Biology subjects

Merritt, M.

Publications and source records attributed to Merritt, M..

4 recordsLinked to original sources

bioRxiv2023

MetaVision3D: Automated framework for the Generation of Spatial Metabolome Atlas in 3D

High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional space and is poised to be extended into the three-dimensional world of biology. Here, we introduce MetaVision3D, a novel pipeline driven by computer vision techniques for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework employs advanced algorithms for image registration, normalization, and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at mesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas (available at https://metavision3d.rc.ufl.edu/) as an interactive online database and web server to further advance brain metabolism and related research.

neuroscience↗

bioRxiv2023

Maturational Differences in Affective Behaviors Involves Changes in Frontal Cortical-Hippocampal Functional Connectivity and Metabolomic Profiles

The differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation. We assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics. Our results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and with re-testing with a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. The results support differential expression of emotionality across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry.

neuroscience↗

bioRxiv2023

Detecting altered hepatic lipid oxidation by MRI in an animal model of NAFLD

Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing annually and affects over a third of U.S. adults. NAFLD can progress to nonalcoholic steatohepatitis (NASH), characterized by severe inflammation and fibrosis. NASH is predicted to become the primary cause of liver transplant by 2030. Although the etiology of NAFLD/NASH is incompletely understood, dysregulated fatty acid oxidation is implicated in disease pathogenesis. Here, we developed a method for estimating hepatic {beta}-oxidation from the metabolism of [D15]octanoate to deuterated water and detection with deuterium magnetic resonance methods. Application of this method to perfused liver from a mouse model of NAFLD revealed dysregulated hepatic {beta}-oxidation, findings that we confirmed with in vivo imaging. The high-fat diet-induced NAFLD mouse studies indicated that decreased {beta}-oxidative efficiency in the fatty liver could serve as a prognostic indicator of NAFLD progression. Furthermore, our method provides a clinically translatable imaging approach for determining hepatic {beta}-oxidation efficiency.

biochemistry↗

bioRxiv2022

In-vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed metabolism in patient-derived xenografts (tumorgrafts) from diverse forms of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engage in oxidative and reductive glutamine metabolism. We used several approaches to suppress glutamine metabolism and test the effect on tumor growth. Genetic silencing of isocitrate dehydrogenase-1 or -2 impaired reductive labeling of TCA cycle intermediates and suppressed tumor growth. Glutaminase inhibition resulted in modest growth suppression and variable effects on glutamine metabolism in vivo. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase. TeaserGlutamine fuels the TCA cycle and amidotransferase pathways in clear cell renal cell carcinoma.

cancer biology↗