Biology subjects

Romero, L.

Publications and source records attributed to Romero, L..

8 recordsLinked to original sources

bioRxiv2026

Electrophysiological dependent antiarrhythmic drug response in population-based models of paroxysmal atrial fibrillation

Response to antiarrhythmic drugs varies markedly across patients with atrial fibrillation (AF), suggesting that treatment efficacy depends on the interaction between drug-specific mechanisms and patient-specific electrophysiological substrate. Here, we used population-based computational models to investigate how electrophysiological substrate and inter-individual ionic variability influence pharmacological efficacy and the underlying mechanisms. Two populations of human atrial models were generated from distinct substrates: a reference left atrial model and a second model incorporating inward-rectifier-enhancement (IRE) through a 2-fold increase in IK1 and IK,ACh. Both populations were independently calibrated against the same experimental datasets from patients with paroxysmal AF (pAF), yielding pAF and IRE-pAF populations. Sustained reentrant activity was induced in two-dimensional tissue simulations and subsequently used to assess cardioversion efficacy of flecainide, vernakalant and tertiapin-Q. Despite satisfying the same calibration criteria, IRE-pAF population exhibited a more arrhythmogenic phenotype: shorter refractoriness, higher dominant frequency (DF) and greater rotor stability. Antiarrhythmic efficacy markedly differed between substrates. Flecainide cardioversion decreased in IRE-pAF compared with pAF (34% vs 21%), whereas IK,ACh-targeting therapies preserved or improved efficacy in IRE-pAF (vernakalant: 41% vs 44%, tertiapin-Q: 11% vs 18%). Across drugs and substrates, rotor DF strongly influenced cardioversion outcome, with higher-frequency rotors showing lower termination rates. Drug-induced DF reduction emerged as a key mechanism associated with successful cardioversion, whereas effective refractory period (ERP) prolongation alone did not consistently explain treatment efficacy. In pAF, vernakalant achieved higher cardioversion efficacy than flecainide despite a smaller increase in ERP and greater DF reduction. Ionic analyses further showed that elevated IK,ACh favored responses to vernakalant and tertiapin-Q. These findings demonstrate that cardioversion efficacy emerges from the interaction between electrophysiological substrate, rotor dynamics and drug-specific mechanisms. In particular, substrates differing in inward rectifier activity exhibit distinct response patterns, while DF emerges as a robust marker of pharmacological susceptibility and a potential guide for drug-mediated AF termination.

bioengineering↗

bioRxiv2025

A clinical-stage oncology compound selectively targets drug-resistant cancers

Re-evaluating existing clinical compounds can uncover previously unrecognized mechanisms that reshape a drugs therapeutic potential. The small molecule Procaspase-Activating Compound 1 (PAC-1) entered oncology testing as a proposed activator of caspase-driven apoptosis. Here, we show that PAC-1-driven cytotoxicity occurs in the absence of executioner caspase expression, demonstrating that its anti-cancer activity occurs via an alternative mechanism. We provide genetic, biochemical, and biophysical evidence demonstrating that PAC-1 functions as a highly selective iron chelator that eliminates cancer cells by disrupting iron homeostasis. Unexpectedly, we discovered that expression of the key chemotherapy-resistance pump MDR1 confers marked hypersensitivity to PAC-1 treatment. While PAC-1 is only weakly effluxed by MDR1 under basal conditions, this process is potentiated when PAC-1 is bound to iron. Consequently, PAC-1 induces progressive iron depletion and selective cytotoxicity in otherwise drug-resistant MDR1-expressing cancer cells. Together, these findings redefine PAC-1s mechanism-of-action and establish a framework for exploiting multidrug resistance as a therapeutic vulnerability through targeted iron starvation.

cancer biology↗

bioRxiv2024

Epigenetic modulation of NLRP6 inflammasome sensor as a therapeutic modality to reduce necroptosis-driven gastrointestinal mucosal dysfunction in HIV/SIV infection

The epigenetic mechanisms driving persistent gastrointestinal mucosal dysfunction in HIV/SIV infection is an understudied topic. Using reduced-representation bisulfite sequencing, we identified HIV/SIV infection in combination anti-retroviral therapy (cART)-naive rhesus macaques (RMs) to induce marked hypomethylation throughout promoter-associated CpG islands (paCGIs) in genes related to inflammatory response (NLRP6, cGAS), cellular adhesion and proliferation in colonic epithelial cells (CEs). Moreover, low-dose delta-9-tetrahydrocannabinol (THC) administration reduced NLRP6 protein expression in CE by hypermethylating the NLRP6 paCGI and blocked polyI:C induced NLRP6 upregulation in vitro. In cART suppressed SIV-infected RMs, NLRP6 protein upregulation associated with significantly increased expression of necroptosis-driving proteins; phosphorylated-RIPK3(Ser199), phosphorylated-MLKL(Thr357/Ser358), and HMGB1. Most strikingly, supplementing cART with THC effectively reduced NLRP6 and necroptosis-driving protein expression to pre-infection levels. These findings for the first time demonstrate that NLRP6 upregulation and ensuing activation of necroptosis promote HIV/SIV-induced gastrointestinal mucosal dysfunction and that epigenetic modulation using phytocannabinoids represents a feasible therapeutic modality for alleviating HIV/SIV-induced gastrointestinal inflammation and associated comorbidities.

pathology↗

bioRxiv2023

Incorporation of 5 methylcytidine alleviates innate immune response to self-amplifying RNA vaccine

In order to improve vaccine effectiveness and safety profile of existing synthetic RNA-based vaccines, we have developed a self-amplifying RNA (saRNA)-based vaccine expressing membrane-anchored receptor binding domain (RBD) of SARS-CoV-2 S protein (S-RBD) and have demonstrated that a minimal dose of this saRNA vaccine elicits robust immune responses. Results from a recent clinical trial with 5-methylcytidine (5mC) incorporating saRNA vaccine demonstrated reduced vaccine-induced adverse effects while maintaining robust humoral responses. In this study, we investigate the mechanisms accounting for induction of efficient innate and adaptive immune responses and attenuated adverse effects induced by the 5mC-incorporated saRNA. We show that the 5mC-incorporating saRNA platform leads to prolonged and robust expression of antigen, while induction of type-I interferon (IFN-I), a key driver of reactogenicity, is attenuated in peripheral blood mononuclear cells (PBMCs), but not in macrophages and dendritic cells. Interestingly, we find that the major cellular source of IFN-I production in PBMCs is plasmacytoid dendritic cells (pDCs), which is attenuated upon 5mC incorporation in saRNA. In addition, we demonstrate that monocytes also play an important role in amplifying proinflammatory responses. Furthermore, we show that the detection of saRNA is mediated by a host cytosolic RNA sensor, RIG-I. Importantly, 5mC-incorporating saRNA vaccine candidate produced robust IgG responses against S-RBD upon injection in mice, thus providing strong support for the potential clinical use of 5mC-incorporating saRNA vaccines.

immunology↗

bioRxiv2023

Immediate and Long-Term Electrophysiological Biomarkers of Antidepressant Behavioral Effects After Subanesthetic Ketamine and Medial Prefrontal Cortex Deep Brain Stimulation Treatment

1Ketamine and medial prefrontal cortex (mPFC) deep brain stimulation (DBS) are emerging depression treatments, however their mechanisms and efficacy biomarkers have not been established. This study investigates immediate and long-term mPFC electrophysiological correlates of their antidepressant effects, and explores the effects of combinatorial treatment. Local field potential electrodes were implanted into the mPFC of male Sprague Dawley rats, then corticosterone was administered for 21 days, except in the control group (n = 8). In the last week of depression induction, the remaining groups received mPFC DBS (n = 8), ketamine (n = 9), both (n = 9), or neither (n = 8). All groups then performed a behavioral assay. We found that DBS treatment immediately suppressed relative low gamma power and improved cognition in the long-term, which correlated with rescued apathy-like behavior in the Groom Test (GT). In contrast, ketamine treatment suppressed sample entropy in the long-term, which correlated with its immediate decrease in sample entropy as well as rescued GT behavior. In the combinatorial group these changes were inhibited, which correlated with a failure to fully rescue GT behavior. Despair-like behavior in the Forced Swim Test was rescued by all three treatments, which correlated with increased relative high frequency oscillation (HFO) power immediately after ketamine and combinatorial treatment. Our findings support the utility of low gamma and HFO power, sample entropy, and cognitive tests in the search for mechanisms and biomarkers of depression and novel treatments. 2 Significance StatementThere is growing interest in psychedelic pharmacological agents, such as ketamine, and direct neurostimulation techniques, like deep brain stimulation, as treatments for depression. However, their mechanisms are poorly understood, particularly those underlying their sustained benefits. Our study addresses this by correlating behavioral rescue with immediate and long-term changes in the function of the medial prefrontal cortex. These antidepressant correlates may represent therapeutically relevant functional changes, and therefore also have potential as biomarkers. Clinically, such biomarkers enable predicting and monitoring of treatment efficacy, and thereby contribute to the personalization of care. In research, utilizing these translatable biomarkers enhances the etiological validity of disease models, and enables the development of more targeted, next-generation treatment strategies.

neuroscience↗

bioRxiv2023

Forest cover is more important than its integrity or configuration of the landscape in determining the habitat use of mammals in a modified landscape in Colombia

Human activities shape the structure of landscapes in different ways and hence modify animal communities depending on the type and intensity of these activities. The Montes de Maria subregion of Colombia has experienced a heavy transformation of most areas despite covering one of the last remnants of dry forest, a critically endangered ecosystem. However, the effects of this transformation have been little explored. Here, we used a multispecies occupancy model (MSOM) to understand the relative influence of three components of land-use change - deforestation (remaining habitat amount), degradation of habitat quality (habitat quality) and fragmentation (landscape configuration) on mammalian habitat use across a mosaic of tropical dry forest in Colombia. Our data suggest that the percentage of forest cover was substantially important for herbivores, and consistently showed a moderate effect on the entire community and some individual species. High variability in species-specific responses to the examined variables hindered broad taxonomic generalizations, nevertheless, we detected a moderate positive effect of forest cover in both diet specialists and generalists species, as well as in species with small home ranges. Although omnivores responses, tended to use less complex landscapes (mosaics of land uses), there was high uncertainty in this response. The lack of substantial effects on most species, and the absence of threatened species across this anthropogenic landscape, suggests that the current community is composed of species tolerant to habitat modifications, but not only diet generalist species. This is most likely the result of a long filtering process caused by land use transformation and hunting which could have caused non-sensitive species to distribute relatively homogenously across this landscape. Our results suggest that conservation strategies in the study area should focus on conserving and expanding as much forest as possible rather than only improving the quality of already existing forest patches.

ecology↗

bioRxiv2022

Climatic niche conservatism in a clade of disease vectors (Diptera: Phlebotominae)

Sandflies of the family Psychodidae show notable diversity in both disease vector status and climatic niche. Some species (in the subfamily Phlebotominae) transmit Leishmania parasites, responsible for the disease leishmaniasis. Other Psychodidae species do not. Psychodid species ranges can be solely tropical, confined to the temperate zones, or span both. Studying the relationship between the evolution of disease vector status and that of climatic niche affords an understanding not only of the climate conditions associated with the presence and species richness of Leishmania vectors, but also allows the study of the extent to which psychodid flies climatic niches are conserved, in a context with implications for global human health. We obtained observation site data, and associated climate data, for 223 psychodid species to understand which aspects of climate most closely predict distribution. Temperature and seasonality are strong determinants of species occurrence within the clade. We built a mitochondrial DNA phylogeny of Psychodidae, and found a positive relationship between pairwise genetic distance and climate niche differentiation, which indicates strong niche conservatism. This result is also supported by strong phylogenetic signals of metrics of climate differentiation. Finally, we used ancestral trait reconstruction to infer the tropicality (i.e., proportion of latitudinal range in the tropics minus the proportion of the latitudinal range in temperate areas) of ancestral species, and counted transitions to and from tropicality states, finding that tropical and temperate species respectively produced almost entirely tropical and temperate descendant species, a result consistent for vector and non-vector species. Taken together, these results imply that while vectors of Leishmania can survive in a variety of climates, their climate niches are strongly predicted by phylogeny.

evolutionary biology↗

bioRxiv2021

MIRO2 regulates prostate cancer cell growth via GCN1-dependent stress signaling

There is a continued need to identify novel therapeutic targets to prevent the mortality associated with prostate cancer. In this context, we discovered a novel mitochondrial signaling pathway that controls androgen-independent and androgen-sensitive prostate cancer cell growth. Mitochondrial Rho GTPase 2 (MIRO2) mRNA was upregulated in prostate cancer compared to localized tumors, and higher MIRO2 levels were correlated with poor patient survival. Using human cell lines that represent AR-independent or androgen-sensitive prostate cancer, we show that MIRO2 depletion impaired cell growth, colony formation and tumor growth in mice. Network analysis of MIRO2s binding partners identified metabolism, cell cycle, and cellular responses to extracellular stimuli amongst the top over-represented pathways. The top hit on our screen was General Control Non-derepressible 1 (GCN1). GCN1 was overexpressed in prostate cancer and MIRO2-GCN1 interacted in prostate cancer cell lines and in primary prostate cancer cells. Our results showed that MIRO2 is necessary for efficient GCN1-mediated GCN2 kinase activation and signaling, triggering translation of the transcription factor ATF4. Importantly, MIRO2 controlled ATF4 levels and transcriptional activity both in amino acid replete and depleted conditions. Furthermore, MIRO2s effect on regulating prostate cancer cell growth was partially mediated by ATF4. Finally, activation of GCN2 and ATF4 expression were correlated with MIRO2 expression in prostate cancer xenografts. Overall, we propose a new mechanism driving prostate cancer growth of both AR-independent and androgen-sensitive tumors.

cancer biology↗