Research square最新文献

{"title":"APOE ε4 Carriage is Associated with Hippocampus-Olfactory Tract Functional Connectivity.","authors":"Toshikazu Ikuta, Taylor Bither","doi":"10.21203/rs.3.rs-6753781/v1","DOIUrl":"10.21203/rs.3.rs-6753781/v1","url":null,"abstract":"<p><p>Olfactory dysfunction often emerges before cognitive symptoms and may signal early vulnerability to neurodegenerative processes. This study examined whether genetic risk, specifically the presence of the epsilon 4 allele in apolipoprotein E, is associated with altered functional connectivity between the hippocampus and olfactory-related brain regions. Resting-state functional imaging data from 126 participants (mean age = 71.8 years, SD = 6.9; 67 females) across a range of clinical stages were analyzed. Functional connectivity was computed between the hippocampus and four olfactory-related regions: anterior piriform cortex, posterior piriform cortex, olfactory bulb, and olfactory tract. Multiple regression models assessed whether genetic risk, age, sex, and clinical diagnosis predicted connectivity strength. Genetic risk was significantly associated with increased connectivity between the hippocampus and both the olfactory bulb and olfactory tract, while no significant effects were observed in the piriform cortex regions. Clinical diagnosis was not a significant predictor of connectivity in any region. These results suggest that genetic risk is linked to early functional reorganization in specific olfactory-hippocampal pathways, particularly the olfactory tract, independent of clinical disease stage. The olfactory-hippocampal network may serve as a sensitive target for detecting early brain changes associated with neurodegenerative risk.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stationary Population Dynamics Reveal a Structural Typology of Global Aging: A Binary Model Approach Across 195 Countries.","authors":"James R Carey, Arni S R Srinivasa Rao","doi":"10.21203/rs.3.rs-6675831/v1","DOIUrl":"10.21203/rs.3.rs-6675831/v1","url":null,"abstract":"<p><p>This study presents a unified structural typology of global population aging using a novel Binary Population Pair framework. Grounded in the Stationary Population Identity, the approach pairs each observed national population with its stationary counterpart to quantify deviations across three core dimensions: age structure, population momentum, and longevity gains. Leveraging new comparative metrics, including the Lifespan Parity Ratio, Stationarity Gap, Terminal Dependency Ratio, Survival Offset, and Net Structural Aging, the study classifies 195 countries into a five-stage demographic succession model, from Youth Dominance to Age Dominance, with a transitional Youth-Age Crossover at the midpoint. Results reveal a broad convergence toward structural stationarity by 2100, as countries transition from youthful to increasingly gerontic profiles. A post-successional condition, the \"Demographic Vortex,\" is introduced to describe populations caught in a feedback loop of chronic low fertility and persistent structural aging. By integrating life lived and life left distributions, this framework captures aging as a directional, cumulative process. More fundamentally, it reconceptualizes aging not as a fixed trajectory toward senescence, but as a dynamic repositioning within an expanding and structurally shifting lifespan-transforming our understanding of what it means to age in the modern era.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative genomic analysis of clinically relevant human skin-associated fungi.","authors":"Beatrice Dyring-Andersen, Sofie Agerbæk, Knud Nielsen, Julie Sølberg, Ying Zhang, Zahra Al-Badran, Marc Stegger, Sonja Kabatnik, Matthias Mann, Rachael Clark, Ditte Saunte, Alberto Santos, Marianne Løvendorf","doi":"10.21203/rs.3.rs-6700810/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6700810/v1","url":null,"abstract":"<p><p>Fungal skin infections represent a significant global health burden, affecting approximately one billion people annually. Despite their prevalence and major global health impact, the molecular mechanisms underlying pathogenicity remain largely uncharacterized. Here we present high quality genomic datasets for 51 fungal strains, representing highly prevalent and clinically relevant species associated with human skin infections. Comparative genomics reveal substantial variation in genome size and gene contents, indicating genome compaction occurred as the fungi transitioned from free-living to host-associated lifestyles. We report two non-hybrid strains of <i>Trichosporon ovoides</i> , the causative agent of white piedra. Our analysis reveals substantial differences in metabolic adaptations across skin-associated fungi, corresponding to distinct body-site and nutrient niches. Significant differences were also present in the distribution of virulence factors and adhesins, which are imperative for biofilm formation and antifungal resistance. We discuss metabolic adaptation and virulence mechanisms revealed by our data in the context of clinical presentations, highlighting shared and lineage-specific adaptations. Together, these insights advance our knowledge of skin-associated fungi and their infection mechanisms while providing valuable resources and a foundation for future analyses to improve diagnostics and therapeutics for diverse diseases.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential contribution of working memory to auditory rhythm discrimination in stuttering and nonstuttering adults.","authors":"Emily Garnett, Toni Smith, Bailey Rann, Nicholas Mularoni, Soo-Eun Chang, J Devin McAuley","doi":"10.21203/rs.3.rs-6686913/v1","DOIUrl":"10.21203/rs.3.rs-6686913/v1","url":null,"abstract":"<p><p>Stuttering is a neurodevelopmental condition characterized by involuntary disruptions in the rhythmic flow of speech. Notably, stuttering is associated with aberrant structure and function of the basal ganglia thalamocortical network. Separately, the BGTC network has been implicated in non-speech beat and rhythm perception. Supporting a link between the two sets of findings, children who stutter exhibit poorer auditory rhythm discrimination compared to non-stutterers, especially for complex rhythms without a consistently marked beat. For adults who stutter (AWS), data showing a link between stuttering and poorer auditory rhythm discrimination has been mixed. One possible reason may be that AWS have developed strategies for rhythm discrimination that leverage an alternative non-BGTC network dependent timing mechanism. One candidate from the timing literature is the use of an interval-based mechanism that involves the cerebellum. From this perspective, rhythm discrimination judgments for AWS would involve interval-by-interval duration comparisons, which should be expected to place a greater burden on working memory compared to the more automatic beat-based timing processes implemented by the BGTC network. To investigate this hypothesis, we combined data from three studies where AWS and age-matched controls performed the same rhythm discrimination and working memory tasks. Across studies, AWS, as hypothesized, showed a significantly stronger positive correlation between working memory and rhythm discrimination than controls where there were no (or very weak) correlations. Moreover, separate group comparison of rhythm discrimination performance for AWS with high and low working memory scores reveals no difference between controls and AWS with high working memory scores, but much poorer performance by AWS with low working memory scores compared to controls. These results support the view that AWS may mask difficulties in rhythm perception and an underlying impairment in beat-based timing by leveraging a distinct working memory dependent interval timing mechanism to discriminate rhythms.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mediating effect analysis of professional identity between emotional intelligence and work readiness of newly graduated nursing students.","authors":"Liping Chen, Liping Wu, Heping Liao, Qin Lin, Yetao Luo","doi":"10.21203/rs.3.rs-6353643/v1","DOIUrl":"10.21203/rs.3.rs-6353643/v1","url":null,"abstract":"<p><strong>Aim: </strong>To collect relevant data through a cross-sectional survey study and analyze the mediating effect of professional identity in the relationship between emotional intelligence and work readiness.</p><p><strong>Background: </strong>Poor work readiness makes new nursing grads leave the profession. Emotional intelligence and professional identity impact it, so it's important to clarify the relationship between them to enhance the work readiness of nursing students.</p><p><strong>Methods: </strong>Cluster sampling was performed on newly graduated nursing students from Chongqing, China. Data were collected using the Emotional Intelligence Scale, Nurses' Work Readiness Scale, and Nurses' Professional Identity Scale. The SAS software (version 9.4) was used for data processing and analysis. Independent sample t-tests and one-way ANOVA were performed to determine influencing factors. Amos (version 29.0) was used to model mediation effects. The maximum likelihood estimation method was used to estimate the model parameters, with adjustments made based on the correction index.</p><p><strong>Results: </strong>In total, 453 valid questionnaires were obtained. The total scores for professional identity, emotional intelligence, and work readiness of the participants were 66.79 ± 11.35, 90.09 ± 14.09, and 271.10 ± 44.26, respectively. professional identity correlated with the other two, mediating their relation, accounting for 69.99% of total effects.</p><p><strong>Conclusions: </strong>Professional identity is an important mediator between emotional intelligence and work readiness. School teachers and healthcare professionals should prioritize developing nursing students' emotional intelligence and professional identity during education. Enhancing professional identity, fostering a sense of professional honor, and improving work readiness can reduce turnover rates and stabilize the nursing workforce.</p><p><strong>Implications for nursing and/or health policy: </strong>Both professional identity and emotional intelligence are positively correlated with work readiness, which deserve more attention. Nursing educators and mangers should cultivate professional identity early.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Signatures as Biomarkers of Atherosclerosis Burden.","authors":"Lanyue Zhang, Murad Omarov, LingLing Xu, Barnali Das, Hong Luo, Stefanie M Hauck, Agnese Petrera, Zhi Yu, Sascha N Goonewardena, Eleftheria Zeggini, Annette Peters, Martin Dichgans, Venkatesh L Murthy, Barbara Thorand, Marios K Georgakis","doi":"10.21203/rs.3.rs-6837440/v1","DOIUrl":"10.21203/rs.3.rs-6837440/v1","url":null,"abstract":"<p><p>Atherosclerosis progresses silently over decades before manifesting clinically as myocardial infarction or stroke. Currently, no circulating biomarker reliably quantifies the burden of atherosclerosis beyond imaging techniques. Here, we sought to define plasma proteomic signatures that reflect the systemic burden of atherosclerosis. Using CatBoost machine learning applied to plasma proteomes (Olink Explore 3072; 2,920 proteins) from 44,788 UK Biobank participants, we derived four proteomic signatures which robustly discriminated individuals with known atherosclerotic disease from propensity score-matched controls (ROC-AUC up to 0.92, 95% CI: 0.90-0.94 in the test set). Each signature was based on distinct protein sets: the whole proteome (WholeProteome; n = 2920), proteins associated with genetic predisposition to atherosclerosis (Genetic; n = 402), those implicated in atherogenesis (Mechanistic; n = 680), and proteins enriched in arterial tissue (Arterial; n = 248). Among 41,200 individuals without atherosclerosis at baseline, all four signatures were strongly associated with future major adverse cardiovascular events over a median follow-up of 13.7 years (HR per SD increase in WholeProteome signature: 1.70, 95% CI: 1.64-1.77), providing significant improvements in risk discrimination (ΔC-index: +0.036; p <0.0001) and reclassification (Net Reclassification Index: 0.085-0.135 at a 10% risk threshold) beyond SCORE2. Signature levels increased with the number of clinically affected vascular beds, correlated with carotid ultrasound-measured plaque burden, and predicted future myocardial infarction and stroke in the external KORA S4 (n=1,361) and KORA-Age1 (n=796) cohorts with a median follow-up period of 15.1 and 6.8 years, respectively. Longitudinal analyses across three serial assessments showed that all signatures followed distinct trajectories, with significantly steeper annual increases among individuals with a higher burden of vascular risk factors. These findings demonstrate that proteomic signatures effectively capture atherosclerotic burden and improve cardiovascular risk prediction in asymptomatic individuals. Plasma proteomics may serve as a scalable and accessible alternative to imaging for identifying subclinical atherosclerosis, thereby supporting prevention strategies for cardiovascular disease.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment with mitochondrial targeting antibiotics improves survival outcomes after Flock House virus infection in young and aged Drosophila melanogaster.","authors":"Dean Bunnell, Madelyn Buhl, Justin McGee, Grace Milas, Stanislava Chtarbanova","doi":"10.21203/rs.3.rs-6816306/v1","DOIUrl":"10.21203/rs.3.rs-6816306/v1","url":null,"abstract":"<p><p>Aged organisms are more susceptible to infectious diseases, including infections with RNA viruses. Mitochondrial dysfunction is one of many hallmarks of aging that could affect this increased susceptibility, as the relationship between immunity and metabolism is crucial to manage infections. Using <i>Drosophila melanogaster</i>- Flock House virus (FHV) host-virus interactions model system, previous work has identified differences in young and aged flies' ability to modulate oxygen consumption rates (OCR). Here, we hypothesized that interventions that reduce OCR could improve survival of FHV, as observed in young flies. Tetracycline (TTC) and rifampicin (RIF) antibiotics disrupt mitochondrial translation and transcription respectively because of mitochondria's bacterial ancestry. The mitochondrial unfolded protein response (UPR^mt) is activated by mitochondrial stressors, including reactive oxygen species, defects in oxidative phosphorylation, and mitonuclear protein imbalance. UPR^mt activation initiates retrograde signaling to the nucleus, prompting transcription, translation, and import of nuclear proteins to resolve stress. We showed TTC or RIF treatment extended survival in young and aged flies after FHV infection, independently of virus load modulation. Furthermore, we demonstrate that bacterial loads are not significantly different between FHV-infected flies and controls, and that the protective effect of TTC likely occurs independently of its antimicrobial properties. We observed increased expression of genes involved in the UPR^mt, glycolysis, and oxidative stress response with TTC treatment. Our results suggest perturbing mitonuclear protein balance with TTC or RIF could activate the UPR^mt and improve outcomes of virus infection.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visualizing cortical laminar architecture in the living human brain using next-generation ultra-high-gradient diffusion MRI.","authors":"Susie Huang, Hansol Lee, Yixin Ma, Kwok-Shing Chan, Eva Krijnen, Laleh Eskandarian, Aneri Bhatt, Julianna Gerold, Mirsad Mahmutovic, Oula Puonti, Xiangrui Zeng, Lucas Jacob Deden Binder, Bruce Fischl, Boris Keil, Gabriel Ramos-Llordén, Eric Klawiter, Hong-Hsi Lee","doi":"10.21203/rs.3.rs-6724971/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6724971/v1","url":null,"abstract":"<p><p>Characterizing cortical laminar microstructure is essential for understanding human brain function. Leveraging the next-generation Connectome MRI scanner (maximum gradient strength = 500mT/m, slew rate = 600T/m/s), we characterized <i>in vivo</i> cortical laminar cytoarchitecture and myeloarchitecture through cortical depth-dependent analyses of soma and neurite density imaging (SANDI) metrics derived from diffusion MRI, enhanced by a super-resolution technique. SANDI revealed distinct laminar profiles: intra-soma signal fraction <i>f</i> _<i>is</i> peaked at ~ 55% cortical depth, while intra-neurite signal fraction <i>f</i> _<i>in</i> increased toward deeper layers, consistent with histological patterns. The visual cortex exhibited higher intra-soma signal fraction <i>f</i> _<i>is</i> than the motor cortex, particularly in deeper layers. Moreover, intra-soma signal fraction <i>f</i> _<i>is</i> correlated positively with cortical curvature in superficial layers and negatively in deeper layers, indicating layer-specific relationships between microstructure and cortical geometry. These findings demonstrate the feasibility of noninvasively mapping cortical laminar architecture, offering a potential surrogate for histology and enabling future studies of normative and pathological brain organization using commercially available high-performance gradient MRI systems.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated histopathology of the human pancreas throughout stages of type 1 diabetes progression.","authors":"Dirk Homann, Verena van der Heide, Sara McArdle, Michael Nelson, Karen Cerosaletti, Sacha Gnjatic, Zbigniew Mikulski, Amanda Posgai, Irina Kusmartseva, Mark Atkinson","doi":"10.21203/rs.3.rs-6673858/v1","DOIUrl":"10.21203/rs.3.rs-6673858/v1","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation and progression yet an integrated perspective onto <i>in situ</i> pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases. Deconvolution of architectural features, endocrine cell composition, immune cell burden, and spatial relations of ~ 25,000 islets effectively contextualizes established and novel pancreatic hallmarks in health and T1D disease. Our results reveal a spatially homogenous and islet size-contingent architectural organization of the endocrine pancreas, a notable coordination of organ-wide pathogenic processes, and multiple histopathological correlates that foreshadow distinctive T1D histopathology already at the preclinical stage. Altogether, we propose a revised natural history of T1D with implications for further histopathological investigations and considerations of pathogenetic modalities.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pluripotent stem cell-derived extracellular vesicles for systemic immune modulation in diabetes therapy.","authors":"Song Li, Jana Zarubova, Mohammad Hasani-Sadrabadi, Yutong Wu, Graciel Diamante, Jenny Cheng, Xiao Han, Fatemeh Majedi, Li Yang, Olivia Wang, In Sook Ahn, Jianyi Zhang, Xiaojun Lian, Zhen Gu, Manish Butte, Reza Ardehali, Peter Butler, Tony Hu, Louis Bouchard, Xia Yang","doi":"10.21203/rs.3.rs-6415252/v1","DOIUrl":"10.21203/rs.3.rs-6415252/v1","url":null,"abstract":"<p><p>Embryos can achieve immune tolerance, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), secrete extracellular vesicles (EVs) that markedly outperform mesenchymal stem cell (MSC)-derived EVs in suppressing pro-inflammatory cytokine secretion, inhibiting activated T-cell proliferation, and inducing regulatory T-cell (Treg) formation through CDK8 downregulation. Nuclear magnetic resonance (NMR) analysis reveals distinct molecular fingerprints of PSC EVs compared to those of MSC EVs. Moreover, comparative analyses show that PSC EVs contain unique proteins and microRNAs, such as the pluripotency-associated proteins ROR1 and CD133 and members of the miR-302 family, which are not found in MSC EVs, as determined by proteomic profiling and microRNA sequencing. Notably, the dynamic suspension culture of PSC aggregates significantly increases EV yield, offering a scalable and reproducible source superior to other cell sources. To evaluate their therapeutic potential, we employed an antigen-specific type 1 diabetes model and found that two local injections of iPSC EVs, particularly when delivered via a biomaterial scaffold, significantly enhanced diabetes-free survival. These treatments increased Treg populations in draining lymph nodes, induced systemic immunomodulation, and preserved β-cell mass from immune-mediated destruction. The immunomodulatory capability of PSC EVs suggests broad applications in treating autoimmune diseases and supporting stem cell-derived cell therapies by promoting immune tolerance. Their scalability, consistency, and superior therapeutic properties position PSC EVs as a compelling platform for next-generation immunotherapies and cell-based treatment strategies.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}