Genome Medicine最新文献

{"title":"Mapping fibroblast plasticity across non-cancer lung diseases at single-cell resolution.","authors":"Junhui Yang, Xin Zhang, Minghui Tang, Yuanpei Jiang, Zhiying Chen, Cuinan Lai, Jingyi Bao, Jin Su, Dan Cui, Jia Li","doi":"10.1186/s13073-026-01730-x","DOIUrl":"https://doi.org/10.1186/s13073-026-01730-x","url":null,"abstract":"<p><strong>Background: </strong>Fibroblast plasticity underlies a wide spectrum of pulmonary diseases, yet the molecular programs governing fibroblast state transitions in non-malignant contexts remain poorly understood.</p><p><strong>Methods: </strong>We integrated 1,470,730 single-cell transcriptomes across three non-cancer lung diseases to construct a comprehensive fibroblast atlas. Integrated clustering and regulon analyses were used to delineate fibroblast subtypes, disease-associated transcriptional programs, and state transitions. ANTXR1, identified as a representative regulator, was validated by tissue immunohistochemistry and siRNA knockdown in primary lung fibroblasts under TGF-β stimulation.</p><p><strong>Results: </strong>Compared with malignancy, fibroblasts in non-cancer lungs exhibited relatively modest transcriptional alterations but maintained distinct disease-associated phenotypes. We further identified a set of fibroblast-specific genes unique to non-malignant contexts, defining molecular features that distinguish fibrotic remodeling from tumor-associated stromal activation. Analysis of fibroblast subtype- and disease-specific regulons revealed 76 gene signatures that were significantly inversely correlated with lung function and distinguished chronic from acute fibrotic fibroblast states. Functional validation demonstrated that ANTXR1 knockdown markedly reduced COL1A1 expression, underscoring its role in fibroblast activation.</p><p><strong>Conclusions: </strong>This work establishes a comprehensive single-cell fibroblast atlas of non-cancer lung diseases, uncovering disease- and subtype-specific regulatory programs and highlighting potential therapeutic targets for fibrotic remodeling.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-resolved genetic risk reveals hyperandrogenism-associated immune and metabolic rewiring in the PMOS follicular microenvironment.","authors":"Yangshuo Li, Di Song, Dongxue Zheng, Xianglin Li, Qianqian Zhao, Yan Liao, Jie Ding, Xiaolan Liang, Mingqing Li, Chaoqin Yu, Zhexin Ni, Jin Yu","doi":"10.1186/s13073-026-01734-7","DOIUrl":"10.1186/s13073-026-01734-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Polyendocrine metabolic ovarian syndrome (PMOS) is a leading cause of anovulatory infertility. Although follicular developmental arrest is a defining feature of PMOS, the cell-type-specific mechanisms linking genetic susceptibility, endocrine imbalance and follicular microenvironmental dysfunction remain incompletely understood, particularly across clinical subtypes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We performed single-cell RNA sequencing of preovulatory follicular-fluid cells from healthy controls and women with uncomplicated PMOS, hyperandrogenic PMOS and metformin-treated insulin-resistant PMOS. We integrated these data with GWAS-derived disease relevance scores and ovarian chromatin-accessibility annotations to map genetic risk to follicular cell populations and regulatory programmes. Ligand-receptor analyses were used to infer intercellular communication networks. Transcriptomic metabolic findings were further assessed by follicular-fluid metabolic and steroid-hormone measurements, DHT-treated granulosa-cell functional assays, and reanalysis of a DHEA-induced mouse PMOS-like ovarian dataset.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We generated a single-cell atlas of the PMOS follicular microenvironment comprising 220,983 high-quality cells. Granulosa cells showed the strongest enrichment of PMOS-related genetic risk, with regulatory-genetic support from ovarian snATAC-seq integration. Among granulosa cell states, a GC2_CYP19A1⁺ population was preferentially associated with hyperandrogenic PMOS and displayed a transcriptional programme characterized by steroidogenic remodelling coupled to reduced energy-metabolic activity. Biochemical profiling supported this endocrine-metabolic imbalance, showing increased follicular-fluid androstenedione (ASD) and estrone, reduced estradiol and E2/ASD ratio, decreased ATP, citrate and fumarate hydratase activity, and increased lactate and β-hydroxybutyrate. Prolonged DHT exposure impaired granulosa-cell mitochondrial respiration, ATP production and mitochondrial membrane potential. In parallel, PMOS subtypes showed immune remodelling and altered ligand-receptor signalling, with hyperandrogenic PMOS associated with increased inflammatory signalling and reduced homeostatic or tissue-repair pathways. Reanalysis of a DHEA-induced mouse ovarian dataset provided supportive evidence for androgen-associated steroidogenic pathway perturbation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study provides a cell-resolved framework linking PMOS genetic susceptibility to endocrine-metabolic and immune remodelling in the preovulatory follicular microenvironment. The identification of a hyperandrogen-associated GC2_CYP19A1⁺ state highlights a candidate cellular programme in which steroidogenic imbalance is coupled to impaired granulosa-cell bioenergetics. These findings provide a resource for future validation and may inform microenvironment-guided stratification of PMOS and the development of strategies","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"clinTALL: machine learning-driven multimodal subtype classification and treatment outcome prediction in pediatric T-ALL.","authors":"Lukas Stoiber, Željko Antić, Stefano Rebellato, Grazia Fazio, Annika Rademacher, Lennart Lenk, Franco Locatelli, Adriana Balduzzi, Gunnar Cario, Carmelo Rizzari, Giovanni Cazzaniga, Jiangyan Yu, Anke Katharina Bergmann","doi":"10.1186/s13073-026-01733-8","DOIUrl":"10.1186/s13073-026-01733-8","url":null,"abstract":"<p><strong>Background: </strong>Childhood T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with poor prognosis. Differently from B-cell precursor ALL, T-ALL lacks effective risk stratification strategies. A recent study has integrated whole genome and whole transcriptome data to define 17 distinct molecular subtypes with prognostic significance. However, clinical translation of this knowledge remains challenging due to the complexity of interpreting high-dimensional multi-omics-based data.</p><p><strong>Methods: </strong>Here, we present clinTALL, a deep learning based multi-task pipeline for pediatric T-ALL subtype classification and treatment outcome estimation. The model integrates multimodal input data and uses a neural network architecture to generate a shared latent embedding for jointly learned multi-task prediction. The competing risk-based model was used to predict event-specific outcomes. The model was trained on a publicly available multimodal dataset comprising clinical, genomic and transcriptomic features of 1309 pediatric T-ALL samples.</p><p><strong>Results: </strong>We observed that the transcriptomic-only model achieved superior single-modality results, with 92.2% accuracy for subtype prediction and a 65.9% concordance index (C-index) for event-free survival (EFS) in a cross-validation setup. Integrating all data modalities maintained high subtype classification accuracy (91.7%) and improved the overall concordance index for EFS estimation to 67.5%. The competing risk-based model enables accurate predictions of induction failure (C-index = 96.0%) and second malignant neoplasm (C-index = 62.1%). We validated molecular subtype predictions on an internal dataset of 120 pediatric T-ALL samples and obtained an accuracy of 81.8%. To facilitate the broad application of multi-omics based subtype prediction and treatment outcome inference, we provide clinTALL as a Docker based application, allowing for user friendly access to the tool.</p><p><strong>Conclusions: </strong>Together, our machine learning-based framework allows for automated, accurate subtype classification and treatment outcome inference using multimodal input data, advancing precision risk stratification for pediatric T-ALL. The full source code of clinTALL is available on GitHub ( https://github.com/UKWgenommedizin/clinTALL ).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561867","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}

{"title":"Correction: Patient induced pluripotent stem cells identify specificities of a reticular pseudodrusen phenotype in age-related macular degeneration.","authors":"Jenna C Hall, Kavitha Krishna Sudhakar, Maciej Daniszewski, Anne Senabouth, Carla J Abbott, Helena H Liang, Himeesh Kumar, Grace E Lidgerwood, Mehdi Mirzaei, Jessica Yw Ma, Trevor Atkeson, Yumiko Hirokawa, Emeline F Nandrot, Alexander Barnett, Chantal Cazevieille, Gaël Manes, Simon Mountford, Philip Thompson, Erica L Fletcher, Zhichao Wu, Melanie Bahlo, Brendan R E Ansell, Daniel Paull, Alex W Hewitt, Robyn H Guymer, Joseph E Powell, Alice Pébay","doi":"10.1186/s13073-026-01728-5","DOIUrl":"10.1186/s13073-026-01728-5","url":null,"abstract":"","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561855","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}

{"title":"Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.","authors":"Christy W LaFlamme, Chris Clarkson, Kristina Ibañez, Jin-Yuan Wang, Soham Sengupta, Jenny Lord, Virginia Valentine, Emily S Bonkowski, Edith P Almanza Fuerte, Athena R Olszewski, Sourav Ghosh, Bharati Jadhav, Taralynn Mack, Jiadong Lin, Sophia B Gibson, Johanna M van Hagen, Mariëlle Alders, Alexandra Martin-Geary, Bida Gu, Mira Kharbanda, Siddharth Banka, Helen M Stuart, Andrew R Webster, Akimoto Hosokawa, Harriet Dashnow, Richa Bajpai, Shondra M Pruett-Miller, Mark J P Chaisson, Danny E Miller, Nicola Whiffin, Evan E Eichler, Sanjay M Sisodiya, Henry Houlden, Andrew J Sharp, Bekim Sadikovic, Marc Valentine, Lynette G Sadleir, Arianna Tucci, Heather C Mefford","doi":"10.1186/s13073-026-01729-4","DOIUrl":"10.1186/s13073-026-01729-4","url":null,"abstract":"<p><strong>Background: </strong>Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders.</p><p><strong>Methods: </strong>We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076).</p><p><strong>Results: </strong>Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions.</p><p><strong>Conclusions: </strong>CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548845","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}

{"title":"Towards culture-free sequencing of Mycobacterium tuberculosis: evaluating new targeted and whole-genome approaches for genotyping and drug resistance profiling.","authors":"Ilaria Iannucci, Federico Di Marco, Kiarash Moghaddasi, Paolo Miotto, Andrea Maurizio Cabibbe, Daniela Maria Cirillo","doi":"10.1186/s13073-026-01726-7","DOIUrl":"10.1186/s13073-026-01726-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The effectiveness of current drug-resistant tuberculosis (DR-TB) regimens is limited by the absence of rapid diagnostics that comprehensively predict resistance to included drugs. Next-generation sequencing (NGS), through culture-free targeted sequencing (tNGS) and culture-based whole-genome sequencing (cWGS) of the Mycobacterium tuberculosis complex (MTBC), offers a powerful framework for precision diagnosis, surveillance, and trial applications. We evaluated two novel assays enabling high-resolution tNGS and enrichment-based direct WGS (dWGS) on respiratory samples, focusing on analytical sensitivity, DR and genotyping concordance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;tNGS Deeplex Myc-TB XL tNGS (Genoscreen, beta-testing) and dWGS QIAseq xHYB MTB (Qiagen) were evaluated on 96 MTBC-positive decontaminated sputum samples from a vaccine trial, spanning a wide range of bacillary loads. DNA was extracted using a host-depletion protocol and quantified by MTBC-specific real-time PCR. Libraries were sequenced on Illumina platforms and analysed using assay-specific pipelines. Associations between genome copy (gc) number and sequencing coverage were assessed. DR concordance was benchmarked against cWGS and the WHO mutation catalogue across first-, second-line, newer, and repurposed drugs. WGS-based phylogenetic trees were constructed using Ridom SeqSphere + .&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Bacillary loads ranged from &lt; 10 to &gt; 1,000 MTBC gc/µL. tNGS generated interpretable resistance profiles in 96.6% of specimens, achieving a limit of detection (LoD) of ~ 10 gc, with 100% positive agreement for all evaluated drugs and 100% negative agreement except for isoniazid/ethionamide (≥ 97%). dWGS yielded data suitable for DR analysis in 75% of samples, with a LoD of ~ 100gc. No false negatives were observed for most drugs; one fluoroquinolone-resistant case was missed due to low-frequency variant thresholds, and resistance to delamanid and clofazimine was misclassified in one case each owing to interpretation rules. Negative agreement was 100% except for rifampicin (≥ 97%). Lineage assignment was concordant with cWGS for both approaches, and dWGS supported transmission analysis in 65% of samples with adequate genome coverage, confirming the cluster detected by cWGS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;In this predominantly drug-susceptible TB cohort, tNGS showed high overall agreement with cWGS for DR profiling with a LoD within the range of low-complexity automated assays used for initial diagnosis. dWGS, while requiring higher DNA input, enables robust culture-free genome-wide analysis, including transmission inference and exploration of candidate DR loci. Bacillary load-guided integration of both approaches may optimize DR-TB clinical management and genomic surveillance. Larger studies are needed to validate clinical and epidemiological predictive performance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Trial registration: &lt;/strong&gt;This trial was registered on ","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548417","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}

{"title":"Multi-threshold polygenic risk improves hippocampal-based cognitive decline prediction.","authors":"Mohammed Janahi, Luigi Lorenzini, Neil P Oxtoby, Frederik Barkhof, Younes Mokrab, Jonathan M Schott, Andre Altmann, For The Alzheimer's Disease Neuroimaging Initiative","doi":"10.1186/s13073-026-01722-x","DOIUrl":"10.1186/s13073-026-01722-x","url":null,"abstract":"<p><strong>Background: </strong>Predicting cognitive decline from brain MRI is a central question in neuroscience. Hippocampal volume (HV) is a key cognitive biomarker, and normative models can be augmented with multimodal information. Here we augment normative models with genetic information and show improvements in cognitive decline prediction across multiple experimental setups.</p><p><strong>Methods: </strong>We improve normative models for HV by integrating multi-threshold polygenic scores (PGS) with demographic and imaging data using Gaussian Process Regression (GPR). Models were trained on 23,997 participants from UK Biobank (UKBB) and validated on 3,000 out-of-sample participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the European Prevention of Alzheimer's Disease (EPAD) cohorts.</p><p><strong>Results: </strong>Our genetically-informed models significantly strengthened associations across six experimental designs and 13 key neurocognitive measures, including Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Alzheimer's Disease Assessment Scale (ADAS), while enhancing prediction of future cognitive decline.</p><p><strong>Conclusions: </strong>Together, these findings underscore the promise of integrating multi-threshold PGS with neuroimaging-based predictive models to improve prognostication and early intervention strategies for neurodegenerative diseases.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470140","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}

{"title":"A short-term randomized clinical trial testing feasibility of and physiological responses to a Ruminococcus torques strain in healthy overweight humans.","authors":"Joachim Gæde, Yong Fan, Liwei Lyu, Evelina Stankevic, Lærke Smidt Gasbjerg, Peter Rossing, Matej Oresic, Tuulia Hyötyläinen, Susanne Brix, Asger B Lund, Dorte Aalund Olsen, Eva Rabing Brix Petersen, Ivan Brandslund, Bolette Hartmann, Jens Juul Holst, Filip Krag Knop, Oluf Pedersen","doi":"10.1186/s13073-026-01708-9","DOIUrl":"10.1186/s13073-026-01708-9","url":null,"abstract":"<p><strong>Background: </strong>The human gut microbiota interacts with host biology as exemplified by the effects of the Ruminococcus torques (RT) ATCC 27756 strain-a commensal human intestinal bacterial strain that synthesizes the polypeptides RORDEP1 and RORDEP2 which in rodents improve metabolism. Motivated by the metabolic effects of the RT strain in the rodent host, we explored in a short-term double blind and placebo-controlled randomized cross-over trial the feasibility and potential physiological responses of the same bacterial strain in humans.</p><p><strong>Methods: </strong>The trial undertaken at Herlev and Gentofte Hospital, Denmark included 32 healthy overweight adults. Decided by block randomization with blocks of six, we infused either 3.1 × 10¹¹ colony forming units of the live RT ATCC 27756 strain or placebo into the duodenum during an observation period of six hours including a two-hour oral glucose tolerance test. Insulin sensitivity measured as Matsuda Insulin Sensitivity Index was the primary endpoint.</p><p><strong>Results: </strong>The infusion of the bacterium was safe and well-tolerated. We found no effects on the primary endpoint of the trial. Compared to placebo, short-term RT infusion induced a relative rise in plasma concentrations of glucagon-like-peptide-1 (GLP-1) and peptide YY (PYY) in parallel with a relative decline in gastric inhibitory polypeptide (GIP). These intestinal hormone responses mirrored those previously reported from studies in rats. The abundance of secondary bile acids in plasma as well as a plasma marker of bone remodeling increased after infusion of RT compared to placebo. Measures of glucose tolerance, energy expenditure, cutaneous thermography, and main markers of systemic low-grade inflammation remained unchanged.</p><p><strong>Conclusions: </strong>Duodenal infusion during six hours of the RT ATCC 27756 strain in healthy overweight humans shows that the bacterial strain is well tolerated, and the short-term effects on intestinal hormone release align with those previously reported in rodents.</p><p><strong>Trial registration: </strong>The trial is registered prospectively in ClinicalTrials.gov on 2022-06-28 with ID NCT05448274 ( https://clinicaltrials.gov/study/NCT05448274?intr=ruminococcus%20torques&viewType=Card&rank=1 ).</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470196","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}

{"title":"A map of intra- and intercellular immune responses across diverse in vitro stimuli and inflammatory disease.","authors":"Oliver Wood, Adam T Braithwaite, Josephine Fisher, Li Li, Lynne Murray, Christopher Paluch, Matthew A Jackson-Wood","doi":"10.1186/s13073-026-01721-y","DOIUrl":"10.1186/s13073-026-01721-y","url":null,"abstract":"<p><strong>Background: </strong>In vitro stimulation of healthy human immune cells is widely used to model the immune states observed in disease, both to investigate pathology and to test therapeutic approaches. However, experiments typically focus on individual cell types or stimuli and a comprehensive cellular comparison of common immunomodulators and their relevance to disease is lacking.</p><p><strong>Methods: </strong>We used single-cell transcriptomics to generate a reference profile of human peripheral blood mononuclear cells treated with 11 different in vitro stimuli, totalling over 150,000 cells across 21 immune cell types. We demonstrate its utility by performing comparative analyses across the immunomodulatory conditions and against peripheral blood profiles from patients with inflammatory disease.</p><p><strong>Results: </strong>We describe transcriptomic responses both unique to and shared across stimuli. For instance, stimulation via the T cell receptor (anti-CD3, CytoStim™) and IFN-α induced broad activation signatures, including indirect effects across multiple cell types, whereas TNF-α and LPS elicited more restricted, cell-specific responses. Ligand-receptor interaction mapping also uncovered the dominant intercellular signalling pathways in each stimulation. Comparing to patient datasets, we identified several aspects of inflammatory disease recapitulated by stimuli. For example, IFN-α stimulation induced SLE-like signatures across cell types, whereas LPS did so specifically within monocytes. However, comparative cell-cell network analysis showed that in vitro stimuli were only able to recapitulate some, but not all, aspects of intercellular interactions upregulated in SLE, highlighting the limitations of these model systems.</p><p><strong>Conclusions: </strong>This dataset provides a valuable resource for understanding the effects of common in vitro blood stimuli, offering insights into their similarities and differences at cellular resolution, and, as demonstrated here, helping to guide the appropriate use of in vitro systems to model disease.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455623","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}

{"title":"Trimodal, uncertainty-guided whole-slide framework for genome-scale spatial expression and image-only virtual perturbation in cancer cohorts.","authors":"Zijun Wang, Chongyi Yang, Xiaoya Tang, Enzhi Yin, Yuxin Yao, Yuejun Luo, Jie He, Nan Sun","doi":"10.1186/s13073-026-01713-y","DOIUrl":"10.1186/s13073-026-01713-y","url":null,"abstract":"<p><p>Spatial transcriptomics is powerful but costly; hematoxylin and eosin (H&E) images are routine. We present Coladan-human3K, the largest human spatial transcriptomics resource (~ 3,000 profiles), and Coladan, a trimodal (image, language, spatial-gene) whole-slide framework predicting genome-wide genes per spot with calibrated uncertainty while preserving foundation-model representations. Across 32 Visium datasets, Coladan improves Pearson correlation from 0.230 to 0.431 (~ 1.9 ×), shows pathway-level enrichment consistency, and transfers zero-shot to VisiumHD and spot-level Xenium. Classification token (CLS) embedding-only perturbation performs on par with expression-based baselines, enabling image-only virtual perturbation without measured expression, illustrated on normal and cancer prostate sections for in-situ hypothesis generation.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445748","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}