Biology subjects

Stewart, S. E.

Publications and source records attributed to Stewart, S. E..

4 recordsLinked to original sources

bioRxiv2025

Executive control in Obsessive-Compulsive Disorder: A worldwide mega-analysis of task-based functional neuroimaging data of the ENIGMA-OCD consortium

ObjectiveObsessive-compulsive disorder (OCD) is associated with impaired executive function and altered activity in associated neural circuits, contributing to reduced goal-directed behavior. To investigate neural activation during executive control, we conducted a mega-analysis in the ENIGMA-OCD consortium pooling individual participant data from 475 individuals with OCD and 345 healthy controls across 15 fMRI tasks collected worldwide. MethodsIndividual participant data was uniformly processed using HALFpipe to construct voxelwise statistical images of executive control and task load contrasts. Parameter estimates extracted from regions of interest were entered into multilevel Bayesian models to examine regional and whole-brain effects of diagnosis, and, within OCD, the influence of medication status, symptom severity, and age of onset on task activation. ResultsWe observed a robust task activation pattern across individuals with OCD and control participants in executive control regions across tasks. Relative to controls, individuals with OCD showed moderate to very strong evidence of weaker activation of the dorsolateral prefrontal cortex, precuneus, frontal eye fields, and inferior parietal lobule during executive control (all positive posterior probabilities [P+]<0.1). Individuals with OCD also showed stronger activation in regions of the default mode network during executive function relative to controls. We found little evidence for differential activation during executive control in task- positive regions related to disease onset, severity and medication status. ConclusionIn the first mega-analysis of fMRI studies of executive function in OCD, we found strong evidence of weaker frontoparietal activation during executive control tasks. Our findings also suggest a failure of default mode network regions to appropriately disengage during task performance in OCD.

neuroscience↗

bioRxiv2019

New factors for protein transport identified by a genome-wide CRISPRi screen in mammalian cells

Protein and membrane trafficking pathways are critical for cell and tissue homeostasis. Traditional genetic and biochemical approaches have shed light on basic principles underlying these processes. However, the list of factors required for secretory pathways function remains incomplete, and mechanisms involved in their adaptation poorly understood. Here, we present a powerful strategy based on a pooled genome-wide CRISPRi screen that allowed the identification of new factors involved in protein transport. Two newly identified factors, TTC17 and CCDC157, localized along the secretory pathway and were found to interact with resident proteins of ER-Golgi membranes. In addition, we uncovered that upon TTC17 knockdown, the polarized organization of Golgi cisternae was altered, creating glycosylation defects, and that CCDC157 is an important factor for the fusion of transport carriers to the Golgi complex. In conclusion, our work identified and characterized new actors in the mechanisms of protein transport and secretion, and opens stimulating perspectives for the use of our platform in physiological and pathological contexts.

cell biology↗

bioRxiv2018

Phospholipid flipping facilitates annexin translocation across membranes

Annexins are phospholipid binding proteins that somehow translocate from the inner leaflet of the plasma membrane to the outer leaflet. For example, Annexin A2 is known to localise to the outer leaflet of the plasma membrane (cell surface) where it is involved in plasminogen activation leading to fibrinolysis and cell migration, among other functions. Despite having well described extracellular functions, the mechanism of annexin transport from the cytoplasmic inner leaflet to the extracellular outer leaflet of the plasma membrane remains unclear. Here, we show that phospholipid flipping activity is crucial for the transport of annexins A2 and A5 across membranes in cells and in liposomes. We identified TMEM16F (anoctamin-6) as a lipid scramblase required for transport of these annexins to the outer leaflet of the plasma membrane. This work reveals a mechanism for annexin translocation across membranes which depends on plasma membrane phospholipid flipping.

cell biology↗

bioRxiv2017

Evolutionary and functional data power search for obsessive-compulsive disorder genes

Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder linked to abnormalities in the cortico-striatal circuit and in glutamate signaling. We sequenced coding and regulatory elements for 608 genes implicated in OCD from humans and two animal models (mouse and dog). Using a new method, PolyStrat, which prioritizes variants disrupting evolutionarily conserved, functional regions, we found four strongly associated genes when comparing 592 cases to 560 controls. These results were validated in a second, larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains, while CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants. The rare coding variant burden in NRXN1 achieves genomewide significance (p=6.37x10-11) when we include public data for 33,370 controls. Of 17 regulatory variants identified in CTTNBP2 and REEP3, we show that at least six alter transcription factor-DNA binding in human neuroblastoma cells. Our findings suggest synaptic adhesion as a key function in compulsive behaviors across three species, and demonstrate how combining targeted sequencing with functional annotations can identify potentially causative variants in both coding and noncoding regions, even when genomic data is limited.

genomics↗