Cell systemsPub Date : 2026-08-19Epub Date: 2026-07-01DOI: 10.1016/j.cels.2026.101652
Yili Qian, Sarvesh D Menon, Hanchen Huang, Nick Quinn-Bohmann, Sean M Gibbons, Ophelia S Venturelli
{"title":"A data-driven modeling framework for mapping genotypes to synthetic microbial community functions.","authors":"Yili Qian, Sarvesh D Menon, Hanchen Huang, Nick Quinn-Bohmann, Sean M Gibbons, Ophelia S Venturelli","doi":"10.1016/j.cels.2026.101652","DOIUrl":"10.1016/j.cels.2026.101652","url":null,"abstract":"<p><p>Synthetic microbial communities offer valuable insights into the mechanisms that govern community functions, and they can be designed to achieve desired functions in order to address societal challenges in precision medicine and agriculture. Existing computational models for predicting synthetic community functions use species abundances as inputs; this makes it impossible to predict the effects of species not included in training data. We bridge this gap using a data-driven community genotype-function (dCGF) modeling framework. By lifting the representation of each species to a high-dimensional genetic feature (GF) space, dCGF learns a mapping from community GF matrices to community functions. Using in silico and experimental data, we demonstrate that dCGF can accurately predict community functions that are composed partly or entirely of new species. In addition, dCGF can generate hypotheses about the contribution of specific GFs to community functions. In sum, dCGF uses genetic information to model synthetic microbial communities in order to empower their model-driven design. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101652"},"PeriodicalIF":7.7,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148371287","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-05-13DOI: 10.1016/j.cels.2026.101610
Iurii Savvateev, Florian Missey, Valeriia Beliaeva, Sofia Peressotti, Marija Markicevic, Diana Kindler, Fabrice Chaudun, Giulia Casarotto, Camilla Bellone, Christian Lüscher, Daniel Razansky, Viktor Jirsa, Adam Williamson, Rafael Polania, Valerio Zerbi
{"title":"Multipair phase-modulated temporal interference electrical stimulation combined with fMRI.","authors":"Iurii Savvateev, Florian Missey, Valeriia Beliaeva, Sofia Peressotti, Marija Markicevic, Diana Kindler, Fabrice Chaudun, Giulia Casarotto, Camilla Bellone, Christian Lüscher, Daniel Razansky, Viktor Jirsa, Adam Williamson, Rafael Polania, Valerio Zerbi","doi":"10.1016/j.cels.2026.101610","DOIUrl":"10.1016/j.cels.2026.101610","url":null,"abstract":"<p><p>Temporal interference stimulation (TIS) is a non-invasive brain stimulation technique that exploits frequency-shifted kHz fields to modulate oscillatory neural activity. While human studies suggest TIS efficacy in targeting relatively deep brain structures, recent computational modeling and animal studies indicate potential off-target stimulations via standard TIS protocols. Here, we computationally optimized TIS targeting for the medial prefrontal cortex (mPFC) in mice. Combining in vivo electrophysiological recordings, intracellular calcium dynamics with fiber photometry, and functional MRI, we confirmed TIS-induced amplitude modulation, neuronal entrainment, and hemodynamic responses in the mPFC, while also identifying off-target modulations. To mitigate off-target effects, we introduced a configuration with three electrode pairs, one of which is actively phase-shifted by 180°. This canceling field enhanced TIS focality, thereby reducing off-target effects without compromising TIS efficacy in the target area. This work effectively addresses one of TIS's most critical shortcomings and opens new avenues for research and clinical applications. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101610"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147944078","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-07-08DOI: 10.1016/j.cels.2026.101677
Simran Kaur Aulakh, Oliver Lemke, Lukasz Szyrwiel, Stephan Kamrad, Yu Chen, Johannes Hartl, Michael Mülleder, Jens Nielsen, Markus Ralser
{"title":"The molecular landscape of cellular metal ion biology.","authors":"Simran Kaur Aulakh, Oliver Lemke, Lukasz Szyrwiel, Stephan Kamrad, Yu Chen, Johannes Hartl, Michael Mülleder, Jens Nielsen, Markus Ralser","doi":"10.1016/j.cels.2026.101677","DOIUrl":"10.1016/j.cels.2026.101677","url":null,"abstract":"","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101677"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148414242","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-06-19DOI: 10.1016/j.cels.2026.101647
Aoife O'Farrell, Zijian Niu, Jingxin Li, Laura C Van Eyndhoven, Kavitha Sarma, Arjun Raj
{"title":"Human macrophages encode stimulus-specific information of prior exposures through trained immunity.","authors":"Aoife O'Farrell, Zijian Niu, Jingxin Li, Laura C Van Eyndhoven, Kavitha Sarma, Arjun Raj","doi":"10.1016/j.cels.2026.101647","DOIUrl":"10.1016/j.cels.2026.101647","url":null,"abstract":"<p><p>Trained immunity (a form of innate immune memory) is defined in part by heightened responses to pathogen restimulation and can be generated by many different stimuli. However, both the quantitative differences in trained states generated by different stimuli and the downstream consequences of those differences remain unclear. Here, we used primary human monocyte-derived macrophages to demonstrate phenotypic and molecular stimulus specificity of trained immunity 6 days after initial exposure. Quantification of cytokine production with single-molecule RNA imaging revealed stimulus-specific patterns of response to restimulation, with trained cells showing stronger responses to secondary stimuli more similar to their initial stimulation. Differential licensing of inflammatory transcription factors was associated with encoding of specificities in chromatin 6 days after training, while memory of some, but not all, training stimuli was lost by 11 days post-training in vitro. Overall, our findings demonstrate that different training stimuli can impart specific memories that generate distinct training phenotypes.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101647"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148284994","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-06-23DOI: 10.1016/j.cels.2026.101648
Aoife O'Farrell, Zijian Niu, Arjun Raj
{"title":"Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.","authors":"Aoife O'Farrell, Zijian Niu, Arjun Raj","doi":"10.1016/j.cels.2026.101648","DOIUrl":"10.1016/j.cels.2026.101648","url":null,"abstract":"<p><p>Macrophages can remember prior activation and subsequently augment their response to restimulation through trained immunity. However, it remains uncertain how trained immunity phenotypes manifest in individual cells. Here, we leverage highly quantitative single-molecule RNA imaging across 90,857 individual macrophages from 26 human donors to reveal inflammatory response dynamics in trained vs. untrained populations at single-cell resolution. Different inflammatory response genes showed distinct single-cell behavior in trained populations upon restimulation. Although training increased transcription of these response genes early after restimulation, untrained populations eventually \"caught up\" to the transcriptional output of trained populations, highlighting the importance of sampling timescale when interpreting transcriptional assays of training. Training did not significantly alter the relationship between the transcriptional activation of different genes within the same single cell, and any single cell appeared to be capable of training. Overall, these results revealed gene-specific single-cell transcriptional changes that generate population-wide training phenotypes in macrophages.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101648"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148310827","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-06-01DOI: 10.1016/j.cels.2026.101615
Henri Schmidt, Benjamin J Raphael
{"title":"The tree labeling polytope: A unified approach to ancestral reconstruction problems.","authors":"Henri Schmidt, Benjamin J Raphael","doi":"10.1016/j.cels.2026.101615","DOIUrl":"10.1016/j.cels.2026.101615","url":null,"abstract":"<p><p>A common problem in phylogeny is to reconstruct the ancestral states of a feature measured at the present time. The classic Fitch-Hartigan and Sankoff algorithms compute the most parsimonious or most likely reconstruction. However, these approaches do not readily extend to structured ancestral reconstruction problems, such as those encountered when inferring the routes of metastases in cancer, deriving the transmission history of viruses, or detecting horizontal gene transfer in phylogenetic networks. We develop a combinatorial optimization approach to ancestral reconstruction problems based on the tree-labeling polytope, a geometric object whose vertices represent the ancestral labelings of a tree. We derive algorithms for three structured ancestral reconstruction problems: parsimonious migration history, softwired small parsimony, and convex recoloring. We apply these algorithms to analyze routes of metastasis in a mouse model of lung adenocarcinoma using lineage-tracing data from thousands of single cells.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101615"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148145584","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}
Cell systemsPub Date : 2026-07-15DOI: 10.1016/j.cels.2026.101672
Alexander E Vlahos
{"title":"Programmable regenerative tissues: Converging mammalian synthetic biology and tissue engineering.","authors":"Alexander E Vlahos","doi":"10.1016/j.cels.2026.101672","DOIUrl":"10.1016/j.cels.2026.101672","url":null,"abstract":"<p><p>Synthetic biology can program cellular behavior but remains underused in regenerative medicine. This commentary argues that integrating synthetic biology with tissue engineering should target vascularization and immune integration through compact, context-aware circuits. Embedded within engineered tissues, these circuits could enable adaptive grafts that sense stress and coordinate regenerative responses.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":"17 7","pages":"101672"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457664","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-05-27DOI: 10.1016/j.cels.2026.101612
Yuan Li, Qian Kong, Zihan Wu, Yanfen Xu, Yiheng Mao, Yunjie Gu, Xi Wang, Weina Gao, Ruijun Tian, Jianhua Yao
{"title":"Digital decoding tissue microenvironment heterogeneity from spatial proteomics through graph-enhanced transfer learning.","authors":"Yuan Li, Qian Kong, Zihan Wu, Yanfen Xu, Yiheng Mao, Yunjie Gu, Xi Wang, Weina Gao, Ruijun Tian, Jianhua Yao","doi":"10.1016/j.cels.2026.101612","DOIUrl":"10.1016/j.cels.2026.101612","url":null,"abstract":"<p><p>Spatial proteomics studies the protein localization patterns within tissues, providing new insights into cellular ecosystems and disease mechanisms. One critical challenge is its restricted spatial resolution, where each measured spot contains mixtures of cells, obscuring cell-type-specific proteomic signatures. Here, we propose spatial digital cytometry (Spatial-DC), a graph-enhanced transfer learning framework that computationally profiles single-cell-type-resolved signatures from spatial proteomics. Comprehensive benchmarking demonstrates that Spatial-DC outperforms eight state-of-the-art transcriptomics-based methods in estimating the cell-type composition accurately. Applied to diverse data from antibody-based and mass spectrometry (MS)-based technologies, Spatial-DC generates more refined cell-type distribution maps than marker-based distributions and successfully reconstructs proteomic profiles resolved by both spatial and cell types. In a self-collected MS-based pancreatic cancer dataset, Spatial-DC identifies cell-type-specific spatial interactions linked to tumor outcomes. Collectively, Spatial-DC serves as a versatile framework for spatial proteomics, enabling multiscale decoding of tissue microenvironments in a single-cell-type- and spatial-context-resolved manner for downstream analysis.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101612"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148044884","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-06-19DOI: 10.1016/j.cels.2026.101643
Shiyuan Zheng, Yi-Hsuan Chiang, Dasia Aldarondo, Alexandra Locke, Jagadambika Gunaje, Jennifer Davis, Zachary R Fox, Belinda S Akpa, Elizabeth Wayne
{"title":"Capturing the dynamics of STAT6 macrophage polarization using bioluminescence temporal signatures.","authors":"Shiyuan Zheng, Yi-Hsuan Chiang, Dasia Aldarondo, Alexandra Locke, Jagadambika Gunaje, Jennifer Davis, Zachary R Fox, Belinda S Akpa, Elizabeth Wayne","doi":"10.1016/j.cels.2026.101643","DOIUrl":"10.1016/j.cels.2026.101643","url":null,"abstract":"<p><p>Signal transducer and activator of transcription 6 (STAT6) signaling is activated by interleukin 4 (IL-4) and IL-13 and drives alternative macrophage polarization, which is pivotal in wound healing, immunosuppression, and tumor progression. STAT6 functions by forming a phosphorylated homodimer and binding to STAT6-responsive promoter elements to regulate anti-inflammatory genes. Measuring STAT6 activity can serve as a proxy for assessing macrophage polarization. We developed a STAT6-responsive-element (RE) THP-1 reporter to assess STAT6 activation in response to inflammatory stimuli. We quantitatively measured macrophage polarization by using bioluminescence temporal spectrometry (BTS). Human THP-1 monocytes were transduced with lentivirus to express STAT6-RE-firefly luciferase (FLuc)-green fluorescent protein (GFP). The STAT6-RE accurately reported endogenous STAT6 activity, as confirmed by ELISA, western blotting, bioluminescence, and imaging techniques. We developed a systems model to connect emergent bioluminescence to the kinetics of relevant STAT6 cellular signaling events. These results indicate a probe for assessing macrophage alternative polarization, enhancing our understanding of the relationship between molecular mechanisms and macrophage polarization.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101643"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148285019","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}
Cell systemsPub Date : 2026-07-15Epub Date: 2026-06-04DOI: 10.1016/j.cels.2026.101621
Yongjie Lin, Xiangru Chen, Long Wu, Yutong Zhou, Yihan Lin
{"title":"Widespread transcriptional memory shapes heritable states and functional heterogeneity in cancer and stem cells.","authors":"Yongjie Lin, Xiangru Chen, Long Wu, Yutong Zhou, Yihan Lin","doi":"10.1016/j.cels.2026.101621","DOIUrl":"10.1016/j.cels.2026.101621","url":null,"abstract":"<p><p>Recent studies show that non-genetic heterogeneity, particularly through heritable cell states, shapes cancer evolution and developmental trajectories. However, single-cell snapshots lack temporal information to identify these states. We employ lineage-resolved single-cell transcriptomics to map heritable cell states that persist across divisions, distinguishing them from transient fluctuations. We reveal that heritable states are underpinned by widespread transcriptional memory, whereby heritable gene expression defines two classes of states: clustered states, characterized by clustered gene expression, and latent states, marked by non-clustered gene expression. This memory shows partial conservation across cell types and conditions and appears to be maintained by robust epigenetic mechanisms that are resistant to environmental perturbations. Functionally, memory genes predict critical behaviors, including metastatic potential and lineage commitment, with latent-state genes often outperforming clustered-state genes. Our findings establish transcriptional memory as a potential basis for heritable cellular heterogeneity, providing a framework for understanding functional cellular variation across biological systems.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"101621"},"PeriodicalIF":7.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165887","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}