Biology subjects

Munoz, S.

Publications and source records attributed to Munoz, S..

6 recordsLinked to original sources

bioRxiv2025

Inference and validation of a dynamic gene regulatory network influencing cell fate during Duchenne muscular dystrophy initiation

The onset of gene regulatory disturbances leading to developmental disorders remains poorly understood, particularly when symptoms begin after birth. Using induced pluripotent stem cells, single-cell transcriptomics and computational modeling, we determined the gene expression waves guiding early myogenesis and how they are affected by a disease-causing mutation. We uncovered a dynamic gene regulatory network organized in two kernels that function as a toggle-switch controlling stochastic cell fate decisions. In cells derived from patients with Duchenne muscular dystrophy, these waves of regulation are less pronounced and the switch remains in the OFF state with a higher probability, resulting in convergence into a restricted cell fate. Experimental reactivation of the switch through RNA interference led to a rescued transcriptomic state and to a refined network topology. This work uncovers a dynamic regulatory mechanism underlying early cell fate divergence and provides a general framework to infer and validate dynamic gene regulatory networks involved in disease initiation.

bioinformatics↗

bioRxiv2025

A fetal oncogene NUAK2 is an emerging therapeutic target in glioblastoma.

Glioblastoma Multiforme (GBM) is the most prevalent and highly malignant form of adult brain cancer characterized by poor overall survival rates. Effective therapeutic modalities remain limited, necessitating the search for novel treatments. Neurodevelopmental pathways have been implicated in glioma formation, with key neurodevelopmental regulators being re- expressed or co-opted during glioma tumorigenesis. Here we identified a serine/threonine kinase, NUAK family kinase 2 (NUAK2), as a fetal oncogene in mouse and human brains. We found robust expression of NUAK2 in the embryonic brain that decreases throughout postnatal stages and then is re-expressed in malignant gliomas. However, the role of NUAK2 in GBM tumorigenesis remains unclear. We demonstrate that CRIPSR-Cas9 mediated NUAK2 deletion in GBM cells results in suppression of proliferation, while overexpression leads to enhanced cell growth in both in vitro and in vivo models. Further investigation of the downstream biological processes dysregulated in the absence of NUAK2 reveals that NUAK2 modulates extracellular matrix (ECM) components to facilitate migratory behavior. Lastly, we determined that pharmaceutical inhibition of NUAK2 is sufficient to impede the proliferation and migration of malignant glioma cells. Our results suggest that NUAK2 is an actionable therapeutic target for GBM treatment.

cell biology↗

bioRxiv2024

Timely lagging strand maturation relies on Ubp10-mediated PCNA dissociation from replicating chromatin

Synthesis and maturation of Okazaki Fragments is an incessant and highly efficient metabolic process completing the synthesis of the lagging strands at replication forks during S phase. Accurate Okazaki fragment maturation (OFM) is crucial to maintain genome integrity and, therefore, cell survival in all living organisms. In eukaryotes, OFM involves the consecutive action of DNA polymerase Pol {partial}, 5 Flap endonuclease Fen1 and DNA ligase I, and constitutes the best example of a sequential process coordinated by the sliding clamp PCNA. For OFM to occur efficiently, cooperation of these enzymes with PCNA must be highly regulated. Here, we present evidence of a role for the PCNA-deubiquitylase Ubp10 in the maturation of Okazaki fragments in the budding yeast Saccharomyces cerevisiae. We show that Ubp10 associates with lagging-strand DNA synthesis machineries on replicating chromatin to ensure timely ligation of Okazaki fragments by promoting an Elg1ATAD5-independent PCNA unloading mechanism. This document was written without the use of AI.

molecular biology↗

bioRxiv2021

Effect of sodium silicate on drinking water biofilm development

Sodium silicates have been studied for sequestration of iron, coagulation, and corrosion control, but their impact on biofilm formation has not been documented in detail. This study investigated the impact of sodium silicate corrosion control on biomass accumulation in drinking water systems in comparison to orthophosphate, a common corrosion inhibitor. Biofilm growth was measured by determining ATP concentrations, and the bacterial community was characterized using 16S ribosomal RNA (rRNA) sequencing. A pilot-scale study with cast-iron pipe loops, annular reactors (ARs), and polycarbonate coupons demonstrated significantly lower biofilm ATP concentrations in the sodium silicate-treated AR than the orthophosphate-treated AR when the water temperature exceeded 20{degrees}C. However, an elevated sodium silicate dose (48 mg L-1 of SiO2) disturbed and dispersed the biofilm formed inside the AR, resulting in elevated effluent ATP concentrations. Two separate experiments confirmed that biomass accumulation was higher in the presence of orthophosphate at high water temperatures (20{degrees}C) only. No significant differences were identified in biofilm ATP concentrations at lower water temperatures (below 20{degrees}C). Differences in bacterial communities between the orthophosphate- and sodium silicate-treated systems were not statistically significant, even though orthophosphate promoted higher biofilm growth. However, the genera Halomonas and Mycobacterium--which include opportunistic pathogens--were present at greater relative abundances in the orthophosphate-treated system compared to the sodium silicate system. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/460503v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@14ac86corg.highwire.dtl.DTLVardef@ac500borg.highwire.dtl.DTLVardef@bb2980org.highwire.dtl.DTLVardef@1a1b5c0_HPS_FORMAT_FIGEXP M_FIG C_FIG Orthophosphate promotes more biofilm growth in comparison to sodium silicates at water temperatures above 20{degrees}C. Water impact statementSodium silicates have been used in drinking water treatment for decades, both as sequestrants and as corrosion inhibitors. However, their impact on biofilm formation is poorly understood, and this risks drinking water quality. This study aims to further clarify the effects of corrosion inhibitors on biofilm development, including inhibitors that are not phosphate-based.

microbiology↗

bioRxiv2021

Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway

Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. Here, we analyze noise suppression in the yeast pheromone signaling pathway and show that the poorly characterized protein Kel1 serves as a major noise suppressor and prevents cell death. At the molecular level, Kel1 prevents spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Only a hypophosphorylated form of Kel1 suppresses signaling, reduces noise and prevents pheromone-associated cell death, and our data indicate that the MAPK Fus3 contributes to Kel1 phosphorylation. Taken together, Kel1 serves as a phospho-regulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency, and to prevent pheromone-associated cell death.

cell biology↗

bioRxiv2019

Phylogeographic reconstruction using air transportation data and its application to the 2009 H1N1 influenza A pandemic

Influenza A viruses cause seasonal epidemics and occasional pandemics in the human population. While the worldwide circulation of seasonal influenza is at least partly understood, the exact migration patterns between countries, states or cities are not well studied. Here, we use the Sankoff algorithm for parsimonious phylogeographic reconstruction together with effective distances based on a worldwide air transportation network. By first simulating geographic spread and then phylogenetic trees and genetic sequences, we confirmed that reconstructions with effective distances inferred phylogeographic spread more accurately than reconstructions with geographic distances and Bayesian reconstructions with BEAST, the current state-of-the-art. Our method extends the state-of-the-art by using fine-grained locations like airports and inferring intermediate locations not observed among sampled isolates. When applied to sequence data of the pandemic H1N1 influenza A virus in 2009, our approach correctly inferred the origin and proposed airports mainly involved in the spread of the virus. In case of a novel outbreak, this approach allows to rapidly analyze sequence data and infer origin and spread routes to improve disease surveillance and control.\n\nAuthor summaryInfluenza A viruses infect up to 5 million people in recurring epidemics every year. Further, viruses of zoonotic origin constantly pose a pandemic risk. Understanding the geographical spread of these viruses, including the origin and the main spread routes between cities, states or countries, could help to monitor or contain novel outbreaks. Based on genetic sequences and sampling locations, the geographic spread can be reconstructed along a phylogenetic tree. Our approach uses a parsimonious reconstruction with air transportation data and was verified using a simulation of the 2009 H1N1 influenza A pandemic. Applied to real sequence data of the outbreak, our analysis gave detailed insights into spread patterns of influenza A viruses, highlighting the origin as well as airports mainly involved in the spread.

bioinformatics↗