Biology subjects

Suarez, N.

Publications and source records attributed to Suarez, N..

5 recordsLinked to original sources

bioRxiv2026

A genome-wide CRIPR-Cas9 screen identifies TGN46 as a host determinant for H-1PV susceptibility in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited response to current therapeutic strategies. Oncolytic viruses such as the rat protoparvovirus H-1PV represent promising alternatives; however, their clinical development is hindered by an incomplete understanding of virus-host interactions that determine tumor susceptibility. Here, we conducted a genome-scale CRISPR-Cas9 knockout screen in primary PDAC cultures to identify host determinants of viral infection and cytotoxicity. The screen confirmed the central role of the sialylation pathway in mediating susceptibility to H-1PV and uncovered several additional genes involved in vesicular trafficking and protein recycling. Among these candidates, TGOLN2, encoding the transmembrane protein TGN46, emerged as a critical host factor. Functional analyses demonstrate that TGN46 supports efficient H-1PV infection, replication, and virus-induced cytotoxicity in pancreatic cancer cells. TGN46 colocalizes with viral particles at the cell surface and facilitates their internalization through dynamin-dependent endocytosis. Molecular studies further indicate that the luminal N-terminal domain of TGN46 interacts with the viral capsid. In vivo, TGOLN2 expression in essential to H-1PV-mediated antitumor activity in experimental models. Collectively, these findings identify TGN46 as a membrane-associated entry factor required for optimal H-1PV infection in PDAC cells. This work refines the mechanistic understanding of H-1PV tropism and provides a rationale for exploring host determinants of viral susceptibility as candidate biomarkers to guide parvovirus-based virotherapy.

cancer biology↗

bioRxiv2025

Dormant viral pathways underlie space-induced neural senescence: a neuroprotective strategy for spaceflight and neurological diseases

Long-duration spaceflight is associated with neurological symptoms in astronauts, yet the underlying molecular mechanisms remain unclear. Using human brain organoids cultured aboard the International Space Station, we analyzed three independent spaceflights to demonstrate that exposure to the space environment triggers Space-Induced Neural Senescence (SINS), characterized by chromatin remodeling, mitochondrial dysfunction, and activation of viral-like transcriptional programs in the absence of infection. Multi-omics analyses identified upregulation of endogenous LINE-1 (L1) retroelements, whose activity was markedly enhanced in organoids lacking MECP2, a known L1 repressor implicated in Rett syndrome. The resulting accumulation of cytoplasmic L1 DNA elicited an IL-6-mediated inflammatory and neurotoxic response, which was reversed by reverse transcriptase inhibitors (RTi) such as lamivudine or stavudine. Parallel preclinical experiments in Mecp2-deficient mice confirmed that RTi treatment restored neuronal morphology, synaptogenesis, function, cognition, and survival. These findings reveal that the space environment reactivates dormant genomic retroelements, providing an unexpected mechanistic insight into astronaut neurobiology and identifying a potential therapeutic strategy for both space-induced and terrestrial neurological conditions. Our pioneering study demonstrates the value of space-enabling research in accelerating drug discovery and disease treatment on Earth.

neuroscience↗

bioRxiv2025

Gut3Gel as an in vitro model to investigate dietary modulation of the intestinal microbiota: An inulin supplementation case study

The intestinal microbiota plays a key role in human health, influencing digestion, immunity, and metabolism. While factors such as genetics and medications shape its composition, diet remains a primary driver of microbial modulation. Despite growing interest in using dietary interventions to beneficially alter the intestinal microbiota, assessing their effects in humans is challenging due to individual variability and the complexity of in vivo systems. This study explores Gut3Gel gradient colonic (G3GG) preclinical model as a tool to assess its representativeness on studying the effect of inulin supplementation on the intestinal microbiota of five healthy individuals compared to clinical evaluation studies. Significant inter-individual variability in baseline microbiota composition was observed, which strongly influenced microbiota response to inulin. While inulin supplementation led to a general decrease in alpha diversity, it significantly increased the abundance of health-associated genera such as Bifidobacterium and Lacticaseibacillus, along with enhanced microbial metabolic activity. Despite the intrinsic selectivity of G3GG for beneficial microbes, the model successfully captured inulins prebiotic effects and inter-individual differences, underscoring its relevance as a physiologically relevant high throughput tool for evaluating microbiota-targeting compounds and supporting personalized nutrition strategies.

microbiology↗

bioRxiv2025

Gut3Gel: A High Throughput Mucus Model for Culturing Human Intestinal Microbiota

The human intestinal microbiota plays a crucial role in health and disease, yet recreating its complex interactions in vitro remains a significant challenge. Gut3Gel introduced herein as a novel in vitro mucus model, designed for culturing complex microbial communities without the need for anaerobic conditions. Intestinal microbiota samples from five donors were individually inoculated in Gut3Gel and cultured for 72 hours. Taxonomic composition assessment revealed that Gut3Gel sustains diverse microbial species and particularly promotes the growth of mucus-associated bacteria including Bifidobacterium, Lactobacillus, and Faecalibacterium. Microbial metabolic activity within Gut3Gel was confirmed by the increased production of acetate and butyrate, as well as of exopolysaccharides. Gut3Gel reproduces physiological features of intestinal mucus, providing a reproducible and scalable culturing platform. These features make Gut3Gel a promising tool for advancing microbiota research with potential applications in drug screening, microbiome mining, and high throughput testing of microbiome-modulating molecules.

microbiology↗

bioRxiv2018

Increased human cytomegalovirus multiple-strain infections and genome diversity in breast milk from HIV-positive women

BackgroundIn developed countries, human cytomegalovirus (HCMV) is a major pathogen in congenitally infected and immunocompromised individuals, in whom multiple-strain infection is linked to disease severity. The situation is less documente in developing countries. In Zambia, breast milk is a key route for transmitting HCMV and carries higher viral loads in HIV-positive women. We investigated HCMV strain diversity. MethodsHigh-throughput sequence datasets were generated from 28 HCMV-positive breast milk samples donated by 22 mothers (15 HIV-positive and seven HIV-negative) at 4 or 16 weeks (or both) postpartum and analysed by genotyping 12 hypervariable HCMV genes. ResultsAmong the 20 samples from 14 donors (13 HIV-positive and one HIV-negative) that yielded data meeting quality thresholds, 89 of the possible 109 genotypes were detected, and multiple-strain infections involving up to five strains per person were apparent in nine HIV-positive women. Strain diversity was extensive among individuals but conserved compartmentally and longitudinally within them. Genotypic linkage was maintained within the hypervariable UL73/UL74 and RL12/RL13/UL1 loci for virus-entry and immunomodulation, but not between genes more distant from each other. ConclusionsBreast milk from HIV-positive women contains multiple HCMV strains of high genotypic complexity and thus constitutes a major source for transmitting viral diversity.

genomics↗