iSciencePub Date : 2025-10-03DOI: 10.1016/j.isci.2025.113682
Prashant Jain , Annabel Guichard , Mahtab Moayeri , Saluja Kaduwal , Margot Mel de Fontenay , Ian Rousseau , Stephen H. Leppla , Ethan Bier
{"title":"Anthrax ET activates Rac1 and RTK signaling to induce F-actin reorganization and endothelial permeability","authors":"Prashant Jain , Annabel Guichard , Mahtab Moayeri , Saluja Kaduwal , Margot Mel de Fontenay , Ian Rousseau , Stephen H. Leppla , Ethan Bier","doi":"10.1016/j.isci.2025.113682","DOIUrl":"10.1016/j.isci.2025.113682","url":null,"abstract":"<div><div>Endothelial permeability induced by the potent adenylate cyclase edema toxin (ET) is central to bacterial dissemination and lethal vascular collapse during infections caused by <em>Bacillus anthracis</em>. Antibiotic and antitoxin treatments are ineffective against anthrax lethal toxemia once high doses of toxins have been released. This study uncovers a critical cAMP-dependent disruption of the F-actin network by ET in human brain microvascular endothelial cells (HBMECs), mediated by Rac1 and cofilin. Rac1 activation by ET leads to a loss of cell area and monolayer permeability. These effects are preceded by the rapid cAMP-independent activation of IGF1R and EGFR and their respective downstream effectors PI3K/AKT and MEK/ERK, which contribute to F-actin remodeling and permeability induced by ET. Consistent with these findings, Rac1, PI3K, and MEK inhibitors prevent ET-induced edema in a mouse footpad model, providing the <em>in vivo</em> pre-clinical validation of their therapeutic potential.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113682"},"PeriodicalIF":4.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-10-03DOI: 10.1016/j.isci.2025.113677
Shuyun Dong , Tianxiao Zhang , Yujia Zhai , Lauren C. Naatz , Noel G. Carlson , John W. Rose , Brian Evavold , Mingnan Chen
{"title":"3-in-one PD-1CAR Tregs: A bioengineered cellular therapy for target engagement, activation, and immunosuppression with reparative potential","authors":"Shuyun Dong , Tianxiao Zhang , Yujia Zhai , Lauren C. Naatz , Noel G. Carlson , John W. Rose , Brian Evavold , Mingnan Chen","doi":"10.1016/j.isci.2025.113677","DOIUrl":"10.1016/j.isci.2025.113677","url":null,"abstract":"<div><div>Chimeric Antigen Receptor (CAR) regulatory T cells (Tregs) represent a promising cell-based therapy for autoimmune diseases, yet conventional designs require multistep activation before suppressing pathogenic cells, limiting precision and efficacy. We developed a “3-in-One” CAR Treg platform targeting Programmed cell death protein 1 (PD-1), enabling direct engagement with, activation by, and suppression of PD-1<sup>+</sup> effector conventional T cells (eTconvs), key drivers of autoimmune inflammation. <sup>PD-1</sup>CAR Tregs stably expressed CAR and FoxP3, displayed high CD25, and upon PD-1 engagement, upregulated Ki67, IL-10, and TGF-β1 without producing IFNγ or IL-2, maintaining a committed regulatory phenotype. Functionally, they inhibited T cell proliferation and preferentially reduced PD-1<sup>+</sup> eTconvs, a specificity not seen in conventional Tregs. Moreover, <sup>PD-1</sup>CAR Tregs promoted oligodendrocyte precursor cell differentiation and secreted CCN3, a reparative factor, suggesting dual benefits in immune regulation and neuronal repair. These findings establish <sup>PD-1</sup>CAR Tregs as a unique therapy with both targeted suppression and tissue repair potential.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113677"},"PeriodicalIF":4.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-10-03DOI: 10.1016/j.isci.2025.113685
Augusto Borges , Jerónimo R. Miranda-Rodríguez , Alberto S. Ceccarelli , Guilherme Ventura , Jakub Sedzinski , Hernán López-Schier , Osvaldo Chara
{"title":"ForSys: Non-invasive stress inference from time-lapse microscopy","authors":"Augusto Borges , Jerónimo R. Miranda-Rodríguez , Alberto S. Ceccarelli , Guilherme Ventura , Jakub Sedzinski , Hernán López-Schier , Osvaldo Chara","doi":"10.1016/j.isci.2025.113685","DOIUrl":"10.1016/j.isci.2025.113685","url":null,"abstract":"<div><div>During tissue development and regeneration, cells interpret and exert mechanical forces that are challenging to measure <em>in vivo</em>. Stress inference algorithms have thus emerged as powerful tools to estimate tissue stresses. Yet, effectively incorporating tissue dynamics into these algorithms remains elusive. Here, we introduce ForSys, a Python-based software that infers intercellular stresses and intracellular pressures from time-lapse microscopy. After validation, we applied ForSys to the migrating zebrafish lateral-line primordium, revealing increased stress during the cell rounding that precedes mitosis and accurately predicting the onset of epithelial rosettogenesis. We further used ForSys to study neuromast development and uncovered mechanical asymmetries linked to cell type-specific adhesion. The software performs both static and dynamic stress inference, supports command-line use, scripting, and a user-friendly graphical interface within Fiji, and accepts segmentation inputs from EPySeg and Cellpose. This versatility of ForSys enables the analysis of spatiotemporal patterns of mechanical forces during tissue morphogenesis <em>in vivo</em>.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113685"},"PeriodicalIF":4.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-10-03DOI: 10.1016/j.isci.2025.113684
Lei Xing , Sophia U. Lamberti , Hannah C. Nourie , Trinity E. Rust , Wenxin Hu , Mark J. Zylka
{"title":"A luminescence-based biosensor to measure endogenous UBE3A activity","authors":"Lei Xing , Sophia U. Lamberti , Hannah C. Nourie , Trinity E. Rust , Wenxin Hu , Mark J. Zylka","doi":"10.1016/j.isci.2025.113684","DOIUrl":"10.1016/j.isci.2025.113684","url":null,"abstract":"<div><div>Loss- and gain-of-function (LOF and GOF) mutations in the E3 ubiquitin ligase UBE3A cause distinct neurodevelopmental disorders. The AZUL domain of UBE3A binds with low nanomolar affinity to a 45 amino acid (aa) region of PSMD4. We fused this 45-aa sequence to Firefly luciferase to generate a luminescence-based biosensor, Firefly-45aa, that acts as an artificial UBE3A substrate and exhibits exceptional sensitivity in measuring UBE3A activity. Testing UBE3A variants using Firefly-45aa in HEK293T cells revealed distinct biosensor activity profiles, enabling the classification of LOF and GOF mutations based on maximum activity, inhibitory concentration-50, and activity per unit of protein. Some strong LOF mutations had dominant negative activity. In addition, Firefly-45aa can be used to quantify endogenous UBE3A activity in primary cells from Angelman syndrome and GOF mouse models. This biosensor reveals a mutational spectrum of UBE3A enzyme activity and is a sensitive tool for functional characterization and therapeutic development in UBE3A-related disorders.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113684"},"PeriodicalIF":4.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-10-03DOI: 10.1016/j.isci.2025.113679
Sangeetha Jayaraman , Shanmuga Mahalingam , Michael M. Lederman , Fady Faddoul , Andre Paes da Silva , Robert Asaad , Leah P. Shriver , Natarajan Bhaskaran , Elizabeth Schneider , Grace Heine , Tobi Taylor , Samantha Horne , Ashley Yoon , Zihan Zhu , Liangliang Zhang , Adam Burgener , Gina Lewin , Pushpa Pandiyan
{"title":"Dysbiosis modulates CD8+ tissue-resident memory cells through a mechanism requiring polyamine metabolism during HIV infection","authors":"Sangeetha Jayaraman , Shanmuga Mahalingam , Michael M. Lederman , Fady Faddoul , Andre Paes da Silva , Robert Asaad , Leah P. Shriver , Natarajan Bhaskaran , Elizabeth Schneider , Grace Heine , Tobi Taylor , Samantha Horne , Ashley Yoon , Zihan Zhu , Liangliang Zhang , Adam Burgener , Gina Lewin , Pushpa Pandiyan","doi":"10.1016/j.isci.2025.113679","DOIUrl":"10.1016/j.isci.2025.113679","url":null,"abstract":"<div><div>Polyamines play crucial roles in modulating T lymphocyte functions. Here, we demonstrate that the oral mucosa of people living with HIV (PLWH), characterized by active polyamine metabolic pathways, exhibits significantly diminished IFN-γ expression and reduced abundance of CD8<sup>+</sup> tissue-resident memory (T<sub>RM</sub>) cells. Salivary 16S rRNA sequencing revealed elevated levels of <em>Fusobacteria,</em> negatively correlating with the levels of CD8<sup>+</sup> T<sub>RM</sub>-like cells in PLWH. <em>In vitro</em> experiments showed that <em>Fusobacterium nucleatum</em> (FN) produced putrescine, which is known to be enriched in PLWH mucosa. Polyamines, HIV infection, and FN led to EIF-5A hypusination, diminished IFN-γ expression in CD8<sup>+</sup> T cells, which impaired the proliferation of TRM-like cells in tonsil organoid cells. The inhibition of polyamine synthesis and EIF-5A hypusination restored IFN-γ expression and T<sub>RM</sub>-like cells. Collectively, these results highlight an essential role of polyamines in the critical interplay between oral resident microbiota, immunometabolic regulation, and immune competence during chronic viral infections.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113679"},"PeriodicalIF":4.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-10-03DOI: 10.1016/j.isci.2025.113672
Yongdae Kim , Beom Ki Kim , Kwang-Seop Kim
{"title":"Far-field wireless power transmission module with MEMS-based laser steering for optogenetic applications","authors":"Yongdae Kim , Beom Ki Kim , Kwang-Seop Kim","doi":"10.1016/j.isci.2025.113672","DOIUrl":"10.1016/j.isci.2025.113672","url":null,"abstract":"<div><div>In this study, we propose a far-field wireless power transmission system utilizing a mobile laser steering module (MOLASM) for optogenetic applications. The system integrates a MEMS-based active micromirror and features a battery-free architecture, enabling a miniaturized, lightweight, and mobile operation. This design allows for precise laser steering while maintaining a compact form factor. Additionally, laser superimposition using multiple MOLASMs enhances wirelessly transmitted power, ensuring scalable and adaptable` energy delivery for diverse experimental needs. High-efficiency photovoltaic module harvests energy from precisely targeted laser beams emitted from MOLASM, enabling continuous, wire-free operation without the need for external recharging or replacement. To validate the feasibility of this concept, we designed, implemented, and experimentally evaluated the dynamic beam steering and power delivery performance of the MOLASM system. The results demonstrate its effectiveness in wirelessly powering optogenetic probes over far-field distances, providing a flexible and practical solution for neuromodulation studies.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113672"},"PeriodicalIF":4.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-10-01DOI: 10.1016/j.isci.2025.113687
Zide Wang , Zhe Meng , Yaosai Liu , Boyan Su , Guoxi Luan , Peihai Zhang , Jia Yang , Kaiyuan Yang , Guihuai Wang , Xiumei Wang , Beibei Yu , Weitao Man
{"title":"Eupatilin ameliorates spinal cord injury by inhibiting damage-associated microglia and optimizing the regenerative microenvironment","authors":"Zide Wang , Zhe Meng , Yaosai Liu , Boyan Su , Guoxi Luan , Peihai Zhang , Jia Yang , Kaiyuan Yang , Guihuai Wang , Xiumei Wang , Beibei Yu , Weitao Man","doi":"10.1016/j.isci.2025.113687","DOIUrl":"10.1016/j.isci.2025.113687","url":null,"abstract":"<div><div>Microglia represent critical therapeutic targets in spinal cord injury (SCI), with damage-associated microglia (DAM) playing key roles in neuroinflammation and tissue repair. Through integrated in-silico analysis of single-cell RNA sequencing (scRNA-seq) and microarray datasets, we identified DAM subsets specific to acute SCI characterized by hub genes <em>Fcer1g</em>, <em>Grn</em>, and <em>Gusb</em>. Using a C57BL/6 mouse spinal cord contusion model, we validated increased DAM accumulation post-injury and demonstrated their propensity to transition toward homeostatic microglia (MG2). Eupatilin treatment promoted DAM-to-MG2 differentiation, as confirmed through bulk and scRNA-seq analyses, revealing supportive gene expression changes. These findings establish DAM as functionally distinct microglial populations in acute SCI and identify Eupatilin as a therapeutic agent that facilitates beneficial microglial polarization. This work provides mechanistic insights into microglial dynamics during SCI and suggests targeted modulation of DAM-to-MG2 transitions as a promising therapeutic strategy for promoting inflammation resolution and functional recovery.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113687"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-09-30DOI: 10.1016/j.isci.2025.113663
Marta Mira-Osuna , Steffen Plunder , Eric Theveneau , Roland Le Borgne
{"title":"The directionality of collective cell delamination is governed by tissue architecture and cell adhesion in a Drosophila carcinoma model","authors":"Marta Mira-Osuna , Steffen Plunder , Eric Theveneau , Roland Le Borgne","doi":"10.1016/j.isci.2025.113663","DOIUrl":"10.1016/j.isci.2025.113663","url":null,"abstract":"<div><div>Epithelial cells contact each other and the extracellular matrix via cell junctions, establishing mechanochemical barriers. During collective delamination, epithelia-derived tumors detach from the tissue with a directionality that dictates their malignancy. How cell junctions contribute to this process and how the directionality of delamination is regulated remains unknown. We used the <em>Drosophila Ras</em><sup><em>V12</em></sup> carcinoma model and found that the loss of septate junctions in epithelial cells triggers apoptosis, whereas in <em>Ras</em><sup><em>V12</em></sup>-cells promotes collective delamination. We found that apical and basal delamination differ in cell identity, polarity, and junctional remodeling, occurring exclusively in squamous and pseudostratified epithelia, respectively. We performed mathematical simulations using a 2D agent-based model and found that tissue architecture and preferential adhesion between mutant cells and with wild-type neighbors regulate the directionality of delamination. Apical delamination initiates with cells constricting apically, emitting apical protrusions, and forming an apical neck via preferential adhesion to collectively detach from the tissue.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113663"},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-09-30DOI: 10.1016/j.isci.2025.113666
Hamidah Raduwan , Jinhee Park , Alejandro Marín López , Mathias H. Skadow , Tse-Yu Chen , Richard A. Flavell , Albert C. Shaw , Ruth R. Montgomery , Erol Fikrig
{"title":"The cutaneous response to a mosquito bite is influenced by the diurnal rhythm","authors":"Hamidah Raduwan , Jinhee Park , Alejandro Marín López , Mathias H. Skadow , Tse-Yu Chen , Richard A. Flavell , Albert C. Shaw , Ruth R. Montgomery , Erol Fikrig","doi":"10.1016/j.isci.2025.113666","DOIUrl":"10.1016/j.isci.2025.113666","url":null,"abstract":"<div><div>The influence of the time of day on the cutaneous immune response to mosquito feeding is not well understood. <em>Aedes aegypti</em> mosquitoes feed on mice throughout the day, and a bloodmeal is most often obtained at times of day that are equivalent to dawn (ZT1) and dusk (ZT11). We observed that cells in the murine skin elicited more differentially expressed genes at ZT11 compared to ZT1. Additionally, we detected more immune cells in the skin at ZT11 in response to a mosquito bite. These results suggest that assessments of host responses to a mosquito bite and mosquito-borne infections may be influenced by the diurnal rhythm.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113666"},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
iSciencePub Date : 2025-09-30DOI: 10.1016/j.isci.2025.113667
Mirko Zanon , Scott E. Fraser , Giorgio Vallortigara
{"title":"Numerical discrimination in Danionella","authors":"Mirko Zanon , Scott E. Fraser , Giorgio Vallortigara","doi":"10.1016/j.isci.2025.113667","DOIUrl":"10.1016/j.isci.2025.113667","url":null,"abstract":"<div><div>The transparent teleost <em>Danionella cerebrum</em> offers unique advantages for neuroscience research, including small size, lifelong cranial transparency, and a simplified brain. Despite its suitability for imaging and neural circuit studies, its cognitive abilities remain largely unexplored. Here, we show that <em>Danionella</em> can discriminate between quantities. Using a habituation/dishabituation paradigm over six trials across five days, fish were exposed to dot arrays of constant numerosity (e.g., 3 dots), while geometric visual properties were systematically varied to ensure responses were driven by actual numerical information. In the final trial, a different numerosity (e.g., 9 dots) was presented. Fish showed significant dishabituation, spending more time near the numerically altered stimulus, indicating discrimination between 3 and 9 elements. These findings contribute to our understanding of <em>Danionella</em>’s cognitive capacities and support its broader use in research, particularly for investigating the neural basis of cognition at high resolution, given its exceptional biological features.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 11","pages":"Article 113667"},"PeriodicalIF":4.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}