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Biology subjects

Munoz, D.

Publications and source records attributed to Munoz, D..

8 recordsLinked to original sources
bioRxiv2026

Extracts of Bacillus proteolyticus strain OSUB18 exhibit cytostatic activity

Although therapeutic advancements have dramatically improved outcomes for cancer patients in recent decades, advanced cancer remains a significant challenge. There is still an urgent need for new and more effective strategies that minimize toxicity and improve survival outcomes in cancer patients. Natural products from microorganisms are a rich and promising source of bioactive compounds with substantial therapeutic potential in cancer treatment. Recently, B. proteolyticus strain OSUB18, isolated from switchgrass, has been demonstrated to promote plant growth and regulate reactive oxygen species (ROS) production. Here, we investigated the anticancer potential of this plant-associated microbe and demonstrated that its crude extracts exhibited broad-spectrum cytostatic activity across diverse solid tumor cell lines. Importantly, OSUB18 extracts displayed limited cytotoxicity toward normal human mammary epithelial cells and mouse fibroblasts. This potentially selective cytostatic activity was retained within a water soluble, heat-labile, and protease-resistant fraction. The extracts primarily suppressed cell proliferation, accompanied by increased lipid peroxidation, with preliminary evidence suggesting the potential involvement of ferroptosis. These findings suggest that the bioactive component may be a selective cytostatic agent with multifaceted mechanisms of action.

cancer biology↗
bioRxiv2025

On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells.

Werner helicase inhibitors (WRNi) are in clinical development for microsatellite-unstable (MSI) tumors with defective DNA mismatch repair. Here, we investigate how cancer cell evolution shapes response to WRN inhibition and informs potential resistance mechanisms. Genome-wide CRISPR screens combined with WRN knockout did not identify bypass mechanisms, underscoring WRNs essential, non-redundant function in MSI cells. Pharmacogenomic screens identified modulators of WRNi sensitivity, including SMARCAL1, which links it to WRN-MSI synthetic lethality. Semi-saturation mutagenesis of WRN and prolonged drug treatment identified on-target WRN mutations driving acquired resistance to multiple WRNi in vitro and in vivo, which was mitigated by combination with standard chemotherapies. Some resistance mutations conferred broad cross-resistance, whereas others preserved sensitivity to alternative clinical-grade WRNi with distinct mechanism of action. Our findings could inform clinical trial design by suggesting the feasibility of real-time tracking of emerging resistance and enabling early therapeutic adaptations. SignificanceWe present the first exploration of how MSI cancer cells evolve under the selective pressure of WRN helicase inhibition, providing a framework for understanding adaptive responses to this newly identified synthetic-lethal dependency. This study identifies on-target WRN mutations as key drivers of resistance in MSI cancers, supporting the use of combination strategies with other standard-of-care treatments to prevent resistance. It highlights how mutation tracking can guide therapeutic switching to clinically available WRN inhibitors with distinct mechanisms of action, thereby refining clinical development and potentially improving biomarker-informed patient outcomes.

cancer biology↗
bioRxiv2025

Targeting histone acetylation to overcome drug resistance in the parasite Trichomonas vaginalis

Resistance to antimicrobial drugs is a major global health challenge, yet the regulatory mechanisms underlying resistance phenotypes remain incompletely understood. In particular, whether epigenetic processes contribute to antimicrobial resistance in microbial eukaryotes is largely unexplored. Here, we show that epigenetic regulation plays a central role in modulating metronidazole resistance in Trichomonas vaginalis, the causative agent of the most common non-viral sexually transmitted infection. Pharmacological inhibition of histone deacetylases restores drug sensitivity in a highly resistant clinical isolate, markedly reducing the minimum inhibitory concentration. Integrative transcriptomic reveal widespread transcriptional reprogramming associated with activation of pathways involved in redox metabolism, transcriptional regulation, and stress responses. Chromatin profiling demonstrates that increased H3K9 acetylation is strongly associated with transcriptional activation. Upon TSA treatment, increased H3K9 acetylation is observed at promoters and gene bodies of genes that may be associated with MTZ resistance. By combining epigenetic perturbation with comparative transcriptomics across multiple strains, we identify a set of genes that are epigenetically silenced in resistant parasites that are constitutively expressed in sensitive backgrounds. Functional re-expression of two candidates, thioredoxin reductase and a Myb-like transcription factor (Myb6), significantly reduces resistance, establishing a direct link between epigenetic regulation and drug sensitivity. Together, our findings uncover a reversible, chromatin-based mechanism underlying antimicrobial resistance in a protozoan parasite and highlight epigenetic reprogramming as a potential therapeutic strategy. More broadly, this work suggests that epigenetic regulation may represent a general and previously underappreciated layer of control over drug resistance in microbial eukaryotes.

microbiology↗
bioRxiv2024

A physiologically inspired hybrid CPG/Reflex controller for cycling simulations that generalizes to walking

Predictive simulations based on explicit, physiologically inspired, control policies, can be used to test theories on motor control and to evaluate the effect of interventions on the different components of control. Several control architectures have been proposed for simulating locomotor tasks, based on fully feedback, reflex-based, controllers, or on feedforward architectures mimicking the Central Pattern Generators. Recently, hybrid architectures integrating both feedback and feedforward components have been shown to represent a viable alternative to fully feedback or feedforward controllers. Current literature on controller-based simulations, however, almost exclusively presents task-specific controllers that do not generalize across different tasks. The task-specificity of current controllers limits the generalizability of the neurophysiological principles behind such controllers. Here we propose a hybrid controller for predictive simulations of cycling based where the feedforward component is based on a well-known theoretical model, the Unit Burst Generation model, and the feedback component includes a limited set of reflex pathways, expected to be active during submaximal steady cycling. We show that this controller can simulate physiological cycling patterns at different desired speeds. We also show that the controller can generalize to walking behaviors by just adding an additional control component for accounting balance needs. The controller here proposed, although simple in design, represent an instance of physiologically inspired generalizable controller for cyclical lower limb tasks. Author SummaryPredictive simulations allow to synthesize human movements and their associated biomechanical quantities without using experimental data. Such simulations can help understand how humans may perform movement tasks in different scenarios and could provide useful information in fields like rehabilitation. One of the methodologies used for developing predictive simulations is based on creating models of the neural control architectures that generate the activation of the muscles. In this work we propose the first neural control architecture for cycling behaviors. We show that our architecture can be used to develop predictive simulations of cycling at different speeds and that the associated biomechanical quantitites are consistent with experimental data. Moreover, we show that our control architecture can also replicate walking behaviors with minimal modifications.

neuroscience↗
bioRxiv2023

A novel modular architecture for a neural controller architecture for predictive simulations of stand-to-walk motions

Computational models of neural control are a powerful tool for evaluating principles of motor control that cannot be tested directly in conventional experimental settings. Current gait controllers struggle with physiological grounding and can replicate a small set of discrete behaviours. Objectivehere we propose a new neural controller, the Internal Model-based Modular Controller, that can transition between multiple lower-limb motor tasks within a single simulation. The architecture comprises a simplified model of the Mesencephalic Locomotor Region, which activates different internal models. These internal models organise functional muscle synergies into task-specific networks that generate coordinated activity across multiple muscles. Resultsthe controller performs Stand-To-Walk-To-Stand and Stand-To-Backward Walking-To-Stand transitions and modulates gait speed within a simulation by adjusting a few control signals. The observed simulated biomechanics and muscle activation patterns are generally consistent with experimental observations. ConclusionsOur results show that the proposed modular architecture represents a plausible mechanism for producing heterogeneous motor behaviours. IMPACT STATEMENTThis study presents a modular neural controller, which employs internal models and functional muscle synergies to reproduce heterogeneous legged behaviours within a single simulation framework.

neuroscience↗
bioRxiv2023

Histone variant H2B.Z acetylation is necessary for maintenance of Toxoplasma gondii biological fitness

Through regulation of DNA packaging, histone proteins are fundamental to a wide array of biological processes. A variety of post-translational modifications (PTMs), including acetylation, constitute a proposed histone code that is interpreted by "reader" proteins to modulate chromatin structure. Canonical histones can be replaced with variant versions that add an additional layer of regulatory complexity. The protozoan parasite Toxoplasma gondii is unique among eukaryotes in possessing a novel variant of H2B designated H2B.Z. The combination of PTMs and the use of histone variants is important for gene regulation in T. gondii, offering new targets for drug development. In this work, T. gondii parasites were generated in which the 5 N-terminal acetylatable lysines in H2B.Z were mutated to either alanine (c-Myc-A) or arginine (c-Myc-R). c-Myc-A mutant only displayed a mild effect in its ability to kill mice. c-Myc-R mutant presented an impaired ability to grow and an increase in differentiation to latent bradyzoites. This mutant line was also more sensitive to DNA damage, displayed no virulence in mice, and provided protective immunity against future infection. While nucleosome composition was unaltered, key genes were abnormally expressed during in vitro bradyzoite differentiation. Our results show that the N-terminal positive charge patch of H2B.Z is important for these procceses. Pull down assays with acetylated N-terminal H2B.Z peptide and unacetylated one retrieved common and differential interactors. Acetylated peptide pulled down proteins associated with chromosome maintenance/segregation and cell cycle, opening the question of a possible link between H2B.Z acetylation status and mitosis.

cell biology↗
bioRxiv2020

Coordination of pupil and saccade responses by the superior colliculus

The appearance of a salient stimulus evokes saccadic eye movements and pupil dilation as part of the orienting response. Although the role of the superior colliculus (SC) in saccade and pupil dilation has been established separately, whether and how these responses are coordinated remains unknown. The SC also receives global luminance signals from the retina, but whether global luminance modulates saccade and pupil responses coordinated by the SC remains unknown. Here, we used microstimulation to causally determine how the SC coordinates saccade and pupil responses, and whether global luminance modulates these responses by varying stimulation frequency and global luminance in male monkeys. Stimulation frequency modulated saccade and pupil responses, with trial-by-trial correlations between the two responses. Global luminance only modulated pupil, but not, saccade responses. Our results demonstrate an integrated role of the SC on coordinating saccade and pupil responses, characterizing luminance independent modulation in the SC, together elucidating the differentiated pathways underlying this behavior.

neuroscience↗