiation in SLE remains unclear.</p><p><strong>Methods: </strong>Transcriptome sequencing and functional assays were performed to elucidate the mechanisms and function of human endogenous retroviruses (HERVs) on T cell differentiation in SLE. The effect of retinoic acid-inducible gene I (RIG-I) deficiency on lupus pathogenesis were assessed in lupus-like mouse models.</p><p><strong>Findings: </strong>We found that many transcripts derived from HERVs were highly expressed in CD4<sup>+</sup> T cells from patients with SLE due to DNA hypomethylation, some of which were characterized by double strand RNAs (dsRNAs). Excessive dsRNAs promoted Th1 cell differentiation and inhibited Treg cell differentiation via the activation of the dsRNA sensor RIG-I pathway, accompanied by a high level of type I interferons (IFN-I) and interferon-stimulated gene expression. In contrast, T cell-specific ablation of RIG-I alleviated disease progression in lupus-like mouse models by reducing the proportion of pathogenic T cells, restoring the percentage of Treg cells, and diminishing cytokine and autoantibody release. Importantly, we demonstrated that the dsRNA-induced RIG-I/IRF3 pathway regulated Th1 cell differentiation in a IFN-I/STAT1 signalling-dependent manner and inhibited Treg cell differentiation via SMAD3 signalling.</p><p><strong>Interpretation: </strong>Our findings reveal the roles of HERV-derived dsRNA/RIG-I pathway in regulating the aberrant differentiation of T cells in patients with SLE and may facilitate the development of potential therapeutic targets for SLE.</p><p><strong>Funding: </strong>A full list of funding sources can be found in the Funding section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105934"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impact of systemic SARS-CoV-2 vaccination on mucosal IgA responses to subsequent breakthrough infection. 系统性SARS-CoV-2疫苗接种对随后突破性感染的黏膜IgA反应的影响
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-16 DOI: 10.1016/j.ebiom.2025.105912
Ulrika Marking, Oscar Bladh, Katherina Aguilera, Tamas Pongracz, Sebastian Havervall, Nina Greilert-Norin, Kim Blom, Jonas Klingström, Yunzhang Wang, Mikael Åberg, Charlotte Thålin
{"title":"Impact of systemic SARS-CoV-2 vaccination on mucosal IgA responses to subsequent breakthrough infection.","authors":"Ulrika Marking, Oscar Bladh, Katherina Aguilera, Tamas Pongracz, Sebastian Havervall, Nina Greilert-Norin, Kim Blom, Jonas Klingström, Yunzhang Wang, Mikael Åberg, Charlotte Thålin","doi":"10.1016/j.ebiom.2025.105912","DOIUrl":"10.1016/j.ebiom.2025.105912","url":null,"abstract":"<p><strong>Background: </strong>Mucosal IgA responses are central to protection against SARS-CoV-2 infection and viral transmission. While systemic immunity following SARS-CoV-2 infection and vaccination is thoroughly investigated, we have limited understanding of factors affecting the generation and boosting of mucosal IgA.</p><p><strong>Methods: </strong>In this cohort study, we investigated factors influencing mucosal SARS-CoV-2 IgA responses among 879 healthcare workers enrolled in the longitudinal COMMUNITY study. Blood samples and clinical data were collected from all participants every four months since April 2020. SARS-CoV-2 immune histories are well characterized through national vaccine and infection registries along with regular monitoring of seroconversion of spike and/or nucleocapsid antigen. Regression models were developed to assess the influence of vaccinations and prior infections on the magnitude of SARS-CoV-2 spike-specific IgA in nasal secretions collected from the cohort in October 2022.</p><p><strong>Findings: </strong>Mucosal SARS-CoV-2 spike-specific IgA was detected in 81% of participants, with a positive association with number of prior infections, indicating a booster effect by reinfection. The increased odds ratio of detectable mucosal IgA remained for at least 22 months post infection. There was a strong association between repeated systemic vaccinations and a lower magnitude of mucosal IgA responses. Moreover, the temporal sequence of infection and vaccination influenced mucosal IgA responses, with higher levels among participants with infection prior to systemic vaccination as compared to those with breakthrough infection as the first viral encounter.</p><p><strong>Interpretation: </strong>The observation that repeated mucosal exposures elicit enhanced and long-lasting mucosal IgA responses strengthens the rationale for developing effective mucosal vaccines. While systemic vaccination remains essential for preventing severe disease, our findings suggest that it may influence subsequent generation of mucosal IgA trough a reduction of viral load and inflammation in the mucosa. This is highly relevant for both understanding the development of population immunity and for optimizing the timing of a sequential systemic and mucosal vaccination approach.</p><p><strong>Funding: </strong>This study was supported by grants from Region Stockholm, and SciLifeLab and the Knut and Alice Wallenberg Foundation, SSMF and European Research Council. We thank the Public Health Agency of Sweden for support.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105912"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Wearable devices in pregnancy health care. 孕期保健中的可穿戴设备。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 DOI: 10.1016/j.ebiom.2025.105974
eBioMedicine
{"title":"Wearable devices in pregnancy health care.","authors":"eBioMedicine","doi":"10.1016/j.ebiom.2025.105974","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105974","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105974"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Iron-sepsis associations in population health revealed by epidemiology. 流行病学揭示铁脓毒症与人群健康的关系。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-15 DOI: 10.1016/j.ebiom.2025.105927
Randi Marie Mohus, Lise T Gustad, Jan Kristian Damås, Hal Drakesmith
{"title":"Iron-sepsis associations in population health revealed by epidemiology.","authors":"Randi Marie Mohus, Lise T Gustad, Jan Kristian Damås, Hal Drakesmith","doi":"10.1016/j.ebiom.2025.105927","DOIUrl":"10.1016/j.ebiom.2025.105927","url":null,"abstract":"<p><p>Sepsis is a leading cause of death and disability worldwide, so identifying preventable risk factors is important. Iron is essential for immune function and microbial growth, and iron status varies substantially between individuals, across demographics, and is therapeutically modifiable. Here, we review the current understanding of iron status and associated risks of bloodstream infection, sepsis and severe COVID-19 highlighting relevant population-based studies and Mendelian randomisation studies. Both low and high iron status are associated with increased risk of sepsis. Low iron status is associated with sepsis, bloodstream infections and pneumonia. High iron status and mutations affecting hepcidin regulation are linked to increased risk of bloodstream infections, sepsis and COVID-19. Both iron status pathologies and sepsis are global health issues, and the epidemiological studies described indicate they may be linked. More population-scale investigations on iron status, infection and immunity, especially in areas of high iron deficiency and infectious burden are warranted.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105927"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multi-region ultrasound-based deep learning for post-neoadjuvant therapy axillary decision support in breast cancer. 基于多区域超声的深度学习在乳腺癌新辅助治疗后腋窝决策支持中的应用。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-10 DOI: 10.1016/j.ebiom.2025.105916
Ziyin Li, Ning Mao
{"title":"Multi-region ultrasound-based deep learning for post-neoadjuvant therapy axillary decision support in breast cancer.","authors":"Ziyin Li, Ning Mao","doi":"10.1016/j.ebiom.2025.105916","DOIUrl":"10.1016/j.ebiom.2025.105916","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105916"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PNPLA3 polymorphism worsens chemotherapy associated liver injury and affects overall survival in colorectal cancer patients with liver metastasis undergoing hepatic resection. PNPLA3多态性加重化疗相关肝损伤,影响行肝切除术的结直肠癌肝转移患者的总生存。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-16 DOI: 10.1016/j.ebiom.2025.105928
Benedikt Rumpf, Jonas Santol, Anna E Kern, Markus Ammann, Joel Probst, Ruth Baumgartner, Anna S Jankoschek, Vanja Podrascanin, Florian Lehner, Felix X Huber, David Pereyra, Gregor Ortmayr, Yawen Dong, Sophia Petschnak, Brigitte Wolf, Alice Assinger, Hubert Hackl, Stefan Gilg, Thomas Gruenberger, Patrick Starlinger
{"title":"PNPLA3 polymorphism worsens chemotherapy associated liver injury and affects overall survival in colorectal cancer patients with liver metastasis undergoing hepatic resection.","authors":"Benedikt Rumpf, Jonas Santol, Anna E Kern, Markus Ammann, Joel Probst, Ruth Baumgartner, Anna S Jankoschek, Vanja Podrascanin, Florian Lehner, Felix X Huber, David Pereyra, Gregor Ortmayr, Yawen Dong, Sophia Petschnak, Brigitte Wolf, Alice Assinger, Hubert Hackl, Stefan Gilg, Thomas Gruenberger, Patrick Starlinger","doi":"10.1016/j.ebiom.2025.105928","DOIUrl":"10.1016/j.ebiom.2025.105928","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant chemotherapy (NAC) has been controversial for patients with colorecal cancer liver metastasis (CRLM) with resectable disease. Chemotherapy associated liver injury (CALI) may explain the lack of overall survival (OS) benefit in some studies. It remains unclear why CALI severity varies between patients despite receiving the same duration and type of NAC. Single nucleotide polymorphisms (SNPs) have been associated with liver disease and could account for these interindividual differences. Within this study we used the APRI + ALBI score, a non-invasive liver function marker that increases in response to CALI development during NAC, to assess whether preoperative liver function affects OS in CRLM patients undergoing hepatectomy and explore the impact of SNPs on CALI development.</p><p><strong>Methods: </strong>551 patients with CRLM undergoing liver surgery after NAC were included. In 149 patients, DNA from histological specimens was genotyped and the presence of SNPs associated with liver disease was assessed.</p><p><strong>Findings: </strong>Patients with APRI + ALBI scores (≥-2.46), associated with the development of CALI, showed decreased OS after hepatectomy (median OS APRI + ALBI < -2.46 = 46.1 months; median OS APRI + ALBI ≥ -2.46 = 34.3, p = 0.027). The mutated rs738409 variant on the patatin-like phospholipase domain-containing protein 3 (PNPLA3) displayed a close association with chemotherapy-associated steatohepatitis (p = 0.007) as well as intrahepatic fat (p = 0.004). Additionally, all PNPLA3 homozygotes shifted into the high-risk APRI + ALBI group during NAC.</p><p><strong>Interpretation: </strong>CALI and its effects on liver function not only impact immediate postoperative outcomes but also significantly affect OS in CRLM patients undergoing liver resection. PNPLA3 polymorphism was associated with CALI development. Considering that PNPLA3 polymorphisms are significantly higher in Asian populations, these results could partly explain the heterogeneity in reported effects of NAC in CRLM patients and might improve patient selection.</p><p><strong>Funding: </strong>None of the authors received funding related to the writing of this manuscript.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105928"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prospective associations of obesity heterogeneity, serum proteins, and carotid atherosclerosis risk. 肥胖异质性、血清蛋白和颈动脉粥样硬化风险的前瞻性关联。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-20 DOI: 10.1016/j.ebiom.2025.105935
Haili Zhong, Jieteng Chen, Shize Jia, Hanzu Chen, Yue Xi, Yan Yan, Zilong Lu, Congmei Xiao, Fengzhe Xu, Jun Tang, Ju-Sheng Zheng, Yu-Ming Chen
{"title":"Prospective associations of obesity heterogeneity, serum proteins, and carotid atherosclerosis risk.","authors":"Haili Zhong, Jieteng Chen, Shize Jia, Hanzu Chen, Yue Xi, Yan Yan, Zilong Lu, Congmei Xiao, Fengzhe Xu, Jun Tang, Ju-Sheng Zheng, Yu-Ming Chen","doi":"10.1016/j.ebiom.2025.105935","DOIUrl":"10.1016/j.ebiom.2025.105935","url":null,"abstract":"<p><strong>Background: </strong>Obese individuals exhibit considerable heterogeneity in developing cardiovascular diseases, yet the underlying molecular mechanisms remain unclear. We aimed to investigate the prospective associations between obesity phenotypes, serum proteomics, and carotid atherosclerosis (CAS) incidence.</p><p><strong>Methods: </strong>This cohort study included 3162 participants from the Guangzhou Nutrition and Health Study, with 413 proteins profiled from 6803 serum samples collected at three time-points. Obesity phenotypes included metabolically healthy non-obesity (MHNO) and metabolically healthy/unhealthy obesity (MHO/MUO).</p><p><strong>Findings: </strong>We identified 11 proteins influenced by MUO (vs. MHO) over time, with their combined score positively associated with incident CAS (HR: 1.16; 95% CI: 1.01-1.34). Additionally, 8 proteins were prospectively associated with MHO-to-MUO transition, which increased the performance of traditional risk factors in predicting this transition (P < 0.001). Among the 8 proteins, bidirectional mediation effects were observed between pigment epithelium-derived factor (PEDF) (36.8%; P = 0.025) and the MHO-to-MUO transition (20.5%; P = 0.010) on CAS incidence. The PEDF genetic risk score was positively associated with MHO-to-MUO transition (OR: 1.20; 95% CI: 1.00-1.43). Our main findings were validated in both the internal and external validation cohorts.</p><p><strong>Interpretation: </strong>This population-scale proteomics study broadens our understanding of the mechanisms underlying obesity heterogeneity and CAS, providing potential targets for the prevention of CAS.</p><p><strong>Funding: </strong>This study was supported by the National Natural Science Foundation of China, the Key Research and Development Program of Guangzhou, \"Pioneer\" and \"Leading goose\" R&D Program of Zhejiang, and the 5010 Program for Clinical Researches of the Sun Yat-sen University.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105935"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A mouse model of HIV in pregnancy: the EcoHIV+ pregnancy model. 小鼠妊娠期HIV模型:EcoHIV+妊娠模型。
IF 10.8 1区 医学
EBioMedicine Pub Date : 2025-10-01 Epub Date: 2025-09-23 DOI: 10.1016/j.ebiom.2025.105943
Michelle Ranjbar, Ingrid Hsieh, Maud Collomb, Lena Serghides
{"title":"A mouse model of HIV in pregnancy: the EcoHIV+ pregnancy model.","authors":"Michelle Ranjbar, Ingrid Hsieh, Maud Collomb, Lena Serghides","doi":"10.1016/j.ebiom.2025.105943","DOIUrl":"10.1016/j.ebiom.2025.105943","url":null,"abstract":"<p><strong>Background: </strong>HIV infection during pregnancy poses risks to maternal and foetal health. Identifying underlying mechanisms can be challenging in humans. While humanised mouse models exist, they are unsuitable for pregnancy research, highlighting the need for alternative models. Here we introduce a mouse pregnancy model using infection with EcoHIV, a chimeric ecotropic HIV virus.</p><p><strong>Methods: </strong>Female C57BL/6J mice were infected with 2.5 × 10<sup>6</sup> pg/mL EcoHIV, or mock infected, either 7 days prior to mating, or on gestational day (GD) 11.5. Dam weight gain was monitored. Pregnant dams were euthanised on GD14.5 or GD18.5. Foetal and placenta weights, foetal viability, litter size and resorptions were recorded. Placenta efficiency (foetal to placental weight ratio) was calculated. Infection was assessed using HIV Gag expression quantified by qPCR in RNA isolated from maternal blood, spleen, and foetal body.</p><p><strong>Findings: </strong>EcoHIV infection was detectable in 90% of dams infected prior to pregnancy and 100% of dams infected during pregnancy. Maternal weight gain was lower in EcoHIV infected mice, with the greatest reduction seen in those infected during pregnancy. EcoHIV infection was associated with significantly lower foetal weight, higher placenta weight, and lower placenta efficiency compared to controls at GD18.5. Perinatal EcoHIV transmission occurred in a portion of foetuses, with litter average transmission rates ranging from 3.1% with infection during pregnancy to 17.9% with infection prior to pregnancy.</p><p><strong>Interpretation: </strong>The EcoHIV pregnancy model mimics clinical aspects and can be a valuable tool to understand HIV infection in pregnancy and its consequences on maternal and foetal health.</p><p><strong>Funding: </strong>This project has been funded by the Canadian Institutes of Health Research (CIHR) (award # PJT-180630, PJH-192202, HAL-157984). MR received salary support from NSERC/CIHR Canada Graduate Scholarship, Institute of Medical Science Fellowship Award, and Emerging & Pandemic Infections Consortium (EPIC) Doctoral Award. LS holds a Tier 1 Canada Research Chair in Maternal-Child Health and HIV.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105943"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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