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PubMed2026

Parental niche construction buffers microbial and competitive challenges and drives offspring dependence in burying beetles.

Parents across diverse taxa modify the biotic or abiotic environments of their offspring. Such modifications may constitute ecological inheritance and are central to developmental niche construction, whereby organisms shape developmental conditions and selective pressures experienced by the next generation. Despite its theoretical importance, parental niche construction is often studied under simplified conditions or by focusing on single components of care, limiting our understanding of how multiple parental modifications interact in ecologically relevant contexts, whether they buffer environmental heterogeneity, and how this shapes offspring development and evolutionary trajectories. Using the burying beetle Nicrophorus vespilloides, we investigated how parents jointly modify chemical and microbial properties of vertebrate carcasses, a highly contested resource on which offspring develop. We show that under natural microbial and competitive conditions, prehatch care enhances larval survival and growth, alters cadaveric volatile emissions, and reduces carcass attractiveness to competitors. While soil type shapes carcass-associated microbial communities, parental care buffers these environmental effects, creating a more consistent microbiome and reducing environmentally induced larval mortality. Larvae of the related species Ptomascopus morio, which lacks prehatch carcass preparation, survived equally well on prepared and unmodified carcasses, whereas N. vespilloides larvae showed reduced survival on unmodified carcasses. This contrast is consistent with the hypothesis that N. vespilloides larvae have evolved a reliance on a parentally constructed developmental environment. Together, these findings show that parental care can constitute an integrated form of niche construction that reshapes developmental environments, enhances offspring performance, and may promote evolutionary feedback leading to increased offspring dependence on parental care.

Animals↗

PubMed2026

Mutations in filamentous bacteriophages spark eco-evolutionary feedbacks in Pseudomonas aeruginosa.

Microbial populations strongly shape their environment, which can re-route adaptation toward organism-generated fitness optima. However, the conditions that promote these eco-evolutionary feedbacks are unclear. Here, we used experimental evolution to test whether high population density, by strengthening niche construction, drives eco-evolutionary feedbacks in the bacterial pathogen Pseudomonas aeruginosa (Pa) MPAO1. We tested for adaptation to organism-modified environments by measuring the relative performance of ancestral and endpoint populations in filtrate generated by each evolutionary line sampled across generations. Contrary to expectations, we found that endpoint populations had higher performance than the ancestral strain in filtrate across nearly all evolutionary lines regardless of population density. This was caused by the emergence of hyperactive filamentous bacterio(phage) mutants during experimental passaging that inhibited the ancestral strain but not endpoint populations in modified media. Hyperactive phages emerged from one of two avirulent prophages in MPAO1's genome (Pf4 or Pf6). Hyperactive phages drove the evolution of phage resistance in bacterial populations via mutations in the type IV pilus (TIVP), the phage's binding receptor. In a follow-up experiment, we showed that these TIVP mutations pleiotropically reduced motility and conferred resistance to a TIVP-targeting virulent phage, both of which are important traits for Pa infection and treatment. Overall, this work suggests that filamentous phage evolution can drive eco-evolutionary feedbacks in bacterial populations, causing phenotypic and genetic changes that would not be anticipated from adaptation to the extrinsic environment alone.

Pseudomonas aeruginosa↗

PubMed2026

Integrative quantum and systems biology of cancer: From molecular fluctuations to ecological outcomes.

This review treats cancer as a multiscale adaptive system, asks what the framework must predict to be worth adopting, and separates at each scale what the evidence establishes from what is proposed. It is an expert narrative synthesis, not a systematic review, and states the limits of that design. Proton transfer and tautomeric shifts contribute to spontaneous mispairing but do not license claims of directed or non-random mutation: replication timing, three-dimensional chromatin organization, sequence context and known mutagenic processes explain most mutational heterogeneity, leaving any quantum contribution as a residual against that baseline. The Waddington quasi-potential is bounded: outside detailed balance the dynamics are not gradient-derivable and require a probability-flux term. Hysteresis, rate-limited bimodality and return to state after perturbation distinguish an attractor from a transcriptomic cluster. Single-cell karyotype and live-imaging evidence supports whole-genome doubling as an unstable intermediate of heterogeneous origin and context-dependent consequence, not a uniform adaptive strategy. Systems and synthetic biology, virtual cells and digital twins are assessed against benchmarks, not promise. Tissue-scale ecology is reported with the spatial measurements now quantifying it, including evidence that stromal niche construction is not uniformly tumor-supporting. RNA modification is a layer in its own right, showing that the interpretation of a regulatory signal, not its magnitude, is biologically decisive. A dedicated section states the framework's commitments, the observable and evidence at each scale, and what would falsify them, asking what this adds to somatic mutation theory with clonal evolution and plasticity.

Neoplasms↗

PubMed2025

Spatial mutual nearest neighbors for spatial transcriptomics data.

MOTIVATION: Mutual nearest neighbors (MNN) is a widely used computational tool to perform batch correction for single-cell RNA-sequencing data. However, in applications such as spatial transcriptomics, it fails to take into account the 2D spatial information. RESULTS: Here, we present spatialMNN, an algorithm that integrates multiple spatial transcriptomic samples and identifies spatial domains. Our approach begins by building a k-nearest neighbors (kNN) graph based on the spatial coordinates, prunes noisy edges, and identifies niches to act as anchor points for each sample. Next, we construct a MNN graph across the samples to identify similar niches. Finally, the spatialMNN graph can be partitioned using existing algorithms, such as the Louvain algorithm to predict spatial domains across the tissue samples. We demonstrate the performance of spatialMNN using large datasets, including one with N = 31 10x Genomics Visium samples. We also evaluate the computing performance of spatialMNN to other popular spatial clustering methods. AVAILABILITY AND IMPLEMENTATION: Our software package is available on GitHub (https://github.com/Pixel-Dream/spatialMNN). The code is available on Zenodo (https://doi.org/10.5281/zenodo.15073963).

Algorithms↗

PubMed2026

HIF1A+CSF3R+ neutrophils-dominated hypoxic niche induced metabolic reprogramming for neoadjuvant therapy resistance in NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the frequently occurring cancers characterized by molecular heterogeneity and multiple immune cell infiltration patterns, which are associated with treatment sensitivity and resistance. However, the specific microenvironmental cells and their mechanisms that lead to treatment resistance in patients need to be explored in greater depth. METHODS: On the basis of patients receiving neoadjuvant therapy in our center, a multicenter, multicohort NSCLC spatial transcriptome, single-cell transcriptome, T-cell receptor repertoire sequencing, bulk RNA transcriptome, phosphorylated proteome, genome mutation, and clinical data were included for a comprehensive assessment of the therapeutic and prognostic impact of HIF1A+ CSF3R+ neutrophils in NSCLC. In vitro experiments validated the functional phenotype of HIF1A+ CSF3R+ neutrophils and co-localization interactions with other cellular subpopulations. Gradient boosting machine (GBM) constructed region of interest (ROI) models for evaluation. Computer-aided drug design (CADD) was used to predict targeted small molecule drugs, and in vivo mouse models were constructed to assess the effectiveness of the combination treatment regimen. RESULTS: Centered on HIF1A+ CSF3R+ neutrophils, recruited exhausted T cells and stromal cells form a hypoxic niche within the tumor region, which was enriched in non-response patients. ROI composed of these specific cellular subpopulations, associated with senescence and glycolysis, accurately predicting NSCLC progression, prognosis, and microenvironment composition. CADD analysis identified that platycodin-D2 specifically targeted CSF3R, reducing HIF1A expression and inhibiting neutrophil activity. Combining navitoclax, platycodin-D2 with anti-programmed cell death protein 1 (PD-1) significantly suppressed tumor proliferation and improved the immunosuppressive microenvironment. CONCLUSION: Our study emphasized the role of HIF1A+ CSF3R+ neutrophils in immunotherapeutic resistance of NSCLC, constructed a microenvironmental immune dysregulation network in a hypoxic ecological niche with HIF1A+ CSF3R+ neutrophils as the center. Platycodin-D2 specifically targeted HIF1A+ CSF3R+ neutrophils, enhancing the efficacy of anti-PD-1 therapy in NSCLC.

Humans↗

PubMed2025

Cloning and validating systems for high throughput molecular recording.

Molecular recording technologies record and store information about cellular history. Lineage tracing is one form of molecular recording and produces information describing cellular trajectories during mammalian development, differentiation and maintenance of adult stem cell niches, and tumor evolution. Our molecular recorder technology utilizes CRISPR-Cas9 barcode editing to generate mutations in genomically integrated, engineered DNA cassettes, which are read out by single-cell RNA sequencing and used to produce high-resolution lineage trees. Here, we describe optimized cloning and validation procedures to construct the molecular recorder lineage tracing system. We include information on considerations of technology design, cloning procedures, the generation of lineage tracing cell lines, and time course experiments to assess their performance.

Cloning, Molecular↗

PubMed2025

Genomic insights into karyotype evolution and adaptive mechanisms in Polygonaceae species.

Polygonaceae, with ecological versatility and global distribution, is an ideal system for investigating plant adaptation. However, the genomic mechanisms underlying its karyotype evolution and environmental resilience remain unclear. We herein present chromosome-level genomes of 11 species from 10 Polygonaceae genera. Our analyses reveal that Gypsy retrotransposons are key drivers of genome size variations in Polygonaceae. We reconstructed a Polygonaceae ancestral karyotype comprising 28 proto-chromosomes and elucidated evolutionary trajectories via extensive chromosomal rearrangements. Furthermore, we constructed a cross-genus super pan-genome for Polygonaceae, identifying 80,055 gene families, of which 9,845 (12.30%) are core gene families. Private genes are found to contribute significantly to interspecific differences in adaptability. Notably, gene copy number variations are identified as a critical factor influencing adaptations to diverse niches involving species-specific increases in metabolic pathways. This study provides a genomic framework for Polygonaceae karyotype plasticity and adaptive innovation, offering insights into plant evolution under environmental challenges.

Karyotype↗

PubMed2026

Metagenomic polymorphic toxin effector and immunity profiling predicts microbiome development and disease-related dysbiosis.

Bacteria use antagonistic interbacterial weapons, such as polymorphic toxin secretion systems (TSS), to compete for niches in the human gut microbiome. We hypothesized that TSS influence gut microbiome development and disease-related dysbiosis. We developed a bioinformatic marker gene approach (PolyProf) to quantify TSS including ~200 effector and immunity genes and applied it to ~15,000 publicly available human metagenomes. PolyProf alpha and beta diversity readily distinguished 12 different human disease states and enabled the construction of highly accurate linear regression classifier machine learning models. Elastic net machine learning models integrating bacterial taxonomy with PolyProf had strong predictive value for 12 disease states, outperforming models utilizing taxonomy alone. During microbiome development in the first year of life, PolyProf alpha diversity increases, and beta diversity becomes increasingly like the maternal microbiome, influenced by vertical transfer, delivery mode, and breastfeeding. PolyProf is related to strain sharing among adults through social interactions. In summary, TSS genes strongly correlate with microbiome development and interpersonal strain sharing, suggesting roles for interbacterial antagonism. Since PolyProf distinguishes diverse adult disease statuses, these dynamics may contribute to non-genetic inheritance.IMPORTANCEPrevious research has demonstrated that bacteria compete within the gut microbiome using toxin secretion systems (TSS). How TSS contribute to human microbiome development and the microbiome alterations observed in human diseases is not known. This study develops a new bioinformatic tool for profiling TSS-related genes in metagenomic data. Application of this approach to large-scale human fecal metagenomic data demonstrates the dynamic association of TSS during microbiome development, including the exchange of strains among social contacts. TSS gene abundance patterns are highly predictive of 12 disease states. This study advances the field by enabling TSS profiling in metagenomes and by identifying disease and microbiome development biomarkers that provide hypotheses for future mechanistic studies and may be useful for disease diagnosis.

Dysbiosis↗

PubMed2026

Species Distribution Models Support Distinct and Non-Random Climatic Constraints on Globally Distributed Generalist Fungi.

Fungi play essential roles in ecosystems as pathogens, mutualists, and ubiquitous decomposers. However, like many important microbes, the spatial distribution of species and natural populations remains poorly understood compared to plants and animals. Many fungi are described as global generalists because they occur across wide geographic areas, but it remains unclear how and if these species are constrained by climate or geographic barriers. In this study, we used Species Distribution Models to infer the global climatic suitability of three common and globally distributed fungi: Aspergillus flavus, Penicillium chrysogenum and Aspergillus fumigatus. Models were constructed using global occurrence data from the Global Biodiversity Information Facility and were trained with Bioclimatic variables from the WorldClim dataset. All species' models showed high prediction fit, with predicted occurrence concentrated in the temperate and subtropical regions and broadly structured patterns. Each species showed distinct predicted distributions, but they displayed considerable spatial overlap on a global scale. Together, these results demonstrate that even apparently globally occurring and generalist fungal species occupy climatically structured niches. This study highlights the utility of SDMs and it provides a framework for future studies integrating ecological, genomics and evolutionary perspectives among the difficult to assess geographically widespread and common fungi.

comparative biogeography↗

PubMed2026

Creating bottom-up RNA transfer vehicles from synthetic protein assemblies.

Evolution guides biological systems to populate ecological niches, with viruses among the most successful examples of this principle. Viruses evolved over billions of years to efficiently transfer genetic information. Although viruses are highly diverse, most have converged towards remarkable similarity in the size and shape of their capsids1,2. By contrast, generative models for protein design enable the creation of protein architectures that are absent from nature3-5. Here we investigate whether protein assemblies designed by artificial intelligence can be functionalized to construct nucleic acid transport vehicles that are independent of evolutionary trajectories. By combining natural protein domains with synthetic protein assemblies, we create more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes. These vehicles surpass the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. In addition, we demonstrate that their tropism can be programmed by incorporation of computationally designed peptide binders and use them to deliver therapeutically relevant cargo RNAs into a wide range of cellular models. We show the in vivo biodistribution of one of these vehicles in a mouse at near-single-cell resolution, confirm its safety, and use it to perform a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig. Our work demonstrates how proteins created by generative artificial intelligence can be harnessed for the rational engineering of RNA transport systems with the desired properties by overcoming the limitations of natural protein diversity.

Journal Article↗

PubMed2025

A single-cell spatial transcriptomic census of human skin anatomy.

The skin is the largest human organ and a site of significant disease burden, yet its cellular and molecular organization across the body are largely undefined. Here, we construct a spatially-resolved single-cell atlas of 1.2 million cells from normal adult human skin to localize 45 cell types across 15 anatomic sites. We define principles of organ-wide cell composition, including axes of cell diversity and specialization, and distinguish site-enriched cell types. Each body site is comprised of 10 multicellular neighborhoods that define cell-cell communication. Notably, we identify a perivascular neighborhood enriched for immune-stromal crosstalk with features resembling a homeostatic immune niche similar to skin-associated lymphoid tissue. Finally, mapping these neighborhoods onto skin disease reveals pathogenic neighborhood disruptions, including pan-disease immune alterations in the perivascular neighborhood. We present a framework charting the skin's multiscale spatial organization across a molecular to macroanatomic scale. This work advances our understanding of organ-wide skin cellular organization and communication, and its architectural disruption in disease.

Journal Article↗

PubMed2025

Exploring phage-host interactions in Burkholderia cepacia complex bacterium to reveal host factors and phage resistance genes using CRISPRi functional genomics and transcriptomics.

Complex interactions of bacteriophages with their bacterial hosts determine phage host range and infectivity. While phage defense systems and host factors have been identified in model bacteria, they remain challenging to predict in non-model bacteria. In this paper, we integrate functional genomics and transcriptomics to investigate phage-host interactions, revealing active phage resistance and host factor genes in Burkholderia cenocepacia K56-2. Burkholderia cepacia complex species are commonly found in soil and are opportunistic pathogens in immunocompromised patients. We studied infection of B. cenocepacia K56-2 with Bcep176, a temperate phage isolated from Burkholderia multivorans. A genome-wide dCas9 knockdown library targeting B. cenocepacia K56-2 was constructed, and a pooled infection experiment identified 63 novel genes or operons coding for candidate host factors or phage resistance genes. The activities of a subset of candidate host factor and resistance genes were validated via single-gene knockdowns. Transcriptomics of B. cenocepacia K56-2 during Bcep176 infection revealed that expression of genes coding for host factor and resistance candidates identified in this screen was significantly altered during infection by 4 h post-infection. Identifying which bacterial genes are involved in phage infection is important to understand the ecological niches of B. cenocepacia and its phages, and for designing phage therapies.IMPORTANCEBurkholderia cepacia complex bacteria are opportunistic pathogens inherently resistant to antibiotics, and phage therapy is a promising alternative treatment for chronically infected patients. Burkholderia bacteria are also ubiquitous in soil microbiomes. To develop improved phage therapies for pathogenic Burkholderia bacteria, or engineer phages for applications, such as microbiome editing, it's essential to know the bacterial host factors required by the phage to kill bacteria, as well as how the bacteria prevent phage infection. This work identified 65 genes involved in phage-host interactions in Burkholderia cenocepacia K56-2 and tracked their expression during infection. These findings establish a knowledge base to select and engineer phages infecting or transducing Burkholderia bacteria.

Bacteriophages↗

PubMed2025

A platform supporting generation and isolation of random transposon mutants in Chlamydia trachomatis.

Chlamydia species represent a paradigm for understanding successful obligate intracellular parasitism. Despite limited genetic malleability, development of genetic tools has facilitated the elucidation of molecular mechanisms governing infectivity. Random mutagenesis approaches provide one of the most powerful strategies available to accomplish untargeted elucidation of gene function. Unfortunately, initial progress in transposon-mediated mutagenesis of Chlamydia has been challenging. To increase efficiency, we developed a plasmid-based system that couples conditional plasmid maintenance with a previously described strategy leveraging inducible expression of the Himar1-derived C9 transposase. Our pOri-Tn(Q) construct was maintained in Chlamydia trachomatis cultivated with antibiotics but was rapidly cured in the absence of antibiotic selection. pOri-Tn(Q) supported transposition events when transposase expression was induced during infection. Induction was accompanied by loss of the plasmid backbone when penicillin G was used to select for only the transposable element. C9 induction during iterative passaging was used to increase the overall insertion frequency and accumulate an expanded pool of transposon mutants. The approach supported isolation of individual mutant strains from the mixed pool, and whole-genome sequencing confirmed that the recovered strains harbored single insertions.IMPORTANCEChlamydia trachomatis is a prevalent human pathogen exerting a tremendous negative impact on human health. A complete understanding of how these bacteria create and maintain an intracellular niche and avoid/subvert host defense mechanisms to cause disease is lacking. The utility of transposon-mediated, random mutagenesis in supporting forward genetic studies is well established in a multitude of genetically tractable systems. This study reports the development of a plasmid-based system capable of generating mutant pools and supporting subsequent isolation of individual transposon mutants. This step is an important advance in providing a mechanism capable of supporting downstream studies interrogating chlamydial biology.

Chlamydia trachomatis↗

PubMed2025

Global emergence and transmission dynamics of carbapenemase-producing Citrobacter freundii sequence type 22 high-risk international clone: a retrospective, genomic, epidemiological study.

BACKGROUND: Carbapenemase-producing Citrobacter (CPC) species have recently been recognised as emerging pathogens associated with nosocomial infections in humans. The increased rate of Citrobacter freundii infections is a public health concern and there is a paucity of genomic data regarding its global transmission dynamics. We aimed to characterise the genetic features of CPC species, and their associated carbapenemase-encoding plasmids, obtained from hospitalised patients in China and from publicly available global data, with a particular focus on high-risk clones. METHODS: This was a retrospective, genomic epidemiological study of CPC species obtained from a tertiary hospital in Zhejiang Province, China, from March 5, 2013, to March 5, 2023. We used antimicrobial susceptibility testing, short-read and long-read whole-genome sequencing, phylogenomic analysis, and plasmid structure analysis. A global dataset of complete plasmid sequences encoding blaKPC, blaNDM, and blaIMP was constructed from the National Center for Biotechnology Information (NCBI) RefSeq database to provide insights into their diversity and distribution. All carbapenemase-producing Citrobacter freundii genomes from the NCBI GenBank database were incorporated in the comparative genomic analyses. Bayesian phylogeographical analysis and growth rate assays were carried out to characterise the high-risk C freundii sequence type (ST) 22 clone. FINDINGS: 1724 Citrobacter species isolates were collected from diverse clinical specimens, with 48 identified as CPC species. Citrobacter koseri (22 [46%] of 48) and C freundii (20 [42%]) were the predominant CPC species. Comparative analysis found C freundii carried significantly higher median numbers of plasmid replicons (5·0 [IQR 3·3-6·0] vs 2·0 [2·0-3·0]; p<0·0001) and acquired antimicrobial resistance genes (12·0 [7·3-15·8] vs 3·0 [3·0-5·3]; p<0·0001) than did C koseri. Molecular characterisation identified Inc-type plasmids, In823::Kl.pn.I3/In1589-like/In837-like integrons, Tn6296/Tn125/Tn5060 transposons, and insertion sequences (eg, IS26, IS3000, IS5, ISAba125, ISCR1), collectively facilitating the dissemination of carbapenemase genes. Global analysis of 3126 carbapenemase-encoding plasmids found epidemic plasmids with broad host ranges and global diversity. Phylogenetic investigation of predominant carbapenemase-encoding plasmids showed their persistence across geographical regions, temporal spans, and Enterobacterales species, exhibiting high genetic similarity to our clinical plasmids. A phylogenetic tree of 726 global carbapenemase-producing C freundii genomes showed that ST22 (227 [31·3%]) represents the predominant multidrug-resistant clone across community, health-care, and environmental niches. Transmission across continents contributes to the global predominance of the ST22 clone, which carries a high load of resistance genes (median 15·0 [IQR 11·0-17·0] vs 12·0 [3·0-16·0]; p<0·0001) and enhanced plasmid maintenance capacity (median replicons 5·0 [IQR 4·0-7·0] vs 4·0 [3·0-6·0]; p<0·0001) relative to non-ST22 clones. INTERPRETATION: Our study provides evidence to suggest that Citrobacter species are emerging carriers of carbapenem-resistance genes. These findings provide insight into the population structure of CPC species and highlight C freundii ST22 as a prominent high-risk international clone. FUNDING: National Natural Science Foundation of China, National Health Commission Scientific Research Fund-Zhejiang Provincial Major Health Science and Technology Plan Project, Zhejiang Province Natural Science Foundation Project, Outstanding Youth Foundation of Jiangsu Province of China, the Priority Academic Program Development of Jiangsu Higher Education Institutions, and Postgraduate Research and Practice Innovation Program of Jiangsu Province.

Citrobacter freundii↗