Biology subjects

Torres, I.

Publications and source records attributed to Torres, I..

8 recordsLinked to original sources

bioRxiv2026

Multihospital expansion of vancomycin-resistant Enterococcus faecium ST117-CT7799 and transmission of linear plasmids co-carrying vanA and linezolid resistance genes, Comunitat Valenciana, Spain (2022-2024)

BackgroundVancomycin-resistant Enterococcus faecium (VREfm) is a WHO priority pathogen. In the Comunitat Valenciana (CV), Spain, VREfm prevalence has increased since 2022. We characterized the population structure, transmission patterns and resistance determinants of VREfm across eight hospitals (2021-2024). MethodsEight hospitals reported 870 VREfm cases during 2021-2024. We sequenced 254 VREfm isolates using WGS (Illumina) and inferred relatedness by MLST, cgMLST, and core-genome SNP analyses. Acquired antimicrobial resistance (AMR) genes, bacteriocins, plasmid replicases and putative virulence markers (PVMs) were identified in silico. Thirty-eight representatives underwent Nanopore long-read sequencing and hybrid assembly to resolve plasmids. ResultsThe predominant vancomycin-resistance genotype was vanB (62%; six hospitals), followed by vanA (19%; five hospitals) and vanA+vanB (17%; five hospitals). Eight sequence types (ST) and 15 clonal complexes (CT) were identified, grouped into seven main phylogenetic clades with close relatedness to publicly available genomes from other regions of Spain and Europe. A single lineage, ST117-CT7799, accounted for 198/254 (78%) isolates, persisted during 2022-2024 across seven hospitals and was enriched in the bacteriocin gene bac43 (or T8) (84%). Linezolid-resistance genes optrA and cfr(D) were present in 34% of isolates, most of which also carried vanA (32%). Hybrid assemblies revealed a diverse plasmidome including RepA_N megaplasmids with PVMs and AMR genes, and small Rep3-like plasmids harbouring bacteriocins (bac43, bac51, bacAS9); a 6 kb repA_pB82 plasmid was bac43-positive in 37/38 (97%) fully resolved carriers. Eight strains across four hospitals carried identical linear plasmids co-harbouring vanA, optrA, cfrD genes within a widespread repUS78_pZY2 background, consistent with inter-lineage plasmid transmission. ConclusionsThis first comprehensive genomic analysis of VREfm in CV indicates extensive inter-hospital spread dominated by expansion of ST117-CT7799 and highlights plasmid-mediated convergence of vancomycin and linezolid resistance via linear plasmids. Strengthened infection prevention and genomic surveillance, including long-read sequencing to track linear plasmids, are warranted.

microbiology↗

bioRxiv2025

N6-methyladenosine RNA methylation is a novel epitranscriptomic regulator of excessive alcohol drinking and vulnerability to relapse

While internal RNA modifications have been known for decades, the contribution of epitranscriptomics to alcohol use disorder (AUD) remains unexplored. Here we investigated, for the first time, the role of the most abundant RNA modification, N6-methyladenosine (m6A) in regulating alcohol drinking and alcohol-induced gene expression. Mice with selective neuronal deletion of the m6A demethylase fat mass and obesity associated gene (Fto) showed enhanced initial motivation for alcohol, achieved escalated drinking more rapidly, and displayed greater relapse-like drinking after abstinence. Alcohol-naive Fto-deficient mice also exhibited potentiated alcohol-induced anxiolysis and sedation and blunted anxiogenic responses, despite unaltered alcohol metabolism. We then performed RNA enrichment coupled with RNA sequencing to characterize alcohol-induced epitranscriptomic and transcriptional remodeling. We observed that a history of alcohol exposure induced robust m6A hypermethylation in the hippocampus and that Fto-deficiency markedly altered m6A methylation and transcriptional dynamics. Gene Set Enrichment Analysis (GSEA) indicated that neuronal Fto-deficiency engages addiction-relevant pathways and that transcriptional programs associated with neuronal Fto deletion overlapped with alcohol-induced gene expression signatures, consistent with increased alcohol vulnerability. Our findings demonstrate that neuronal m6A RNA methylation is a novel regulator of excessive alcohol drinking and alcohol-dependent gene expression, and suggest that dysregulated epitranscriptomic control may contribute to the pathogenesis of AUD.

neuroscience↗

bioRxiv2025

Sphingosine-1-phosphate (S1P) signaling as a novel therapeutic target for alcohol abuse.

Sphingosine-1-phosphate (S1P) is a lipid mediator signaling through broadly expressed G protein-coupled receptors. We found that S1P is regulated by alcohol and that S1P receptor agonists reduce alcohol drinking in rodent models. Specifically, we observed that two S1P receptor agonists FDA-approved for multiple sclerosis, fingolimod and ozanimod, and the more brain penetrant S1P1 receptor agonist CYM5442, reduced binge alcohol drinking in the drinking in the dark (DID) paradigm in mice. CYM5442 also reduced drinking in dependent mice in the chronic intermittent ethanol vapor paradigm of dependence-induced increased drinking paired with 2 bottle-choice (CIE-2BC) as well as in non-dependent mice. CYM5442 reduced operant oral alcohol self-administration in both non-dependent and dependent rats made dependent by vapor exposure, and reduced motivation for alcohol in dependent rats tested in a progressive ratio schedule of reinforcement. CYM5442 significantly prevented cue-induced reinstatement in alcohol-dependent rats, a model of relapse to alcohol seeking. CYM5442 also reduced intake of non-drug reinforcers, including sucrose, food, water and, to a lesser extent, saccharine. Notably, CYM5442 was less aversive than naltrexone, an FDA-approved medication for the treatment of alcohol use disorder that shares a similar broad reducing action on alcohol intake and consummatory behavior. CYM5442 had no effect on loss of righting reflex, alcohol metabolism, motor coordination or spontaneous locomotor activity in rodents. Lastly, gene expression analysis by RNA-Seq revealed that S1P regulates a complex set of genes in the transition to alcohol dependence. Overall, our results establish S1P signaling as a novel therapeutic target for alcohol use disorder.

neuroscience↗

bioRxiv2025

Gene network inference and master regulator analysis identifies the estrogen-related receptor gamma (ERRγ) as a therapeutic target for alcohol use disorder (AUD).

Differential gene expression is often inadequate to predict the activity of transcription factors and their contribution to the phenotypes associated with specific gene expression states. Here we used a systems biology approach based on gene network inference and master regulator analysis (MRA) to identify candidate drivers of the gene network dysregulations in the prefrontal cortex (PFC) of human subjects with a history of alcohol dependence. The estrogen-related receptor gamma (ERR{gamma}) gene ESRRG, an orphan nuclear receptor protein that acts as a transcription activator, emerged as a high-ranking Master Regulator (MR) based on the expression of its targets and was selected for functional validation due to its translational and druggability potential. The ERR{gamma} agonist, GSK4716, reduced alcohol drinking in the mouse binge drinking paradigm of drinking in the dark (DID) and in both non-dependent mice as well as in mice made dependent by chronic intermittent vapor exposure (CIE). GSK4716 also prevented alcohol-conditioned place preference without affecting saccharin intake or mouse locomotion. Similarly, in rats, GSK4716 reduced operant oral alcohol self-administration in non-dependent and dependent (by CIE) rats under fixed and progressive ratio schedules of reinforcement. Overall, these results support the efficacy of transcriptome-wide gene regulatory network approaches for the identification of key druggable regulators of long-term transcriptional adaptations that sustain the molecular and behavioral pathology of alcohol dependence and identify ERR{gamma} as a regulator of excessive alcohol drinking and seeking, and a therapeutic target for AUD.

neuroscience↗

bioRxiv2025

Metagenomes and Metagenome-Assembled Genomes from Tidal Lagoons at a New York City Waterfront Park

We report the sequencing and analysis of 15 shotgun metagenomes, including the reconstruction of 129 high-quality metagenome-assembled genomes, from tidal lagoons and bay water at Bush Terminal Piers Park in Brooklyn, NY sampled from July to September 2024.. Our metagenomic database for this site provides an important baseline for ongoing studies of the microbial communities of public parks and waterfront areas. In particular, we provide rich functional and taxonomic annotations that enable the use of these metagenomes and metagenome-assembled genomes for a wide variety of downstream applications.

microbiology↗

bioRxiv2022

Genomic accordions may hold the key to Monkeypox Clade IIb's increased transmissibility

The currently expanding monkeypox epidemic is caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. In contrast to monkeypox cases caused by clade I and subclade IIa MPXV, the prognosis of current cases is generally favorable, but person-to-person transmission is much more efficient. MPXV evolution is driven by selective pressure from hosts and loss of virus-host interacting genes. However, there is no satisfactory genetic explanation using single-nucleotide polymorphisms (SNPs) for the observed increased MPXV transmissibility. We hypothesized that key genomic changes may occur in the genomes low-complexity regions (LCRs), which are highly challenging to sequence and have been dismissed as uninformative. Using a combination of highly sensitive techniques, we determined a first high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This effort revealed significant variation in short-tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of SNPs and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs) 153, 204, and 208 could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. Consequently, we posit that genomic studies focusing on phenotypic MPXV clade-/subclade-/lineage-/strain differences should change their focus to the study of LCR variability instead of SNP variability.

genomics↗

bioRxiv2020

Tumor heterogeneity assessed by sequencing and fluorescence in situ hybridization (FISH) data

Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration (CNA) and structural variation (SV) events in tumor evolution, which are difficult to profile accurately by prevailing sequencing methods in such a way that subsequent reconstruction by phylogenetic inference algorithms is accurate. In the present work, we develop computational methods to combine sequencing with multiplex interphase fluorescence in situ hybridization (miFISH) to exploit the complementary advantages of each technology in inferring accurate models of clonal CNA evolution accounting for both focal changes and aneuploidy at whole-genome scales. We demonstrate on simulated data that incorporation of FISH data substantially improves accurate inference of focal CNA and ploidy changes in clonal evolution from deconvolving bulk sequence data. Analysis of real glioblastoma data for which FISH, bulk sequence, and single cell sequence are all available confirms the power of FISH to enhance accurate reconstruction of clonal copy number evolution in conjunction with bulk and optionally single-cell sequence data. Availabilitygithub.com/CMUSchwartzLab/FISH_deconvolution Contactrussells@andrew.cmu.edu

bioinformatics↗

bioRxiv2019

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimers disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and forms neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed conflicting results between the two neuronal cultures.This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases.

neuroscience↗