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Williamson, M.

Publications and source records attributed to Williamson, M..

6 recordsLinked to original sources

Bacterial Protein Signatures Identified in Porphyromonas gingivalis Containing-Autophagic Vacuoles Reveal Evolutionary History Between Oral Red/Orange Complex Bacteria and Gut Resident Bacteria

Modern oral bacterial species present as a concoction of commensal and opportunistic pathogens originating from their evolution in humans. Due to the intricate colonization mechanisms shared amongst oral and gut bacteria, these bacteria have likely evolved together to establish and adapt in the human oro-digestive tract, resulting in the transfer of genetic information. Our liquid chromatography-with-tandem-mass-spectrometry (LC-MS-MS) analyses have revealed protein signatures, Elongation Factor Tu, RagB/SusD nutrient uptake outer membrane protein and DnaK, specifically from Porphyromonas gingivalis-containing autophagic vacuoles isolated from the infected human primary gingival epithelial cells. Interestingly, our Mass-Spectrometry analysis reported similar proteins from closely related oral bacteria, Tannerella forsythia and Prevotella intermedia. In our phylogenetic study of these key protein signatures, we have established that pathogenic oral bacteria share extensive relatedness to each other and gut resident bacteria. We show that in the virulence factors identified from gut bacteria, Elongation Factor Tu and DnaK, there are several structural similarities and conservations with proteins from oral pathogenic bacteria. There are also major similarities in the RagB/SusD proteins of oral bacteria to prominent gut bacteria. These findings not only highlight the shared virulence mechanisms amongst oral bacterial pathogens/pathobionts but also gut bacteria and elucidate their co-evolutions in the human host.

microbiology↗

Remote neuronal activity drives glioma infiltration via Sema4f

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

cancer biology↗

Relative roles of genetic variation and phenotypic plasticity in the invasion of monkeyflower Erythranthre gutatta in New Zealand

Evolutionary processes which increase the probability of an introduced plant species becoming invasive include high levels of genetic diversity and phenotypic plasticity. Naturalised in New Zealand, monkeyflower, (Erythranthre gutatta), a clonally spreading herb of waterways and seepage areas native to the Western USA, shows marked variation in a range of vegetative, reproductive and inflorescence traits. We used two common gardens differing in elevation to explore the relative contribution of genetic versus plastic variation within nine traits among 34 monkeyflower clones from across the New Zealand South Island. We looked for evidence of clinal variation across elevation gradients and for home site advantage. We found both high genetic diversity and trait plasticity explain the observed variation, although less evidence for adaptive plasticity. Most genetic variation was observed in the lowland garden (9m a.s.l.), where the overall trend was for above ground dry weight to be lower, and horizontal shoot length greater, than at the montane garden (560m a.s.l). We found no evidence of local adaptation to any of the measured environmental variables. However, we observed a pattern of higher biomass and higher plasticity at lower versus higher elevations and in clones originating from lower elevation sites.

ecology↗

Plexin-B1 mutation drives prostate cancer metastasis

Prostate cancer mortality is associated with the metastatic spread of tumour cells. A better understanding of the mechanisms which allow a locally advanced tumour to disseminate around the body will identify new therapeutic targets to block this process. One of set of genes implicated in metastasis are plexins, which can promote or suppress tumour progression depending on cancer type and cellular context. We have taken a mouse genetics approach to gain insight into the role of Plexin-B1 in prostate cancer progression in vivo. We show here that genetic deletion of Plexin-B1 in PbCre+Ptenfl/flKrasG12V and PbCre+Ptenfl/flp53fl/fl mouse prostate cancer models significantly decreased metastasis. High levels of prostate epithelial cell-specific expression of wild-type Plexin-B1 in knock-in mice with a PbCre+Ptenfl/flKrasG12V background also significantly decreased metastasis. In contrast, expression of a Plexin-B1 mutant (P1597L; identified from metastatic deposits in prostate cancer patients) in prostate epithelial cells in PbCre+Ptenfl/flKrasG12V and PbCre+Ptenfl/flp53fl/fl mice significantly increased metastasis, in particular metastasis to distant sites. In line with these findings, both deletion and overexpression of wild-type Plexin-B1 reduced invasion of tumour cells into the prostate stroma, while overexpression of mutant Plexin-B1 significantly increased invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Invasion and metastasis also correlated with phosphorylation of myosin light chain, suggesting that Plexin-B1 signals via the Rho/ROCK pathway to promote metastasis. Our results demonstrate that mutant Plexin-B1 promotes metastasis in prostate cancer and represents a new therapeutic target to suppress tumour spread.

cancer biology↗

Segmentation-less, automated vascular vectorization robustly extracts neurovascular network statistics from in vivo two-photon images

Recent advances in two-photon microscopy (2PM) have allowed large scale imaging and analysis of blood vessel networks in living mice. However, extracting a network graph and vector representations for vessels remain bottlenecks in many applications. Vascular vectorization is algorithmically difficult because blood vessels have many shapes and sizes, the samples are often unevenly illuminated, and large image volumes are required to achieve good statistical power. State-of-the-art, three-dimensional, vascular vectorization approaches often require a segmented (binary) image, relying on manual or supervised-machine annotation. Therefore, voxel-by-voxel image segmentation is biased by the human annotator or trainer. Furthermore, segmented images oftentimes require remedial morphological filtering before skeletonization or vectorization. To address these limitations, we present a vectorization method to extract vascular objects directly from unsegmented images without the need for machine learning or training. The Segmentation-Less, Automated, Vascular Vectorization (SLAVV) source code in MATLAB is openly available on GitHub. This novel method uses simple models of vascular anatomy, efficient linear filtering, and low-complexity vector extraction algorithms to remove the image segmentation requirement, replacing it with manual or automated vector classification. SLAVV is demonstrated on three in vivo 2PM image volumes of microvascular networks (capillaries, arterioles and venules) in the mouse cortex. Vectorization performance is proven robust to the choice of plasma- or endothelial-labeled contrast, and processing costs are shown to scale with input image volume. Fully-automated SLAVV performance is evaluated on simulated 2PM images of varying quality all based on the large (1.4x0.9x0.6 mm3 and 1.6x108 voxel) input image. Vascular statistics of interest (e.g. volume fraction, surface area density) calculated from automatically vectorized images show greater robustness to image quality than those calculated from intensity-thresholded images. Author summarySamuel Mihelic is a PhD candidate in the Biomedical Engineering Department at the University of Texas at Austin. He graduated from Oregon State University (Chemical Engineering BS, Mathematics BS). He hosts the GitHub repository for the code used in this article: https://github.com/UTFOIL/Vectorization-Public. His research interests are in-vivo neural microvascular image analysis, anatomy, and plasticity. William Sikora graduated with a BS in Computational Biomedical Engineering from The University of Texas at Austin in May 2020. He is working with Dr. Yuan Yang and the Laureate Institute for Brain Research as a PhD student of Biomedical Engineering at the University of Oklahoma in Tulsa, researching the highly non-linear world of neural coupling and its link to common neurological pathologies such as stroke. Ahmed Hassan is a graduate of the University of California, Los Angeles and the University of Texas at Austin with a Bachelor's degree in Microbiology, Immunology, and Molecular Genetics and an MSE/PhD in Biomedical Engineering. His graduate research was concentrated in imaging and instrumentation, and his interests include developing optical and laser systems for neuroimaging, image processing and reconstruction, and advanced image analysis. Michael Williamson earned a BSc (Honours) in Neuroscience in 2016 from the University of Alberta, where he trained with Dr. Fred Colbourne. He is currently a doctoral student at the University of Texas at Austin working in the labs of Drs. Theresa Jones and Michael Drew. Theresa Jones is a Professor in the Department of Psychology and Neuroscience at The University of Texas at Austin. Her laboratory studies plasticity of neural structure and synaptic connectivity following brain damage and injury. Andrew K. Dunn is the Donald J. Douglass Centennial Professor of Engineering in the Department of Biomedical Engineering at The University of Texas at Austin and the Director of the Center for Emerging Imaging Technologies. His research focuses on the development of innovative optical imaging techniques for studying the brain.

bioengineering↗

Elucidating the molecular determinants of Aβ aggregation with deep mutational scanning

Despite the importance of A{beta} aggregation in Alzheimers disease etiology, our understanding of the sequence determinants of aggregation is sparse and largely derived from in vitro studies. For example, in vitro proline and alanine scanning mutagenesis of A{beta}40 proposed core regions important for aggregation. However, we lack even this limited mutagenesis data for the more disease-relevant A{beta}42. Thus, to better understand the molecular determinants of A{beta}42 aggregation in a cell-based system, we combined a yeast DHFR aggregation assay with deep mutational scanning. We measured the effect of 791 of the 798 possible single amino acid substitutions on the aggregation propensity of A{beta}42. We found that ~75% of substitutions, largely to hydrophobic residues, maintained or increased aggregation. We identified 11 positions at which substitutions, particularly to hydrophilic and charged amino acids, disrupted A{beta} aggregation. These critical positions were similar but not identical to critical positions identified in previous A{beta} mutagenesis studies. Finally, we analyzed our large-scale mutagenesis data in the context of different A{beta} aggregate structural models, finding that the mutagenesis data agreed best with models derived from fibrils seeded using brain-derived A{beta} aggregates.

molecular biology↗