Biology subjects

Garcia, I.

Publications and source records attributed to Garcia, I..

10 recordsLinked to original sources

bioRxiv2026

Beta-adrenergic receptor activation during stress reduces the abundance of commensal Clostridia in the mouse gut

Stress-related psychiatric disorders and inflammatory bowel diseases share high co-morbidity and contribute to the symptom severity of one another. In mice, ten days of Chronic Social Defeat Stress (CSDS) is sufficient to reduce gut microbiome diversity and the relative abundance of Firmicutes, which are hallmarks of inflammatory bowel diseases. However, mechanisms by which stress causes gut microbiome dysbiosis are largely unknown. Here, we demonstrate that pharmacologically inhibiting {beta}-adrenergic receptors (ARs), which are activated by (nor)adrenaline during stress, mitigates gut dysbiosis otherwise caused by CSDS. Compared to vehicle-treated mice following CSDS, propranolol-treated mice displayed a modest increase in sociability, increased alpha diversity, and increased abundance of anaerobic commensal Clostridia. Abundance of short-chain fatty acid-producing anaerobic Firmicutes abundance correlated with sociability following CSDS across all treatments. Pharmacologically blocking -ARs during stress increased subsequent sociability, but had little effect on gut microbiome composition. Together, our findings support the hypothesis that {beta}-AR activation contributes to stress-induced changes of the gut microbiome. One Sentence SummaryPharmacologically inhibiting beta-adrenergic receptors during chronic stress mitigates reductions in anaerobic, short-chain fatty acid-producing bacteria in the gut.

systems biology↗

bioRxiv2026

VesSynth: Tubes Are All You Need for Robust Cross-Scale Cross-Modal 3D Vessel Segmentation

The cerebral vasculature is central to brain function, with alterations linked to numerous cerebrovascular and neurological disorders. Yet, no single imaging modality can capture the entire cerebral vascular network in humans. Instead, an array of techniques are sensitized to different spatial scales, while trading off resolution for coverage. Magnetic Resonance Imaging (MRI) typically resolves only large pial vessels, while high-resolution microscopy allows micrometer-scale vessels to be mapped over limited spatial extents. These techniques must therefore be combined to obtain a complete mapping of the cerebral angioarchitecture, which underscores the need for automatic, cross-modal vessel segmentation. Here, we introduce VesSynth, a flexible vessel segmentation framework that achieves state-of-the-art accuracy across multiple modalities and spatial resolutions (MR, optical and X-ray imaging), despite being trained entirely on synthetic data. By enabling consistent vascular mapping across scales, this framework paves the way to comprehensive investigation of cerebrovascular organization and its role in health and disease.

bioengineering↗

bioRxiv2024

Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates the expression of genes associated with anxiolytic-like behavior

We previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents stress-mediated reductions in sociability. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability and/or serve as novel, preclinical treatments for social anxiety. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and promotes social anxiety-like behavior in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used as novel anxiolytics. S1PR3 might be an important hub gene for anxiolytic effects as it reduces inflammatory processes caused by stress and increases transcripts linked to anxiolytic neurotransmission. HighlightsO_LIThe Sphingosine-1-phosphate receptor 3 (S1PR3) agonist CYM5541 promotes sociability C_LIO_LIThe S1PR3 antagonist CAY10444 reduces sociability and promotes anxiety-like behavior in females C_LIO_LICAY10444 increases neuronal activity markers in the amygdala C_LIO_LIPharmacological activation of S1PR3 regulates the expression of genes in the prefrontal cortex that control a wide range of biological processes, including increasing GABAergic neurotransmission and reducing inflammatory processes C_LI

neuroscience↗

bioRxiv2024

Genome-wide profiling of the hierarchical control of autophagy dynamics using deep learning

Recycling of cellular components through autophagy maintains homeostasis in dynamic nutrient environments, and its dysregulation is linked to several human disorders. Although extensive research has characterized the core mechanisms of autophagy, limited insight into its systems-wide dynamic control has hampered predictive modeling and effective in vivo manipulation. In this study, we mapped the genetic network that controls both the dynamic activation and inactivation of autophagy during nitrogen changes, using a combination of time-resolved high-content imaging, deep learning, and latent feature analysis. This approach generated a comprehensive genome-wide profiling repository, termed AutoDRY, categorizing 5919 mutants based on their nutrient response kinetics and differential contributions to autophagosome formation and clearance. Integrating these profiles with functional and genetic network data unveiled a hierarchical and multi-layered control of autophagy, identifying new regulatory aspects of the core machinery and established nutrient-sensing pathways. By leveraging multi-omics resources and explainable machine learning to predict genetic perturbation effects and infer new regulatory mechanisms, we identified the retrograde pathway as a pivotal, time-varying autophagy modulator through transcriptional tuning of core genes. By charting the systems-wide dynamical control of autophagy, we have laid the groundwork for connecting the complexity of genome-wide influences with specific core mechanisms. This represents a significant advancement in studying complex genetic phenotypes, guides functional genomics of dynamic cellular processes in any organism, and provides a powerful starting point for hypothesis-based research on autophagy.

systems biology↗

bioRxiv2023

Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole

Fungal infections are a growing global health concern due to the limited number of available antifungal therapies as well as the emergence of fungi that are resistant to first-line antimicrobials, particularly azoles and echinocandins. Development of novel, selective antifungal therapies is challenging due to similarities between fungal and mammalian cells. An attractive source of potential antifungal treatments is provided by ecological niches co-inhabited by bacteria, fungi and multicellular organisms, where complex relationships between multiple organisms has resulted in evolvement of a wide variety of selective antimicrobials. Here, we characterized several analogs of the one such natural compound, Collismycin A. We show that NR-6226C has antifungal activity against several pathogenic Candida species, including C. albicans and C. glabrata, whereas it only has little toxicity against mammalian cells. Mechanistically, NR-6226C selectively chelates iron, which is a limiting factor for pathogenic fungi during infection. As a result, NR-6226C treatment causes severe mitochondrial dysfunction, leading to formation of reactive oxygen species, metabolic reprogramming and a severe reduction in ATP levels. Using an in vivo model for fungal infections, we show that NR-6226C significantly increases survival of Candida-infected Galleria mellonella larvae. Finally, our data indicate that NR-6226C synergizes strongly with fluconazole in inhibition of C. albicans. Taken together, NR-6226C is a promising antifungal compound that acts by chelating iron and disrupting mitochondrial functions. Importance statementDrug-resistant fungal infections are an emerging global threat, and pan-resistance to current antifungal therapies is an increasing problem. Clearly, there is a need for new antifungal drugs. In this study, we characterized a novel antifungal agent, the Collismycin analog NR-6226C. NR-6226C has a favorable toxicity profile for human cells, which is essential for further clinical development. We unraveled the mechanism of action of NR-6226C and found that it disrupts iron homeostasis and thereby depletes fungal cells of energy. Importantly, NR-6226C strongly potentiates the antifungal activity of fluconazole, thereby providing inroads for combination therapy that may reduce or prevent azole resistance. Thus, NR-6226C is a promising compound for further development into antifungal treatment.

microbiology↗

bioRxiv2022

Inactivation of Vascular Stem Cells Suppresses Intimal Hyperplasia in Vein Grafts

Chronic vein graft (VG) failure (VGF) is associated with VG intimal hyperplasia characterized by abnormal proliferation and accumulation of vascular smooth muscle cells (SMCs), which are derived predominantly from pre-existing vascular SMCs via a process of vascular SMC dedifferentiation.1 Therapeutic approaches focused on vascular SMCs, however, have not changed chronic VGF rates,2 indicating additional and yet unrecognized causes of chronic VGF. Herein, we uncover a novel diagram in which after transplantation, recipient vascular stem cells (VSCs) expressing Sca1 are activated and accumulated in the adventitia of VGs, and they do not differentiate into SMCs but promote intimal hyperplasia via paracrine enforcement of medial SMC dedifferentiation into synthetic SMCs in VGs, suggesting that VSCs may be a novel target for the treatment of chronic VGF.

cell biology↗

bioRxiv2022

New insights on the role of HCN in root hair elongation through single cell proteomics

Root hairs are specialized structures involved in water and nutrient uptake by plants. They elongate from epidermal cells following a complex developmental program. {beta}-cyanoalanine synthase (CAS), which is mainly involved in hydrogen cyanide (HCN) detoxification in Arabidopsis thaliana, plays a role in root hair elongation, as evidenced by the fact that cas-c1 mutants show a severe defect in root hair shape. In addition to root hairs, CAS C1 is expressed in the quiescent center and meristem. However, the cas-c1 mutation has no visible effect on either tissue, in both control and nutrient-deprivation conditions. To identify its role in root hair formation, we conducted single cell proteomics analysis by isolating root hair cells using Fluorescence-Activated Cell Sorting (FACS) from wild type and cas-c1 mutants. We also analyzed the presence of S-cyanylation, a protein post-translational modification (PTM) mediated by HCN and affecting cysteine residues and protein activity, in proteins of wild type and cas-c1 mutants. We found that several proteins involved in root hair development, related to the receptor kinase FERONIA signaling and to DNA methylation, are modified by this new post-translational modification. One sentence summaryArabidopsis root hair proteomics unveals that several proteins involved in root hair development are susceptible of modification by S-cyanylation.

plant biology↗

bioRxiv2021

Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway

Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. Here, we analyze noise suppression in the yeast pheromone signaling pathway and show that the poorly characterized protein Kel1 serves as a major noise suppressor and prevents cell death. At the molecular level, Kel1 prevents spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Only a hypophosphorylated form of Kel1 suppresses signaling, reduces noise and prevents pheromone-associated cell death, and our data indicate that the MAPK Fus3 contributes to Kel1 phosphorylation. Taken together, Kel1 serves as a phospho-regulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency, and to prevent pheromone-associated cell death.

cell biology↗

bioRxiv2020

Gravin-associated kinase signaling networks coordinate γ-tubulin organization at mitotic spindle poles

Mitogenic signals that regulate cell division often proceed through multi-enzyme assemblies within defined intracellular compartments. The anchoring protein Gravin restricts the action of mitotic kinases and cell-cycle effectors to defined mitotic structures. In this report we discover that genetic deletion of Gravin disrupts proper accumulation and asymmetric distribution of {gamma}-tubulin during mitosis. We utilize a new precision pharmacology tool, Local Kinase Inhibition (LoKI), to inhibit the Gravin binding partner polo-like kinase 1 (Plk1) at spindle poles. Using a combination of gene-editing approaches, quantitative imaging, and biochemical assays we provide evidence that disruption of local Plk1 signaling underlies the {gamma}-tubulin distribution defects observed with Gravin loss. Our study uncovers a new role for Gravin in coordinating {gamma}-tubulin recruitment during mitosis and illuminates the mechanism by which signaling enzymes regulate this process at a distinct subcellular location.

cell biology↗

bioRxiv2019

Aggregated and hyperstable damage-associated molecular patterns are released during ER stress to modulate immune function

Chronic ER stress occurs when protein misfolding in the ER lumen remains unresolved despite activation of the unfolded protein response. We have shown that traumatic injury such as a severe burn leads to chronic ER stress in vivo leading to systemic inflammation which can last for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory responses is not clear. Here we show that induction of chronic ER stress leads to the release of known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells which are then capable of polarizing naive T cells. Our findings indicate that induction of chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in persistent systemic inflammation and adverse outcomes.

cell biology↗