iScience最新文献_第8页

Groups of familiar male rats form unstable partner preferences when play fighting during the juvenile period 在幼年时期，一群熟悉的雄鼠在玩打斗时形成了不稳定的伴侣偏好

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-05-02 DOI: 10.1016/j.isci.2025.112562

Jackson R. Ham , Sergio M. Pellis

引用次数: 0

Development and external validation of a model for post-endoscopic retrograde cholangiopancreatography pancreatitis 内镜后逆行胆管胰造影术胰腺炎模型的建立和外部验证

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-05-02 DOI: 10.1016/j.isci.2025.112570

Gang Wang , Qikai Sun , Hai Zhu , Song Qiao , Peng Xu , Xiangyu He , Xiangkun He , Xiaosi Hu , Mingming Song , Qiuyan Zhang , Zhenyu Feng , Yue Chen , Yue Gao , Zhiyuan Jin , Wen Li , Haizheng Tang , Chaoqun Yan , Yajun Wei , Shibo Xu , Gang Hu , Cheng Wang

{"title":"Development and external validation of a model for post-endoscopic retrograde cholangiopancreatography pancreatitis","authors":"Gang Wang , Qikai Sun , Hai Zhu , Song Qiao , Peng Xu , Xiangyu He , Xiangkun He , Xiaosi Hu , Mingming Song , Qiuyan Zhang , Zhenyu Feng , Yue Chen , Yue Gao , Zhiyuan Jin , Wen Li , Haizheng Tang , Chaoqun Yan , Yajun Wei , Shibo Xu , Gang Hu , Cheng Wang","doi":"10.1016/j.isci.2025.112570","DOIUrl":"10.1016/j.isci.2025.112570","url":null,"abstract":"<div><div>Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a common complication in patients undergoing ERCP for choledocholithiasis, yet effective predictive models are lacking. This study included 2,247 patients who underwent ERCP for complete stone removal at the First Affiliated Hospital of USTC from January 2015 to January 2023. Six machine learning algorithms were utilized, incorporating 25 clinical parameters, to develop a predictive model for PEP risk. The random forest (RF) algorithm achieved the highest accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.947 in the internal dataset. Key risk factors for PEP identified include difficult cannulation, a history of pancreatitis, smaller common bile duct diameter, and female gender. Validation with datasets from 12 external centers showed AUC values ranging from 0.576 to 0.913, with an average of 0.768. An interactive R Shiny web application was also developed, offering a user-friendly tool for predicting PEP risk and enabling individualized management.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112570"},"PeriodicalIF":4.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069027","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}

引用次数: 0

IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma 在默克尔细胞癌中抑制IMPDH诱导DNA复制应激和ATR敏感性

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-05-02 DOI: 10.1016/j.isci.2025.112567

Julia L. Schnabel , Thomas C. Frost , Adam C. Wang , Varsha Ananthapadmanabhan , Satvik Gurram , Kara M. Soroko , Prafulla C. Gokhale , James A. DeCaprio

{"title":"IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma","authors":"Julia L. Schnabel , Thomas C. Frost , Adam C. Wang , Varsha Ananthapadmanabhan , Satvik Gurram , Kara M. Soroko , Prafulla C. Gokhale , James A. DeCaprio","doi":"10.1016/j.isci.2025.112567","DOIUrl":"10.1016/j.isci.2025.112567","url":null,"abstract":"<div><div>The rate-limiting isozyme of <em>de novo</em> guanosine biosynthesis, <em>IMPDH2</em>, was identified as an essential gene in Merkel cell carcinoma (MCC) but the consequences of its functional disruption were unclear. Inhibition of IMPDH2 led to reduced MCC cell viability, independent of functional p53 or Merkel cell polyomavirus status, but dependent on depletion of guanylate nucleotides. In contrast to other cancer models, inhibition of IMPDH2 in MCC led to rapid ablation of nascent DNA synthesis and the onset of replication stress without a significant effect on total or ribosomal RNA biosynthesis. Combining IMPDH inhibitors with ataxia telangiectasia mutated and Rad3-related (ATR) inhibitors significantly increased levels of replication stress <em>in vitro</em> and reduced tumor growth <em>in vivo</em>. These findings support replication stress as the dominant consequence of IMPDH2 inhibition in MCC and, when combined with ATR inhibition, indicate a potential therapeutic strategy.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112567"},"PeriodicalIF":4.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089100","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}

引用次数: 0

Effect of dopant-induced local vibration modes on pressure-driven structural phase transition in Mn- and Co-doped ZnO 掺杂剂诱导的局部振动模式对Mn和共掺杂ZnO压力驱动结构相变的影响

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-05-02 DOI: 10.1016/j.isci.2025.112560

Chih-Ming Lin , Yi-Jia Tsai , Yi-Sheng Huang , Chia-Hung Hsu , Bo-Shiuan Chen , Ming-Fong Tai , Sheng-Rui Jian , Jenh-Yih Juang

{"title":"Effect of dopant-induced local vibration modes on pressure-driven structural phase transition in Mn- and Co-doped ZnO","authors":"Chih-Ming Lin , Yi-Jia Tsai , Yi-Sheng Huang , Chia-Hung Hsu , Bo-Shiuan Chen , Ming-Fong Tai , Sheng-Rui Jian , Jenh-Yih Juang","doi":"10.1016/j.isci.2025.112560","DOIUrl":"10.1016/j.isci.2025.112560","url":null,"abstract":"<div><div><em>In-situ</em> laser Raman spectroscopy was performed on pristine ZnO, Zn<sub>0.98</sub>Mn<sub>0.02</sub>O, and Zn<sub>0.98</sub>Co<sub>0.02</sub>O at pressures up to 18.6, 18.4, and 13.1 GPa, respectively, to explore how minute amount of Mn- and Co-doping affects the high-pressure wurtzite-to-rocksalt transition in ZnO. Pristine ZnO exhibited characteristic wurtzite phonon modes, whereas Mn- and Co-doping introduced distinct local vibrational modes that shifted differently under compression. These shifts revealed that Zn<sub>0.98</sub>Mn<sub>0.02</sub>O undergoes a unique phase transition path compared to pristine and Co-doped ZnO. By connecting local vibrational features to structural evolution at high pressures, this study demonstrates the capability of Raman spectroscopy to detect doping-induced changes in lattice dynamics. These insights advance our understanding of how local lattice effects influence phase transitions and guide the design of ZnO-based materials with tunable properties for optoelectronic and high-pressure applications.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112560"},"PeriodicalIF":4.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941927","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}

引用次数: 0

TP53 upregulation via aurora kinase inhibition overcomes primary failure to venetoclax in BCL2-rearranged lymphomas 通过极光激酶抑制的TP53上调克服了bcl2重排淋巴瘤中venetoclax的主要失败

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-05-02 DOI: 10.1016/j.isci.2025.112584

Rajeswaran Mani , Samon Benrashid , Margaret D. Templeton , Lawrence J. Druhan , Sara L. Seegers , Supriya Chakraborty , Sarah E. Teague , Scott C. Jaros , Hsih-Te Yang , David M. Foureau , Nury M. Steuerwald , Dhananjaya Pal , Nilanjan Ghosh , Edward A. Copelan , Donald L. Durden , Belinda R. Avalos , Steven I. Park

{"title":"TP53 upregulation via aurora kinase inhibition overcomes primary failure to venetoclax in BCL2-rearranged lymphomas","authors":"Rajeswaran Mani , Samon Benrashid , Margaret D. Templeton , Lawrence J. Druhan , Sara L. Seegers , Supriya Chakraborty , Sarah E. Teague , Scott C. Jaros , Hsih-Te Yang , David M. Foureau , Nury M. Steuerwald , Dhananjaya Pal , Nilanjan Ghosh , Edward A. Copelan , Donald L. Durden , Belinda R. Avalos , Steven I. Park","doi":"10.1016/j.isci.2025.112584","DOIUrl":"10.1016/j.isci.2025.112584","url":null,"abstract":"<div><div>Bcl2 inhibition has excellent antitumor activity against hematologic malignancies. However, the clinical results in lymphomas harboring <em>BCL2</em> gene rearrangements have been disappointing, and the mechanism of this intrinsic resistance remains unknown. Herein, we report that Bcl2 inhibition rapidly repressed p53 with poor response in <em>BCL2</em>-rearranged lymphoma cells. However, concurrent inhibition of aurora kinase (Aurk) overcame this primary resistance to Bcl2 inhibition by restoring the p53/p21 proapoptotic axis via a post-transcriptional increase in p53. Two independent <em>BCL2</em>-rearranged lymphoma murine models showed complete tumor regression in all animals treated with combined Bcl2/Aurk inhibition, whereas mice treated with single-agents demonstrated rapid progression. Transcriptome analysis confirmed that <em>BCL2</em>-rearranged lymphomas rapidly downregulated the p53 target CDKN1A (p21) in response to Bcl2 inhibition <em>in vivo</em>. However, concurrent inhibition of Aurk restored the TP53/CDKN1A pathway, sensitizing the tumors to Bcl2 inhibitor-mediated apoptosis. These data lay the groundwork for evaluation of this combination in the clinical setting.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112584"},"PeriodicalIF":4.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069028","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}

引用次数: 0

Cannabinoid overrides triggers of GABAergic plasticity in vestibular circuits and distorts the development of navigation 大麻素在前庭回路中覆盖gaba能可塑性的触发器并扭曲导航的发展

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-04-30 DOI: 10.1016/j.isci.2025.112566

Wei Shi , Kenneth Lap-Kei Wu , Mengliu Yang , Francisco Paulo De Nogueira Botelho , Oscar Wing-Ho Chua , Hui-Jing Hu , Ka-Pak Ng , Ulysses Tsz-Fung Lam , Kin-Wai Tam , Chun-Wai Ma , Daisy Kwok-Yan Shum , Ying-Shing Chan

{"title":"Cannabinoid overrides triggers of GABAergic plasticity in vestibular circuits and distorts the development of navigation","authors":"Wei Shi , Kenneth Lap-Kei Wu , Mengliu Yang , Francisco Paulo De Nogueira Botelho , Oscar Wing-Ho Chua , Hui-Jing Hu , Ka-Pak Ng , Ulysses Tsz-Fung Lam , Kin-Wai Tam , Chun-Wai Ma , Daisy Kwok-Yan Shum , Ying-Shing Chan","doi":"10.1016/j.isci.2025.112566","DOIUrl":"10.1016/j.isci.2025.112566","url":null,"abstract":"<div><div>Early life exposure to cannabis can result in long-lasting deficits in spatial navigation. We ask if the development of this behavior is subject to early life activity of type I cannabinoid receptor (CB1R) in the vestibular nucleus. In rodents, we found that local exposure to CB1R agonist within the first postnatal week, but not thereafter, led to a decline in the induction efficacy of long-term depression at GABAergic synapses (LTD<sub>GABA</sub>), a key step in the hard-wiring of vestibular circuits. Within this critical period, endocannabinoid-mediated LTD<sub>GABA</sub> at inhibitory neurons was selectively triggered by cholecystokinin, whereas that at excitatory neurons was by serotonin. Neonatal exposure to cannabinoids extended the phase of high GABAergic synaptic plasticity and overrode the synapse-specific, modulatory mechanism for plasticity. Such treatment delayed the postnatal emergence of vestibular-dependent reflexes and deranged adult navigational behavior. Deficits in higher functions are thus attributable to the maldevelopment of sensory processing circuits resulting from early cannabis exposure.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112566"},"PeriodicalIF":4.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108138","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}

引用次数: 0

Natural plant-derived nanovesicles for effective psoriasis therapy via dual modulation of IL-17 and NRF2 pathway 天然植物源性纳米囊泡通过IL-17和NRF2通路的双重调节有效治疗银屑病

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-04-30 DOI: 10.1016/j.isci.2025.112556

Sreeram Peringattu Kalarikkal , Meghana N. Kumar , Soundaram Rajendran , Cathrine M.S. Bethi , Jahnavi Ravilla , Janakiraman Narayanan , Gopinath M. Sundaram

{"title":"Natural plant-derived nanovesicles for effective psoriasis therapy via dual modulation of IL-17 and NRF2 pathway","authors":"Sreeram Peringattu Kalarikkal , Meghana N. Kumar , Soundaram Rajendran , Cathrine M.S. Bethi , Jahnavi Ravilla , Janakiraman Narayanan , Gopinath M. Sundaram","doi":"10.1016/j.isci.2025.112556","DOIUrl":"10.1016/j.isci.2025.112556","url":null,"abstract":"<div><div>Psoriasis is an inflammatory skin disease with aberrant epidermal differentiation and chronic inflammation. Plant-derived exosome-like nanovesicles (PDNVs) are exosome-mimetic structures isolated from plants with enhanced bioavailability and solubility. Herein, we investigated the therapeutic efficacy of PDNVs for psoriasis treatment. In our initial phenotype-driven screen, PDNVs from apple, garlic, and shallot displayed both pro-differentiation and anti-inflammatory activity <em>in vitro</em>. In imiquimod (IMQ)-induced psoriasis-like murine model, topical application of either shallot or garlic PDNV hydrogels led to complete recovery of normal skin phenotype. In porcine skin <em>ex vivo</em> assay, both shallot and garlic PDNVs displayed percutaneous penetration up to the suprabasal epidermis. Using next generation sequencing and quantitative mRNA profiling in keratinocytes and murine skin, we elucidated a suppressive effect of shallot and garlic PDNVs on IL-17 signaling via modulation of upstream nuclear factor erythroid-2-related factor 2 (NRF2) pathway. Since PDNVs are economical to produce, shallot and garlic PDNVs could be natural and cost-effective topical alternative for psoriasis.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112556"},"PeriodicalIF":4.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069021","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}

引用次数: 0

Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug 结核分枝杆菌氨基酸生物合成途径抑制剂DRILS-1398作为潜在抗结核药物的早期临床前开发

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-04-29 DOI: 10.1016/j.isci.2025.112537

Deepesh Biswas , Rebecca Kristina Edwin , K. Shiva Kumar , Anwar Alam , Dhiraj Kumar , Sandipan Chakraborty , Gopalakrishnan Bulusu , Farhan Jalees Ahmad , Gautham G. Shenoy , Lakshyaveer Singh , Mansi Agarwal , Fouzia Siraj , Srinivas Oruganti , Parimal Misra , Nasreen Zafar Ehtesham , Manojit Pal , Seyed Ehtesham Hasnain

{"title":"Early preclinical development of Mycobacterium tuberculosis amino acid biosynthesis pathway inhibitor DRILS-1398 as a potential anti-TB drug","authors":"Deepesh Biswas , Rebecca Kristina Edwin , K. Shiva Kumar , Anwar Alam , Dhiraj Kumar , Sandipan Chakraborty , Gopalakrishnan Bulusu , Farhan Jalees Ahmad , Gautham G. Shenoy , Lakshyaveer Singh , Mansi Agarwal , Fouzia Siraj , Srinivas Oruganti , Parimal Misra , Nasreen Zafar Ehtesham , Manojit Pal , Seyed Ehtesham Hasnain","doi":"10.1016/j.isci.2025.112537","DOIUrl":"10.1016/j.isci.2025.112537","url":null,"abstract":"<div><div>The search for new anti-tubercular agents is vital for the fight against <em>Mycobacterium tuberculosis</em>, particularly given the rise of drug-resistant strains. DRILS-1398, a pyrazolo[4,3-<em>d</em>]pyrimidine derivative, was discovered as a potent inhibitor of <em>M.tb</em> chorismate mutase (<em>M.tb</em>-CM) with an IC<sub>50</sub> = 3.0 ± 0.2 <em>μ</em>M (<em>n</em> = 3) and IC<sub>90</sub> = 10 <em>μ</em>M. The compound demonstrated efficacy against multi-drug resistant <em>M.tb</em> strains (MIC = 4 μg/mL, ∼10.0 μM) and effective inhibition of intracellular <em>M.tb</em> in THP-1 macrophages. With favorable pharmacokinetics, moderate stability <em>in vitro</em>, and a promising safety profile, DRILS-1398 showed no toxicity at doses up to 500 mg/kg b.w./day when dosed orally daily once for 7 consecutive days in mice. Both DRILS-1398 and its formulation DRILS-1398(F) were successful in clearing <em>M.tb</em> infection from the lungs and spleen in murine models. These findings suggest DRILS-1398 as a promising lead candidate for developing a first-in-class anti-tubercular drug.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112537"},"PeriodicalIF":4.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069022","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}

引用次数: 0

Stable platelet production via the bypass pathway explains long-term hematopoietic stem cell reconstitution 通过旁路途径稳定的血小板生成解释了长期的造血干细胞重建

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-04-29 DOI: 10.1016/j.isci.2025.112547

Shoya Iwanami , Toshiko Sato , Hiroshi Haeno , Longchen Xu , Keimyo Imamura , Jun Ooehara , Xun Lan , Hiromitsu Nakauchi , Shingo Iwami , Ryo Yamamoto

{"title":"Stable platelet production via the bypass pathway explains long-term hematopoietic stem cell reconstitution","authors":"Shoya Iwanami , Toshiko Sato , Hiroshi Haeno , Longchen Xu , Keimyo Imamura , Jun Ooehara , Xun Lan , Hiromitsu Nakauchi , Shingo Iwami , Ryo Yamamoto","doi":"10.1016/j.isci.2025.112547","DOIUrl":"10.1016/j.isci.2025.112547","url":null,"abstract":"<div><div><em>In vivo</em> differentiation pathways into several blood cell lineages of Hematopoietic stem cells (HSCs) remain challenging to track over time. Using data from single-cell transplantation assays and mathematical modeling, we examined HSC differentiation kinetics, including the myeloid bypass pathway. We found that myeloid cell production was unchanged with age, whereas B cell production declined, quantitatively confirming myeloid lineage skewing. Estimated dependence on the platelet-bypass correlated with the long-term reconstitution capacity of HSCs. Time-dependent blood cell production patterns calculated by our model distinguished the reconstitution potential of HSCs into subgroups, suggesting a link between the bypass pathway and the multilineage differentiation dynamics of HSCs. Notably, platelet bypass dependence could be determined by the platelet-to-erythrocyte chimerism ratio at 8 weeks after transplantation, serving as a predictive indicator of long-term HSC function. These findings provide quantitative insights into HSC aging and differentiation dynamics, emphasizing the role of the bypass pathway in defining HSC properties.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112547"},"PeriodicalIF":4.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069093","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}

引用次数: 0

Growth of human regulatory CD4+ T cells is more tightly controlled than effector T cells due to distinctive molecular programming 人类调节性CD4+ T细胞的生长由于其独特的分子编程而比效应T细胞受到更严格的控制

IF 4.6 2区综合性期刊

iScience Pub Date : 2025-04-29 DOI: 10.1016/j.isci.2025.112553

Alejandro Moro , Aixin Yu , Luis Nivelo , Zhen Gao , Yuguang Ban , Alejandro V. Villarino , Thomas R. Malek

{"title":"Growth of human regulatory CD4+ T cells is more tightly controlled than effector T cells due to distinctive molecular programming","authors":"Alejandro Moro , Aixin Yu , Luis Nivelo , Zhen Gao , Yuguang Ban , Alejandro V. Villarino , Thomas R. Malek","doi":"10.1016/j.isci.2025.112553","DOIUrl":"10.1016/j.isci.2025.112553","url":null,"abstract":"<div><div>Foreign and self-antigens activate CD4<sup>+</sup> conventional and regulatory T cells (Tregs) to promote immunity and tolerance, respectively. These cell populations, which depend on interleukin-2 (IL-2), are being expanded and engineered <em>in vitro</em> for adoptive cell therapy (ACT) for cancer and autoimmunity. Here, we investigate the molecular pathways underlying the <em>in vitro</em> expansion of human CD4<sup>+</sup> Teff and Tregs to TCR/CD28/IL-2 signaling over 12-days. Temporal integration of differential chromatin accessibility and gene expression revealed similar responses over the first 6 days. After this time, T effector (Teff) cells showed greater expansion that was associated with more robust gene activation and chromatin opening that supported increased activation of mTORC1-dependent signaling and a more energetic phenotype. Thus, Tregs are programmed temporally for more limited expansion <em>in vitro</em> that may benefit ACT for cancer but may be a drawback for autoimmunity. These findings may reflect a mechanism to finely tune Treg numbers to maintain homeostasis <em>in vivo</em>.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 6","pages":"Article 112553"},"PeriodicalIF":4.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107627","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}

引用次数: 0