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Astrocytic RNA editing regulates the host immune response to alpha-synuclein.
No full textRNA editing is a posttranscriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte-specific, ADAR1-mediated RNA editing in neuroinflammation in Parkinson's disease (PD). We generated human induced pluripotent stem cell-derived astrocytes, neurons and cocultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with Toll-like receptor activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to up-regulation and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in postmortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson's
Axonal RNA localization is essential for long-term memory.
No full textLocalization of mRNAs to neuronal terminals, coupled to local translation, has emerged as a prevalent mechanism controlling the synaptic proteome. However, the physiological regulation and function of this process in the context of mature in vivo memory circuits has remained unclear. Here, we combined synaptosome RNA profiling with whole brain high-resolution imaging to uncover mRNAs with different localization patterns in the axons of Drosophila Mushroom Body memory neurons, some exhibiting regionalized, input-dependent, recruitment along axons. By integrating transcriptome-wide binding approaches and functional assays, we show that the conserved Imp RNA binding protein controls the transport of mRNAs to Mushroom Body axons and characterize a mutant in which this transport is selectively impaired. Using this unique mutant, we demonstrate that axonal mRNA localization is required for long-term, but not short-term, behavioral memory. This work uncovers circuit-dependent mRNA targeting in vivo and demonstrates the importance of local RNA regulation in memory consolidation
Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction.
No full textBiomarkers accurately informing prognostic assessment and therapeutic strategy are critical for improving patient outcome in oncology. Here, we apply a whole-genome, tumor-informed circulating tumor DNA (ctDNA) detection approach to address this challenge, leveraging 1,800 variants across 2,994 plasma samples from 431 patients with non-small cell lung cancer (NSCLC) from the TRACERx study. We show that ultrasensitive ctDNA detection below 80 parts per million both pre- and postoperatively is highly prognostic, and combinatorial analysis of the pre- and postoperative ctDNA status identifies an intermediate risk group, improving disease stratification. ctDNA kinetics demonstrate clinical utility during adjuvant therapy, where patients that "clear" ctDNA during adjuvant therapy experience improved outcomes. Moreover, characterization of patterns in postoperative ctDNA kinetics reveals insights into the timing, risk, and anatomical pattern of relapses. By incorporating longitudinal ultrasensitive ctDNA detection, we propose a refined schema for guiding the stratification and treatment recommendations in early stage NSCLC
Signaling-dependent refinement of cell fate choice during tissue remodeling in Drosophila pupal wings.
No full textHow cell fate decisions and tissue remodeling are coordinated to establish precise and robust patterns is a fundamental question in developmental biology. Here, we investigate this interplay during the refinement of Drosophila wing veins. We show by live imaging that vein refinement is driven initially by local tissue deformation, followed by cell fate adjustments orchestrated by a signaling network involving Notch, EGFR, and Dpp. Dynamic tracking of signaling reporter activity uncovers a wave of Notch signaling that converts wide crude proveins into thin stereotypical veins. Perturbing large-scale convergence and extension does not affect vein refinement, and optogenetically induced veins refine irrespective of their orientation, demonstrating that the signaling network suffices for refinement, independently of large-scale tissue flows. A minimal biophysical description recapitulates the signaling network's ability to coordinate vein refinement in various experimental situations. Our results illustrate how cell fate decisions are updated for robust patterning in a remodeling tissue
Identifying the Most Appropriate Order for Categorical Responses
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Development and characterisation of improved unifocal primary mouse lung cancer models with metastatic potential.
No full textLung cancer is the leading cause of cancer-related death globally. To better understand the biology of lung cancer, mouse models have been developed using either tail vein-injected tumour cell lines or genetically modified mice. The current gold-standard models typically present with multiple lung foci. However, although these models are widely used, their correlation with human disease are limited, as early-stage human lung cancer usually presents as a single lesion rather than multiple foci. Additionally, a major challenge of using multifocal lung tumour models is the difficulty in distinguishing primary lung tumours from intrathoracic metastasis and lethal levels of lung congestion before distant metastases develop. Here, we present a refined and detailed surgical method in which murine tumour cells [Lewis lung carcinoma (LLC), alveogenic lung carcinoma (CMT), or Kras/Trp53-KP mutant cells] were injected directly into the left lung lobe of C57BL/6 mice, or, alternatively, adenoviral-Cre or adenoviral-FlpO was administered directly into the left lung lobe of KrasLSL-G12D;Trp53fl/fl or KrasFSF-G12D;Trp53frt/frt (KP) mice, respectively. This method generated unifocal primary left lung lobe tumours with traceable spread to local and distant sites. A cross-comparison of the unifocal models described commonalties and differences between LLC, CMT, KP cells, and adenoviral-Cre or -FlpO methods in terms of timings for primary lung tumour growth and traceable spread to local and distant sites, histological analysis of CD3 and CD11b immune cell infiltration, and Picrosirius Red analysis of extracellular matrix complexity. Lastly, the frequency of clinical histopathological features typical of human lung cancer were assessed across the unifocal mouse models to provide a direct comparison with human lung cancer. Overall, this study details a refined and reproducible protocol for intralobular lung injection to generate unifocal lung cancer models that resemble key features of human lung cancer. This approach can be applied to other lung cancer initiation strategies. The cross-comparative histological analysis across the models tested here offers a valuable resource to aid researchers in selecting the most appropriate next-generation unifocal lung cancer models for their specific research needs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland
Capture, mutual inhibition and release mechanism for aPKC-Par6 and its multisite polarity substrate Lgl.
No full textThe mutually antagonistic relationship of atypical protein kinase C (aPKC) and partitioning-defective protein 6 (Par6) with the substrate lethal (2) giant larvae (Lgl) is essential for regulating polarity across many cell types. Although aPKC-Par6 phosphorylates Lgl at three serine sites to exclude it from the apical domain, aPKC-Par6 and Lgl paradoxically form a stable kinase-substrate complex, with conflicting roles proposed for Par6. We report the structure of human aPKCι-Par6α bound to full-length Llgl1, captured through an aPKCι docking site and a Par6PDZ contact. This complex traps a phospho-S663 Llgl1 intermediate bridging between aPKC and Par6, impeding phosphorylation progression. Thus, aPKCι is effectively inhibited by Llgl1pS663 while Llgl1 is captured by aPKCι-Par6. Mutational disruption of the Lgl-aPKC interaction impedes complex assembly and Lgl phosphorylation, whereas disrupting the Lgl-Par6PDZ contact promotes complex dissociation and Lgl phosphorylation. We demonstrate a Par6PDZ-regulated substrate capture-and-release model requiring binding by active Cdc42 and the apical partner Crumbs to drive complex disassembly. Our results suggest a mechanism for mutual regulation and spatial control of aPKC-Par6 and Lgl activities
A single amino acid in the Salmonella effector SarA/SteE triggers supraphysiological activation of STAT3 for anti-inflammatory gene expression
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Beneficial and detrimental consequences of AHR activation in intestinal infection.
No full textThe ligand-dependent transcription factor aryl hydrocarbon receptor (AHR) is an environmental sensor whose activation can have physiologically beneficial or detrimental consequences for host immune responses depending on the ligand. Here, we investigated the hypothesis that prolonged AHR activation either because of inefficient ligand metabolism or because of genetic manipulation may underlie the distinction between beneficial and detrimental effects. Our data indicate that prolonged AHR activation caused toxic endpoints for liver and thymus but was not per se interfering with the host response to infection with the intestinal pathogen C. rodentium Genetically driven constitutive AHR activation improved resistance to infection, whereas prolonged AHR activation by the pollutant TCDD resulted in delayed clearance of C. rodentium associated with a suppression in antibody production. Combined single-cell RNA-seq and ATAC-seq analysis provided evidence that TCDD, but not genetic AHR activation, negatively affected dendritic cell functions such as activation, maturation, and antigen presentation. Thus, the detrimental impact of environmental pollutants such as TCDD on immune responses cannot solely be attributed to aberrantly prolonged activation of AHR.</p
AI-based hardware and software tools in microscopy to boost research in immunology and virology.
No full textThe integration of computational advances in microscopy has enhanced our ability to visualise immunological events at scales. However, data generated with these techniques is often complex, multi-dimensional, and multi-modal. Data science and artificial intelligence (AI) play a key role in untangling the wealth of information hidden in microscopy data by enhancing image processing, automating image analysis, and assisting in interpreting the results. With this Review, we aim to inform the reader about the advances in the fields of fluorescence and electron microscopy with a focus on their applications to immunology and virology, and the AI approaches to aid image acquisition, analysis, and data interpretation. We also outline the open-source tools for image acquisition and analysis and how these tools can be programmed for an image-informed, AI-assisted acquisition