Biology subjects

Jimenez, N.

Publications and source records attributed to Jimenez, N..

5 recordsLinked to original sources

bioRxiv2025

Selecting methods for draft GEM generation in multicellular eukaryotes: a comparative analysis

Motivated by multiple strategies that have successfully implemented genome-scale models (GEMs) into their pipeline, several approaches have been developed for automatic generation of draft GEMs. However, most of these methods are not optimized for their use for multicellular eukaryotes and their performance for this task is unclear. In this work we present a comparative analysis of seven automated reconstruction tools (AuReMe, carveMe, Merlin, modelSEED, Pathway tools, Raven and Reconstructor) applied to three multicellular eukaryotes: the mosquito Aedes aegypti, the CHO (Chinese Hamster Ovary) cell line from Cricetulus griseus and the brown algae Ectocarpus siliculosus. Evaluation of these tools was based on metrics for network size, functionality, consistency, representation of organelle-specific functions and organism-specific metabolites, annotation quality and execution time. Finding that similarity of obtained metabolic networks is highly influenced by databases in which these methods base their predictions over phylogeny. Our works aims at providing a practical resource to guide researchers in selecting methods for draft generation tailored to organism characteristics and research goals. Author summaryGenome-scale models (GEMs) represent all the potential biochemical transformations that a specific organism can carry out based on the information encoded in its genome. Although these models are a powerful tool for analyzing omics datasets and simulating the metabolic effects of genetic modifications or changing media composition, the process of manually reconstructing a genome-scale model is complex and time-consuming. Motivated by their potential applications, several tools have been developed for the automated generation of draft GEMs, however, most of them are oriented to simpler organisms such as bacteria or single-cell eukaryotes, while their relative performance for modeling multicellular eukaryotes is unclear. In this work, we compared seven tools for draft GEMs reconstruction of three organisms: for the mosquito Aedes aegypti, the brown algae Ectocarpus siliculosus and the CHO cell line from Cricetulus griseus. Our results showed that no tool systematically outperformed others, suggesting that method selection is influenced by several factors such as organism-specific data availability and their intended application.

systems biology↗

bioRxiv2023

A look into the future: Using a transcriptomic meta-analysis of Diptera-Wolbachia systems to project the sustainability of arboviral control strategies

BackgroundAn effective strategy for arboviral control consists in transfecting Aedes aegypti mosquitoes with the intracellular bacteria Wolbachia pipientis, which reduces host viral susceptibility and spreads itself into wild populations via reproductive manipulations. However, the prospect of losing the efficacy of this strategy underscores the need for deepening the mechanistic knowledge of Diptera-Wolbachia systems and identifying relevant Wolbachia effects that could decline upon adaptation of A. aegypti transfections. A systematic comparison of publicly available Diptera-Wolbachia transcriptomic datasets could yield progress in this matter. Methodology/Principal findingsWe derived differentially expressed gene (DEG) sets from previously published Diptera-Wolbachia transcriptomic datasets, subjected them to enrichment analysis of Gene Ontology terms, and intersected the results to identify patterns of host gene/function regulation by Wolbachia. A putative farnesoic acid methyl transferase (AAEL004667) and a flavin-containing monooxygenase (AAEL000834) were consistently upregulated in transfected A. aegypti and linked to cytoplasmic incompatibility and viral susceptibility, being proposed as novel targets of study. Genes implicated in viral blocking --GNBPA1, PGRPS1, DEFC, Tf1, serine-type endopeptidases and endopeptidase inhibitors-- were consistently upregulated in transfected A. aegypti but not in native infections, indicating that they could lose responsiveness to Wolbachia over time and should be considered to keep the efficacy of arboviral control. The commonality of chitinase regulation by Wolbachia was identified and proposed as an explanation for the loss of desiccation resistance in transfected A. aegyptis eggs, which is a main obstacle for the introgression of Wolbachia in mosquito populations. Conclusions/SignificanceThe present work points out relevant gene targets to consider for arboviral control sustainability and provides new hypotheses for deepening the understanding of Diptera-Wolbachia systems. Author SummaryArboviral diseases (e.g. dengue), which are mainly transmitted by the mosquito Aedes aegypti, impose a global public health crisis. An effective strategy for controlling the spread of these diseases is to artificially infect A. aegypti populations with the bacteria Wolbachia pipientis, which reduces its capacity to transmit arboviruses. However, future adaptive changes in the novel A. aegypti-Wolbachia association could diminish the efficacy of this approach. To prevent this, it is crucial to have a solid biological understanding of Wolbachia infections and predictions about specific changes that artificial infections could undergo. By analyzing publicly available biological data from Wolbachia-infected mosquitoes and flies we were able to propose new hypotheses regarding general aspects of Wolbachia infection and to identify antiviral effects of Wolbachia in A. aegypti that could decline over time, thus providing relevant information for keeping sustainability of a key arboviral control strategy.

bioinformatics↗

bioRxiv2022

A critical period for neurogenesis loss and cognitive decline in patients with mesial temporal lobe epilepsy patients

Mesial temporal lobe epilepsy (MTLE) is a syndromic disorder presenting with seizures and cognitive comorbidities. While seizure etiology is increasingly understood, the pathophysiological mechanisms contributing to cognitive decline and epilepsy progression remain less recognized. We have previously shown that adult hippocampal neurogenesis, a process contributing to visual spatial learning and memory in rodents, dramatically declines in MTLE patients with increased disease duration. Here, we investigate when multiple cognitive domains become effected by epilepsy disease duration and how human neurogenesis levels contribute to it. We find that intelligence, and verbal learning and memory decline at a critical period of 20 years disease duration. Surprisingly, the number of human immature neurons positively associate with auditory verbal, rather than visuospatial, learning and memory. Moreover, we uncover cognitive functions enriched to either immature or mature granule neurons and functions shared between them. Our study provides cellular evidence of how adult neurogenesis contributes to human cognition, and signifies an opportunity to advance regenerative medicine for patients with MTLE and other cognitive disorders. O_FIG O_LINKSMALLFIG WIDTH=108 HEIGHT=200 SRC="FIGDIR/small/507339v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@12d6c9forg.highwire.dtl.DTLVardef@13670aborg.highwire.dtl.DTLVardef@11efda3org.highwire.dtl.DTLVardef@19de537_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Taxane induces attenuation of the CXCR2/BCL-2 axis and sensitize prostate cancer to platinum-based treatments

BackgroundTaxanes are the most active chemotherapy agents in metastatic castration resistant prostate cancer (mCRPC) patients, yet resistance almost invariably occurs representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients but the mechanistic basis and biomarkers remain elusive. ObjectiveTo identify mechanisms and response biomarkers for the antitumor efficacy of taxane-platinum combinations in mCRPC. Design, setting, and participantsTranscriptomic data from a publicly available mCRPC dataset of taxane-exposed and naive patients was analysed to identify response biomarkers and emerging vulnerabilities. Functional and preclinical validation was performed in taxane resistant mCRPC cell lines and genetically engineered mouse models (GEMM). InterventionmCRPC cells were treated with docetaxel, cisplatin, carboplatin and the CXCR2 inhibitor, SB265610. Gain and loss of function in culture of CXCR2 was achieved by overexpression or siRNA-silencing. Preclinical assays in GEMM mice tested the anti-tumor efficacy of taxane-platinum combinations. Outcome measurements and statistical analysisProliferation, apoptosis and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival and histopathology. Changes in CXCR2, BCL-2 and chemokines were analysed by RT-qPCR and Western Blot. Human expression data was analyzed using GSEA, hierarchical clustering and correlation studies. GraphPad Prism software, R-studio, were used for statistical and data analyses. Results and limitationsTranscriptomic data from taxane-exposed human mCRPC tumors correlates with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel treatment inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated that taxane resistance is directly associated to CXCR2 expression and that targeting of CXCR2 sensitizes prostate cancer (PC) cells to cisplatin. Finally, taxane-platinum combinations in vivo are highly synergistic and previous exposure to taxanes sensitizes mCRPC tumors to second line cisplatin treatment. ConclusionsTogether our data identifies an acquired vulnerability in taxane treated mCRPC patients with potential predictive activity for platinum-based treatments. Patient summaryA subset of patients with aggressive and therapy resistant PC benefits from taxane-platinum combination chemotherapy however, we lack biomarkers and mechanistic basis about how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell scape mechanisms to chemotherapy-induced cell death, hence turning these cells more vulnerable to additional platinum treatment.

cancer biology↗

bioRxiv2019

Conserved function of ether lipids and sphingolipids in the early secretory pathway

Sphingolipids have been shown to play important roles in physiology and cell biology, but a systematic examination of their functions is lacking. We performed a genome-wide CRISPRi screen in sphingolipid-depleted cells and identified hypersensitive mutants in genes of membrane trafficking and lipid biosynthesis, including ether lipid synthesis. Systematic lipidomic analysis showed a coordinate regulation of ether lipids with sphingolipids, where depletion of one of these lipid types resulted in increases in the other, suggesting an adaptation and functional compensation. Biophysical experiments on model membranes show common properties of these structurally diverse lipids that also share a known function as GPI anchors in different kingdoms of life. Molecular dynamics simulations show a selective enrichment of ether phosphatidylcholine around p24 proteins, which are receptors for the export of GPI-anchored proteins and have been shown to bind a specific sphingomyelin species. Our results support a model of convergent evolution of proteins and lipids, based on their physico-chemical properties, to regulate GPI-anchored protein transport and maintain homeostasis in the early secretory pathway.

biochemistry↗