Biology subjects

Garcia, P. A.

Publications and source records attributed to Garcia, P. A..

5 recordsLinked to original sources

bioRxiv2026

An Altered Glycome Shapes IgA B-Cell Responses and Gut Immunity During Intestinal Inflammation

A healthy gut immune system balances pathogen defense and tolerance to beneficial microbes. This equilibrium is sustained by coordinated mechanisms where B cells (BCs) play a central role, and secretory immunoglobulin A (SIgA) regulates microbiome composition. In ulcerative colitis (UC), impaired tolerogenic pathways result in exaggerated immune activation, epithelial dysfunction, and tissue damage; however, the contribution of BCs to disease pathogenesis remains unclear. Notably, sialylation is crucial to B-cell function, but its relevance in the intestinal IgA B-cell response has been scarcely explored. Here, we show that SIgA from active UC patients displays an inflammation-dependent reduction in (2,6)-sialylation. This desiaylation is recapitulated in dextran sodium sulfate-induced colitis, where IgA plasma cells (IgA+ PCs) and BCs exhibit a similar glycophenotype. Functional analyses reveal that BCs lacking (2,6)-sialylation on N-glycans exhibit defective differentiation into IgA PCs and diminished capacity to suppress intestinal inflammation in vivo, with increased neutrophil infiltration. Moreover, transcriptomic analyses of UC patient samples suggest a synergistic contribution of neuraminidase activity and reduced bioavailability of sialic acid precursors, leading to SIgA desialylation. Collectively, these findings uncover a glycosylation-dependent pathological circuit in which altered sialylation of SIgA and BCs disrupts their function, compromising mucosal homeostasis in intestinal inflammation.

immunology↗

bioRxiv2024

Circulating extracellular microRNAs in the blood promote sociability in mice

Extracellular vesicles (EVs) are cell-derived small membrane vesicles and circulate throughout the body, but the impact of circulating EVs on brain function and behavior remains elusive. Here, we report that wild-type (WT) mouse blood, particularly EVs, increases sociability in socially impaired immunodeficient Rag1-/- mice, mimicking the effects of WT T cell transfer. These EVs localized to neurons and regulated PKC{varepsilon} expression, GABAA receptor synaptic localization, and inhibitory postsynaptic signaling in prefrontal cortex (PFC) pyramidal neurons. Injection of Rag1-/- EVs supplemented with miR-23a-3p and miR-103-3p enhanced synaptic function and sociability in Rag1-/- mice. T cells secreted miR-23a-3p via EVs, and Mir23a-/- T cells failed to increase sociability. Similar beneficial effects of WT blood EVs were observed in additional mouse models with sociability deficits, Cntnap2-/- and Shank3-/- mice. These findings uncover a previously unrecognized role of EV miRNAs in mediating immune modulation of synaptic function and social behavior, revealing a novel molecular pathway for immune-neuron communication.

neuroscience↗

bioRxiv2023

A mutant fitness compendium in Bifidobacteria reveals molecular determinants of colonization and host-microbe interactions

Bifidobacteria commonly represent a dominant constituent of human gut microbiomes during infancy, influencing nutrition, immune development, and resistance to infection. Despite interest as a probiotic therapy, predicting the nutritional requirements and health-promoting effects of Bifidobacteria is challenging due to major knowledge gaps. To overcome these deficiencies, we used large-scale genetics to create a compendium of mutant fitness in Bifidobacterium breve (Bb). We generated a high density, randomly barcoded transposon insertion pool in Bb, and used this pool to determine Bb fitness requirements during colonization of germ-free mice and chickens with multiple diets and in response to hundreds of in vitro perturbations. To enable mechanistic investigation, we constructed an ordered collection of insertion strains covering 1462 genes. We leveraged these tools to improve models of metabolic pathways, reveal unexpected host- and diet-specific requirements for colonization, and connect the production of immunomodulatory molecules to growth benefits. These resources will greatly reduce the barrier to future investigations of this important beneficial microbe.

microbiology↗

bioRxiv2021

Electro-mechanical transfection for non-viral primary immune cell engineering

Non-viral approaches to transfection have emerged a viable option for gene transfer. Electro-mechanical transfection involving use of electric fields coupled with high fluid flow rates is a scalable strategy for cell therapy development and manufacturing. Unlike purely electric field-based or mechanical-based delivery methods, the combined effects result in delivery of genetic material at high efficiencies and low toxicity. This study focuses on delivery of reporter mRNA to show electro-mechanical transfection can be used successfully in human T cells. Rapid optimization of delivery to T cells was observed with efficiency over 90% and viability over 80%. Confirmation of optimized electro-mechanical transfection parameters was assessed in multiple use cases including a 50-fold scale up demonstration. Transcriptome and ontology analysis show that delivery, via electro-mechanical transfection, does not result in gene dysregulation. This study demonstrates that non-viral electro-mechanical transfection is an efficient and scalable method for cell and gene therapy engineering and development. One Sentence SummaryThis study demonstrates that non-viral electro-mechanical transfection is an efficient and scalable method for development of engineered cellular therapies.

bioengineering↗

bioRxiv2020

Climatic drivers of Verticillium dahliae occurrence in Mediterranean olive-growing areas of southern Spain

Verticillium wilt, caused by the soil-borne fungus Verticillium dahliae, is one of the most harmful diseases in Mediterranean olive-growing areas. Although, the effects of both soil temperature and moisture on V. dahliae are well known, there is scant knowledge about what climatic drivers affect the occurrence of the pathogen on a landscape scale. Here, we investigate what climatic drivers determine V. dahliae occurrence in olive-growing areas in southern Spain. In order to bridge this gap in knowledge, a landscape-scale field survey was carried out to collect data on the occurrence of V. dahliae in 779 olive groves in Granada province. Forty models based on competing combinations of climatic variables were fitted and evaluated using information-theoretic methods. A model that included a multiplicative combination of seasonal and extreme climatic variables was found to be the most viable one. Isothermality and the seasonal distribution of precipitation were the most important variables influencing the occurrence of the pathogen. The isothermal effect was in turn modulated by the seasonality of rainfall, and this became less negative as seasonality increases. Thus, V. dahliae occurs more frequently in olive-growing areas where the day-night temperature oscillation is lower than the summer-winter one. We also found that irrigation reduced the influence of isothermality on occurrence. Our results demonstrate that long-term “sophisticated” climatic factors rather than “primary” variables, such as annual trends, can better explain the spatial patterns of V. dahliae occurrence in Mediterranean, southern Spain. One important implication of our study is that appropriate irrigation management, when temperature oscillation approaches optimal conditions for V. dahliae to thrive, may reduce the appearance of symptoms in olive trees.View Full Text

pathology↗