Elucid Bioimaging

<title>Abstract</title> A growing body of evidence supports that targeting the tumour extracellular matrix (ECM) in solid cancers holds great promises to reactivate T cell migration in immune-excluded patients. By matrisome profiling of triple-negative breast cancer (TNBC) patients, we identified two core ECM proteins enriched in fibrotic immune-excluded tumours and associated with reduced CD8+ T cell stromal infiltration, versican (VCAN) and fibronectin (FN1). Both cancer-associated fibroblasts and aggressive cancer cell lines were found to deposit these two proteins in vitro, conferring resistance to T-cell-mediating cytotoxicity. Characterisation of in vivo murine breast cancer models 4T1 and EMT6 revealed significant differences in tumour ECM deposition and immune cell composition. Accordingly, targeting Fn1 and Vcan in both models induced opposite effects on tumour growth. While it appeared unfavourable in inflamed non fibrotic tumours, deletion of Fn1 in cancer cells was beneficial in immune-excluded tumours by promoting TCF7+ T cells and restoring anti-PD1 response.

Abstract We introduce the IDR searcher, an open-source search engine designed to ease the exploration of datasets hosted in public bioimaging resources. The application offers a fast, efficient, cost-effective solution for datasets discovery and has the potential to address current disparities in finding quality datasets for exploratory research and to provide the foundation for cross-resource search.

Abstract Microbiomes and their hosts influence one another in a complex and dynamic ecosystem. While bacteria in the root microbiome are recognized for their role in plant health, it still remains unclear whether their viral (phage) activity indirectly influences plant growth. Using machine learning-based viral detection tools, we identified a putative 63.7 kb double-stranded DNA prophage in the plant growth promoting rhizobacterium Pseudomonas simiae WCS417 and experimentally confirmed its lysogenic potential. We co-cultivated the GFP-labeled wild-type (WT) and prophage absent (Δphage) strains with Arabidopsis thaliana and Brachypodium distachyon to assess the prophage’s impact on both bacterial host and plant physiology. Our results demonstrate that prophage presence impacted plant root architecture, root exudate metabolic profiles, and shoot biomass under thermal stress without affecting bacterial colonization ability. Collectively, these findings reveal a triadic plant-bacterium-phage axis in the rhizosphere, underscoring a critical role of phages in shaping community dynamics and plant-microbiome interactions.

Background: Carotid endarterectomy (CEA) for symptomatic carotid stenosis is recommended for patients with the &gt;70% (NASCET) stenosis but not for those with &lt;50%. Since low-degree stenoses may still cause strokes, refined risk stratification is necessary, which could be improved by incorporating biological features of plaque instability. In order to challenge risk-stratification by the degree of stenosis, we compared biological features of carotid plaques from symptomatic patients with &lt;50% stenosis vs. &gt;70% and explored mechanisms behind plaque instability in low-degree stenoses. Methods: CEA specimens were retrieved from symptomatic patients with &gt;70% (n=204) and &lt;50% stenosis (n=34), all part of the Biobank of Karolinska Endarterectomies (BiKE). Patient demographics, plaque morphology from image analyses of preoperative computed tomography angiography (CTA), and RNA-seq analyses of lesions were used for comparisons. Plaque biology was assessed by transcriptomics using principal component analyses (PCA), differential gene expression (DGE)- and gene-set enrichment analyses (GSEA). Immunohistochemistry (IHC) was used to study proteins corresponding to upregulated genes. Results: The demographics of the two groups were statistically similar. They also showed similar plaque morphology with respect to intraplaque hemorrhage (IPH), plaque burden and fibrous cap thickness, whereas calcification was higher in the &lt;50% group and lipid-rich necrotic core higher in the &gt;70% group. PCA analysis indicated poor clustering, while DGE and GSEA identified enrichment of genes and pathways related to tissue hypoxia and angiogenesis in &lt;50% lesions. Corresponding proteins were detected by IHC in neo-vascularized plaque regions. Conclusions: Plaques from symptomatic patients with &lt;50% carotid stenoses exhibit largely similar morphological and biological features as those from &gt;70% stenoses, emphasizing the need for improved stratification of patients for CEA of symptomatic carotid stenosis. However, pathways associating plaque burden, hypoxia and angiogenesis were particularly enriched in low-grade stenosis lesions suggesting mechanisms behind plaque instability and symptoms in patients with both low- and high-degree stenosis.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.

We previously observed sustained fMRI BOLD signal in the basal ganglia in focal hand dystonia patients after a repetitive finger tapping task. Since this was observed in a task-specific dystonia, for which excessive task repetition may play a role in pathogenesis, in the current study we asked if this effect would be observed in a focal dystonia (cervical dystonia [CD]) that is not considered task-specific or thought to result from overuse. We evaluated fMRI BOLD signal time courses before, during, and after the finger tapping task in CD patients. We observed patient/control differences in post-tapping BOLD signal in left putamen and left cerebellum during the non-dominant (left) hand tapping condition, reflecting abnormally sustained BOLD signal in CD. BOLD signals in left putamen and cerebellum were also abnormally elevated in CD during tapping itself and escalated as tapping was repeated. There were no cerebellar differences in the previously studied FHD cohort, either during or after tapping. We conclude that some elements of pathogenesis and/or pathophysiology associated with motor task execution/repetition may not be limited to task-specific dystonias, but there may be regional differences in these effects across dystonias, associated with different types of motor control programs.

ObjectiveGuidance for preventing myocardial infarction and ischemic stroke by tailoring treatment for individual patients with atherosclerosis is an unmet need. Such development may be possible with computational modeling. Given the multifactorial biology of atherosclerosis, modeling must be based on complete biological networks that capture protein-protein interactions estimated to drive disease progression. Here, we aimed to develop a clinically relevant scale model of atherosclerosis, calibrate it with individual patient data, and use it to simulate optimized pharmacotherapy for individual patients. Approach and resultsThe study used a uniquely constituted plaque proteomic dataset to create a comprehensive systems biology disease model for simulating individualized responses to pharmacotherapy. Plaque tissue was collected from 18 patients with 6735 proteins at two locations per patient. 113 pathways were identified and included in the systems biology model of endothelial cells, vascular smooth muscle cells, macrophages, lymphocytes, and the integrated intima, altogether spanning 4411 proteins, demonstrating a range of 39–96% plaque instability. After calibrating the systems biology models for individual patients, we simulated intensive lipid-lowering, anti-inflammatory, and anti-diabetic drugs. We also simulated a combination therapy. Drug response was evaluated as the degree of change in plaque stability, where an improvement was defined as a reduction of plaque instability. In patients with initially unstable lesions, simulated responses varied from high (20%, on combination therapy) to marginal improvement, whereas patients with initially stable plaques showed generally less improvement. ConclusionIn this pilot study, proteomics-based system biology modeling was shown to simulate drug response based on atherosclerotic plaque instability with a power of 90%, providing a potential strategy for improved personalized management of patients with cardiovascular disease.

Abstract During the rapid and reductive cleavage divisions of early embryogenesis, subcellular structures such as the nucleus and mitotic spindle scale to decreasing cell size. Mitotic chromosomes also decrease in size during development, presumably to coordinately scale with mitotic spindles, but underlying mechanisms are unclear. Here we combinein vivoandin vitroapproaches using eggs and embryos from the frogXenopus laevisto show that mitotic chromosome scaling is mechanistically distinct from other forms of subcellular scaling. We found that mitotic chromosomes scale continuously with cell, spindle and nuclear sizein vivo. However, unlike for spindles and nuclei, mitotic chromosome size cannot be re-set by cytoplasmic factors from earlier developmental stages.In vitro, increasing nucleo-cytoplasmic (N/C) ratio is sufficient to recapitulate mitotic chromosome scaling, but not nuclear or spindle scaling, through differential loading of maternal factors during interphase. An additional pathway involving importin α scales mitotic chromosomes to cell surface area/volume (SA/V) during metaphase. Finally, single-chromosome immunofluorescence and analysis of Hi-C data suggest that mitotic chromosomes scale through decreased recruitment of condensin I, resulting in major rearrangements of DNA loop architecture to accommodate the same amount of DNA on a shorter axis. Together, our findings demonstrate how mitotic chromosome size is set by spatially and temporally distinct developmental cues in the early embryo.