Biology subjects

Stavropoulos, A.

Publications and source records attributed to Stavropoulos, A..

5 recordsLinked to original sources

bioRxiv2025

In vivo validation of novel non-invasive PHP.eB AAVs as a potential therapeutic approach for alpha-Synucleinopathies

Parkinsons disease (PD) is characterized by the accumulation of alpha-synuclein (aSyn) aggregates in specific brain regions, which are likely to be the disease-causing entities. Herein, we employed novel, systemically administered, brain-penetrating viral vectors (PHP.eB AAVs) in order to evaluate the potential therapeutic utility of lowering the endogenous aSyn protein burden in the aSyn pre-formed fibril (PFF)-mouse model. Such vectors expressing short hairpin RNAs or micro RNAs targeting the mouse Snca transcript (or respective scrambled control sequences) were intravenously administered in adult wild-type mice and two weeks later human aSyn PFFs were injected into the dorsal striatum. Following the administration of the Snca-targeting PHP.eB AAVs, a successful widespread viral transduction was achieved throughout the brain, accompanied by an efficient reduction of endogenous aSyn protein levels within transduced dopaminergic neurons. Intrastriatal injection of human aSyn PFFs led to the formation of pSer129-aSyn-rich cytoplasmic inclusions in brain regions connected to the PFF-injection site, nigrostriatal degeneration and relevant behavioral motor deficits, at 2.5 months post PFF-injection. Importantly, PHP.eB AAV-mediated down-regulation of endogenous aSyn reduced the accumulation of pSer129-aSyn+ inclusions, mitigated nigrostriatal degeneration and alleviated motor impairments. Spread of pathology to other brain regions was also attenuated. Overall, such data highlight further the contribution of the intracellular aSyn protein load to the spread of pathology and suggest that this non-invasive delivery strategy holds promise in the research avenues for treating neurodegenerative diseases with widespread pathology, such as Synucleinopathies.

neuroscience↗

bioRxiv2024

Comparative proteomics of biofilm development in Pseudoalteromonas tunicata discovers a distinct family of Ca2+-dependent adhesins

The marine bacterium, Pseudoalteromonas tunicata, is a useful model for studying mechanisms of biofilm development due to its ability to colonize and form biofilms on a variety of marine and eukaryotic host-associated surfaces. However, the pathways responsible for P. tunicata biofilm formation are still incompletely understood, in part due to a lack of functional information for a large proportion of its proteome. Here, we used comparative shotgun proteomics to examine P. tunicata biofilm development throughout the planktonic phase to three stages of biofilm development at 24, 48, and 72 h. Proteomic analysis identified 232 proteins that were up-regulated during different stages of biofilm development, including many hypothetical proteins as well as proteins known to be important for P. tunicata biofilm development such as the autocidal enzyme AlpP, violacein proteins, S-layer protein SLR4, and various pili proteins. We further investigated the top identified biofilm-associated protein (Bap), a previously uncharacterized 1600 amino acid protein (EAR30327), which we designated as "BapP". Based on AlphaFold modeling and genomic context analysis, we predicted BapP as a distinct Ca2+-dependent biofilm adhesin. Consistent with this prediction, a {Delta}bapP knockout mutant was defective in forming both pellicle and surface-associated biofilms, which was rescued by re-insertion of bapP into the genome. Similar to mechanisms of RTX adhesins, BapP-mediated biofilm formation was influenced by Ca2+ levels, and BapP is likely exported by a type 1 secretion system. Ultimately, our work not only provides a useful proteomic dataset for studying biofilm development in an ecologically relevant organism, but it also adds to our knowledge of bacterial adhesin diversity, emphasizing Bap-like proteins as widespread determinants of biofilm formation in bacteria.

microbiology↗

bioRxiv2023

Belief embodiment through eye movements facilitates memory-guided navigation

Neural network models optimized for task performance often excel at predicting neural activity but do not explain other properties such as the distributed representation across functionally distinct areas. Distributed representations may arise from animals strategies for resource utilization, however, fixation-based paradigms deprive animals of a vital resource: eye movements. During a naturalistic task in which humans use a joystick to steer and catch flashing fireflies in a virtual environment lacking position cues, subjects physically track the latent task variable with their gaze. We show this strategy to be true also during an inertial version of the task in the absence of optic flow and demonstrate that these task-relevant eye movements reflect an embodiment of the subjects dynamically evolving internal beliefs about the goal. A neural network model with tuned recurrent connectivity between oculomotor and evidence-integrating frontoparietal circuits accounted for this behavioral strategy. Critically, this model better explained neural data from monkeys posterior parietal cortex compared to task-optimized models unconstrained by such an oculomotor-based cognitive strategy. These results highlight the importance of unconstrained movement in working memory computations and establish a functional significance of oculomotor signals for evidence-integration and navigation computations via embodied cognition.

neuroscience↗

bioRxiv2021

Coordinated activation of both TGFβ and BMP canonical pathways regulates autophagy and tissue regeneration in acetaminophen induced liver injury

Transforming Growth Factor-{beta}s (TGF{beta}s)/Activins and Bone Morphogenetic Proteins (BMPs) have been implicated in numerous aspects of hepatic pathophysiology. However, the way by which hepatocytes integrate and decode the interplay between the TGF{beta}/Activin and BMP branches in health and disease is still not fully understood. To address this, TGF{beta}/BMP Smad- responsive double transgenic reporter mice were generated and utilized to map patterns of TGF{beta}- and/or BMP-pathway activation during acetaminophen- induced liver injury. TGF{beta} signaling was blocked either pharmacologically or by Smad7 over-expression and the transcriptomes of canonical TGF{beta}- and/or BMP4-treated hepatospheres and Smad7-treated livers were analyzed to highlight TGF{beta}-superfamily-regulated pathways and processes. Acetaminophen administration led to dynamically evolving, stage- and context-specific, patterns of hepatic TGF{beta}/Activin and BMP-reporter expression. TGF{beta}-superfamily signaling was activated in an autophagy prone zone at the borders between healthy and injured tissue. Inhibition of TGF{beta}-superfamily signaling attenuated autophagy, exacerbated liver histopathology, and finally led to accelerated tissue-recovery. Hallmarks of this process were the paraptosis-like cell death and the attenuation of immune and reparatory cell responses. Transcriptomic analysis highlighted autophagy as a prominent TGF{beta}1- and BMP4-regulated process and recognized Trp53inp2 as the top TGF{beta}-superfamily-regulated autophagy-related gene. Collectively, these findings implicate the coordinated activation of both canonical TGF{beta}-superfamily signalling branches in balancing autophagic response and tissue-reparatory and -regenerative processes upon acetaminophen-induced hepatotoxicity, highlighting opportunities and putative risks associated with their targeting for treatment of hepatic diseases.

physiology↗

bioRxiv2020

Influence of sensory modality and control dynamics on human path integration

Path integration is a sensorimotor computation that can be used to infer latent dynamical states by integrating self-motion cues. We studied the influence of sensory observation (visual/vestibular) and latent control dynamics (velocity/acceleration) on human path integration using a novel motion-cueing algorithm. Sensory modality and control dynamics were both varied randomly across trials, as participants controlled a joystick to steer to a memorized target location in virtual reality. Visual and vestibular steering cues allowed comparable accuracies only when participants controlled their acceleration, suggesting that vestibular signals, on their own, fail to support accurate path integration in the absence of sustained acceleration. Nevertheless, performance in all conditions reflected a failure to fully adapt to changes in the underlying control dynamics, a result that was well explained by a bias in the dynamics estimation. This work demonstrates how an incorrect internal model of control dynamics affects navigation in volatile environments in spite of continuous sensory feedback.

neuroscience↗