Molecular Systems Biology最新文献_第9页

Single cell transcriptional perturbome in pluripotent stem cell models. 多能干细胞模型中的单细胞转录微扰。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-02-01 Epub Date: 2025-12-10 DOI: 10.1038/s44320-025-00172-8

Elisa Balmas, Maria L Ratto, Kirsten E Snijders, Silvia Becca, Carla Liaci, Irene Ricca, Giorgio R Merlo, Raffaele A Calogero, Luca Alessandrì, Sasha Mendjan, Alessandro Bertero

{"title":"Single cell transcriptional perturbome in pluripotent stem cell models.","authors":"Elisa Balmas, Maria L Ratto, Kirsten E Snijders, Silvia Becca, Carla Liaci, Irene Ricca, Giorgio R Merlo, Raffaele A Calogero, Luca Alessandrì, Sasha Mendjan, Alessandro Bertero","doi":"10.1038/s44320-025-00172-8","DOIUrl":"10.1038/s44320-025-00172-8","url":null,"abstract":"Functional genomics screens in human induced pluripotent stem cells (hiPSCs) remain challenging despite their transformative potential. We developed iPS2-seq: an inducible, clone-aware screening platform that enables phenotype-agnostic, single-cell resolved dissection of loss-of-function effects in hiPSC derivatives, including complex multicellular models such as organoids. iPS2-seq distinguishes true perturbation effects from genetic and epigenetic variability. It supports pooled and arrayed formats, integrates with microfluidic or split-pool single-cell RNA sequencing, and extends to multi-omic profiling of chromatin and proteins. A dedicated pipeline, catcheR, streamlines design and analysis. The platform enables stage-specific follow-up dissection of screen hits. We demonstrate this by targeting congenital heart disease-associated genes in monolayer cardiomyocytes and organoids. This reveals that epigenetic neuroectodermal priming interferes with germ layer differentiation in specific clones. Accounting for this bias, we show that SMAD2 controls cardiac progenitor specification, with knockdown redirecting cells toward fibroblast and epicardial fates. iPS2-seq unlocks rigorous functional genomics in hiPSC-based models.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"179-227"},"PeriodicalIF":6.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Suppression of bacterial cell death underlies the antagonistic interaction between ciprofloxacin and tetracycline. 抑制细菌细胞死亡是环丙沙星和四环素之间拮抗相互作用的基础。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-10-27 DOI: 10.1038/s44320-025-00162-w

James Broughton, Achille Fraisse, Meriem El Karoui

{"title":"Suppression of bacterial cell death underlies the antagonistic interaction between ciprofloxacin and tetracycline.","authors":"James Broughton, Achille Fraisse, Meriem El Karoui","doi":"10.1038/s44320-025-00162-w","DOIUrl":"10.1038/s44320-025-00162-w","url":null,"abstract":"Antibiotic combinations aim to maximise drug treatment efficiency and minimise resistance evolution, but a full understanding of their effect on bacterial cells is lacking. The interaction between the DNA-damaging antibiotic ciprofloxacin and the translation inhibitor tetracycline is antagonistic, resulting in a weaker effect on bacterial growth than expected from each drug individually. While this antagonism has been analysed at the population level, it has not been investigated at the single-cell level. We used a microfluidic device to quantify the antagonism between ciprofloxacin and tetracycline in single bacterial cells under three nutrient conditions. Improved growth results from increased survival of cells under the drug combination compared to ciprofloxacin alone. This effect depends on the initial drug-free growth rate, with better suppression in nutrient-rich conditions. Quantifying the DNA damage response (SOS response) revealed two sub-populations among cells that died upon ciprofloxacin treatment. The larger low-SOS sub-population, which showed increased survival compared to high-SOS cells, explains the stronger antagonistic effect in nutrient-rich conditions. Our results underscore the importance of single-cell quantification in understanding bacterial responses to antibiotic combinations.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"102-118"},"PeriodicalIF":6.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145378042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A single-cell multiomics roadmap of zebrafish spermatogenesis reveals regulatory principles of male germline formation. 斑马鱼精子发生的单细胞多组学路线图揭示了雄性种系形成的调节原理。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-10-14 DOI: 10.1038/s44320-025-00157-7

Ana María Burgos-Ruiz, Fan-Suo Geng, Gala Pujol, Estefanía Sanabria, Thirsa Brethouwer, María Almuedo-Castillo, Aurora Ruiz-Herrera, Juan J Tena, Ozren Bogdanovic

{"title":"A single-cell multiomics roadmap of zebrafish spermatogenesis reveals regulatory principles of male germline formation.","authors":"Ana María Burgos-Ruiz, Fan-Suo Geng, Gala Pujol, Estefanía Sanabria, Thirsa Brethouwer, María Almuedo-Castillo, Aurora Ruiz-Herrera, Juan J Tena, Ozren Bogdanovic","doi":"10.1038/s44320-025-00157-7","DOIUrl":"10.1038/s44320-025-00157-7","url":null,"abstract":"Spermatogenesis is the biological process by which male sperm cells (spermatozoa) are produced in the testes. Beyond facilitating the transmission of genetic information, spermatogenesis also provides a potential framework for inter- and transgenerational inheritance of gene-regulatory states. While extensively studied in mammals, our understanding of spermatogenesis in anamniotes remains limited. Here we present a comprehensive single-cell multiomics resource, combining single-cell RNA sequencing (scRNA-seq) and single-cell chromatin accessibility (scATAC-seq) profiling, with base-resolution DNA methylome (WGBS) analysis of sorted germ cell populations from zebrafish (Danio rerio) testes. We identify the major germ cell types involved in zebrafish spermatogenesis as well as key drivers associated with these transcriptional states. Moreover, we describe localised DNA methylation changes associated with spermatocyte populations, as well as local and global changes in chromatin accessibility leading to chromatin compaction in spermatids. Notably, we identify loci that evade global chromatin compaction, and which remain accessible, suggesting a potential mechanism for the intergenerational transmission of gene-regulatory states. In summary, this high-resolution atlas of zebrafish spermatogenesis provides a valuable resource for studying vertebrate germ cell development and epigenetic inheritance, while offering a robust framework for comparative analyses across diverse models of germ cell biology.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"42-68"},"PeriodicalIF":6.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From denaturant to ribosome: rethinking chaperone requirements in cells. 从变性剂到核糖体：重新思考细胞中的伴侣需求。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-10-28 DOI: 10.1038/s44320-025-00167-5

Yevheniia Bushman, Andrew W Truman

引用次数: 0

Chaperone dependency during biogenesis does not correlate with chaperone dependency during refolding. 生物发生过程中的伴侣依赖性与再折叠过程中的伴侣依赖性无关。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-10-28 DOI: 10.1038/s44320-025-00166-6

Divya Yadav, İdil I Demiralp, Mark Fakler, Stephen D Fried

{"title":"Chaperone dependency during biogenesis does not correlate with chaperone dependency during refolding.","authors":"Divya Yadav, İdil I Demiralp, Mark Fakler, Stephen D Fried","doi":"10.1038/s44320-025-00166-6","DOIUrl":"10.1038/s44320-025-00166-6","url":null,"abstract":"Many proteins require molecular chaperones to fold into their functional native forms. However, the roles of chaperones during primary biogenesis in vivo can differ from the functions they play during in vitro refolding experiments. Here, we use limited proteolysis mass spectrometry (LiP-MS) to probe structural changes incurred by the E. coli proteome when two key chaperones, trigger factor and DnaKJ, are deleted. While knocking out DnaKJ induces pervasive structural perturbations across the soluble E. coli proteome, trigger factor deletion only impacts a small number of proteins' structures. Overall, proteins which cannot spontaneously refold (or require chaperones to refold in vitro) are not more likely to be dependent on chaperones to fold in vivo. We find that chaperone-nonrefolders (proteins that cannot refold even with chaperone assistance) do not generally require chaperones to fold in vivo, strengthening the view that chaperone-nonrefolders are obligate co-translational folders. Hence, for some E. coli proteins, the vectorial nature of co-translational folding is the most important \"chaperone\".","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"139-164"},"PeriodicalIF":6.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145391530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

FACT depletion demonstrates a role for nucleosome organization in TAD formation. FACT缺失证明了核小体组织在TAD形成中的作用。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-10-27 DOI: 10.1038/s44320-025-00165-7

Clemens Mauksch, Yi Zhu, Taras Velychko, Spyridoula Sagropoulou, Abrar Aljahani, Shyam Ramasamy, Kristina Žumer, A Marieke Oudelaar

{"title":"FACT depletion demonstrates a role for nucleosome organization in TAD formation.","authors":"Clemens Mauksch, Yi Zhu, Taras Velychko, Spyridoula Sagropoulou, Abrar Aljahani, Shyam Ramasamy, Kristina Žumer, A Marieke Oudelaar","doi":"10.1038/s44320-025-00165-7","DOIUrl":"10.1038/s44320-025-00165-7","url":null,"abstract":"Mammalian genomes are organized into distinct chromatin structures, which include small-scale nucleosome arrays and large-scale topologically associating domains (TADs). The mechanistic interplay between chromatin structures across scales is poorly understood. Here, we investigate how changes in nucleosome organization impact TAD structure by studying the role of the histone chaperone facilitates chromatin transcription (FACT) in 3D genome organization. We show that FACT depletion perturbs TADs, causing decreased insulation and weaker CTCF loops. These changes in TAD structure cannot be attributed to changes in chromatin occupancy of CTCF or cohesin and occur specifically in transcribed regions of the genome, where we observe perturbed nucleosome organization in the absence of FACT. FACT depletion therefore allows us to separate the role of nucleosome organization and CTCF binding and to demonstrate that the organization of nucleosomes at TAD boundaries contributes to TAD formation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"119-138"},"PeriodicalIF":6.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145378067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering mammalian cells for detection and treatment of cardiac injury. 用于检测和治疗心脏损伤的工程哺乳动物细胞。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-10-10 DOI: 10.1038/s44320-025-00161-x

Yaqing Si, Yuxuan Fan, Leo Scheller, Bozhidar-Adrian Stefanov, Jian Lv, Zhihua Wang, Mingqi Xie, Martin Fussenegger

{"title":"Engineering mammalian cells for detection and treatment of cardiac injury.","authors":"Yaqing Si, Yuxuan Fan, Leo Scheller, Bozhidar-Adrian Stefanov, Jian Lv, Zhihua Wang, Mingqi Xie, Martin Fussenegger","doi":"10.1038/s44320-025-00161-x","DOIUrl":"10.1038/s44320-025-00161-x","url":null,"abstract":"Early detection of myocardial abnormalities or other ischemic heart diseases is critical for effective treatment. Here, we aimed to engineer a cell-based system to sense cardiac troponin I (cTnI), an early marker of acute myocardial infarction (AMI), and respond by releasing a thrombolytic agent. To detect cTnI, we engineered a chimeric troponin receptor (TropR) that contains extracellular single-chain variable fragments (scFvs) and signals via intracellular domains of interleukin 6 receptor subunit beta (IL6RB), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2b (FGFR2b) or vascular endothelial growth factor receptor 2 (VEGFR2) that are associated with cardioprotective signaling. cTnI-dependent TropR functionality was confirmed in human embryonic kidney (HEK)-derived cell lines as well as iPSC-derived cardiomyocytes, and enabled rapid, reversible, tunable control of gene expression via synthetic-signaling-specific promoters. We then constructed monoclonal cell lines for cTnI-induced secretion of the thrombolytic protein tenecteplase (TNK), together with an off-switch triggered by FDA-approved doxycycline. We selected a clone, designated CardioProtect, whose sensitivity was optimized to detect human AMI-relevant cTnI levels. To validate thrombolytic efficacy, we established an ex vivo blood culture system and show that alginate-microencapsulated CardioProtect cells triggered complete lysis of fibrin clots in a strict cTnI-inducible, doxycycline-repressible manner. This closed-loop strategy serves as a proof-of-concept for using cell therapy in the early detection and treatment of AMI.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"88-101"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of potent high-affinity secondary nucleation inhibitors of Aβ42 aggregation from an ultra-large chemical library using deep docking. 利用深度对接技术从超大型化学文库中鉴定Aβ42聚集的强效高亲和二级成核抑制剂。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-11-05 DOI: 10.1038/s44320-025-00159-5

Michaela Brezinova, Z Faidon Brotzakis, Robert I Horne, Vaidehi Roy Chowdhury, Rebecca C Gregory, Yuqi Bian, Alicia González Díaz, Francesco Gentile, Michele Vendruscolo

{"title":"Identification of potent high-affinity secondary nucleation inhibitors of Aβ42 aggregation from an ultra-large chemical library using deep docking.","authors":"Michaela Brezinova, Z Faidon Brotzakis, Robert I Horne, Vaidehi Roy Chowdhury, Rebecca C Gregory, Yuqi Bian, Alicia González Díaz, Francesco Gentile, Michele Vendruscolo","doi":"10.1038/s44320-025-00159-5","DOIUrl":"10.1038/s44320-025-00159-5","url":null,"abstract":"Alzheimer's disease is characterized by the aggregation of the Aβ peptide into amyloid fibrils. According to the amyloid hypothesis, pharmacologically targeting Aβ aggregation could result in disease-modifying treatments. The identification of inhibitors of Aβ aggregation, however, is complicated by complex technical challenges, which typically restrict to tens of thousands the number of compounds that can be screened in experimental aggregation assays. Here, we report a computational route to increase by 4 orders of magnitude the number of screenable compounds. We achieve this result by developing an open source pipeline version of the Deep Docking protocol, and illustrate its application to the discovery of secondary nucleation inhibitors of Aβ aggregation from an ultra-large chemical library of over 539 million compounds. The pipeline was used to prioritize 35 candidate compounds for in vitro testing in Aβ aggregation assays. We found that 19 of these compounds inhibit Aβ aggregation (54% hit rate). The two most potent compounds showed potency better than adapalene, a previously reported potent inhibitor of Aβ aggregation. Consistent with the intended mechanism of action, these two compounds also proved to be high-affinity binders of Aβ fibrils with an equilibrium dissociation constant in the low nanomolar range in surface plasmon resonance experiments. These results provide evidence that structure-based docking methods based on deep learning represent a cost-effective and rapid strategy to identify potent hits for drug development targeting protein misfolding diseases.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"69-87"},"PeriodicalIF":6.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-cell heterogeneity underpins antagonistic antibiotic interactions. 单细胞异质性是拮抗抗生素相互作用的基础。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-10-27 DOI: 10.1038/s44320-025-00163-9

João Pedro Teuber Carvalho, Daniel Schultz

引用次数: 0

Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets. 卵巢癌前体的空间蛋白质组学描述了早期疾病变化和药物靶点。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-01-01 Epub Date: 2025-11-13 DOI: 10.1038/s44320-025-00168-4

Anuar Makhmut, Mihnea P Dragomir, Sonja Fritzsche, Markus Moebs, Wolfgang D Schmitt, Eliane T Taube, Fabian Coscia

{"title":"Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets.","authors":"Anuar Makhmut, Mihnea P Dragomir, Sonja Fritzsche, Markus Moebs, Wolfgang D Schmitt, Eliane T Taube, Fabian Coscia","doi":"10.1038/s44320-025-00168-4","DOIUrl":"10.1038/s44320-025-00168-4","url":null,"abstract":"High-grade serous ovarian cancer (HGSOC) is often detected at an advanced stage, where curative treatment options are limited. Recent advances in ultrasensitive mass spectrometry-based spatial proteomics have provided a unique opportunity to uncover molecular drivers of early tumorigenesis and novel therapeutic targets. Here, we present a comprehensive proteomic analysis of serous tubal intraepithelial carcinoma (STIC), the HGSOC precursor lesion, and concurrent invasive carcinoma, covering more than 10,000 proteins from ultra-low input archival tissue. STIC and HGSOC showed highly similar proteomes, clustering into two subtypes with distinct tumor-immune microenvironments and common remodeling of the extracellular matrix. We discovered cell-of-origin signatures from secretory fallopian tube epithelial cells in STICs and identified early dysregulated pathways of therapeutic relevance. Targeting cholesterol biosynthesis by inhibiting the terminal steps via DHCR7 showed therapeutic effects in ovarian cancer cell lines and synergized with standard-of-care carboplatin treatment. This study demonstrates the power of spatially resolved quantitative proteomics in understanding early carcinogenesis and provides a rich resource for biomarker and drug target research.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"7-41"},"PeriodicalIF":6.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0