Biology subjects

Moran, G.

Publications and source records attributed to Moran, G..

4 recordsLinked to original sources

bioRxiv2025

In vitro analysis of Fusobacterium Polymorphum from oral leukoplakia patients identifies 'high-risk' isolates

IntroductionMounting evidence links F. nucleatum, particularly subsp. polymorphum (now classified as F. polymorphum) to oral squamous cell carcinoma (OSCC). However, not all studies support this association, and its ubiquitous presence in health complicates its role as a driver of disease, raising a fundamental question: Can some isolates be pathogenic "high risk" while others are not? Here, we investigated the carcinogenic potential of clinical isolates of F. polymorphum from oral dysplastic lesions. MethodsSixteen, fully sequenced F. polymorphum isolates from healthy subjects (6 isolates) or patients with mild epithelial dysplasia (3 isolates), moderate dysplasia (3 isolates) or severe dysplasia/OSCC (4 isolates) were included. The isolates were assessed for their effect on the proliferation, migration, invasion, transcriptome and cytokinome of dysplastic oral keratinocytes (DOK). The isolates were also subject to RNA-seq and secreted amyloid FadA analyses. ResultsAlthough genetically indistinguishable, the isolates differed markedly in their effects on dysplastic oral keratinocytes (DOK) with isolates from dysplastic lesions demonstrating enhanced proliferation, migration, and invasion of DOK in proportion to the dysplasia severity of their clinical origin. Strikingly, amyloid-like FadA levels were also significantly higher in dysplasia-associated "high-risk" isolates and correlated with their pro-carcinogenic effects. RNA-seq further showed upregulation of heme acquisition genes in high risk isolates. Transcriptome and cytokine profiling of DOK revealed a uniform pro-inflammatory response across all isolates, independent of origin, but genes and pathways related to proliferation correlated with dysplasia severity. Supporting this, 45% of the most severity-correlated host genes identified in vitro were also differentially expressed in the same direction in tumors versus normal tissues in the TCGA OSCC dataset. ConclusionThese results show, for the first time, that clinical oral isolates of F. polymorphum vary in their carcinogenic properties, establishing the novel concept of "high-risk" versus "low-risk" isolates in oral carcinogenesis, potentially driven by genome-independent regulation.

microbiology↗

bioRxiv2024

Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfa-tase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among sub-missions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborate techniques. These findings underscore the utility of variant effect prediction, and the potential for models trained with modest resources to accurately classify VUS in genetic and clinical research.

genetics↗

bioRxiv2021

CALIPER: A software for blood-free parametric Patlak mapping using PET/MRI input function.

Routine clinical use of absolute PET quantification techniques is limited by the need for serial arterial blood sampling for input function and more importantly by the lack of automated pharmacokinetic analysis tools that can be readily implemented in clinic with minimal effort. PET/MRI provides the ability for absolute quantification of PET probes without the need for serial arterial blood sampling using image-derived input functions (IDIFs). Here we introduce caliPER, a modular and scalable software for simplified pharmacokinetic modelling of PET probes with irreversible uptake or binding based on PET/MR IDIFs and Patlak Plot analysis. caliPER generates regional values or parametric maps of net influx rate (Ki) using reconstructed dynamic PET images and anatomical MRI aligned to PET for IDIF vessel delineation. We evaluated the performance of caliPER for blood-free region-based and pixel-wise Patlak analyses of [18F] FDG by comparing caliPER IDIF to serial arterial blood input functions and its application in imaging brain glucose hypometabolism in Frontotemporal dementia. IDIFs corrected for partial volume errors including spill-out and spill-in effects were similar to arterial blood input functions with a general bias of around 6-8%, even for arteries <5 mm. The Ki and cerebral metabolic rate of glucose estimated using caliPER IDIF were similar to estimates using arterial blood sampling (<2%) and within limits of whole brain values reported in literature. Overall, caliPER is a promising tool for irreversible PET tracer quantification and can simplify the ability to perform parametric analysis in clinical settings without the need for blood sampling. HighlightsO_LIcaliPER is an adaptable image processing software for extracting image-derived input functions and generating parametric maps of irreversible PET tracer uptake. C_LIO_LIAnatomical (T1-weighted/T2-weighted/time-of-flight angiography) MRI carefully aligned to PET provides a robust approach for delineation of vessels on PET, eliminating the need for serial blood sampling for input functions. C_LIO_LIApplication of caliPER in modelling glucose uptake in patients with Frontotemporal dementia, demonstrates the feasibility of absolute quantification of cerebral metabolic rate of glucose in clinical populations. C_LI

bioinformatics↗

bioRxiv2018

Candida albicans hyphal expansion causes phagosomal membrane damage and luminal alkalinization

Macrophages rely on phagosomal acidity to destroy engulfed microorganisms. To survive this hostile response, opportunistic fungi such as Candida albicans developed strategies to evade the acidic environment. C. albicans is polymorphic, able to convert from yeast to hyphae, and this transition is required to subvert the microbicidal activity of the phagosome. However, the phagosomal lumen, which is acidic and nutrient-deprived, inhibits yeast-to-hypha transition. To account for this apparent paradox, it was recently proposed that C. albicans produces ammonia that alkalinizes the phagosome, thus facilitating yeast-to-hypha transformation. We re-examined the mechanism underlying phagosomal alkalinization by applying dual-wavelength ratiometric pH measurements. The phagosomal membrane was found to be highly permeable to ammonia, which is therefore unlikely to account for the pH elevation. Instead, we find that yeast-to-hypha transition begins within acidic phagosomes, and that alkalinization is a consequence of proton leakage induced by excessive membrane distension caused by the expanding hypha.\n\nIMPORTANCEC. albicans is the most common nosocomial fungal infection, and over three million people acquire life-threatening invasive fungal infections every year. Even if antifungal drugs exist, almost half of these patients will die. Despite this, fungi remain underestimated as pathogens. Our study uses quantitative biophysical approaches to demonstrate that the yeast-to-hypha transition occurs within the nutrient deprived, acidic phagosome and that alkalinization is a consequence, as opposed to the cause of hyphal growth.

cell biology↗