Biology subjects

Garcia, J. C.

Publications and source records attributed to Garcia, J. C..

5 recordsLinked to original sources

bioRxiv2026

Convergent Mitochondrial and Oxidative Stress Signatures in Spaceflight and Tauopathy: A Comparative Multi-Omics Reanalysis in Drosophila melanogaster

Mitochondrial dysfunction is a shared biological thread between terrestrial Alzheimer's disease (AD) and in the unique stress environment of spaceflight, making mitochondrial pathophysiology a compelling target for comparative investigation. In AD, mitochondrial impairment is closely linked to defective oxidative phosphorylation, reactive oxygen species accumulation, calcium dysregulation, and neuronal injury, while spaceflight stressors such as microgravity and radiation disrupt mitochondrial homeostasis and increase oxidative stress. Understanding how the extreme stressors of spacelight affect mitochondrial function may provide insights into conserved mitochondrial stress responses and their implications for neurodegenerative diseases, including AD. Our study compares datasets from ground control Drosophila melanogaster RNA-seq with isolated radiation and microgravity exposure to discern conserved mitochondrial pathways and molecular signatures that may provide insights into AD mechanisms.

cell biology↗

bioRxiv2026

Actionable spatial prostanoid barriers constrain BiTE-driven adoptive T cell immunity in intact human tumors

Adoptive cell therapy (ACT) in solid tumors is limited by tumor microenvironment (TME)-imposed resistance mechanisms that are inadequately addressed by conventional systems. We developed tissue-preserving patient-derived explants (PDEs) from lung and ovarian cancer to interrogate redirected T cell immunity in intact human tissue. Using mesothelin-targeting bispecific T cell engager (BiTE(R), Amgen trademark)-secreting T cells, we observed antigen-dependent but heterogeneous responses across lesions. An integrated ex vivo response score stratified responder and non-responder TMEs, revealing that resistance associates with reduced antigen density, stromal dominance, and limited myeloid licensing rather than baseline lymphocyte abundance. Elevated prostaglandin E2 (PGE2) inversely correlated with BiTE-induced T cell activation, identifying the COX/PGE2 axis as a tissue-imposed constraint. COX inhibition amplified interferon-driven immune programs enhanced intratumoral CD8 infiltration, and increased tumor-restricted apoptosis. Spatial transcriptomics localized these effects to tumor-proximal immune hubs in responders, whereas non-responders remained stromally insulated. These findings position PDEs as human-based new approach methodologies enabling combinatorial ACT pharmacodynamics and stratification. Statement of significancePatient-derived explants provide a human-based new approach methodology to interrogate adoptive immunotherapy pharmacodynamics within intact tumor microenvironments in NSCLC and HGSOC. We uncover a COX/PGE2-mediated tissue ceiling that limits BiTE-driven T cell function and demonstrate that COX inhibition reactivates tumor-proximal immune hubs to enhance intratumoral CD8 infiltration and tumor-restricted apoptosis, informing patient stratification and rational combinations.

systems biology↗

bioRxiv2025

Alveolar epithelial cell plasticity and injury memory in human pulmonary fibrosis

Acute and repetitive lung epithelial injury can lead to irreversible and even progressive pulmonary fibrosis; Idiopathic pulmonary fibrosis (IPF) is a fatal disease and quintessential example of this phenomenon. The composition of epithelial cells in human pulmonary fibrosis - irrespective of disease etiology - is marked by the presence of Aberrant Basaloid cells: an abnormal cell phenotype with pro-fibrotic and senescent features, localized to the surface of fibrotic lesions. Despite their relevance to human pulmonary fibrosis, the exotic molecular profile of Aberrant Basaloid cells has obscured their etiology, preventing insights into how or why these cells emerge with fibrosis. Here we identify cellular intermediaries between Aberrant Basaloid and normal alveolar epithelial cells in human IPF tissue. We track the emergence of Aberrant Basaloid cells from alveolar epithelial cells ex vivo and uncover a role for similar cells in epithelial regeneration under normal conditions. Lastly, we characterize the epigenetic changes that distinguish Aberrant Basaloid cells from their progenitors and identify hallmarks of AP-1 injury memory retention. This study elucidates the phenomenon of maladaptive epithelial plasticity and regeneration in pulmonary fibrosis and re-contextualizes therapeutic strategies for epithelial dysfunction.

cell biology↗

bioRxiv2024

Neural Circuit Revision in Retinal Remodeling, A Pathoconnectomics Approach

Retinitis pigmentosa (RP), a retinal degenerative disease, is characterized by progressive photoreceptor loss and ongoing remodeling and rewiring of the inner retina. This study investigates rod network rewiring through pathoconnectomic evaluation and its impacts on signaling patterns. The glycinergic Aii amacrine cell (Aii) plays a central role in the healthy retina bridging rod and cone pathways, enabling an increased dynamic range of vision. Pathoconnectomics reveals altered connectivity in both the excitatory drive and gap junctional coupling of Aiis in retinal degeneration. A computational model of the rewired network was developed to assess the functional consequences of these structural changes by simulating light-evoked responses and changes in excitatory postsynaptic potentials (EPSPs). The model predicts significant changes in bipolar and Aii EPSPs between active and baseline conditions, driven by newly formed gap junctions in the degenerate retina. Notably, the aberrant circuitry induces rhythmic firing of up to 10 Hz in retinal ganglion cells, consistent with network depolarization relative to the healthy baseline state. These findings align with patch-clamp observations in rd1 and rd10 mouse models of RP, suggesting that Aii-mediated network alterations may underlie early clinical symptoms, including impaired adaptation between photopic and scotopic vision. More broadly, this work demonstrates that integrating computational modeling with pathoconnectomics enables predictive analysis of signaling in early-stage retinal degeneration and may help identify windows for therapeutic intervention. Such models could be further extended with multi-scale bioelectromagnetic simulations to optimize neurostimulation strategies aimed at slowing disease progression. Author summaryUnderstanding how retinal degeneration alters wiring topologies of the inner retina is important for the success of multiple therapeutic interventions, including cell replacement strategies, optogenetics, and electrode implants. Here, we continue our evaluation of retinal pathoconnectome 1 (RPC1), describing additional network-level changes occurring early in retinal degeneration. This analysis extends our previous findings on the emergence of gap junctions in rod bipolar cells in retinal degeneration to include the effects of these changes on the synaptic strength of inputs to the Aii. We then model how these network changes overall effect retinal processing through the creation of a more complete degenerate retina model. From these results we propose the emergence of aberrant gap junctions in the rod pathway as the network cause of atypical retinal ganglion cell firing and provide the field with a realistic network model for evaluating and optimizing therapeutic strategies.

neuroscience↗

bioRxiv2020

A Pathoconnectome of Early Neurodegeneration

Connectomics has demonstrated that synaptic networks and their topologies are precise and directly correlate with physiology and behavior. The next extension of connectomics is pathoconnectomics: to map neural network synaptology and circuit topologies corrupted by neurological disease in order to identify robust targets for therapeutics. In this report, we characterize the first pathoconnectome, in this case, generated from a retina with photoreceptor degeneration. We observe aberrant connectivity in the rod-network pathway and novel synaptic connections deriving from neurite sprouting. These observations reveal principles of neuron responses to the loss of network components and can be extended to other neurodegenerative diseases.

neuroscience↗