Biology subjects

Moreno-Caceres, S.

Publications and source records attributed to Moreno-Caceres, S..

4 recordsLinked to original sources

bioRxiv2026

8-Oxoguanine transcriptional miscoding can transiently reproduce PAH-associated premature-stop transcripts

Pulmonary arterial hypertension (PAH) is associated with increased oxidative DNA damage, while haploinsufficiency of BMPR2 and other dosage-sensitive genes contributes directly to disease. Template-strand 8-oxoguanine (8-oxoG) provides a potential transient route to the same loss-of-function outcome through transcriptional mutagenesis without altering genomic DNA. RNA polymerase II can insert adenine opposite the lesion and generate a coding-sense C>A error in the nascent transcript. We asked whether this chemistry could generate premature-stop transcripts in dosage-sensitive PAH genes. Across 17,880 C>A-accessible coding positions in pulmonary vascular genes, 1,192 could generate premature termination codons, including 883 predicted to engage nonsense-mediated decay (NMD). Restricting these sites to expressed autosomal-dominant PAH genes with definitive ClinGen validity and established haploinsufficiency identified 116 NMD-prone positions in BMPR2, KDR, SMAD9, and TBX4. Eight exactly reproduce ClinVar pathogenic or likely pathogenic stop variants, including five in BMPR2. At BMPR2 c.1424, template-strand 8-oxoG and the expert-panel-reviewed genomic c.1424C>A allele is predicted to generate the same UAA-containing transcript. Published oxidized-guanine maps detect signal at seven of the eight coordinates, providing coordinate-level support for oxidative modification at these sites. These findings define a sequence-resolved route through which repairable oxidative DNA damage could transiently reproduce loss-of-function transcripts encoded by pathogenic PAH alleles without permanent genomic mutation.

bioinformatics↗

bioRxiv2026

COPD Preferentially Disrupts Constitutive Redox Support Relative to Inducible Antioxidant Defense

Redox homeostasis requires both inducible antioxidant defense and constitutive machinery that continuously regenerates cellular reducing capacity. How these systems are altered across lung cell populations in chronic obstructive pulmonary disease (COPD) remains unclear. We integrated donor-level single-nucleus lung transcriptomes with smoke-exposure models, independent cohorts, and large-scale pharmacologic perturbation data. Both redox programs were reduced in established COPD, but constitutive redox support showed the greater loss, concentrated in fibroblasts and lymphatic endothelium. In fibroblasts, PGC-1 target-program output showed the most negative effect among 515 regulator programs despite preserved PPARGC1A expression. Smoke exposure activated inducible antioxidant defense across experimental models, whereas this adaptive program was reduced in established COPD. Pharmacologic perturbations further separated the two arms of redox homeostasis, with redox-directed interventions producing larger transcriptional responses in inducible defense and a distinct set of compounds increasing constitutive support together with PGC-1 target output and movement away from an independently defined COPD fibroblast state. These findings identify a cell-selective loss of constitutive redox support in COPD and implicate reduced PGC-1 target-program output in the fibroblast redox phenotype.

bioinformatics↗

bioRxiv2026

Disease-associated protein states accessible to 8-oxoguanine transcriptional miscoding without genomic mutation

8-Oxoguanine (8-oxoG) is a common oxidative DNA lesion that can alter coding output during transcription without changing the underlying DNA sequence. When present on the template strand, 8-oxoG can direct RNA polymerase II to insert adenine, generating a transient coding-sense C>A error restricted by the genetic code to 18 directional amino-acid substitutions. Mapping these substitutions onto ClinVar identified 3,910 disease-associated protein states across 1,333 genes, representing 5.7% of evaluable pathogenic or likely pathogenic missense states. In 211 cases, transcriptional miscoding and the corresponding genomic disease variant affect different nucleotides within the same codon yet converge on the same amino acid substitution, allowing the disease-associated protein state to arise while the implicated genomic nucleotide remains wild type. Accessible states were enriched among genes with post-mitotic expression and neurological disease annotation, particularly in neuronal signaling pathways. Published oxidized-guanine maps supported 2,146 accessible genomic coordinates, while human proteogenomic data contained 78 exact codon-compatible protein states not explained by sample-specific transcript sequence. Together, these analyses define a chemically constrained set of disease-associated protein states accessible through 8-oxoG transcriptional miscoding without permanent genomic mutation.

bioinformatics↗

bioRxiv2025

Accelerated plastic aging in suspension (APAS): A simple, reproducible approach for the generation of model micro- and nanoplastics through simulated environmental forces

The environmental fragmentation of plastic waste leads to the formation of micro- and nanoplastics (MNPs), which pose serious ecological and human health concerns. Despite increasing interest in their biological effects, many studies rely on artificial, uniform particles that fail to mimic the diverse physical and chemical characteristics of real-world MNPs. To address this limitation, we developed the Accelerated Plastic Aging in Suspension (APAS) system--a scalable, reproducible method that mimics natural aging processes by combining ultraviolet (UV) radiation, thermal stress, and mechanical shear to generate environmentally relevant MNPs from commonly used polymers. We used APAS to fragment polyethylene terephthalate (PET), polyamide 6 (Nylon), and polyacrylonitrile (PAN), and observed time-dependent degradation, including the spontaneous formation of nanoplastics (<100 nm). Flow cytometry revealed substantial increases in particle number and reductions in average particle size over 12 weeks. Imaging flow cytometry confirmed consistent generation of heterogeneous, irregular particles across replicate batches. High-resolution imaging via AFM, TEM, and SEM confirmed the presence of nanoplastics with textured and irregular morphologies. Chemical characterization showed APAS aging altered particle surface charge and induced polymer-specific changes in autofluorescence and Raman spectral profiles, consistent with oxidative surface modifications. Laser Direct Infrared (LDIR) imaging further confirmed structural and chemical changes in polymer spectra post-aging. Functionally, under physiologically relevant shear flow conditions, endothelial cells internalized APAS-generated PET MNPs at significantly higher levels than polystyrene (PS) beads of similar size. Uptake was enhanced particularly under oscillatory flow, highlighting the influence of particle physicochemical properties on cellular interactions. Together, these findings demonstrate the ability of the APAS system to produce complex and realistic MNPs for use in environmental and toxicological studies. The system enables generation of nanoplastics and supports more accurate modelling of biological exposure scenarios compared to conventional synthetic particles.

pharmacology and toxicology↗