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Journal articleBrożek A, Ceccarelli A, Jørgensen ACS, et al., 2025,
Inference of a three-gene network underpinning epidermal stem cell development in Caenorhabditis elegans
, iScience, Vol: 28, ISSN: 2589-0042Gene regulatory networks are crucial in cellular decision-making, making the inference of their architecture essential for understanding organismal development. The gene network of Caenorhabditis elegans epidermal stem cells, known as seam cells, remains undefined. Here, we integrate experimental data, mathematical modeling, and statistical inference to investigate this network, focusing on three core transcription factors (TFs), namely ELT-1, EGL-18, and CEH-16. We use single-molecule FISH to quantify TF mRNA levels in single seam cells of wild-type and mutant backgrounds across four early larval stages. Using Modular Response Analysis, we predict TF interactions and uncover a repressive interaction between CEH-16 and egl-18 consistent across time points. We validate its significance at the L1 stage with ordinary differential equations and Bayesian modeling, making testable predictions for a double mutant. Our findings reveal TF regulatory relationships in seam cells and demonstrate a flexible mathematical framework for inferring gene regulatory networks from gene expression data.
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Journal articleAdlakha A, Williams TJ, Shou X, et al., 2025,
Interferon-gamma rescues dendritic cell calcineurin-dependent responses to Aspergillus fumigatus via Stat3 to Stat1 switching
, iScience, Vol: 28, ISSN: 2589-0042Invasive pulmonary aspergillosis is a lethal opportunistic fungal infection in transplant recipients receiving calcineurin inhibitors. We previously identified a role for the calcineurin pathway in innate immune responses to A. fumigatus and have used exogenous interferon-gamma successfully to treat aspergillosis in this setting. Here we show that calcineurin inhibitors block dendritic cell maturation in response to A. fumigatus, impairing the Th1 polarization of CD4 cells. Interferon gamma, an immunotherapeutic option for invasive aspergillosis, restored maturation and promoted Th1 polarization via a dendritic cell dependent effect that was co-dependent on T cell interaction. We find that interferon gamma activates alternative transcriptional pathways to calcineurin-NFAT for the augmentation of pathogen handling. Histone modification ChIP-Seq analysis revealed dominant control by an interferon gamma induced regulatory switch from STAT3 to STAT1 transcription factor binding underpinning these observations. These findings provide key insight into the mechanisms of immunotherapy in organ transplant recipients with invasive fungal diseases.
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Thesis dissertationVersi A, 2025,
Analysis of microbiome-based asthma phenotypes
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Journal articleSabelleck B, Deb S, Levecque SCJ, et al., 2025,
A powdery mildew core effector protein targets the host endosome tethering complexes HOPS and CORVET in barley.
, Plant PhysiolPowdery mildew fungi are serious pathogens affecting many plant species. Their genomes encode extensive repertoires of secreted effector proteins that suppress host immunity. Here, we revised and analyzed the candidate secreted effector protein (CSEP) effectome of the powdery mildew fungus, Blumeria hordei (Bh). We identified seven putative effectors that are broadly conserved in powdery mildew species, suggesting that they are core effectors of these phytopathogens. We showed that one of these effectors, CSEP0214, interacts with the barley (Hordeum vulgare) vacuolar protein sorting 18 (VPS18) protein, a shared component of the class C core vacuole/endosome tethering (CORVET) and homotypic fusion and protein-sorting (HOPS) endosomal tethering complexes that mediate fusion of early endosomes and multivesicular bodies, respectively, with the central vacuole. Overexpression of CSEP0214 and knockdown of either VPS18, HOPS-specific VPS41 or CORVET-specific VPS8 blocked the vacuolar pathway and the accumulation of the fluorescent vacuolar marker protein (SP)-RFP-AFVY in the endoplasmic reticulum. Moreover, CSEP0214 inhibited the interaction between VPS18 and VPS16, which are both shared components of CORVET as well as HOPS. Additionally, introducing CSEP0214 into barley leaf cells blocked the hypersensitive cell death response associated with resistance gene-mediated immunity, indicating that endomembrane trafficking is required for this process. CSEP0214 expression also prevented callose deposition in cell wall appositions at attack sites and encasements of fungal infection structures. Our results indicate that the powdery mildew core effector CSEP0214 is an essential suppressor of plant immunity.
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Journal articleNevot G, Santos-Moreno J, Campamà-Sanz N, et al., 2025,
Synthetically programmed antioxidant delivery by a domesticated skin commensal
, Cell Systems, Vol: 16, ISSN: 2405-4720Bacteria represent a promising dynamic delivery system for the treatment of disease. In the skin, the relevant location of Cutibacterium acnes within the hair follicle makes this bacterium an attractive chassis for dermal biotechnological applications. Here, we provide a genetic toolbox for the engineering of this traditionally intractable bacterium, including basic gene expression tools, biocontainment strategies, markerless genetic engineering, and dynamic transcriptional regulation. As a proof of concept, we develop an antioxidant-secreting strain capable of reducing oxidative stress in a UV stress model.
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Journal articleWaterer GW, Chotirmall SH, 2025,
Dancing With DPP-1: The Inflammatory Tango of Bronchiectasis.
, Am J Respir Crit Care Med -
Journal articleVaraden D, Barratt B, Dallman MJ, et al., 2025,
West London Healthy Home and Environment (WellHome) Study: Protocol for a Community-Based Study Investigating Exposures Across the Indoor-Outdoor Air Pollution Continuum in Urban Communities.
, Int J Environ Res Public Health, Vol: 22The relationship between indoor air quality and public health remains under-researched. WellHome is a transdisciplinary community-based study that will engage with residents to co-design feasible and acceptable research to quantify air pollution exposure in 100 homes in West London and examine its potential to exacerbate asthma symptoms in children. Sampling strategies such as using air quality monitors and passive samplers placed in kitchens, children's bedrooms, and living rooms, will be developed in collaboration with local ambassadors and participating households to measure multiple physical, chemical, microplastic, and biological contaminants. This will provide a comprehensive understanding of indoor air quality across the city's socio-economic gradient. Other data collected will include housing types and tenure, ventilation practices, occupant behaviours, time-activity, and airway symptoms. Epidemiological analysis will examine air pollution exposure impacts on children's respiratory health. The particulate mixture's relative hazard will be evaluated in toxicity studies based on source profiles and activity patterns of participants, focusing on asthma exacerbation related pathways. The study's findings will be communicated to participants through co-designed reports and inform evidence-based recommendations for reducing indoor air pollution in London and urban areas worldwide. By raising awareness and providing actionable insights, WellHome seeks to contribute to global efforts to improve the health and well-being of vulnerable communities.
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Journal articleCase NT, Gurr SJ, Fisher MC, et al., 2025,
Fungal impacts on Earth’s ecosystems
, Nature, Vol: 638, Pages: 49-57, ISSN: 0028-0836Over the past billion years, the fungal kingdom has diversified to more than two million species, with over 95% still undescribed. Beyond the well-known macroscopic mushrooms and microscopic yeast, fungi are heterotrophs that feed on almost any organic carbon, recycling nutrients through the decay of dead plants and animals and sequestering carbon into Earth’s ecosystems. Human-directed applications of fungi extend from leavened bread, alcoholic beverages and biofuels to pharmaceuticals, including antibiotics and psychoactive compounds. Conversely, fungal infections pose risks to ecosystems ranging from crops to wildlife to humans; these risks are driven, in part, by human and animal movement, and might be accelerating with climate change. Genomic surveys are expanding our knowledge of the true biodiversity of the fungal kingdom, and genome-editing tools make it possible to imagine harnessing these organisms to fuel the bioeconomy. Here, we examine the fungal threats facing civilization and investigate opportunities to use fungi to combat these threats.
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Journal articleYoung-Kyoung P, Lucie S, Piotr H, et al., 2025,
Efficient biosynthesis of β-caryophyllene by engineered Yarrowia lipolytica
, Microbial Cell Factories, Vol: 24, ISSN: 1475-2859Backgroundβ-Caryophyllene, a sesquiterpenoid, holds considerable potential in pharmaceutical, nutraceutical, cosmetic, and chemical industries. In order to overcome the limitation of β-caryophyllene production by the extraction from plants or chemical synthesis, we aimed the microbial production of β-caryophyllene in non-conventional yeast Yarrowia lipolytica in this study.ResultsTwo genes, tHMG1 from S. cerevisiae to boost the mevalonate pool and QHS1 from Artemisia annua, were expressed under different promoters and copy numbers in Y. lipolytica. The co-expression of 8UAS pEYK1-QHS1 and pTEF-tHMG1 in the obese strain yielded 165.4 mg/L and 201.5 mg/L of β-caryophyllene in single and double copies, respectively. Employing the same combination of promoters and genes in wild-type-based strain with two copies resulted in a 1.36-fold increase in β-caryophyllene. The introduction of an additional three copies of 8UAS pEYK1-tHMG1 further augmented the β-caryophyllene, reaching 318.5 mg/L in flask fermentation. To maximize the production titer, we optimized the carbon source ratio between glucose and erythritol as well as fermentation condition that led to 798.1 mg/L of β-caryophyllene.ConclusionsA biosynthetic pathway of β-caryophyllene was firstly investigated in Y. lipolytica in this study. Through the modulation of key enzyme expression, we successfully demonstrated an improvement in β-caryophyllene production. This strategy suggests its potential extension to studies involving the microbial production of various industrially relevant terpenes.
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Journal articleBercusson A, Williams TJ, Simmonds NJ, et al., 2025,
Increased NFAT and NFκB signalling contribute to the hyperinflammatory phenotype in response to Aspergillus fumigatus in a mouse model of cystic fibrosis
, PLoS Pathogens, Vol: 21, ISSN: 1553-7366Aspergillus fumigatus (Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading to Aspergillus bronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance of Af in the lung. However, their contribution to the inflammatory phenotype in CF during Af infection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response to Af which, as in in vivo models, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF.
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