Biology subjects

Robinson, T. D.

Publications and source records attributed to Robinson, T. D..

6 recordsLinked to original sources

bioRxiv2026

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor

Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed a green fluorescent protein-based intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals the temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.

biochemistry↗

bioRxiv2025

Association between white-matter lesion volume and heart-rate variability: A comparison of T1, T1-T2 and T1-FLAIR-based segmentations using FreeSurfer SAMSEG

BackgroundHeart disease is a crucial risk factor for brain degeneration, but the exact mechanisms are still under investigation. Notably, a growth in white-matter lesion (WML) volume, a hallmark of cerebral small-vessel disease (cSVD) with connections to progressive neurodegeneration and cognitive decline, has been linked to cardiovascular disease. As such, measures of cardiovascular function such as heart rate variability may represent early and accessible predictors of WML development. MethodsThis study used data from healthy adults drawn from the Leipzig Study for Mind-Body-Emotion Interactions (LEMON) dataset to examine heart function through measures of heart rate variability (HRV), as well as their relationship to cSVD as quantified through WML volumes, using FreeSurfer SAMSEG. WML volumes were segmented using 3T T1+FLAIR, T1+T2 or T1 images alone. ResultsResults indicate that both young and old adults exhibited WMLs, and that lower HRV was associated with higher WML volume. This was particularly strong for high-frequency HRV across both young and older adults, but it was low-frequency HRV that was related to WML volume in an age-specific manner. Moreover, we showed that the WML-HRV relationship that is apparent using T1+FLAIR or T1+T2 based WML volumes could be observed even with T1w-based WML estimation alone. ConclusionsThese results suggest HRV not only as an avenue through which cardiovascular risk translates into brain degeneration, but also as a potential early and readily measurable non-invasive predictor of later WML development and cognitive impairment. Research Perspective- Differences in heart rate variability show consistent associations with the volume of white-matter lesions in the brain, with low-frequency heart rate variability uniquely sensitive to age effects on lesion volume. - Associations between heart rate variability and white matter lesion volume are detectable using T1-weighted volume estimation in absence of more intensive T1-weighted + T2-weighted or T1-weighted + FLAIR lesion estimations. - The neuroanatomical basis for this relationship, particularly the difference in high- and low-frequency heart rate variability associations, will require incorporating lifestyle, hormonal, and genetic factors, as well as targeted examination of high-versus low-frequency heart rate variability bands.

neuroscience↗

bioRxiv2024

A Genetically Encoded Fluorescent Biosensor for Intracellular Measurement of Malonyl-CoA

Malonyl-CoA is the essential building block of fatty acids and regulates cell function through protein malonylation and allosteric regulation of signaling networks. Accordingly, the production and use of malonyl-CoA is finely tuned by the cellular energy status. Most studies of malonyl-CoA dynamics rely on bulk approaches that take only a snapshot of the average metabolic state of a population of cells, missing out on dynamic changes in malonyl-CoA and fatty acid biosynthesis that could be occurring within a single cell. To overcome this limitation, we have developed a genetically encoded fluorescent protein-based biosensor for malonyl-CoA that can be used to capture malonyl-CoA dynamics in single cells. This biosensor, termed Malibu (malonyl-CoA intracellular biosensor to understand dynamics), exhibits an excitation-ratiometric change in response to malonyl-CoA binding. We first used Malibu to monitor malonyl-CoA dynamics during inhibition of fatty acid biosynthesis using cerulenin in E. coli, observing an increase in Malibu response in a time- and dose-dependent manner. In HeLa cells, we used Malibu to monitor the impact of fatty acid biosynthesis inhibition on malonyl-CoA dynamics in single cells, finding that two inhibitors of fatty acid biosynthesis, cerulenin and orlistat, which inhibit different steps of fatty acid biosynthesis, increase malonyl-CoA levels. Altogether, we have developed a new genetically encoded biosensor for malonyl-CoA, which can be used to sensitively study malonyl-CoA dynamics in single cells, providing an unparalleled view into fatty acid biosynthesis.

biochemistry↗

bioRxiv2024

Developmental order, fibre caliber, and vascularization predict tract-wise declines: Testing retrogenesis and physiological predictions in white matter aging

To understand the consistently observed spatial distribution of white-matter (WM) aging, developmentally driven theories termed "retrogenesis" have gained traction, positing that the order of WM tract development predicts the order of declines. Regions that develop first are expected to deteriorate the last, i.e. "last-in-first-out". Alternatively, regions which develop most rapidly may also decline most rapidly in aging, or "gains-predict-loss". The validity of such theories remains uncertain, in part due to lack of clarity on the definition of developmental order. Importantly, our recent findings suggest that WM aging is also associated with physiological parameters such as perfusion, which may be linked to fibre metabolic need, which in turn varies with fibre size. Here we address the extent to which the degree of WM aging is determined by development trajectory (i.e. retrogenesis) and/or by physiological state. We obtained microstructural and perfusion measures using data from the Human Connectome Project in Aging (HCP-A), complemented by a meta-analysis involving maps of fibre calibre and macrovascular volume. Our results suggest that (1) while tracts that appear last or finish myelinating first in development display the slowest aging, the pattern of aging is not fully explained by retrogenesis; in fact, time courses of tract emergence and myelination give rise to opposite associations with WM decline; (2) tracts that appear earlier also have higher mean axon calibre and are also associated with lower degrees of WM microstructural aging; (3) such tracts also tend to exhibit relatively sustained CBF with a higher rate of lengthening of the arterial transit times (ATT), suggestive of collateral blood supply. These findings were also sex dependent in a tract-specific manner. Future work will investigate whether these are ultimately influenced by each tracts metabolic demand and the role of macrovascular collateral flow.

neuroscience↗

bioRxiv2023

In search of a unifying theory of white matter aging: tract perfusion-microstructure relationships

One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, we posit that regional WM hypoperfusion precedes deteriorating WM integrity. Using the Human Connectome Project Aging (HCP-A) data set, we examine tract-wise associations between WM microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) and perfusion (i.e. cerebral blood flow and arterial transit time) in ten major bilateral WM tracts. Results show that tracts displaying the largest CBF decline in aging do not necessarily display the largest ATT decline, and vice versa. Moreover, significant WM perfusion-microstructure canonical correlations were found in all tracts, but the drivers of these correlations vary by both tract and sex, with female subjects demonstrating more tracts with large microstructural variations contributing to the correlations. Additionally, arterial transit time appears to be the earliest indicator of WM declines, preceding age-related microstructural differences and CBF in several tracts. This study contributes compelling evidence to the vascular hypothesis of WM degeneration, and highlights the utility of blood-flow timing as an early marker of aging.

neuroscience↗

bioRxiv2023

In search of a unifying theory of white matter aging: tract morphometry-microstructure relationships

While tract-wise differences in volume and microstructure are common targets of investigation in age-related changes in the white matter (WM), there has been relatively little exploration into other attributes of tract morphometry or its relation to microstructure in vivo, and limited understanding on how they jointly inform the interpretation of the WM aging trajectory. This study examines ten WM tracts for tract-wise differences in morphometry (i.e. volume, length, and volume-to-length ratio) and microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) using diffusion MRI data from the Human Connectome Project in Aging (HCP-A) with the goal of laying the foundation for a unified model of age-related WM microstructure-morphometry trajectories with a special focus on sex differences. Results indicated widely heterogeneous patterns of decline and morphometry-microstructural associations across tracts. Multi-parametric signatures of decline suggest stages or mechanisms of degeneration that differ between sexes. This work highlights the value of integrating microstructural and morphometric measures of WM health instead of observing them separately, suggesting multiple modes of WM degeneration.

neuroscience↗