Cell systems最新文献_第3页

FlowDesign: Improved design of antibody CDRs through flow matching and better prior distributions. FlowDesign：通过流程匹配和更好的先验分布，改进抗体cdr的设计。

Cell systems Pub Date : 2025-04-24 DOI: 10.1016/j.cels.2025.101270

Jun Wu, Xiangzhe Kong, Ningguan Sun, Jing Wei, Sisi Shan, Fuli Feng, Feng Wu, Jian Peng, Linqi Zhang, Yang Liu, Jianzhu Ma

{"title":"FlowDesign: Improved design of antibody CDRs through flow matching and better prior distributions.","authors":"Jun Wu, Xiangzhe Kong, Ningguan Sun, Jing Wei, Sisi Shan, Fuli Feng, Feng Wu, Jian Peng, Linqi Zhang, Yang Liu, Jianzhu Ma","doi":"10.1016/j.cels.2025.101270","DOIUrl":"https://doi.org/10.1016/j.cels.2025.101270","url":null,"abstract":"Designing antibodies with desired binding specificity and affinity is essential for pharmaceutical research. While diffusion-based models have advanced the co-design of the complementarity-determining region (CDR) sequences and structures, challenges remain, including non-informative priors, incompatibility with discrete amino acid types, and impractical computational costs in large-scale sampling. To address these, we propose FlowDesign, a sequence-structure co-design approach via flow matching, offering (1) flexible prior selection, (2) direct matching of discrete distributions, and (3) enhanced efficiency for large-scale sampling. By leveraging various priors, data-driven structural models proved the most informative. FlowDesign outperformed baselines in amino acid recovery (AAR), root-mean-square deviation (RMSD), and Rosetta energy. We also applied FlowDesign to design antibodies targeting the HIV-1 receptor CD4. FlowDesign yielded antibodies with improved binding affinity and neutralizing potency compared with the antibody ibalizumab across multiple HIV mutants, validated by biolayer interferometry (BLI) and pseudovirus neutralization. This highlights FlowDesign's potential in antibody and protein design. A record of this paper's transparent peer review process is included in the supplemental information.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101270"},"PeriodicalIF":0.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrase enables synthetic intercellular logic via bacterial conjugation. 整合酶使合成细胞间逻辑通过细菌偶联。

Cell systems Pub Date : 2025-04-22 DOI: 10.1016/j.cels.2025.101268

Fang Ba, Yufei Zhang, Luyao Wang, Xiangyang Ji, Wan-Qiu Liu, Shengjie Ling, Jian Li

引用次数: 0

Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells. 基于microrna的基因电路的模型引导设计支持转基因货物进入不同原代细胞的精确剂量。

Cell systems Pub Date : 2025-04-22 DOI: 10.1016/j.cels.2025.101269

Kasey S Love, Christopher P Johnstone, Emma L Peterman, Stephanie Gaglione, Michael E Birnbaum, Kate E Galloway

{"title":"Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells.","authors":"Kasey S Love, Christopher P Johnstone, Emma L Peterman, Stephanie Gaglione, Michael E Birnbaum, Kate E Galloway","doi":"10.1016/j.cels.2025.101269","DOIUrl":"https://doi.org/10.1016/j.cels.2025.101269","url":null,"abstract":"In a therapeutic context, supraphysiological expression of transgenes can compromise engineered phenotypes and lead to toxicity. To ensure a narrow range of transgene expression, we developed a single-transcript, microRNA-based incoherent feedforward loop called compact microRNA-mediated attenuator of noise and dosage (ComMAND). We experimentally tuned the ComMAND output profile, and we modeled the system to explore additional tuning strategies. By comparing ComMAND to two-gene implementations, we demonstrate the precise control afforded by the single-transcript architecture, particularly at low copy numbers. We show that ComMAND tightly regulates transgene expression from lentiviruses and precisely controls expression in primary human T cells, primary rat neurons, primary mouse embryonic fibroblasts, and human induced pluripotent stem cells. Finally, ComMAND effectively sets levels of the clinically relevant transgenes frataxin (FXN) and fragile X messenger ribonucleoprotein 1 (Fmr1) within a narrow window. Overall, ComMAND is a compact tool well suited to precisely specify the expression of therapeutic cargoes. A record of this paper's transparent peer review process is included in the supplemental information.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101269"},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition. 早期适应致癌BRAF抑制的信号和转录动力学。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-20 DOI: 10.1016/j.cels.2025.101239

Cameron T Flower, Chunmei Liu, Hui-Yu Chuang, Xiaoyang Ye, Hanjun Cheng, James R Heath, Wei Wei, Forest M White

{"title":"Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition.","authors":"Cameron T Flower, Chunmei Liu, Hui-Yu Chuang, Xiaoyang Ye, Hanjun Cheng, James R Heath, Wei Wei, Forest M White","doi":"10.1016/j.cels.2025.101239","DOIUrl":"10.1016/j.cels.2025.101239","url":null,"abstract":"A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing (RNA-seq) to monitor the dynamics of thousands of growth- and survival-related signals over the first minutes, hours, and days of oncogenic BRAF inhibition in human melanoma cells. We observed sustained inhibition of the BRAF-ERK axis, gradual downregulation of cell cycle signaling, and three distinct, reversible phase transitions toward quiescence. Statistical inference of kinetically defined regulatory modules revealed a dominant compensatory induction of SRC family kinase (SFK) signaling, promoted in part by excess reactive oxygen species, rendering cells sensitive to co-treatment with an SFK inhibitor in vitro and in vivo, underscoring the translational potential for assessing early drug-induced adaptive signaling. A record of this paper's transparent peer review process is included in the supplemental information.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101239"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674913","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}

引用次数: 0

Proliferation history and transcription factor levels drive direct conversion to motor neurons. 增殖历史和转录因子水平驱动直接转化为运动神经元。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-13 DOI: 10.1016/j.cels.2025.101205

Nathan B Wang, Brittany A Lende-Dorn, Adam M Beitz, Patrick Han, Honour O Adewumi, Timothy M O'Shea, Kate E Galloway

{"title":"Proliferation history and transcription factor levels drive direct conversion to motor neurons.","authors":"Nathan B Wang, Brittany A Lende-Dorn, Adam M Beitz, Patrick Han, Honour O Adewumi, Timothy M O'Shea, Kate E Galloway","doi":"10.1016/j.cels.2025.101205","DOIUrl":"10.1016/j.cels.2025.101205","url":null,"abstract":"The sparse and stochastic nature of conversion has obscured our understanding of how transcription factors (TFs) drive cells to new identities. To overcome this limit, we develop a tailored, high-efficiency conversion system that increases the direct conversion of fibroblasts to motor neurons 100-fold. By tailoring the cocktail to a minimal set of transcripts, we reduce extrinsic variation, allowing us to examine how proliferation and TFs synergistically drive conversion. We show that cell state-as set by proliferation history-defines how cells interpret the levels of TFs. Controlling for proliferation history and titrating each TF, we find that conversion correlates with levels of the pioneer TF Ngn2. By isolating cells by both their proliferation history and Ngn2 levels, we demonstrate that levels of Ngn2 expression alone are insufficient to predict conversion rates. Rather, proliferation history and TF levels combine to drive direct conversion. Finally, increasing the proliferation rate of adult human fibroblasts generates morphologically mature induced human motor neurons at high rates.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101205"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630934","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}

引用次数: 0

Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders. 突触的综合多组学特征揭示了与神经发育障碍相关的RNA加工因子和泛素连接酶。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-06 DOI: 10.1016/j.cels.2025.101204

Yuan Mei, Maya L Gosztyla, Xinzhu Tan, Lara E Dozier, Brent Wilkinson, Justin McKetney, John Lee, Michael Chen, Dorothy Tsai, Hema Kopalle, Marina A Gritsenko, Nicolas Hartel, Nicholas A Graham, Ilse Flores, Stephen K Gilmore-Hall, Shuhao Xu, Charlotte A Marquez, Sophie N Liu, Dylan Fong, Jing Chen, Kate Licon, Derek Hong, Sarah N Wright, Jason F Kreisberg, Alexi Nott, Richard D Smith, Wei-Jun Qian, Danielle L Swaney, Lilia M Iakoucheva, Nevan J Krogan, Gentry N Patrick, Yang Zhou, Guoping Feng, Marcelo P Coba, Gene W Yeo, Trey Ideker

{"title":"Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders.","authors":"Yuan Mei, Maya L Gosztyla, Xinzhu Tan, Lara E Dozier, Brent Wilkinson, Justin McKetney, John Lee, Michael Chen, Dorothy Tsai, Hema Kopalle, Marina A Gritsenko, Nicolas Hartel, Nicholas A Graham, Ilse Flores, Stephen K Gilmore-Hall, Shuhao Xu, Charlotte A Marquez, Sophie N Liu, Dylan Fong, Jing Chen, Kate Licon, Derek Hong, Sarah N Wright, Jason F Kreisberg, Alexi Nott, Richard D Smith, Wei-Jun Qian, Danielle L Swaney, Lilia M Iakoucheva, Nevan J Krogan, Gentry N Patrick, Yang Zhou, Guoping Feng, Marcelo P Coba, Gene W Yeo, Trey Ideker","doi":"10.1016/j.cels.2025.101204","DOIUrl":"10.1016/j.cels.2025.101204","url":null,"abstract":"The molecular composition of the excitatory synapse is incompletely defined due to its dynamic nature across developmental stages and neuronal populations. To address this gap, we apply proteomic mass spectrometry to characterize the synapse in multiple biological models, including the fetal human brain and human induced pluripotent stem cell (hiPSC)-derived neurons. To prioritize the identified proteins, we develop an orthogonal multi-omic screen of genomic, transcriptomic, interactomic, and structural data. This data-driven framework identifies proteins with key molecular features intrinsic to the synapse, including characteristic patterns of biophysical interactions and cross-tissue expression. The multi-omic analysis captures synaptic proteins across developmental stages and experimental systems, including 493 synaptic candidates supported by proteomics. We further investigate three such proteins that are associated with neurodevelopmental disorders-Cullin 3 (CUL3), DEAD-box helicase 3 X-linked (DDX3X), and Y-box binding protein-1 (YBX1)-by mapping their networks of physically interacting synapse proteins or transcripts. Our study demonstrates the potential of an integrated multi-omic approach to more comprehensively resolve the synaptic architecture.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101204"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Minding the synapse: A multi-omic approach reveals hidden regulators of neurodevelopment. 注意突触：一种多组学方法揭示了隐藏的神经发育调节因子。

Cell systems Pub Date : 2025-04-16 DOI: 10.1016/j.cels.2025.101263

Alicia Ljungdahl, Ryan S Dhindsa

引用次数: 0

SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data. SpaGRN：研究空间解析转录组学数据的空间知情调控路径。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-04-02 DOI: 10.1016/j.cels.2025.101243

Yao Li, Xiaobin Liu, Lidong Guo, Kai Han, Shuangsang Fang, Xinjiang Wan, Dantong Wang, Xun Xu, Ling Jiang, Guangyi Fan, Mengyang Xu

{"title":"SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data.","authors":"Yao Li, Xiaobin Liu, Lidong Guo, Kai Han, Shuangsang Fang, Xinjiang Wan, Dantong Wang, Xun Xu, Ling Jiang, Guangyi Fan, Mengyang Xu","doi":"10.1016/j.cels.2025.101243","DOIUrl":"10.1016/j.cels.2025.101243","url":null,"abstract":"Cells spatially organize into distinct cell types or functional domains through localized gene regulatory networks. However, current spatially resolved transcriptomics analyses fail to integrate spatial constraints and proximal cell influences, limiting the mechanistic understanding of tissue organization. Here, we introduce SpaGRN, a statistical framework that reconstructs cell-type- or functional-domain-specific, dynamic, and spatial regulons by coupling intracellular spatial regulatory causality with extracellular signaling path information. Benchmarking across synthetic and real datasets demonstrates SpaGRN's superior precision over state-of-the-art tools in identifying context-dependent regulons. Applied to diverse spatially resolved transcriptomics platforms (Stereo-seq, STARmap, MERFISH, CosMx, Slide-seq, and 10x Visium), complex cancerous samples, and 3D datasets of developing Drosophila embryos and larvae, SpaGRN not only provides a versatile toolkit for decoding receptor-mediated spatial regulons but also reveals spatiotemporal regulatory mechanisms underlying organogenesis and inflammation.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101243"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Assembly of stool-derived bacterial communities follows "early-bird" resource utilization dynamics. 粪便衍生细菌群落的组装遵循“早起鸟”的资源利用动态。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-28 DOI: 10.1016/j.cels.2025.101240

Andrés Aranda-Díaz, Lisa Willis, Taylor H Nguyen, Po-Yi Ho, Jean Vila, Tani Thomsen, Taylor Chavez, Rose Yan, Feiqiao Brian Yu, Norma Neff, Brian C DeFelice, Alvaro Sanchez, Sylvie Estrela, Kerwyn Casey Huang

{"title":"Assembly of stool-derived bacterial communities follows \"early-bird\" resource utilization dynamics.","authors":"Andrés Aranda-Díaz, Lisa Willis, Taylor H Nguyen, Po-Yi Ho, Jean Vila, Tani Thomsen, Taylor Chavez, Rose Yan, Feiqiao Brian Yu, Norma Neff, Brian C DeFelice, Alvaro Sanchez, Sylvie Estrela, Kerwyn Casey Huang","doi":"10.1016/j.cels.2025.101240","DOIUrl":"10.1016/j.cels.2025.101240","url":null,"abstract":"Diet can impact host health through changes to the gut microbiota, yet we lack mechanistic understanding linking nutrient availability and microbiota composition. Here, we use thousands of microbial communities cultured in vitro from human stool to develop a predictive model of community composition upon addition of single nutrients from central carbon metabolism to a complex medium. Among these communities, membership was largely determined by the donor stool, whereas relative abundances were determined by the supplemental carbon source. The absolute abundance of most taxa was independent of the supplementing nutrient due to the ability of a few organisms to quickly exhaust their niche in the complex medium and then exploit and monopolize the supplemental carbon source. Relative abundances of dominant taxa could be predicted from the nutritional preferences and growth dynamics of species in isolation, and exceptions were consistent with strain-level variation in growth capabilities. Our study reveals that assembly of this community of gut commensals can be explained by nutrient utilization dynamics that provide a predictive framework for manipulating community composition through nutritional perturbations.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101240"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Compact transcription factor cassettes generate functional, engraftable motor neurons by direct conversion. 紧凑的转录因子盒式磁带通过直接转化产生功能性的、可移植的运动神经元。

Cell systems Pub Date : 2025-04-16 Epub Date: 2025-03-13 DOI: 10.1016/j.cels.2025.101206

Nathan B Wang, Honour O Adewumi, Brittany A Lende-Dorn, Adam M Beitz, Timothy M O'Shea, Kate E Galloway

{"title":"Compact transcription factor cassettes generate functional, engraftable motor neurons by direct conversion.","authors":"Nathan B Wang, Honour O Adewumi, Brittany A Lende-Dorn, Adam M Beitz, Timothy M O'Shea, Kate E Galloway","doi":"10.1016/j.cels.2025.101206","DOIUrl":"10.1016/j.cels.2025.101206","url":null,"abstract":"Direct conversion generates patient-specific, disease-relevant cell types, such as neurons, that are rare, limited, or difficult to isolate from common and easily accessible cells, such as skin cells. However, low rates of direct conversion and complex protocols limit scalability and, thus, the potential of cell-fate conversion for biomedical applications. Here, we optimize the conversion protocol by examining process parameters, including transcript design; delivery via adeno-associated virus (AAV), retrovirus, and lentivirus; cell seeding density; and the impact of media conditions. Thus, we report a compact, portable conversion process that boosts proliferation and increases direct conversion of mouse fibroblasts to induced motor neurons (iMNs) to achieve high conversion rates of above 1,000%, corresponding to more than ten motor neurons yielded per cell seeded, which we achieve through expansion. Our optimized, direct conversion process generates functional motor neurons at scales relevant for cell therapies (>107 cells) that graft with the mouse central nervous system. High-efficiency, compact, direct conversion systems will support scaling to patient-specific, neural cell therapies.","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101206"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0