Systems Biology
The cellular and molecular cardiac tissue responses in human inflammatory cardiomyopathies after SARS-CoV-2 infection and COVID-19 vaccination
Nat Cardiovasc Res. 2025 Feb 24. doi: 10.1038/s44161-025-00612-6. Online ahead of print.
ABSTRACT
Myocarditis, characterized by inflammatory cell infiltration, can have multiple etiologies, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or, rarely, mRNA-based coronavirus disease 2019 (COVID-19) vaccination. The underlying cellular and molecular mechanisms remain poorly understood. In this study, we performed single-nucleus RNA sequencing on left ventricular endomyocardial biopsies from patients with myocarditis unrelated to COVID-19 (Non-COVID-19), after SARS-CoV-2 infection (Post-COVID-19) and after COVID-19 vaccination (Post-Vaccination). We identified distinct cytokine expression patterns, with interferon-γ playing a key role in Post-COVID-19, and upregulated IL16 and IL18 expression serving as a hallmark of Post-Vaccination myocarditis. Although myeloid responses were similar across all groups, the Post-Vaccination group showed a higher proportion of CD4+ T cells, and the Post-COVID-19 group exhibited an expansion of cytotoxic CD8+ T and natural killer cells. Endothelial cells showed gene expression changes indicative of vascular barrier dysfunction in the Post-COVID-19 group and ongoing angiogenesis across all groups. These findings highlight shared and distinct mechanisms driving myocarditis in patients with and without a history of SARS-CoV-2 infection or vaccination.
PMID:39994453 | DOI:10.1038/s44161-025-00612-6
Circadian clock features define novel subtypes among breast cancer cells and shape drug sensitivity
Mol Syst Biol. 2025 Feb 24. doi: 10.1038/s44320-025-00092-7. Online ahead of print.
ABSTRACT
The circadian clock regulates key physiological processes, including cellular responses to DNA damage. Circadian-based therapeutic strategies optimize treatment timing to enhance drug efficacy and minimize side effects, offering potential for precision cancer treatment. However, applying these strategies in cancer remains limited due to a lack of understanding of the clock's function across cancer types and incomplete insights into how the circadian clock affects drug responses. To address this, we conducted deep circadian phenotyping across a panel of breast cancer cell lines. Observing diverse circadian dynamics, we characterized metrics to assess circadian rhythm strength and stability in vitro. This led to the identification of four distinct circadian-based phenotypes among 14 breast cancer cell models: functional, weak, unstable, and dysfunctional clocks. Furthermore, we demonstrate that the circadian clock plays a critical role in shaping pharmacological responses to various anti-cancer drugs and we identify circadian features descriptive of drug sensitivity. Collectively, our findings establish a foundation for implementing circadian-based treatment strategies in breast cancer, leveraging clock phenotypes and drug sensitivity patterns to optimize therapeutic outcomes.
PMID:39994450 | DOI:10.1038/s44320-025-00092-7
Activation of the bacterial defense-associated sirtuin system
Commun Biol. 2025 Feb 24;8(1):297. doi: 10.1038/s42003-025-07743-3.
ABSTRACT
The NADase activity of the defense-associated sirtuins (DSRs) is activated by the phage tail tube protein (TTP). Herein, we report cryo-EM structures of a free-state Bacillus subtilis DSR2 tetramer and a fragment of the tetramer, a phage SPR tail tube, and two DSR2-TTP complexes. DSR2 contains an N-terminal SIR2 domain, a middle domain (MID) and a C-terminal domain (CTD). The DSR2 CTD harbors the α-solenoid tandem-repeats like the HEAT-repeat proteins. DSR2 assembles into a tetramer with four SIR2 clustered at the center, and two intertwined MID-CTD chains flank the SIR2 core. SPR TTPs self-assemble into a tube-like complex. Upon DSR2 binding, the D1 domain of SPR TTP is captured between the HEAT-repeats domains of DSR2, which conflicts with TTPs self-assembly. Binding of TTPs induces conformational changes in DSR2 tetramer, resulting in increase of the NAD+ pocket volume in SIR2, thus activates the NADase activity and leads to cellular NAD+ depletion.
PMID:39994439 | DOI:10.1038/s42003-025-07743-3
PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors
Nat Neurosci. 2025 Feb 24. doi: 10.1038/s41593-024-01865-3. Online ahead of print.
ABSTRACT
Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH.
PMID:39994410 | DOI:10.1038/s41593-024-01865-3
Metformin modulates FJX1 via upregulation of Hsa-miR-1306-3p to suppress colon adenocarcinoma viability
Sci Rep. 2025 Feb 24;15(1):6658. doi: 10.1038/s41598-025-91022-y.
ABSTRACT
Metformin, widely used for the treatment of type 2 diabetes, has recently gained attention for its potential anticancer properties. Several studies have shown that metformin treatment inhibits cell viability in colon adenocarcinoma (COAD); however, the research related to the tumor-node-metastasis (TNM) stage is limited. As COAD is frequently diagnosed at an advanced stage, understanding the genetic factors that regulate the pathogenesis of COAD at each TNM stage and the effects of metformin for potential treatment. Therefore, we identified differentially expressed factors at the TNM stage in metformin-treated COAD cells and investigated their regulatory mechanisms using microRNAs (miRNAs). Through bioinformatics analyses, four-jointed box kinase 1 (FJX1) and hsa-miR-1306-3p were identified as differentially expressed in COAD upon metformin treatment. Metformin treatment significantly reduced cell viability, with an observed decrease of approximately 50%. Analysis using quantitative real-time PCR showed an increase in hsa-miR-1306-3p and a decrease in FJX1 expression upon metformin treatment compared to untreated cells. Luciferase assay confirmed the sequence-specific binding of hsa-miR-1306-3p to FJX1. These findings highlight the potential of metformin as a therapeutic agent for COAD by modulating FJX1 expression via upregulation of hsa-miR-1306-3p, revealing novel avenues for COAD treatment.
PMID:39994354 | DOI:10.1038/s41598-025-91022-y
Dissecting the properties of circulating IgG against streptococcal pathogens through a combined systems antigenomics-serology workflow
Nat Commun. 2025 Feb 24;16(1):1942. doi: 10.1038/s41467-025-57170-5.
ABSTRACT
This study showcases an integrative mass spectrometry-based strategy combining systems antigenomics and systems serology to characterize human antibodies in clinical samples. This strategy involves using antibodies circulating in plasma to affinity-enrich antigenic proteins in biochemically fractionated pools of bacterial proteins, followed by their identification and quantification using mass spectrometry. A selected subset of the identified antigens is then expressed recombinantly to isolate antigen-specific IgG, followed by characterization of the structural and functional properties of these antibodies. We focused on Group A streptococcus (GAS), a major human pathogen lacking an approved vaccine. The data shows that both healthy and GAS-infected individuals have circulating IgG against conserved streptococcal proteins, including toxins and virulence factors. The antigenic breadth of these antibodies remains relatively constant across healthy individuals but changes considerably in GAS bacteremia. Moreover, antigen-specific IgG analysis reveals individual variation in titers, subclass distributions, and Fc-signaling capacity, despite similar epitope and Fc-glycosylation patterns. Finally, we show that GAS antibodies may cross-react with Streptococcus dysgalactiae (SD), a bacterial pathogen that occupies similar niches and causes comparable infections. Collectively, our results highlight the complexity of GAS-specific antibody responses and the versatility of our methodology to characterize immune responses to bacterial pathogens.
PMID:39994218 | DOI:10.1038/s41467-025-57170-5
Integrated Pharmacogenetic Signature for the Prediction of Prostatic Neoplasms in Men With Metabolic Disorders
Cancer Genomics Proteomics. 2025 Mar-Apr;22(2):285-305. doi: 10.21873/cgp.20502.
ABSTRACT
BACKGROUND/AIM: Oncogenic processes are delineated by metabolic dysregulation. Drug likeness is pharmacokinetically tested through the CYP450 enzymatic system, whose genetic aberrations under epigenetic stress could shift male organisms into prostate cancer pathways. Our objective was to predict the susceptibility to prostate neoplasia, focused on benign prostatic hyperplasia (BPH) and prostate cancer (PCa), based on the pharmacoepigenetic and the metabolic profile of Caucasians.
MATERIALS AND METHODS: Two independent cohorts of 47,389 individuals in total were assessed to find risk associations of CYP450 genes with prostatic neoplasia. The metabolic profile of the first cohort was statistically evaluated and frequencies of absorption-distribution-metabolism-excretion-toxicity (ADMET) properties were calculated. Prediction of miRNA pharmacoepigenetic targeting was performed.
RESULTS: We found that prostate cancer and benign prostatic hyperplasia patients of the first cohort shared common cardiometabolic trends. Drug classes C08CA, C09AA, C09CA, C10AA, C10AX of the cardiovascular, and G04CA, G04CB of the genitourinary systems, were associated with increased prostate cancer risk, while C03CA and N06AB of the cardiovascular and nervous systems were associated with low-risk for PCa. CYP3A4*1B was the most related pharmacogenetic polymorphism associated with prostate cancer susceptibility. miRNA-200c-3p and miRNA-27b-3p seem to be associated with CYP3A4 targeting and prostate cancer predisposition. Metabolomic analysis indicated that 11β-OHT, 2β-OHT, 15β-OHT, 2α-OHT and 6β-OHT had a high risk, and 16α-OHT, and 16β-OHT had an intermediate disease-risk.
CONCLUSION: These findings constitute a novel integrated signature for prostate cancer susceptibility. Further studies are required to assess their predictive value more fully.
PMID:39993800 | DOI:10.21873/cgp.20502
Structural variant and nucleosome occupancy dynamics postchemotherapy in a HER2+ breast cancer organoid model
Proc Natl Acad Sci U S A. 2025 Mar 4;122(9):e2415475122. doi: 10.1073/pnas.2415475122. Epub 2025 Feb 24.
ABSTRACT
The most common chemotherapeutics induce DNA damage to eradicate cancer cells, yet defective DNA repair can propagate mutations, instigating therapy resistance and secondary malignancies. Structural variants (SVs), arising from copy-number-imbalanced and -balanced DNA rearrangements, are a major driver of tumor evolution, yet understudied posttherapy. Here, we adapted single-cell template-strand sequencing (Strand-seq) to a HER2+ breast cancer model to investigate the formation of doxorubicin-induced de novo SVs. We coupled this approach with nucleosome occupancy (NO) measurements obtained from the same single cell to enable simultaneous SV detection and cell-type classification. Using organoids from TetO-CMYC/TetO-Neu/MMTV-rtTA mice modeling HER2+ breast cancer, we generated 459 Strand-seq libraries spanning various tumorigenesis stages, identifying a 7.4-fold increase in large chromosomal alterations post-doxorubicin. Complex DNA rearrangements, deletions, and duplications were prevalent across basal, luminal progenitor (LP), and mature luminal (ML) cells, indicating uniform susceptibility of these cell types to SV formation. Doxorubicin further elevated sister chromatid exchanges (SCEs), indicative of genomic stress persisting posttreatment. Altered nucleosome occupancy levels on distinct cancer-related genes further underscore the broad genomic impact of doxorubicin. The organoid-based system for single-cell multiomics established in this study paves the way for unraveling the most important therapy-associated SV mutational signatures, enabling systematic studies of the effect of therapy on cancer evolution.
PMID:39993200 | DOI:10.1073/pnas.2415475122
The mutational landscape and its longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma
Ann Hematol. 2025 Feb 24. doi: 10.1007/s00277-025-06274-5. Online ahead of print.
ABSTRACT
In classic Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with responders. Therefore, ultra-deep next-generation panel-sequencing was performed on a total of 59 FFPE-samples (20 responders, 26 relapsed (rHL: 11 initial-diagnosis, 15 relapse) and 13 primary-refractory (prHL: 8 initial-diagnosis, 5 progression) from 44 cHL-patients applying a hybrid-capture approach. We compared samples associated with distinct disease courses concerning their oncogenic drivers, mutational signatures, and perturbed pathways. Compared to responders, mutations in genes such as PMS2, PDGFRB, KAT6A, EPHB1, and HGF were detected more frequently in prHL/rHL. Additionally, we observed that in rHL or prHL, BARD1-mutations occur, whereas ETV1, NF1, and MET-mutations were eliminated through clonal selection. A significant enrichment of non-synonymous variants was detected in prHL compared to responders and a significant selection process in favor of NOTCH-pathway mutations driving rHL or prHL was observed. However, our analysis revealed a negative selection process for non-synonymous variants affecting the hippo-pathway. This study delineates distinct mutational signatures between responders and rHL/prHL, whilst illustrating longitudinal dynamics in mutational profiles using paired samples. Further, several exploitable therapeutic vulnerabilities for rHL and prHL were identified.
PMID:39992429 | DOI:10.1007/s00277-025-06274-5
HIV-1 gp120 Interactions with Nicotine Modulate Mitochondrial Network Properties and Amyloid Release in Microglia
Neurochem Res. 2025 Feb 24;50(2):103. doi: 10.1007/s11064-025-04357-3.
ABSTRACT
Human immunodeficiency virus (HIV) infections remain a significant public health burden globally with infected individuals at high risk for cognitive decline and memory loss even on combination antiretroviral therapy. Almost half of HIV infected individuals smoke, which drives poorer health outcomes including a higher dementia rate. Microglia are the brain's immune cells that serve as a persistent HIV reservoir contributing to neuroinflammatory signaling. We examined interactions between the HIV envelope glycoprotein gp120 and nicotine within human microglia cells (HMC3) that endogenously express chemokine receptor 5 (CCR5) and nicotinic acetylcholine receptors (nAChRs). Liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI/MS) shows that gp120 alters mitochondria proteins within HMC3 cells. In the presence of nicotine, gp120 increased the expression of mitochondrial prohibitin 2 (PHB2), cytochrome c (cyt c), and mitofusin 2 (MFN2) but decreased fission 1 (FIS1) levels. An analysis of mito-YFP expression confirms that interaction between nicotine and gp120 increases the size and branching of mitochondrial networks. Interaction between nicotine and gp120 is also surprisingly found to promote the release of amyloid precursor protein (APP) peptides from microglia. This was accompanied by visualization of amyloid containing vesicles that colocalized with the autophagy protein LC3B-II in the cell. Taken together, our findings show that interaction between nicotine and gp120 impact microglia in a manner that regulates mitochondrial proteins and network properties and impacts amyloid protein management and release within microglia. These mechanisms may contribute to understanding neuroinflammatory signaling in smokers with HIV.
PMID:39992414 | DOI:10.1007/s11064-025-04357-3
Editorial: The non-coding RNA world in animals and plants
Front Genet. 2025 Feb 7;16:1558406. doi: 10.3389/fgene.2025.1558406. eCollection 2025.
NO ABSTRACT
PMID:39991320 | PMC:PMC11842322 | DOI:10.3389/fgene.2025.1558406
Unraveling the influence of microbial necromass on subsurface microbiomes: metabolite utilization and community dynamics
ISME Commun. 2025 Jan 29;5(1):ycaf006. doi: 10.1093/ismeco/ycaf006. eCollection 2025 Jan.
ABSTRACT
The role of microbial necromass (nonliving microbial biomass), a significant component of belowground organic carbon, in nutrient cycling and its impact on the dynamics of microbial communities in subsurface systems remains poorly understood. It is currently unclear whether necromass metabolites from various microbes are different, whether certain groups of metabolites are preferentially utilized over others, or whether different microbial species respond to various necromass metabolites. In this study, we aimed to fill these knowledge gaps by designing enrichments with necromass as the sole nutrient source for subsurface microbial communities. We used the soluble fraction of necromass from bacterial isolates belonging to Arthrobacter, Agrobacterium, and Pseudomonas genera, and our results indicate that metabolite composition of necromass varied slightly across different strains but generally included amino acids, organic acids, and nucleic acid constituents. Arthrobacter-derived necromass appeared more recalcitrant. Necromass metabolites enriched diverse microbial genera, particularly Massilia sp. responded quickly regardless of the necromass source. Despite differences in necromass utilization, microbial community composition converged rapidly over time across the three different necromass amendments. Uracil, xanthine, valine, and phosphate-containing isomers were generally depleted over time, indicating microbial assimilation for maintenance and growth. However, numerous easily assimilable metabolites were not significantly depleted, suggesting efficient necromass recycling and the potential for necromass stabilization in systems. This study highlights the dynamic interactions between microbial necromass metabolites and subsurface microbial communities, revealing both selective utilization and rapid community and necromass convergence regardless of the necromass source.
PMID:39991274 | PMC:PMC11843093 | DOI:10.1093/ismeco/ycaf006
Multi-Pass Arrival Time Correction in Cyclic Ion Mobility Mass Spectrometry for Imaging and Shotgun Lipidomics
ACS Meas Sci Au. 2024 Dec 27;5(1):109-119. doi: 10.1021/acsmeasuresciau.4c00077. eCollection 2025 Feb 19.
ABSTRACT
Direct-infusion mass spectrometry (DI-MS) and mass spectrometry imaging (MSI) are powerful techniques for lipidomics research. However, annotating isomeric and isobaric lipids with these methods is challenging due to the absence of chromatographic separation. Recently, cyclic ion mobility mass spectrometry (cIM-MS) has been proposed to overcome this limitation. However, fluctuations in room conditions can affect ion mobility multipass arrival times, potentially reducing annotation confidence. In this study, we developed a multipass arrival time correction method that proved effective across various dates, room temperatures, ion mobility settings, and laboratories using mixtures of reference standards. We observed slight variations in the linear correction lines between lipid and nonlipid molecules, underscoring the importance of choosing appropriate reference molecules. Based on these results, we demonstrated that an accurate multipass arrival time database can be constructed from corrected t 0 and t p for interlaboratory use and can effectively identify isomeric lipids in MSI using only a single measurement. This approach significantly simplifies the identification process compared to determining multipass collision cross-section, which requires multiple measurements that are both sample- and time-intensive for MSI. Additionally, we validated our multipass drift time correction method in shotgun lipidomics analyses of human and mouse serum samples and observed no matrix effect for the analysis. Despite variations in dates, room temperatures, instruments, and ion mobility settings, our approach reduced the mean drift time differences from over 2% to below 0.2%.
PMID:39991034 | PMC:PMC11843504 | DOI:10.1021/acsmeasuresciau.4c00077
Investigating Gene Expression Noise Reduction by MicroRNAs and MiRISC Reinforcement by Self-Feedback Regulation of mRNA Degradation
bioRxiv [Preprint]. 2025 Feb 15:2025.02.11.637731. doi: 10.1101/2025.02.11.637731.
ABSTRACT
MicroRNA (miRNA) induced silencing complex (miRISC) is the targeting apparatus and arguably rate-limiting step of the miRNA-mediated regulatory subsystem - the major noise reducing though metabolically wasteful mechanism. Recently, we reported that miRISC channels miRNA-mediated regulatory activity back onto their own mRNAs to form negative self-feedback loops, a noise-reduction technique in engineering and synthetic/systems biology. Here, we describe mathematical modeling that predicts mRNA expression noise to correlate negatively with degradation rate (K deg ) and noise reduction by self-feedback control of K deg . We also calculated K deg and expression noise of mRNAs detected in a cutting-edge total-RNA single-cell RNA-seq (scRNA-seq) dataset. As predicted, miRNA-targeted mRNAs exhibited higher K deg values in conjunction with lower inter-cell expression noise. Moreover, as predicted by our self-feedback loop model, miRISC mRNAs (AGO1/2/3 and TNRC6A/B/C) exhibited further reduced expression noise. In short, mathematical-modeling and total-RNA scRNA-seq data-analysis shed insight into operational trade-off between noise reduction and metabolic/energetic expenditure in producing miRNA-targeted mRNAs destined for enhanced degradation and translational inhibition, as well as negative self-feedback loop reinforcement of miRISC - the core of miRNA-mediated noise-reduction subsystem. To our knowledge, this is the first report of concurrent mRNA degradation and expression noise analyses and of noise reduction by self-feedback control of mRNA degradation.
PMID:39990448 | PMC:PMC11844488 | DOI:10.1101/2025.02.11.637731
The MicroMap is a network visualisation resource for microbiome metabolism
bioRxiv [Preprint]. 2025 Feb 16:2025.02.13.637616. doi: 10.1101/2025.02.13.637616.
ABSTRACT
The human microbiome plays a crucial role in metabolism and thereby influences health and disease. Constraint-based reconstruction and analysis (COBRA) has proven an attractive framework to generate mechanism-derived hypotheses along the nutrition-host-microbiome-disease axis within the computational systems biology community. Unlike for human, no large-scale visualisation resource for microbiome metabolism has been available to date. To address this gap, we created the MicroMap, a manually curated microbiome metabolic network visualisation, which captures the metabolic content of over a quarter million microbial genome-scale metabolic reconstructions. The MicroMap contains 5,064 unique reactions and 3,499 unique metabolites, including for 98 drugs. The MicroMap allows users to intuitively explore microbiome metabolism, inspect microbial metabolic capabilities, and visualise computational modelling results. Further, the MicroMap shall serve as an educational tool to make microbiome metabolism accessible to broader audiences beyond computational modellers. For example, we utilised the MicroMap to generate a comprehensive collection of 257,429 visualisations, corresponding to the entire scope of our current microbiome reconstruction resources, to enable users to visually compare and contrast the metabolic capabilities for different microbes. The MicroMap seamlessly integrates with the Virtual Metabolic Human (VMH, www.vmh.life) and the COBRA Toolbox (opencobra.github.io), and is freely accessible at the MicroMap dataverse (https://dataverse.harvard.edu/dataverse/micromap), in addition to all the generated reconstruction visualisations.
PMID:39990405 | PMC:PMC11844556 | DOI:10.1101/2025.02.13.637616
Editorial: Exploring genomic instability of cancers: applications in diagnosis and treatment
Front Cell Dev Biol. 2025 Feb 7;13:1528281. doi: 10.3389/fcell.2025.1528281. eCollection 2025.
NO ABSTRACT
PMID:39989984 | PMC:PMC11842372 | DOI:10.3389/fcell.2025.1528281
Epistasis and cryptic QTL identified using modified bulk segregant analysis of copper resistance in budding yeast
Genetics. 2025 Feb 24:iyaf026. doi: 10.1093/genetics/iyaf026. Online ahead of print.
ABSTRACT
The contributions of genetic interactions to natural trait variation are challenging to estimate experimentally, as current approaches for detecting epistasis are often underpowered. Powerful mapping approaches such as bulk segregant analysis, wherein individuals with extreme phenotypes are pooled for genotyping, obscure epistasis by averaging over genotype combinations. To accurately characterize and quantify epistasis underlying natural trait variation, we have engineered strains of the budding yeast Saccharomyces cerevisiae to enable crosses where one parent's chromosome is fixed while the rest of the chromosomes segregate. These crosses allow us to use bulk segregant analysis to identify quantitative trait loci (QTL) whose effects depend on alleles on the fixed parental chromosome, indicating a genetic interaction with that chromosome. Our method, which we term epic-QTL (for epistatic-with-chromosome QTL) analysis, can thus identify interaction loci with high statistical power. Here we perform epic-QTL analysis of copper resistance with chromosome I or VIII fixed in a cross between divergent naturally derived strains. We find seven loci that interact significantly with chromosome VIII and none that interact with chromosome I, the smallest of the 16 budding yeast chromosomes. Each of the seven interactions alters the magnitude, rather than the direction, of an additive QTL effect. We also show that fixation of one source of variation-in this case chromosome VIII, which contains the large-effect QTL mapping to CUP1-increases power to detect the contributions of other loci to trait differences.
PMID:39989051 | DOI:10.1093/genetics/iyaf026
Interleukin-10 production by innate lymphoid cells restricts intestinal inflammation in mice
Mucosal Immunol. 2025 Feb 21:S1933-0219(25)00023-6. doi: 10.1016/j.mucimm.2025.02.005. Online ahead of print.
ABSTRACT
Interleukin-10 (IL-10) is an immunomodulatory cytokine critical for intestinal immune homeostasis. IL-10 is produced by various immune cells but IL-10 receptor signaling in intestinal CX3CR1+ mononuclear phagocytes is necessary to prevent spontaneous colitis in mice. Here, we utilized fluorescent protein reporters and cell-specific targeting and found that Rorc-expressing innate lymphoid cells (ILCs) produce IL-10 in response to anti-CD40-mediated intestinal inflammation. Deletion of Il10 specifically in Rorc-expressing ILCs led to phenotypic changes in intestinal macrophages and exacerbated both innate and adaptive immune-mediated models of experimental colitis. The population of IL-10+ producing ILCs shared markers with both ILC2 and ILC3 with nearly all ILC3s being of NCR+ subtype. Interestingly, Ccl26 was enriched in IL-10+ ILCs and markedly reduced in IL-10-deficient ILC3s. Since CCL26 is a ligand for CX3CR1, we employed RNA in situ hybridization and observed increased numbers of ILCs in close proximity to Cx3cr1-expressing cells under inflammatory conditions. Finally, we generated a transgenic RorctdTomato reporter mouse that faithfully marked RORγt+ cells that could rescue disease pathology and aberrant macrophage phenotype following adoptive transfer into mice with selective Il10 deficiency in ILC3s. These results demonstrate that IL-10 production by a population of ILCs functions to promote immune homeostasis in the intestine possibly via direct effects on intestinal macrophages.
PMID:39988202 | DOI:10.1016/j.mucimm.2025.02.005
Production and Characterization of Copolymers Consisting of 3-Hydroxybutyrate and Increased 3-Hydroxyvalerate by β-Oxidation Weakened Halomonas
Metab Eng. 2025 Feb 21:S1096-7176(25)00024-2. doi: 10.1016/j.ymben.2025.02.009. Online ahead of print.
ABSTRACT
Polyhydroxyalkanoates (PHA) with high 3-hydroxyvalerate (3HV) monomer ratios lead to their accelerated biodegradation and improved thermal and mechanical properties. In this study, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) with a broad range of 3HV ratios were produced and characterized using the next generation industrial biotechnology (NGIB) chassis Halomonas bluephagenesis (H. bluephagenesis). Wild type H. bluephagenesis was found to produce P(3HB-co-66.31mol% 3HV) when cultured in the presence of valerate. Deletion on the functional enoyl-CoA hydratase (fadB1) increased to 93.11 mol% 3HV in the PHBV copolymers. Through tuning the glucose and valerate co-feeding, PHBV with controllable 3HV ratios were adjusted to range from 0-to-93.6 mol% in shake-flask studies. Metabolic weakening of the β-oxidation pathway paired with flux limitation to the native 3HB synthesis pathway were used to reach the highest reported 98.3 mol% 3HV by H. bluephagenesis strain G34B grown in shake flasks. H. bluephagenesis strain G34B was grown to 71.42 g/L cell dry weight (CDW) containing 74.12 wt% P(3HB-co-17.97 mol% 3HV) in 7 L fermentors. Mechanical properties of PHBV with 0, 22.81, 42.76, 73.49 and 92.17 mol% 3HV were characterized to find not linearly related to increased 3HV ratios. Engineered H. bluephagenesis has demonstrated as a platform for producing PHBV of various properties.
PMID:39988026 | DOI:10.1016/j.ymben.2025.02.009
Carbon dioxide enhances Akkermansia muciniphila fitness and anti-obesity efficacy in high-fat diet mice
ISME J. 2025 Feb 23:wraf034. doi: 10.1093/ismejo/wraf034. Online ahead of print.
ABSTRACT
Numerous studies and clinical applications have underscored the therapeutic potential of the indigenous gut bacterium Akkermansia muciniphila in various diseases. However, our understanding of how A. muciniphila senses and responds to host gastrointestinal signals remains limited. Here, we demonstrate that A. muciniphila exhibits rapid growth, facilitated by its self-produced carbon dioxide, with key enzymes such as glutamate decarboxylase, carbonic anhydrase, and pyruvate ferredoxin oxidoreductase playing pivotal roles. Additionally, we design a novel delivery system, comprising calcium carbonate, inulin, A. muciniphila, and sodium alginate, which enhances A. muciniphila growth and facilitates the expression of part probiotic genes in mice intestinal milieu. Notably, the administration of this delivery system induces weight loss in mice fed high-fat diets. Furthermore, we elucidate the significant impact of carbon dioxide on the composition and functional genes of the human gut microbiota, with genes encoding carbonic anhydrase and amino acid metabolism enzymes exhibiting heightened responsiveness. These findings reveal a novel mechanism by which gut commensal bacteria sense and respond to gaseous molecules, thereby promoting growth. Moreover, they suggest the potential for designing rational therapeutic strategies utilizing live bacterial delivery systems to enhance probiotic growth and ameliorate gut microbiota-related diseases.
PMID:39987558 | DOI:10.1093/ismejo/wraf034