Pub Date : 2025-12-06DOI: 10.1016/j.isci.2025.114363
Shahid Aziz , Asma Ahmed , Parul Singh , Sangita Mukhopadhyay
The immune system employs complex metabolic pathways to regulate host-pathogen interactions. Among these, the arginase-polyamine axis is a crucial modulator of both innate and adaptive immunity. Despite significant progress, the precise roles and regulatory mechanisms governing the arginase-polyamine axis in immune cell function remain incompletely understood. This review aims to provide a comprehensive analysis of the arginase-polyamine axis, highlighting its role in maintaining immune homeostasis and preserving the functional integrity of various immune cell types. Furthermore, we discuss the strategies used by diverse pathogens to manipulate this pathway, facilitating the creation of immunosuppressive microenvironments that promote their intracellular survival and replication in the host. Finally, we highlight the potential of innovative therapeutic strategies that target arginase-polyamine signaling pathways, which can effectively modulate immune responses in the context of infectious diseases.
{"title":"The arginase-polyamine signaling axis in immune cells: Implications for immune modulation and host-pathogen interactions","authors":"Shahid Aziz , Asma Ahmed , Parul Singh , Sangita Mukhopadhyay","doi":"10.1016/j.isci.2025.114363","DOIUrl":"10.1016/j.isci.2025.114363","url":null,"abstract":"<div><div>The immune system employs complex metabolic pathways to regulate host-pathogen interactions. Among these, the arginase-polyamine axis is a crucial modulator of both innate and adaptive immunity. Despite significant progress, the precise roles and regulatory mechanisms governing the arginase-polyamine axis in immune cell function remain incompletely understood. This review aims to provide a comprehensive analysis of the arginase-polyamine axis, highlighting its role in maintaining immune homeostasis and preserving the functional integrity of various immune cell types. Furthermore, we discuss the strategies used by diverse pathogens to manipulate this pathway, facilitating the creation of immunosuppressive microenvironments that promote their intracellular survival and replication in the host. Finally, we highlight the potential of innovative therapeutic strategies that target arginase-polyamine signaling pathways, which can effectively modulate immune responses in the context of infectious diseases.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114363"},"PeriodicalIF":4.1,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788833","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}
Pub Date : 2025-12-06DOI: 10.1016/j.isci.2025.114358
Cheoljun Choi , Junhyuck Lee , Gyeongran Park , Sik Namgoong , Yun-Hee Lee
Triggering receptor expressed on myeloid cells 2 (TREM2) is a key marker of lipid-associated macrophages (LAMs), but its role in adipose tissue homeostasis remains unclear due to conflicting results. This study aimed to investigate the role of TREM2 in adipose tissue inflammation and metabolic dysfunction during high-fat diet (HFD)–induced obesity. HFD feeding enhanced proteolytic cleavage of TREM2 in gonadal white adipose tissue (GWAT), driven by upregulation of the metalloproteinase ADAM10 and ADAM17. In vitro co-culture of RAW264.7 cells with pyroptotic, but not apoptotic, adipocytes increased stimulator of interferon genes (STING) activation, upregulated ADAM10/17 expression, and promoted TREM2 shedding. Pharmacological inhibition of ADAM10/17 by GM6001 reduced TREM2 cleavage and enhanced phagocytosis of dying pyroptotic adipocytes. In vivo GM6001 treatment attenuated HFD-induced weight gain, improved metabolic parameters, and shifted macrophage polarization toward anti-inflammatory TREM2+CD206+ subsets. These findings demonstrate that pyroptotic adipocyte death promotes pathological TREM2 shedding, contributing to macrophage dysfunction and adipose tissue inflammation.
{"title":"Obesity-induced pyroptotic adipocyte death leads to TREM2-dependent macrophage dysfunction and adipose tissue inflammation","authors":"Cheoljun Choi , Junhyuck Lee , Gyeongran Park , Sik Namgoong , Yun-Hee Lee","doi":"10.1016/j.isci.2025.114358","DOIUrl":"10.1016/j.isci.2025.114358","url":null,"abstract":"<div><div>Triggering receptor expressed on myeloid cells 2 (TREM2) is a key marker of lipid-associated macrophages (LAMs), but its role in adipose tissue homeostasis remains unclear due to conflicting results. This study aimed to investigate the role of TREM2 in adipose tissue inflammation and metabolic dysfunction during high-fat diet (HFD)–induced obesity. HFD feeding enhanced proteolytic cleavage of TREM2 in gonadal white adipose tissue (GWAT), driven by upregulation of the metalloproteinase ADAM10 and ADAM17. <em>In vitro</em> co-culture of RAW264.7 cells with pyroptotic, but not apoptotic, adipocytes increased stimulator of interferon genes (STING) activation, upregulated ADAM10/17 expression, and promoted TREM2 shedding. Pharmacological inhibition of ADAM10/17 by GM6001 reduced TREM2 cleavage and enhanced phagocytosis of dying pyroptotic adipocytes. <em>In vivo</em> GM6001 treatment attenuated HFD-induced weight gain, improved metabolic parameters, and shifted macrophage polarization toward anti-inflammatory TREM2+CD206+ subsets. These findings demonstrate that pyroptotic adipocyte death promotes pathological TREM2 shedding, contributing to macrophage dysfunction and adipose tissue inflammation.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114358"},"PeriodicalIF":4.1,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788984","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}
Pub Date : 2025-12-06DOI: 10.1016/j.isci.2025.114362
Hai-Ding Zou , Qing Liu , Jie Zhang , Yun-Xuan Huang , Zhao-Lan Hu , Pei Zhou , Cong Luo , Ru-Yi Luo
Hypoxemia is common during sedated gastrointestinal endoscopy (SGIE), especially in overweight and obese patients, yet the effectiveness of nasopharyngeal airways (NAs) for prevention remains unclear. This prospective randomized trial compared NA with standard nasal cannula (NC) in 256 overweight and obese patients. Results revealed that the NA group demonstrated a statistically significant reduction of hypoxemia (20/128 [15.6%] vs. 52/128 [40.6%]; p < 0.001) and severe hypoxemia (4/128 [3.1%] vs. 13/128 [10.2%]; p = 0.024), along with fewer jaw-thrust maneuvers (9/128 [7.0%] vs. 34/128 [26.6%]; p < 0.001), compared to the NC group. Multivariable analysis confirmed that higher STOP-BANG scores independently predicted hypoxemia risk, while the use of NA was an independent protective factor (odds ratio, OR, 0.23, 95% CI, 0.12–0.44, p < 0.001). These findings support using NA to reduce hypoxemia in high-risk patients and underscore the value of STOP-BANG for preoperative screening.
{"title":"Effect of nasopharyngeal airway on hypoxemia in overweight and obese patients undergoing sedated endoscopy: A randomized trial","authors":"Hai-Ding Zou , Qing Liu , Jie Zhang , Yun-Xuan Huang , Zhao-Lan Hu , Pei Zhou , Cong Luo , Ru-Yi Luo","doi":"10.1016/j.isci.2025.114362","DOIUrl":"10.1016/j.isci.2025.114362","url":null,"abstract":"<div><div>Hypoxemia is common during sedated gastrointestinal endoscopy (SGIE), especially in overweight and obese patients, yet the effectiveness of nasopharyngeal airways (NAs) for prevention remains unclear. This prospective randomized trial compared NA with standard nasal cannula (NC) in 256 overweight and obese patients. Results revealed that the NA group demonstrated a statistically significant reduction of hypoxemia (20/128 [15.6%] vs. 52/128 [40.6%]; <em>p</em> < 0.001) and severe hypoxemia (4/128 [3.1%] vs. 13/128 [10.2%]; <em>p</em> = 0.024), along with fewer jaw-thrust maneuvers (9/128 [7.0%] vs. 34/128 [26.6%]; <em>p</em> < 0.001), compared to the NC group. Multivariable analysis confirmed that higher STOP-BANG scores independently predicted hypoxemia risk, while the use of NA was an independent protective factor (odds ratio, OR, 0.23, 95% CI, 0.12–0.44, <em>p</em> < 0.001). These findings support using NA to reduce hypoxemia in high-risk patients and underscore the value of STOP-BANG for preoperative screening.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114362"},"PeriodicalIF":4.1,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788826","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}
Pub Date : 2025-12-05DOI: 10.1016/j.isci.2025.114311
Wansu Yu , Yong Li , Siyi Jiang , Jia Tian , Shu-Wei Sun , Lubo Zhang , DaLiao Xiao
Fat mass and obesity-associated (FTO) protein plays a critical role in N6-methyladenosine (m6A) demethylation, linked to metabolic disorders such as diabetes and obesity. This study investigates FTO-dependent m6A methylation in fetal programming of cardiac dysfunction due to gestational diabetes mellitus (GDM). Using a Sprague-Dawley rat model of GDM, we observed that GDM exposure repressed FTO, increasing m6A RNA methylation, consequently developing a cardiac hypertrophic dysfunctional phenotype in neonatal offspring. FTO inhibition replicated the effects of GDM, while overexpression of FTO via FTO lentivirus (Lenti-FTO) reversed GDM-induced hypertrophy, cardiac senescence, and dysfunction. These results illuminate the molecular mechanisms by which GDM negatively impacts offspring cardiac health and highlight the potential for targeting FTO-mediated RNA methylation pathways as a therapeutic strategy for GDM-related cardiac issues.
{"title":"FTO-dependent m6A methylation mediates gestational diabetes mellitus-induced offspring cardiac senescent hypertrophy and dysfunction","authors":"Wansu Yu , Yong Li , Siyi Jiang , Jia Tian , Shu-Wei Sun , Lubo Zhang , DaLiao Xiao","doi":"10.1016/j.isci.2025.114311","DOIUrl":"10.1016/j.isci.2025.114311","url":null,"abstract":"<div><div>Fat mass and obesity-associated (FTO) protein plays a critical role in N6-methyladenosine (m6A) demethylation, linked to metabolic disorders such as diabetes and obesity. This study investigates FTO-dependent m6A methylation in fetal programming of cardiac dysfunction due to gestational diabetes mellitus (GDM). Using a Sprague-Dawley rat model of GDM, we observed that GDM exposure repressed FTO, increasing m6A RNA methylation, consequently developing a cardiac hypertrophic dysfunctional phenotype in neonatal offspring. FTO inhibition replicated the effects of GDM, while overexpression of FTO via FTO lentivirus (Lenti-FTO) reversed GDM-induced hypertrophy, cardiac senescence, and dysfunction. These results illuminate the molecular mechanisms by which GDM negatively impacts offspring cardiac health and highlight the potential for targeting FTO-mediated RNA methylation pathways as a therapeutic strategy for GDM-related cardiac issues.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114311"},"PeriodicalIF":4.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788912","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}
Pub Date : 2025-12-05DOI: 10.1016/j.isci.2025.114338
Travis Park , Robert.J. Brocklehurst , Stephanie E. Pierce , William M.G. Parker , Ellen J. Coombs , Tahlia I. Pollock , James P. Rule , Alistair R. Evans
Functional trade-offs are inherent in phenotypes due to the need to balance multiple competing selection pressures. Traditionally regarded as constraints on evolution, trade-offs have recently been reframed as facilitators of adaptation via the changing relative importance of competing functions. Here, we examine these ideas through the lens of aquatic mammal feeding, testing a behavioral aquatic feeding framework where feeding strategies form an evolutionary continuum from terrestrial to increasingly more specialized water-based feeding styles. Specifically, we hypothesized that suction, suction filter, and ram filter feeding would have adaptive peaks closer together than raptorial feeding, and that taxa follow the functionally optimal evolutionary path (Pareto front) between adaptive peaks. Constructing morphofunctional adaptive landscapes from cetacean mandibles revealed strong support for this framework. Surprisingly, most cetaceans do not lie along the Pareto front between peaks, suggesting that novel functional innovations— most likely the specialized cetacean auditory pathway—are also influencing mandibular evolution.
{"title":"Functional trade-offs and innovation shape the adaptive landscape of aquatic mammal feeding","authors":"Travis Park , Robert.J. Brocklehurst , Stephanie E. Pierce , William M.G. Parker , Ellen J. Coombs , Tahlia I. Pollock , James P. Rule , Alistair R. Evans","doi":"10.1016/j.isci.2025.114338","DOIUrl":"10.1016/j.isci.2025.114338","url":null,"abstract":"<div><div>Functional trade-offs are inherent in phenotypes due to the need to balance multiple competing selection pressures. Traditionally regarded as constraints on evolution, trade-offs have recently been reframed as facilitators of adaptation via the changing relative importance of competing functions. Here, we examine these ideas through the lens of aquatic mammal feeding, testing a behavioral aquatic feeding framework where feeding strategies form an evolutionary continuum from terrestrial to increasingly more specialized water-based feeding styles. Specifically, we hypothesized that suction, suction filter, and ram filter feeding would have adaptive peaks closer together than raptorial feeding, and that taxa follow the functionally optimal evolutionary path (Pareto front) between adaptive peaks. Constructing morphofunctional adaptive landscapes from cetacean mandibles revealed strong support for this framework. Surprisingly, most cetaceans do not lie along the Pareto front between peaks, suggesting that novel functional innovations— most likely the specialized cetacean auditory pathway—are also influencing mandibular evolution.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114338"},"PeriodicalIF":4.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788766","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}
Pub Date : 2025-12-05DOI: 10.1016/j.isci.2025.114279
Cem Özel , Khawla Abualia , Duc Nguyen-Minh , Mahsa Matin , David Unnersjö-Jess , Martin Höhne , Wilhelm Bloch , Henning Hagmann , Richard J.M. Coward , Sebastian Brähler , Bernhard Schermer , Thomas Benzing , Philipp Antczak , Paul T. Brinkkötter
Mitochondrial dysfunction has emerged as a key contributor to the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) and genetic focal-segmental glomerulosclerosis (FSGS). This study explores the role of mitochondrial integrity in podocyte biology, focusing on the impact of OMA1, a critical regulator of mitochondrial morphology. Using a model of disrupted mitochondrial homeostasis, we show that mitochondrial dysfunction sensitizes podocytes to insulin, triggering the overactivation of mTOR signaling. Disruption of OMA1 function was achieved through the deletion of Oma1 or a podocyte-specific knockout of its regulator Phb2. Remarkably, simultaneous Oma1 deletion extended the lifespan of severely affected Phb2pko mice, alleviated proteinuria, and restored mitochondrial morphology. Increased mTOR activity was observed in Phb2pko, Oma1del, and Phb2/Oma1 double-knockout mice. Our findings highlight the critical role of mitochondrial integrity in podocyte function and disease mitigation, providing potential therapeutic insights for mitochondrial dysfunction-associated nephropathies.
{"title":"Mitochondrial integrity modulates mTOR signaling and podocyte function","authors":"Cem Özel , Khawla Abualia , Duc Nguyen-Minh , Mahsa Matin , David Unnersjö-Jess , Martin Höhne , Wilhelm Bloch , Henning Hagmann , Richard J.M. Coward , Sebastian Brähler , Bernhard Schermer , Thomas Benzing , Philipp Antczak , Paul T. Brinkkötter","doi":"10.1016/j.isci.2025.114279","DOIUrl":"10.1016/j.isci.2025.114279","url":null,"abstract":"<div><div>Mitochondrial dysfunction has emerged as a key contributor to the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) and genetic focal-segmental glomerulosclerosis (FSGS). This study explores the role of mitochondrial integrity in podocyte biology, focusing on the impact of OMA1, a critical regulator of mitochondrial morphology. Using a model of disrupted mitochondrial homeostasis, we show that mitochondrial dysfunction sensitizes podocytes to insulin, triggering the overactivation of mTOR signaling. Disruption of OMA1 function was achieved through the deletion of <em>Oma1</em> or a podocyte-specific knockout of its regulator <em>Phb2</em>. Remarkably, simultaneous <em>Oma1</em> deletion extended the lifespan of severely affected <em>Phb2</em><sup>pko</sup> mice, alleviated proteinuria, and restored mitochondrial morphology. Increased mTOR activity was observed in <em>Phb2</em><sup><em>pko</em></sup>, <em>Oma1</em><sup><em>del</em></sup>, and <em>Phb2/Oma1</em> double-knockout mice. Our findings highlight the critical role of mitochondrial integrity in podocyte function and disease mitigation, providing potential therapeutic insights for mitochondrial dysfunction-associated nephropathies.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114279"},"PeriodicalIF":4.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788983","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}
Pub Date : 2025-12-05DOI: 10.1016/j.isci.2025.114317
Isaura M. Frost , Ruby Sims , Anya Yakimenko , Rachel Ma , Maximilian Floridia , Ruth A. Foley , Emily C. Duggan , Kelly Y. Cai , Kelsey Jorgensen , Emily Skuratovsky , Paul S. Weiss , Steven J. Jonas
Mechanical disruption of cell membranes to enable intracellular delivery has been gaining traction as a methodology. Here, we show that a mechanical disruption-based strategy, filtroporation (FP), can be applied to edit the beta globin gene efficiently in human hematopoietic stem and progenitor cells. Gene expression analyses from RNA-Seq datasets demonstrate that electroporation (EP) yields greater transcriptional changes compared to FP globally, and gene pathway enrichment analyses suggest EP promotes stem cell differentiation while FP promotes cell division. Membrane repair occurs within 30 s of disruption by FP, and calcium signaling plays a key role in membrane repair in this context. Studies with fluorescently tagged membrane repair proteins, GRAF1, SNAP23, and CHMP4B, implicate the involvement of three mechanisms to reconstitute the cell barrier following FP. This work supports the evidence that the choice of intracellular delivery method affects transcriptional stem cell profile, and that membrane repair after mechanical disruption is a fast, multi-pathway process.
{"title":"Membrane repair following filtroporation-induced cell permeabilization","authors":"Isaura M. Frost , Ruby Sims , Anya Yakimenko , Rachel Ma , Maximilian Floridia , Ruth A. Foley , Emily C. Duggan , Kelly Y. Cai , Kelsey Jorgensen , Emily Skuratovsky , Paul S. Weiss , Steven J. Jonas","doi":"10.1016/j.isci.2025.114317","DOIUrl":"10.1016/j.isci.2025.114317","url":null,"abstract":"<div><div>Mechanical disruption of cell membranes to enable intracellular delivery has been gaining traction as a methodology. Here, we show that a mechanical disruption-based strategy, filtroporation (FP), can be applied to edit the beta globin gene efficiently in human hematopoietic stem and progenitor cells. Gene expression analyses from RNA-Seq datasets demonstrate that electroporation (EP) yields greater transcriptional changes compared to FP globally, and gene pathway enrichment analyses suggest EP promotes stem cell differentiation while FP promotes cell division. Membrane repair occurs within 30 s of disruption by FP, and calcium signaling plays a key role in membrane repair in this context. Studies with fluorescently tagged membrane repair proteins, GRAF1, SNAP23, and CHMP4B, implicate the involvement of three mechanisms to reconstitute the cell barrier following FP. This work supports the evidence that the choice of intracellular delivery method affects transcriptional stem cell profile, and that membrane repair after mechanical disruption is a fast, multi-pathway process.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114317"},"PeriodicalIF":4.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788824","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}
Pub Date : 2025-12-05DOI: 10.1016/j.isci.2025.114355
André U. Deutschmann , Lucie Pifkova , Betül Findik , Moritz Klingenstein , Anton Betz , Maksim Klimiankou , Julia Skokowa , Stefan Liebau , Ellen Reisinger , Stefanie Klingenstein
Organoids are valuable models to study human diseases. Cochlear implants (CIs) electrically stimulate spiral ganglion neurons (SGNs) to enable severely hearing-impaired people vocal communication. However, some studies found in patients with mutations in the TMPRSS3 gene that speech comprehension with CI was lower than for other etiologies. The reduced CI performance might be associated with reduced SGN excitability, the causes for which are largely unclear. We refined a protocol for generating SGN-like cells in otic organoids from human induced pluripotent stem cells (iPSC) and confirmed their identity through marker expression and electrophysiological characterization. TMPRSS3-deficient iPSC clones developed smaller and less differentiated organoids. Moreover, TMPRSS3-deficient SGN-like cells displayed smaller currents and were less likely to exhibit action potentials, which recapitulate the expected disease phenotype. Ultimately, we seek to use this organoid model to study SGN function in human patients for enhancing our understanding and prediction of CI performance.
{"title":"Otic organoids: A model to study spiral ganglion neuron characteristics in Tmprss3-deficiency","authors":"André U. Deutschmann , Lucie Pifkova , Betül Findik , Moritz Klingenstein , Anton Betz , Maksim Klimiankou , Julia Skokowa , Stefan Liebau , Ellen Reisinger , Stefanie Klingenstein","doi":"10.1016/j.isci.2025.114355","DOIUrl":"10.1016/j.isci.2025.114355","url":null,"abstract":"<div><div>Organoids are valuable models to study human diseases. Cochlear implants (CIs) electrically stimulate spiral ganglion neurons (SGNs) to enable severely hearing-impaired people vocal communication. However, some studies found in patients with mutations in the TMPRSS3 gene that speech comprehension with CI was lower than for other etiologies. The reduced CI performance might be associated with reduced SGN excitability, the causes for which are largely unclear. We refined a protocol for generating SGN-like cells in otic organoids from human induced pluripotent stem cells (iPSC) and confirmed their identity through marker expression and electrophysiological characterization. TMPRSS3-deficient iPSC clones developed smaller and less differentiated organoids. Moreover, TMPRSS3-deficient SGN-like cells displayed smaller currents and were less likely to exhibit action potentials, which recapitulate the expected disease phenotype. Ultimately, we seek to use this organoid model to study SGN function in human patients for enhancing our understanding and prediction of CI performance.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114355"},"PeriodicalIF":4.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788759","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}
Pub Date : 2025-12-05DOI: 10.1016/j.isci.2025.114349
Kseniia Boxleitner , Robert N. Spengler III , Valentina Alekseitseva , Temirlan Chargynov , Aida Abdykanova , Nuritdin Sayfuloev , Svetlana Shnaider
Central Asia, located at the crossroads of Eurasia, played a crucial role in the prehistoric spread of cultivated plants. Archaeobotanical evidence from rockshelters in the Fergana foothills and the Pamir Mountains reveals exchange between lowland and highland zones. Radiocarbon dating shows that broomcorn millet reached the lowlands of northern Central Asia by the late third millennium BCE and foxtail millet by the early second millennium BCE. Walnut and pistachio remains from the Fergana Valley indicate nut foraging as early as 7,800 years ago. The high-altitude site of Kurteke demonstrates cultural and economic links with lowland areas through shared technologies, while its plant assemblage differs from contemporaneous Tien Shan sites, suggesting distinct subsistence strategies. This study identifies early cultivation and foraging patterns along mountain ecoclines and proposes likely routes of crop dispersal across high-elevation Inner Asia, helping fill major gaps in the chronology of prehistoric trans-Eurasian agricultural exchange.
{"title":"Archaeobotanical investigations at high-elevation sites of the Pamir Mountains and fergana foothills","authors":"Kseniia Boxleitner , Robert N. Spengler III , Valentina Alekseitseva , Temirlan Chargynov , Aida Abdykanova , Nuritdin Sayfuloev , Svetlana Shnaider","doi":"10.1016/j.isci.2025.114349","DOIUrl":"10.1016/j.isci.2025.114349","url":null,"abstract":"<div><div>Central Asia, located at the crossroads of Eurasia, played a crucial role in the prehistoric spread of cultivated plants. Archaeobotanical evidence from rockshelters in the Fergana foothills and the Pamir Mountains reveals exchange between lowland and highland zones. Radiocarbon dating shows that broomcorn millet reached the lowlands of northern Central Asia by the late third millennium BCE and foxtail millet by the early second millennium BCE. Walnut and pistachio remains from the Fergana Valley indicate nut foraging as early as 7,800 years ago. The high-altitude site of Kurteke demonstrates cultural and economic links with lowland areas through shared technologies, while its plant assemblage differs from contemporaneous Tien Shan sites, suggesting distinct subsistence strategies. This study identifies early cultivation and foraging patterns along mountain ecoclines and proposes likely routes of crop dispersal across high-elevation Inner Asia, helping fill major gaps in the chronology of prehistoric trans-Eurasian agricultural exchange.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114349"},"PeriodicalIF":4.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788923","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}
Legionella pneumophila establishes its replicative niche through the deployment of multiple effector proteins. During this process, the host v-SNARE Sec22b is recruited from the endoplasmic reticulum to bacterial phagosomes and engages in non-canonical pairings with plasma membrane syntaxins. We previously reported that Sec22b undergoes polyubiquitination at early stages of infection and that the Legionella deubiquitinase LotB cleaves polyubiquitin chains from Sec22b, resulting in Sec22b dissociating from syntaxin 3. The current study investigates the molecular mechanisms underlying Sec22b ubiquitination and its physiological function during L. pneumophila infection. SdeA, a Legionella ubiquitin ligase, is identified as a crucial factor in promoting Sec22b polyubiquitination. SdeA catalyzes the conjugation of phosphoribosyl-linked ubiquitin to serine 137 of Sec22b; subsequently, the canonical ubiquitin system appears to polyubiquitinate Sec22b. Additionally, multimodal ubiquitination of Sec22b facilitates non-canonical SNARE pairing during early infection. This research outlines a bacterial strategy for modulating SNARE protein dynamics via reversible post-translational modifications.
{"title":"Legionella employs the multimodal ubiquitination of Sec22b to modulate SNARE pairing","authors":"Tomoe Kitao , Rina Iida , Hideki Kondo , Yoshiki Miura , Hikari Taka , Susan Kiiru , Toru Okamoto , Kohei Arasaki , Hideaki Higashi , Tomoko Kubori , Hiroki Nagai","doi":"10.1016/j.isci.2025.114341","DOIUrl":"10.1016/j.isci.2025.114341","url":null,"abstract":"<div><div><em>Legionella pneumophila</em> establishes its replicative niche through the deployment of multiple effector proteins. During this process, the host v-SNARE Sec22b is recruited from the endoplasmic reticulum to bacterial phagosomes and engages in non-canonical pairings with plasma membrane syntaxins. We previously reported that Sec22b undergoes polyubiquitination at early stages of infection and that the <em>Legionella</em> deubiquitinase LotB cleaves polyubiquitin chains from Sec22b, resulting in Sec22b dissociating from syntaxin 3. The current study investigates the molecular mechanisms underlying Sec22b ubiquitination and its physiological function during <em>L. pneumophila</em> infection. SdeA, a <em>Legionella</em> ubiquitin ligase, is identified as a crucial factor in promoting Sec22b polyubiquitination. SdeA catalyzes the conjugation of phosphoribosyl-linked ubiquitin to serine 137 of Sec22b; subsequently, the canonical ubiquitin system appears to polyubiquitinate Sec22b. Additionally, multimodal ubiquitination of Sec22b facilitates non-canonical SNARE pairing during early infection. This research outlines a bacterial strategy for modulating SNARE protein dynamics via reversible post-translational modifications.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114341"},"PeriodicalIF":4.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788765","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号