Molecular Systems Biology最新文献_第6页

Fast analysis and engineering of protein function by microbe-independent deep assembly and screening. 不依赖微生物的深度组装和筛选的蛋白质功能快速分析和工程。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-06-01 Epub Date: 2026-04-23 DOI: 10.1038/s44320-026-00210-z

Yan Wu, Pengli Wang, Lan Xiang Liu, Daesun Song, Qin Qin, Chao Gao, Matt Hageman, Thomas A Kirkland, Yichi Su, Michael Z Lin

{"title":"Fast analysis and engineering of protein function by microbe-independent deep assembly and screening.","authors":"Yan Wu, Pengli Wang, Lan Xiang Liu, Daesun Song, Qin Qin, Chao Gao, Matt Hageman, Thomas A Kirkland, Yichi Su, Michael Z Lin","doi":"10.1038/s44320-026-00210-z","DOIUrl":"10.1038/s44320-026-00210-z","url":null,"abstract":"Traditional methods for engineering and sequence-fitness analysis of proteins in mammalian cells are limited by the time, cost, and labor associated with plasmid cloning and preparation. Here we present Microbe-Independent Deep Assembly and Screening (MIDAS), a deterministic platform for rapid protein variant expression and characterization in mammalian cells that bypasses microbial cloning by directly transfecting PCR-assembled genes. MIDAS enables high-quality sequence-fitness assessment of arbitrary mutational spaces, including truly deep saturation mutagenesis and combinatorial variant assembly, requiring less than one workday from initial PCR to cell transfection. Using MIDAS, we engineer a high-performance acetylcholine neurotransmitter bioluminescent indicator (ACh-NeuBI), achieving stepwise improvements in responsivity through linker engineering, single-site, and multi-site mutagenesis. We also apply MIDAS to engineer improved NanoLuc luciferase variants for multiple substrates, and to characterize the structural basis of mutational tolerance and substrate specificity. Thus, MIDAS is a versatile method for rapid plasmid-free protein engineering and sequence-fitness analysis in mammalian cells, offering a practical alternative to cloning-based approaches for many protein optimization and characterization tasks.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1003-1034"},"PeriodicalIF":6.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13230610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777147","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

Integrative multi-omics defines melanoma drug response networks and ARID1A-dependent resistance mechanisms. 整合多组学定义黑色素瘤药物反应网络和arid1a依赖的耐药机制。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-02-18 DOI: 10.1038/s44320-025-00183-5

Charlie George Barker, Sumana Sharma, Ana Mafalda Santos, Konstantinos-Stylianos Nikolakopoulos, Athanassios D Velentzas, Cristina Tormo-Garcia, Anushka Sharma, Franziska I Völlmy, Angeliki Minia, Vicky Pliaka, Joseph Clarke, Maarten Altelaar, Gavin J Wright, Leonidas G Alexopoulos, Dimitrios J Stravopodis, Evangelia Petsalaki

{"title":"Integrative multi-omics defines melanoma drug response networks and ARID1A-dependent resistance mechanisms.","authors":"Charlie George Barker, Sumana Sharma, Ana Mafalda Santos, Konstantinos-Stylianos Nikolakopoulos, Athanassios D Velentzas, Cristina Tormo-Garcia, Anushka Sharma, Franziska I Völlmy, Angeliki Minia, Vicky Pliaka, Joseph Clarke, Maarten Altelaar, Gavin J Wright, Leonidas G Alexopoulos, Dimitrios J Stravopodis, Evangelia Petsalaki","doi":"10.1038/s44320-025-00183-5","DOIUrl":"10.1038/s44320-025-00183-5","url":null,"abstract":"Resistance to BRAF/MAPK inhibitors is a significant challenge in melanoma treatment, driven by adaptive and acquired mechanisms allowing tumor cells to evade therapy. We explored early signaling responses to BRAF and MAPK inhibition in a BRAFV600E-sensitive melanoma cell line and a drug-resistant ARID1A-knockout (KO) derivative. ARID1A, frequently mutated in melanoma, is linked to resistance and immune evasion. Through an innovative systems biology approach integrating multi-omics datasets, we identified critical resistance mechanisms. We found that ARID1A-KO cells exhibited transcriptional rewiring, sustaining MAPK1/3 and JNK activity post-treatment, suppressing PRKD1 activation, increasing JUN activity, and disrupting PKC dynamics via elevated RTKs (e.g., EGFR, ROS1) and Ephrin receptor activity. ARID1A-KO also reduced HLA-related protein expression and enhanced extracellular matrix components, potentially limiting immune infiltration and immunotherapy efficacy. Our multi-omics analysis revealed PRKD1, JUN, and NCK1 as key resistance nodes, offering potential targets for therapeutic strategies to counter resistance in melanoma.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"685-711"},"PeriodicalIF":6.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220416","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

Differential nucleosome organization in human interphase and metaphase chromosomes. 人类间期和中期染色体的差异核小体组织。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-02-02 DOI: 10.1038/s44320-026-00192-y

Keren Li, Irem Unlu, Yiren Tu, Lilien N Voong, Yanyan Lu, Brody Kendall, Xiaotian Ma, Sin Lei Pui, Meng Tao, Ji-Ping Wang, Xiaozhong Wang

{"title":"Differential nucleosome organization in human interphase and metaphase chromosomes.","authors":"Keren Li, Irem Unlu, Yiren Tu, Lilien N Voong, Yanyan Lu, Brody Kendall, Xiaotian Ma, Sin Lei Pui, Meng Tao, Ji-Ping Wang, Xiaozhong Wang","doi":"10.1038/s44320-026-00192-y","DOIUrl":"10.1038/s44320-026-00192-y","url":null,"abstract":"DNA bendability plays a critical role in stabilizing nucleosome assembly, yet its contribution to nucleosome dynamics in vivo remains poorly understood. Here, we applied chemical mapping to generate high-resolution nucleosome positioning maps at single-base-pair resolution from human interphase and metaphase chromosomes, revealing distinct patterns of nucleosome organization between the two states. Notably, we observed a unifying pattern of nucleosome positioning near euchromatic landmarks, including promoters, enhancers, and insulators, during mitosis. Interphase nucleosomes exhibited extensive repositioning, marked by increased nucleosome density, reduced spacing between nucleosomes, and the appearance of additional fragile nucleosomes compared to metaphase. Furthermore, our results show that metaphase nucleosomes display significantly higher DNA cyclizability around the dyad axis, whereas interphase nucleosomes, particularly those near regulatory regions, tend to position DNA with greater cyclizability at the edges of the nucleosome. Together, these findings highlight a dynamic interplay between DNA mechanics and nucleosome organization during the cell cycle.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"738-765"},"PeriodicalIF":6.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106038","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

Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease. 多队列、跨物种尿蛋白组学揭示帕金森病中LRRK2功能障碍的特征

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-01-29 DOI: 10.1038/s44320-026-00190-0

Duc Tung Vu, William Sibran, Andreas Metousis, Laurine Vandewynckel, Basak Eraslan, Liesel Goveas, Ericka Cm Itang, Claire Deldycke, Adriana Figueroa-Garcia, Réginald Lefèbvre, Johannes Bruno Müller-Reif, Sebastian Virreira Winter, Marie-Christine Chartier-Harlin, Jean-Marc Taymans, Matthias Mann, Ozge Karayel

{"title":"Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease.","authors":"Duc Tung Vu, William Sibran, Andreas Metousis, Laurine Vandewynckel, Basak Eraslan, Liesel Goveas, Ericka Cm Itang, Claire Deldycke, Adriana Figueroa-Garcia, Réginald Lefèbvre, Johannes Bruno Müller-Reif, Sebastian Virreira Winter, Marie-Christine Chartier-Harlin, Jean-Marc Taymans, Matthias Mann, Ozge Karayel","doi":"10.1038/s44320-026-00190-0","DOIUrl":"10.1038/s44320-026-00190-0","url":null,"abstract":"Pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD) and often increase kinase activity, making LRRK2 inhibitors promising treatment options. Although LRRK2 kinase inhibitors are advancing clinically, non-invasive readouts of LRRK2-linked pathway modulation remain limited. Profiling urinary proteomes from 1215 individuals across three cohorts and integrating whole-genome sequencing from >500 participants to map genotype-proteome associations, we identified 177 urinary proteins associated with pathogenic LRRK2, enriched for lysosomal/glycosphingolipid, immune, and membrane-trafficking pathways. Machine learning narrowed the features to a cohort-agnostic 30-protein panel that classified G2019S carriers with a mean ROC AUC of 0.91 across independent tests. To evaluate translation, we performed multi-organ and urinary proteomics in rat gain- and loss-of-function models (BAC-LRRK2G2019S and Lrrk2KO) and after Lrrk2 inhibition (MLi-2 and PF-475), revealing tissue-specific responses-strongest in kidney-and cross-species overlap, including 24 brain proteins detectable in human urine. Rat-derived perturbations predicted LRRK2 mutation status in patients (AUC 0.75) and reversed with Lrrk2 inhibition, supporting their pharmacodynamic utility. Together, our findings establish urine as a scalable, non-invasive matrix that captures systemic and brain-relevant consequences of LRRK2 dysfunction and nominate candidate pharmacodynamic markers set to support LRRK2-directed trials.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"712-737"},"PeriodicalIF":6.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086478","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

Five dominant amino acid substitution signatures shape tumour immunity. 五个主要的氨基酸取代特征形成肿瘤免疫。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-01-28 DOI: 10.1038/s44320-026-00193-x

Szilvia Juhász, Benjamin Tamás Papp, Anna Tácia Fülöp, Zoltán Farkas, Dávid Kókai, Dóra Alexandra Gyémánt, Franciska Tóth, Zsófia Nacsa, Dóra Spekhardt, Balázs Koncz, Péter Burkovics, Csaba Pál, Máté Manczinger

{"title":"Five dominant amino acid substitution signatures shape tumour immunity.","authors":"Szilvia Juhász, Benjamin Tamás Papp, Anna Tácia Fülöp, Zoltán Farkas, Dávid Kókai, Dóra Alexandra Gyémánt, Franciska Tóth, Zsófia Nacsa, Dóra Spekhardt, Balázs Koncz, Péter Burkovics, Csaba Pál, Máté Manczinger","doi":"10.1038/s44320-026-00193-x","DOIUrl":"10.1038/s44320-026-00193-x","url":null,"abstract":"Although numerous mutational processes operate in cancer, their functional impacts are unclear. We hypothesised that certain mutation sources preferentially generate amino acid substitutions that evade immune recognition, producing immune-cold tumours regardless of tissue or mutation load. By analysing 9300 cancer exomes and performing mutagenesis experiments, we mapped links between mutagens, DNA-repair defects, and amino acid substitution signatures (AAS). Surprisingly, the spectrum collapsed into five recurrent AAS with distinct functional profiles. AAS4-generated by alkylating agents and mismatch-repair (MMR) deficiency and enriched in kidney and liver cancers-is less likely to accumulate hydrophobic residues, yielding poorly immunogenic neopeptides. These tumours display immune-desert microenvironments and respond poorly to immunotherapy. However, certain human leukocyte antigen (HLA) class I variants, such as HLA-B*07:02, correlate with immune-hot tumours in this subgroup. HLA-B*07:02, common in Europeans, presents proline-enriched neopeptides derived from AAS4 mutations. Supporting this, B*07:02-positive cancer cells harbouring AAS4-type mutations stimulated T-cell proliferation in vitro. These results show that neoantigen quality, not merely quantity, dictates anti-tumour immunity, explain inconsistent immunotherapy responses in MMR-deficient cancers, and advocate incorporating amino acid substitution patterns into predictive biomarkers and therapy design.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"22 5","pages":"766-786"},"PeriodicalIF":6.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840610","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

Convergence of aging- and rejuvenation-related epigenetic alterations on PRC2 targets. 衰老和返老还童相关的表观遗传改变在PRC2靶点上的收敛。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-02-10 DOI: 10.1038/s44320-026-00195-9

Oscar Camacho, Michael A Koldobskiy, Pradeep Reddy, Atharv Oak, Yuxiang Sun, Kenna Sherman, Juan Carlos Izpisua Belmonte, Andrew P Feinberg

{"title":"Convergence of aging- and rejuvenation-related epigenetic alterations on PRC2 targets.","authors":"Oscar Camacho, Michael A Koldobskiy, Pradeep Reddy, Atharv Oak, Yuxiang Sun, Kenna Sherman, Juan Carlos Izpisua Belmonte, Andrew P Feinberg","doi":"10.1038/s44320-026-00195-9","DOIUrl":"10.1038/s44320-026-00195-9","url":null,"abstract":"Rejuvenation of tissues in physiologically aging mice can be accomplished by long-term partial reprogramming via expression of reprogramming factors (Oct4, Sox2, Klf4, and c-Myc). To investigate the epigenetic determinants of partial reprogramming-mediated rejuvenation, we used whole-genome bisulfite sequencing to carry out unbiased comprehensive profiling of DNA methylation changes in skin from mice subjected to partial reprogramming, as well as young and untreated old controls. We found a striking convergence of age- and rejuvenation-related epigenetic alterations on targets of the Polycomb repressive complex 2 (PRC2), with increased DNA methylation level and entropy over these regions. Native ChIP demonstrated extensive loss of H3K27me3 in aged epidermis compared to young, partially overlapping regions with age- and rejuvenation-related DNA methylation changes. In addition, large H3K9me2-marked \"LOCK\" heterochromatin domains defined the boundaries for hypomethylated highly entropic regions during aging. These results are also supported by a likewise prominent enrichment of PRC2 targets in gene expression data, suggesting that PRC2 activity can modulate aging and mediate tissue rejuvenation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"787-810"},"PeriodicalIF":6.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157762","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

Dissecting reversible and irreversible single cell state transitions from gene regulatory networks. 剖析基因调控网络中可逆和不可逆的单细胞状态转变。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-02-09 DOI: 10.1038/s44320-026-00196-8

Daniel A Ramirez, Mingyang Lu

引用次数: 0

Genetic barcoding uncovers the clonal makeup of solid and liquid biopsies and their ability to capture intra-tumoral heterogeneity. 遗传条形码揭示了固体和液体活检的克隆组成及其捕获肿瘤内异质性的能力。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-02-11 DOI: 10.1038/s44320-026-00194-w

Antonin Serrano, Tom S Weber, Jean Berthelet, Sarah Ftouni, Farrah El-Saafin, Samuel Lee, Elgene Lim, Emmanuelle Charafe-Jauffret, Christophe Ginestier, David Williams, Frédéric Hollande, Belinda Yeo, Sarah-Jane Dawson, Shalin H Naik, Delphine Merino

{"title":"Genetic barcoding uncovers the clonal makeup of solid and liquid biopsies and their ability to capture intra-tumoral heterogeneity.","authors":"Antonin Serrano, Tom S Weber, Jean Berthelet, Sarah Ftouni, Farrah El-Saafin, Samuel Lee, Elgene Lim, Emmanuelle Charafe-Jauffret, Christophe Ginestier, David Williams, Frédéric Hollande, Belinda Yeo, Sarah-Jane Dawson, Shalin H Naik, Delphine Merino","doi":"10.1038/s44320-026-00194-w","DOIUrl":"10.1038/s44320-026-00194-w","url":null,"abstract":"Intratumoral heterogeneity (ITH) is fueling tumor progression in breast cancer, as specific clones present within a tumor may have a selective advantage to colonize distant organs and escape therapy. Accurate sampling of ITH is therefore a pressing challenge in clinical oncology to adequately predict recurrence and inform rational and personalized therapies. Here, we used genetic barcoding to track the spatiotemporal composition of human breast cancer clones in six preclinical models-across two cell lines and four patient-derived xenografts (PDXs). This allowed a direct side-by-side quantitative comparison of both intra-tumor clonal composition and how that composition was reflected in needle biopsies and cell-free DNA (cfDNA). These analyses highlighted several biologically and clinically relevant findings. First, the use of barcoding revealed that clonal diversity in the center of non-necrotic primary tumors was significantly higher than in the periphery. Second, cfDNA barcode analysis suggested that DNA 'shedding' in the vasculature varied widely, not only depending on necrosis and tumor burden but also across models. Third, combining information captured in both solid and liquid biopsies can provide a more robust assessment of tumor clonal composition. Taken together, these results showcase the utility of these barcoded models to optimize the use of solid and liquid biopsies as surrogates of tumor heterogeneity.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"659-684"},"PeriodicalIF":6.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166035","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

Progress and new challenges in image-based profiling. 基于图像分析的进展和新挑战。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-05-01 Epub Date: 2026-03-27 DOI: 10.1038/s44320-026-00197-7

Erik Serrano, John Peters, Jesko Wagner, Rebecca E Graham, Zhenghao Chen, Brian Y Feng, Gisele Miranda, Alexandr A Kalinin, Loan Vulliard, Jenna Tomkinson, Cameron Mattson, Michael J Lippincott, Ziqi Kang, Divya Sitani, Dave Bunten, Srijit Seal, Neil O Carragher, Anne E Carpenter, Shantanu Singh, Paula A Marin Zapata, Juan C Caicedo, Gregory P Way

{"title":"Progress and new challenges in image-based profiling.","authors":"Erik Serrano, John Peters, Jesko Wagner, Rebecca E Graham, Zhenghao Chen, Brian Y Feng, Gisele Miranda, Alexandr A Kalinin, Loan Vulliard, Jenna Tomkinson, Cameron Mattson, Michael J Lippincott, Ziqi Kang, Divya Sitani, Dave Bunten, Srijit Seal, Neil O Carragher, Anne E Carpenter, Shantanu Singh, Paula A Marin Zapata, Juan C Caicedo, Gregory P Way","doi":"10.1038/s44320-026-00197-7","DOIUrl":"10.1038/s44320-026-00197-7","url":null,"abstract":"For over two decades, image-based profiling has revolutionized cell phenotype analysis. Image-based profiling processes rich, high-throughput, microscopy data into thousands of unbiased measurements that reveal phenotypic patterns powerful for drug discovery, functional genomics, and cell state classification. Here, we review the evolving computational landscape of image-based profiling, detailing the bioinformatics processes involved from feature extraction to normalization and batch correction. We discuss how deep learning has fundamentally reshaped the field. We examine key methodological advancements, such as single-cell analysis, the development of robust similarity metrics, and the expansion into new modalities like optical pooled screening, temporal imaging, and 3D organoid profiling. We also highlight the growth of public benchmarks and open-source software ecosystems as a key driver for fostering reproducibility and collaboration. Despite these advances, the field still faces substantial challenges, particularly in developing methods for emerging temporal and 3D data modalities, establishing robust quality control standards and workflows, and interpreting the processed features. By focusing on the technical evolution of image-based profiling rather than the wide-ranging biological applications, our aim with this review is to provide researchers with a roadmap for navigating the progress and new challenges in this rapidly advancing domain.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"624-658"},"PeriodicalIF":6.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147531167","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

Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen. 揭示酵母菌病原体抗真菌抗性的可行权衡。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-04-01 Epub Date: 2026-01-12 DOI: 10.1038/s44320-025-00185-3

Juan Carlos Nunez-Rodriguez, Miquel Àngel Schikora-Tamarit, Toni Gabaldón

{"title":"Uncovering actionable trade-offs of antifungal resistance in a yeast pathogen.","authors":"Juan Carlos Nunez-Rodriguez, Miquel Àngel Schikora-Tamarit, Toni Gabaldón","doi":"10.1038/s44320-025-00185-3","DOIUrl":"10.1038/s44320-025-00185-3","url":null,"abstract":"The increasing prevalence of antifungal resistance represents a major clinical challenge. To explore potential new therapeutic avenues, we investigated fitness trade-offs associated with azole and echinocandin resistance in Nakaseomyces glabratus (syn. Candida glabrata), a priority yeast pathogen showing growing incidence of drug and multidrug resistance. For this, we comprehensively phenotyped a large collection (n = 77) of azole- and echinocandin-resistant strains to uncover resistance-associated stress sensitivity trade-offs. Our results show that increased stress sensitivity is a common trade-off of drug resistance in this species, with 98% of resistant strains exhibiting reduced fitness under at least one of six assayed stresses. Despite the diversity of genetic backgrounds and resistance mechanisms represented by our collection, we identified consistent trends in some resistance-associated vulnerabilities. Using multivariate modeling we uncovered complex genetic interactions underlying these trade-offs. As a proof of concept for therapeutic potential, we experimentally validated the inhibitory effects of targeting some fitness trade-offs. Cyclosporin A selectively inhibited anidulafungin-resistant strains, while NaCl effectively suppressed the emergence of fluconazole resistance. This study highlights the widespread occurrence of fitness costs associated with antifungal resistance and emphasizes their potential as a novel therapeutic strategy against this growing threat.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"537-562"},"PeriodicalIF":6.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13046754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958800","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