Biology subjects

Rico, A.

Publications and source records attributed to Rico, A..

10 recordsLinked to original sources

bioRxiv2025

Development and Characterization of Triazole-Based WDR5 Inhibitors for the Treatment of Glioblastoma

Glioblastoma (GBM) cancer stem cells (CSCs) contribute to tumor recurrence, treatment resistance, and dismal clinical outcomes. Genetic and pharmacological evidence suggests that the nuclear scaffolding protein WD-repeat containing protein 5 (WDR5) is a therapeutic vulnerability of the CSC population. However, previously reported WDR5 inhibitors display low permeability and are unable to penetrate the blood-brain barrier (BBB), limiting their utility in GBM. Herein, we report the structure-guided development of a novel series of triazole-based WDR5 WIN-site inhibitors designed to increase passive brain penetration. We identified triazole-based WDR5 inhibitors that are potent, passively permeable, and in some cases more brain penetrant than other scaffolds. We phenotypically assessed our novel WDR5 inhibitors in a panel of patient-derived CSC models and uncovered unique WDR5-regulated metabolic genes in GBM. We also evaluated their antiproliferative activity against CSCs both in vitro and in vivo. Finally, to identify novel combination opportunities, we screened a 2,100-compound chemical probe library and identified that the ATAD2 inhibitor BAY-850 synergizes with WDR5 inhibitors to enhance CSC killing. Our work diversifies the chemical matter targeting WDR5, clarifies the in vitro consequences of WIN-site inhibition in CSCs, and encourages the future development of next-generation WDR5 inhibitors with the potential to achieve in vivo efficacy in the brain.

cancer biology↗

bioRxiv2024

MAIA: An open-source, modular, bioreactor for cities

This work presents the design and fabrication of MAIA, an open-source, modular, low-cost, and portable bioreactor for democratizing the development of synthetic biology based projects for urban settings. The integration of open-source synthetic biology (synbio) tools in a citys infrastructure planning and design is crucial for addressing the great challenges related to urbanization. Synbio tools have great potential to help us complement our current sensing and actuating urban infrastructure. The MAIA reactor controls bacterial growth variables, making it suitable for cell-based experiments while reducing the need for expensive laboratory equipment. Its low-cost and open-source design allow for easy replication and modification, making it accessible to a broader audience. Its portability makes it suitable for use outside of traditional laboratory settings. We qualitatively and quantitatively validated the reactors capability to support cell growth, stimulate gene expression, and act as a creative tool for students and users.

synthetic biology↗

bioRxiv2023

Extreme high-elevation mammal surveys reveal unexpectedly high upper range limits of Andean mice

In the worlds highest mountain ranges, uncertainty about the upper elevational range limits of alpine animals represents a critical knowledge gap regarding the environmental limits of life and presents a problem for detecting range shifts in response to climate change. Here we report results of mountaineering mammal surveys in the Central Andes, which led to the discovery of multiple species of mice living at extreme elevations that far surpass previously assumed range limits for mammals. We live-trapped small mammals from ecologically diverse sites spanning >6700 m of vertical relief, from the desert coast of northern Chile to the summits of the highest volcanoes in the Andes. We used molecular sequence data and whole-genome sequence data to confirm the identities of species that represent new elevational records and to test hypotheses regarding species limits. These discoveries contribute to a new appreciation of the environmental limits of vertebrate life.

evolutionary biology↗

bioRxiv2022

A Bayesian network approach to assess the influence of climate change and pesticide use practices on the ecological risks of pesticides in a protected Mediterranean wetland

Pollution by agricultural pesticides is one of the most important pressures affecting Mediterranean coastal wetlands. Pesticide risks are expected to be influenced by climate change, which will result in an increase of temperatures and a decrease in annual precipitation rates in this region. On the other hand, pesticide dosages are expected to change given the increase in pest resistance and the implementation of environmental policies like the European Farm-to-Fork strategy, which aims for a 50% reduction in pesticide usage by 2030. The influence of climate change and pesticide use practices on the ecological risks of pesticides needs to be evaluated making use of realistic environmental scenarios. This study aimed to assess how different climate change and pesticide use practices affect the ecological risks of pesticides in the Albufera Natural Park (Valencia, Spain), a protected Mediterranean coastal wetland. We performed a probabilistic risk assessment for nine pesticides applied in rice production using scenarios comprised of three climatic regimes (the 2008 record, and projections for 2050 and 2100), three pesticide application regimes (the recommended dose, and 50% increase and 50% decrease), and their combinations. The scenarios were used to simulate pesticide exposure concentrations in the water column of the rice paddies using the RICEWQ model. Pesticide effects were characterized using acute and chronic Species Sensitivity Distributions built with laboratory toxicity data for aquatic organisms. Risk quotients were calculated as probability distributions making use of a Bayesian network approach, and best fitting distributions for the calculated exposure data and the SSDs. Our results show that future climate projections will influence exposure concentrations for some of the studied pesticides, yielding higher dissipation and lower exposure in scenarios dominated by an increase of temperatures, and higher exposure for scenarios in which heavy precipitation events occur after pesticide application. Our case study shows that pesticides such as azoxystrobin, difenoconazole and MCPA are posing high ecological risks for aquatic organisms, and that the implementation of the Farm-to-Fork strategy is crucial to reduce them, although will need additional measures to eliminate them.

ecology↗

bioRxiv2022

Using a Bayesian network model to predict effects of pesticides on aquatic community endpoints in a rice field - A southern European case study

In recent years, Bayesian network (BN) models have become more popular as a tool to support probabilistic environmental risk assessments (ERA). They can better account for and communicate uncertainty compared to the deterministic approaches currently used in traditional ERA. In this study, we used the BN as a meta-model to predict the potential effect of various pesticides on different biological levels in the aquatic ecosystem. The meta-model links the inputs and outputs of a process-based exposure model (RICEWQ), that is run with various scenarios combination built on meteorological, hydrological, and agricultural scenarios, and a probabilistic case-based effect model (PERPEST), which bases its prediction on a database of microcosm and mesocosm experiments. The research focused on the pesticide exposure in rice fields surrounding a Spanish Natural Park, considering three selected pesticides for this case study: acetamiprid (insecticide), MCPA (herbicide), and azoxystrobin (fungicide). For each of the pesticide types, the developed BN model enabled the prediction of their effects on biological endpoints, endpoint groups, and community in an aquatic ecosystem. Also, it enables comparison between the different pesticide types, their effects on endpoint groups and community. While directly linking future scenarios of climate and agricultural practice to the exposure concentration and indirectly linking them to the effect on biological endpoints as well as community. In summary, azoxystrobin and MCPA seem to have a higher predicted risk for the community with at least one of the biological endpoint being effected compared to acetamiprid. Generally, the developed approach facilitates the communication of uncertainties associated with the predicted effect on different biological levels of the aquatic ecosystem. This transparency in all model components can aid risk management and decision making.

ecology↗

bioRxiv2020

Changes in community composition determine recovery trajectories from multiple agricultural stressors in freshwater ecosystems

Pesticides have been identified worldwide as a threat for aquatic biodiversity due to their widespread use in agriculture and their capacity to reach freshwater ecosystems. Very little is known about the consequences of pesticide mixtures targeting different organism groups on community dynamics. Especially, how horizontal changes within one trophic level are propagated vertically across the food web has been rarely investigated. To get insight on the effects of pesticide mixtures on community dynamics, we performed a mesocosm experiment manipulating three common agricultural stressors: chlorpyrifos (an insecticide), diuron (an herbicide) and nutrients. The results of this study show that all stressors had significant effects on community composition, species richness and abundance. However, recovery trajectories and ecosystem functioning effects largely depended on the type of stressor as well as on post-disturbance trophic and non-trophic interactions. Effects of pesticides were generally recovered by the end of the experimental period when considering abundance, whereas community composition further departed from control systems. High nutrient loads led to a shift in community composition characterized by high taxa dominance and lower species richness, which in turn contributed to increased total organism abundance and reduced recovery times to pesticide exposure. We found interactions between the tested stressors to be significant only few times at the community level, while interactions were more common at the population level. Our findings indicate that management of freshwater ecosystems should consider pre-disturbance community composition and long-term changes in interactions across different organism groups to set effective protection measures.

ecology↗

bioRxiv2019

Classification of hospital and urban wastewater resistome and microbiota over time and their relationship to the eco-exposome.

Wastewaters (WW) are important sources for the dissemination of antimicrobial resistance (AMR) into the environment. Hospital WW (HWW) contain higher loads of micro-pollutants and AMR markers than urban WW (UWW). Little is known about the long-term dynamics of H and U WW and the impact of their joined treatment on the general burden of AMR. Here, we characterized the resistome, microbiota and eco-exposome signature of 126 H and U WW samples treated separately for three years, and then mixed, over one year. Multi-variate analysis and machine learning revealed a robust signature for each WW with no significant variation over time before mixing, and once mixed, both WW closely resembled U signatures. We demonstrated a significant impact of pharmaceuticals and surfactants on the resistome and microbiota of H and U WW. Our results present considerable targets for AMR related risk assessment of WW.

microbiology↗

bioRxiv2018

Genomic epidemiology supports multiple introductions and cryptic transmission of Zika virus in Colombia

BackgroundColombia was the second most affected country during the American Zika virus (ZIKV) epidemic, with over 109,000 reported cases. Despite the scale of the outbreak, limited genomic sequence data were available from Colombia. We sought to sequence additional samples and use genomic epidemiology to describe ZIKV dynamics in Colombia.\n\nMethodsWe sequenced ZIKV genomes directly from clinical diagnostic specimens and infected Aedes ae-gypti samples selected to cover the temporal and geographic breadth of the Colombian outbreak. We performed phylogeographic analysis of these genomes, along with other publicly-available ZIKV genomes from the Americas, to estimate the frequency and timing of ZIKV introductions to Colombia.\n\nResultsWe attempted PCR amplification on 184 samples; 19 samples amplified sufficiently to perform sequencing. Of these, 8 samples yielded sequences with at least 50% coverage. Our phylogeo-graphic reconstruction indicates two separate introductions of ZIKV to Colombia, one of which was previously unrecognized. We find that ZIKV was first introduced to Colombia in February 2015 (95%CI: Jan 2015 - Apr 2015), corresponding to 5 to 8 months of cryptic ZIKV transmission prior to confirmation in September 2015. Despite the presence of multiple introductions, we find that the majority of Colombian ZIKV diversity descends from a single introduction. We find evidence for movement of ZIKV from Colombia into bordering countries, including Peru, Ecuador, Panama, and Venezuela.\n\nConclusionsSimilarly to genomic epidemiologic studies of ZIKV dynamics in other countries, we find that ZIKV circulated cryptically in Colombia. This more accurate dating of when ZIKV was circulating refines our definition of the population at risk. Additionally, our finding that the majority of ZIKV transmission within Colombia was attributable to transmission between individuals, rather than repeated travel-related importations, indicates that improved detection and control might have succeeded in limiting the scale of the outbreak within Colombia.

genomics↗

bioRxiv2018

Cyclophilins A and B Oppositely Regulate Renal Tubular Epithelial Phenotype

Cyclophilins (Cyp) are peptidil-prolyl-isomerases and the intracellular receptors for the immunosuppressant Cyclosporine-A (CsA), which produces epithelial-mesenchymal-transition (EMT) and renal tubule-interstitial fibrosis. Since CsA inhibits Cyp enzymatic activity, we hypothesized that Cyp could be involved in EMT and fibrosis. Here, we demonstrate that CypB is a critical regulator of tubule epithelial cell plasticity on the basis that: i) CypB silencing caused epithelial differentiation in proximal tubule-derived HK-2 cells, ii) CypB silencing prevented TGF{beta}-induced EMT in HK-2, and iii) CypB knockdown mice exhibited reduced UUO-induced inflammation and kidney fibrosis. By contrast, silencing of CypA induces a more undifferentiated phenotype and favors TGF{beta} effects. EMT mediators Slug and Snail were up-regulated in CypA-silenced cells, while in CypB silencing, Slug, but not Snail, was down-regulated; thus, reinforcing the role of Slug in kidney fibrosis. CypA regulates Slug through its PPIase activity whereas CypB depends on its ER location, where interacts with calreticulin, a calcium modulator which is involved in TGF{beta} signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating proximal tubular cell plasticity.

molecular biology↗

bioRxiv2018

Robustness of Transposable Element regulation but no genomic shock observed in interspecific Arabidopsis hybrids

The merging of two divergent genomes in a hybrid is believed to trigger a \"genomic shock\", disrupting gene regulation and transposable element (TE) silencing. Here, we tested this expectation by comparing the pattern of expression of transposable elements in their native and hybrid genomic context. For this, we sequenced the transcriptome of the Arabidopsis thaliana genotype Col-0, the A. lyrata genotype MN47 and their F1 hybrid. Contrary to expectations, we observe that the level of TE expression in the hybrid is strongly correlated to levels in the parental species. We detect that at most 1.1% of expressed transposable elements belonging to two specific subfamilies change their expression level upon hybridization. Most of these changes, however, are of small magnitude. We observe that the few hybrid-specific modifications in TE expression are more likely to occur when TE insertions are close to genes. In addition, changes in epigenetic histone marks H3K9me2 and H3K27me3 following hybridization do not coincide with TEs with changed expression. Finally, we further examined TE expression in parents and hybrids exposed to severe dehydration stress. Despite the major reorganization of gene and TE expression by stress, we observe that hybridization does not lead to increased disorganization of TE expression in the hybrid. We conclude that TE expression is globally robust to hybridization and that the term \"genomic shock\" is no longerappropriate to describe the anticipated consequences of merging divergent genomes in a hybrid.

genomics↗