Biology subjects

Baker, F.

Publications and source records attributed to Baker, F..

5 recordsLinked to original sources

bioRxiv2024

Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces

Background and PurposeAn association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI). Materials and MethodsThis analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm3/white matter cm3). ResultsOn average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a persons BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a persons average BMI was associated with a 0.021 mm3/cm3 increase in MV-PVS volume (p<0.001). ConclusionThis longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a persons mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.

neuroscience↗

bioRxiv2024

An in vivo screen for proteolytic switches that can mediate Notch activation

Notch proteins are single pass transmembrane receptors activated by sequential extracellular and intramembrane cleavages that release their cytosolic domains to function as transcription factors in the nucleus. Upon binding, Delta/Serrate/LAG-2 (DSL) ligands activate Notch by exerting a "pulling" force across the intercellular ligand/receptor bridge. This pulling force is generated by Epsin-mediated endocytosis of ligand into the signal-sending cell, and results in the extracellular cleavage of the force-sensing Negative Regulatory Region (NRR) of the receptor by an ADAM10 protease [Kuzbanian (Kuz) in Drosophila]. Here, we have used chimeric Notch and DSL proteins to screen for other domains that can function as ligand-dependent proteolytic switches in place of the NRR in the developing Drosophila wing. While most of the tested domains are either refractory to cleavage or constitutively cleaved, we identify several that mediate Notch activation in response to ligand. These NRR analogues derive from widely divergent source proteins and have strikingly different predicted structures. Yet, almost all depend on force exerted by Epsin-mediated ligand endocytosis and cleavage catalyzed by Kuz. We posit that the sequence space of protein domains that can serve as force-sensing proteolytic switches in Notch activation is unexpectedly large, a conclusion that has implications for the mechanism of target recognition by Kuz/ADAM10 proteases and is consistent with a more general role for force dependent ADAM10 proteolysis in other cell contact-dependent signaling mechanisms. Our results also validate the screen for increasing the repertoire of proteolytic switches available for synthetic Notch (synNotch) therapies and tissue engineering. One sentence summaryA scalable in vivo screen for Epsin and ADAM10 dependent proteolytic switches that can mediate Notch activation in response to force.

cell biology↗

bioRxiv2022

Defining the Ligand-dependent Interactome of the Sigma 1 Receptor

Sigma 1 Receptor (S1R) is a therapeutic target for a wide spectrum of pathological conditions ranging from neurodegenerative diseases to cancer and COVID-19. S1R is ubiquitously expressed throughout the visceral organs, nervous, immune and cardiovascular systems. It is proposed to function as a ligand-dependent molecular chaperone that modulates multiple intracellular signaling pathways. The purpose of this study was to define the S1R interactome under native conditions and upon binding to well-characterized ligands. This was accomplished by fusing the biotin ligase, Apex2, to the C terminus of S1R. Cells stably expressing S1R-Apex or a GFP-Apex control were used to map specific protein interactions. Biotinylated proteins were labeled under native conditions and in a ligand dependent manner, then purified and identified using quantitative mass spectrometry. Under native conditions, S1R biotinylates over 200 novel proteins, many of which localize within the endomembrane system (ER, Golgi, secretory vesicles) and function within the secretory pathway. Under conditions of cellular exposure to either S1R agonist or antagonist, results show enrichment of proteins integral to secretion, extracellular matrix formation, and cholesterol biosynthesis. Notably, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) displays increased binding to S1R under conditions of treatment with Haloperidol, a well-known S1R antagonist; whereas Low density lipoprotein receptor (LDLR) binds more efficiently to S1R upon treatment with (+)-Pentazocine ((+)-PTZ), a classical S1R agonist. Our results are consistent with the postulated role of S1R as an intracellular chaperone and further suggest important and novel functionalities related to cholesterol metabolism and biosynthesis.

cell biology↗

bioRxiv2021

A Comprehensive Overview of the Physical Health of the Adolescent Brain Cognitive Development Study (ABCD) Cohort at Baseline

Physical health in childhood is crucial for neurobiological as well as overall development, and can shape long-term outcomes into adulthood. The landmark, longitudinal Adolescent Brain Cognitive Development StudySM (ABCD study(R)), was designed to investigate brain development and health in almost 12,000 youth who were recruited when they were 9-10 years old and will be followed through adolescence and early adulthood. The overall goal of this paper is to provide descriptive analyses of physical health measures in the ABCD study at baseline, including but not limited to sleep, physical activity and sports involvement, and body mass index, and how these measures vary across demographic groups. This paper outlines how the physical health of the ABCD sample corresponds with that of the US population and highlights important avenues for health disparity research. This manuscript will provide important information for ABCD users and help guide analyses investigating physical health as it pertains to adolescent and young adult development.

developmental biology↗

bioRxiv2021

Adolescent Binge Drinking is Associated with Accelerated Decline of Gray Matter Volume

The age- and time-dependent effects of binge-drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume development was examined using longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). Non-binge drinkers (n=177) were matched to binge drinkers (n=164) on potential confounders. Number of binge drinking episodes in the past year was linked to decreased volumes for total gray matter, frontal, parietal, temporal, and occipital lobes (ps<.001). Interactions of binge drinking episodes and age demonstrated stronger effects in younger subjects for total gray matter, frontal, temporal, and occipital lobes (ps<.001). Subsequent models included binge drinking coded in multiple ways. Models sensitive to number of episodes and temporal proximity to outcomes provided the best fits. Declines in gray matter volume association with binge drinking are potentially related to changes in cognition frequently reported among binge drinking adolescents. Results underscore the potential importance of delaying initiation of binge drinking and provide evidence for a dose-response relationship of binge drinking to gray matter decline. Temporally proximal binge drinking was associated more strongly with gray matter decline, suggesting the potential for recovery.

neuroscience↗