Biology subjects

Araya, J.

Publications and source records attributed to Araya, J..

6 recordsLinked to original sources

bioRxiv2024

A novel HLA Class II presentation prediction algorithm deciphers immunogenic CD4 epitopes specific to KRAS G12C

Accurate prediction of peptide presentation by HLA molecules is important for generation of effective individualized cancer vaccines and immunotherapies. While presentation prediction algorithms for HLA class I have been successfully applied in the context of such therapies, improved prediction algorithms for class II are needed. EDGE-II is a novel algorithm based on a protein large language model that has a learned allele deconvolution network trained on existing and new immunopeptidomics data. It delivers state-of-the-art performance on prediction of peptide presentation by HLA class II and immunogenicity elicited by CD4+ T-cell epitopes. In a patient with a KRAS G12C positive tumor treated with a KRAS G12C targeting immunotherapy, EDGE-II identified KRAS G12C class II neoantigens that elicited clonally expanded CD4+ T cells with cytotoxic transcriptional profiles post-vaccination. EDGE-II could play an important role in the development of effective cancer immunotherapies by elucidating an enriched understanding of the immunopeptidome.

bioinformatics↗

bioRxiv2024

Lipogenic Lung Fibroblast-derived Extracellular Vesicles Mitigate Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Pathologies through LAT1-mediated Alveolar Type II Cell Restoration

Emerging research has revealed specific cellular aberrations in Chronic Obstructive Pulmonary Disease (COPD), with a particular focus on alveolar type 2 (AT2) cells, which play a pivotal role in the restoration of damaged lung tissue and promotion of normal cellular differentiation. Lipofibroblasts (LipoFBs), which are stromal fibroblasts that house lipid droplets, have been identified in close proximity to AT2 cells and have been demonstrated to support AT2 function. In this study, we present a comprehensive investigation into the therapeutic potential of extracellular vesicles (EVs) derived from LipoFBs (LipoFB-EVs) in COPD treatment. They effectively mitigate key COPD pathologies such as cellular senescence and inflammatory responses in lung epithelial cells. This is achieved by reducing reactive oxygen species (ROS) levels and modulating DNA damage response pathways. Moreover, LipoFB-EVs demonstrate antifibrotic properties by inhibiting TGF-{beta}-induced myofibroblast differentiation, surpassing conventional antifibrotic drugs. They also aid in restoring impaired AT2 stem cells, which are crucial for lung homeostasis, by enhancing their viability, colony-forming ability, and proliferation. Furthermore, we identify the presence of L-type amino acid transporter 1 (LAT1) within LipoFB-EVs, which mediates amino acid uptake, particularly leucine transport, and contributes to the restoration of AT2 cell dysfunction. Importantly, the administration of LipoFB-EVs in murine models of COPD resulted in significant improvements in airway inflammation, remodeling, obstruction, cellular senescence, and alveolar emphysema induced by both short- and long-term CS exposure. Overall, our findings highlight the therapeutic potential of LipoFB-EVs as a novel regenerative therapy for COPD, offering promising avenues for future clinical interventions.

molecular biology↗

bioRxiv2021

Parallel processing of natural images by overlapping retinal neuronal ensembles

Even though the retinal microcircuit organization has been described in detail at the single-cell level, little is known about how groups of retinal cells coordinated activity encode and process parallel information representing the spatial and temporal structure of changing environmental conditions. To describe the population dynamics of retinal neuronal ensembles, we used microelectrode array recordings that describe hundreds of retinal ganglion cells simultaneous activity in response to a short movie captured in the natural environment where our subject develops their visual behaviors. The vectorization of population activity allowed the identification of retinal neuronal ensembles that synchronize to specific segments of natural stimuli. These synchronous retinal neuronal ensembles were reliably activated by the same stimuli at different trials, indicating a robust population response of retinal microcircuits. The generation of asynchronous events required integrating a physiologically meaningful time window larger than 80 ms, demonstrating that retinal neuronal ensembles time integration filters non-structured visual information. Interestingly, individual neurons could be part of several ensembles indicating that parallel circuits could encode environmental conditions changes. We conclude that parallel neuronal ensembles could represent the functional unit of retinal computations and propose that the further study of retinal neuronal ensembles could reveal emergent properties of retinal circuits that individual cells activity cannot explain.

neuroscience↗

bioRxiv2020

Human bronchial epithelial cell-derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF-β-WNT crosstalk

Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)-{beta} and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signaling, human bronchial epithelial cell-derived EVs (HBEC EVs) inhibit TGF-{beta} mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell-derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non-canonical WNT signaling pathways. Among enriched miRNA species present in HBEC EVs, miR-16, miR-26a, miR-26b, miR-141, miR-148a, and miR-200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin-induced lung fibrosis development accompanied by reduced expression of both {beta}-catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti-fibrotic properties. They further suggest that, via miRNA-mediated inhibition of TGF-{beta}-WNT crosstalk, HBEC EVs administration can be a promising anti-fibrotic modality of treatment for IPF.

molecular biology↗

bioRxiv2020

Scalable and accurate automated method for neuronal ensemble detection in spiking neural networks

We propose a novel, scalable, and accurate automated method for detecting neuronal ensembles from a population of spiking neurons. Our approach offers a simple yet powerful tool to study ensemble activity. It allows the participation of neurons in different ensembles, has few parameters to tune and is computationally efficient. We used spike trains of retinal ganglion cells obtained from multi-electrode array recordings under a simple ON-OFF light stimulus to test our method. We found a consistent stimuli-evoked ensemble activity intermingled with spontaneously active ensembles and irregular activity. Our results suggest that the early visual system activity is already organized in clearly distinguishable functional ensembles. To validate the performance and generality of our method, we generated synthetic data, where we found that our method accurately detects neuronal ensembles for a wide range of simulation parameters. Additionally, we found that our method outperforms current alternative methodologies. Finally, we provide a Graphic User Interface, which aims to facilitate our methods use by the scientific community. Author summaryNeuronal ensembles are strongly interconnected groups of neurons that tend to fire together (Hebb 1949). However, even when this concept was proposed more than 70 years ago, only recent advances in multi-electrode arrays and calcium imaging, statistical methods, and computing power have made it possible to record and analyze multiple neurons activities spiking simultaneously, providing a unique opportunity to study how groups of neurons form ensembles spontaneously and under different stimuli scenarios. Using our method, we found that retinal ganglion cells show a consistent stimuli-evoked ensemble activity, and, when validated with synthetic data, the method shows good performance by detecting the number of ensembles, the activation times, and the core-cells for a wide range of firing rates and number of ensembles accurately.

neuroscience↗

bioRxiv2018

Functional Asymmetries between Central and Peripheral Retinal Ganglion Cells in a Diurnal Rodent

The segregated properties of the visual system processing central or peripheral regions of the visual field have been widely studied in the visual cortex and the LGN, but rarely reported in retina. The retina performs complex computational strategies to extract spatial-temporal features that are in coherence with animal behavior and survival. Even if a big effort has been done to functionally characterize different retinal ganglion cell (RGC) types, a clear account of the particular functionality of central and peripheral cells is still missing. Here, using electrophysiological data obtained with a 256-MEA recording system on female diurnal rodent retinas (Octodon degus), we evidenced that peripheral RGCs have larger receptive fields, more sustained, faster and shorter temporal responses and sensitive to higher temporal frequencies with a broader frequency bandwidth than the center. Additionally, we also compared the asymmetries between ON and OFF cell populations present in each region, reporting that these asymmetries are dependent on the eccentricity. Finally, the presence of the asymmetries here reported emphasizes even more the complexity of computational strategies performed by the retina, which could serve as inspiration for the development of artificial visual systems.

neuroscience↗