Biology subjects

Vega, A.

Publications and source records attributed to Vega, A..

8 recordsLinked to original sources

bioRxiv2025

Genetic mechanisms of resistance to targeted KRAS inhibition

KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), yet the mechanisms of therapeutic resistance to KRAS inhibitors in these cancers remains poorly understood. Here, we deploy high-throughput CRISPR base editing screens to systematically map resistance mutations to three mechanistically distinct KRAS-targeted therapies, including KRAS-G12C(OFF) inhibitor (adagrasib), RAS(ON) G12C-selective tri-complex inhibitor (RMC-4998), and RAS(ON) multi-selective tri-complex inhibitor (RMC-7977). Using both a saturation Kras tiling approach and cancer-associated mutation library, we identify common and compound-selective second-site resistance mutations in Kras, as well as gain-of-function and loss-of-function variants across cancer-associated genes that rewire signaling networks in a context-dependent manner. Notably, we identify a recurrent missense mutation in capicua (Cic), that promotes resistance to RMC-7977 in vitro and in vivo. Moreover, we show that targeting NF{kappa}B signaling in CIC-mutant cells can resensitize them to RAS pathway inhibition and overcome resistance.

cancer biology↗

bioRxiv2023

The Horizontal Ladder Test (HLT) protocol: A novel, optimized, and reliable means of assessing motor coordination in Sus scrofa domesticus

Pigs can be an important model for preclinical biological research, including neurological diseases such as Alcohol Use Disorder. Such research often involves longitudinal assessment of changes in motor coordination as the disease or disorder progresses. Current motor coordination tests in pigs are derived from behavioral assessments in rodents and lack critical aspects of face and construct validity. While such tests may permit for the comparison of experimental results to rodents, a lack of validation studies of such tests in the pig itself may preclude the drawing of meaningful conclusions. Here, we present a novel, optimized, and reliable horizontal ladder test (HLT) test protocol for evaluating motor coordination in pigs and an initial validation of its construct validity using voluntary alcohol consumption as an experimental manipulation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/571517v2_ufig1.gif" ALT="Figure 1"> View larger version (101K): org.highwire.dtl.DTLVardef@167924eorg.highwire.dtl.DTLVardef@b674f2org.highwire.dtl.DTLVardef@b7c369org.highwire.dtl.DTLVardef@7e5a42_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2022

The Botrytis cinerea Gene Expression Browser.

To analyze and visualize comprehensive gene expression patterns in the phytopathogenic fungus Botrytis cinerea, we developed BEB -- a web-based B. cinerea gene expression browser. This tool and associated databases (DB) contain manually-curated RNA-Seq experiments conducted in B. cinerea. BEB allows easy gene expression analyses of genes of interest under different culture conditions by providing publication-ready heatmaps depicting transcripts levels. BEB is a computationally-inexpensive web-based application and gene expression DB that allows effortless visualization of the transcript levels of genes of interest without needing advanced computational skills. BEB also provides details of each experiment under analysis and user-defined gene expression clustering and visualization options. If needed, tables of gene expression values can be downloaded for further exploration, employing more sophisticated bioinformatics tools. The BEB implementation is based on open-source computational technologies that can be easily deployed for other organisms of interest with little additional effort. To demonstrate BEBs usability and potential, we selected genes of interest in B. cinerea to determine their expression patterns across different conditions. We thus focused our analysis on secondary metabolite gene clusters, chromosome-wide gene expression, previously described virulence factors, and reference genes, leading to a comprehensive expression overview of these groups of genes in this relevant fungal phytopathogen.

bioinformatics↗

bioRxiv2021

Genetic isolation by distance underlies color pattern divergence in red-eyed treefrogs (Agalychnis callidryas)

Investigating the spatial distribution of genetic and phenotypic variation can provide insights into the evolutionary processes that shape diversity in natural systems. We characterized patterns of genetic and phenotypic diversity to learn about drivers of color-pattern diversification in red-eyed treefrogs (Agalychnis callidryas) in Costa Rica. Along the Pacific coast, red-eyed treefrogs have conspicuous leg color patterning that transitions from orange in the north to purple in the south. We measured phenotypic variation of frogs, with increased sampling at sites where the orange-to-purple transition occurs. At the transition zone, we discovered the co-occurrence of multiple color-pattern morphs. To explore possible causes of this variation, we generated a SNP dataset to analyze population genetic structure, measure genetic diversity, and infer the processes that mediate genotype-phenotype dynamics. We investigated how patterns of genetic relatedness correspond with individual measures of color pattern along the coast, including testing for the role of hybridization in geographic regions where orange and purple phenotypic groups co-occur. We found no evidence that color-pattern polymorphism in the transition zone arose through recent hybridization. Instead, a strong pattern of genetic isolation by distance (IBD) indicates that color-pattern variation was either retained through other processes such as ancestral color polymorphisms or ancient secondary contact, or else it was generated by novel mutations. We found that phenotype changes along the Pacific coast more than would be expected based on genetic divergence and geographic distance alone. Combined, our results suggest the possibility of selective pressures acting on color pattern at a small geographic scale.

evolutionary biology↗

bioRxiv2020

A continuously self-sterilizing form of copper capable of 99% SARS-CoV-2 deactivation in 30 seconds.

The coronavirus disease 2019 (COVID-19) has created an acute worldwide demand for sustained broadband pathogen suppression in households, hospitals, and public spaces. The US recently passed a new sad milestone of 500,000 deaths due to COVID-19, the highest rate anywhere in the world. In response, we have created a rapid-acting, self-sterilizing PPE configurations capable of killing SARS-CoV-2 and other microbes in seconds. The highly active material destroys pathogens faster than any conventional copper configuration. The material maintains its antimicrobial efficacy over sustained use and is shelf stable. We have performed rigorous testing in accordance with guidelines from U.S. governing authorities and believe that the material could offer broad spectrum, non-selective defense against most microbes via integration into masks and other protective equipment. SummaryA novel configuration of copper offering continued fast-acting protection against viruses and bacteria, including SARS-CoV-2.

immunology↗

bioRxiv2020

Phosphoproteomics after nitrate treatments reveal an important role for PIN2 phosphorylation in control of root system architecture.

Nitrate is an important signaling molecule that commands genome-wide gene expression changes that impact metabolism, physiology, plant growth and development. Although gene expression responses to nitrate at the mRNA level have been characterized in great detail, the impact of nitrate signaling at the proteome level has been much less explored. Most signaling pathways involve post-translational modifications of key protein factors and chiefly among these modifications is protein phosphorylation. In an effort to identify new components involved in nitrate responses in plants, we performed analyses of the Arabidopsis thaliana root phosphoproteome in response to nitrate treatments via liquid chromatography coupled to tandem mass spectrometry. We identified 268 phosphoproteins that show significant changes at 5 min or 20 min after nitrate treatments. The large majority of these proteins (96%) are coded by genes that are not modulated at the expression level in response to nitrate treatments in publicly available transcriptome data. Proteins identified by 5 min include potential signaling-components such as kinases or transcription factors. In contrast, by 20 min, proteins identified were associated with protein binding, transporter activity or hormone metabolism functions. Interestingly, the phosphorylation profile of NITRATE TRANSPORTER 1.1 (NRT1.1) mutant plants in response to nitrate at 5 min was significantly different (95%) as compared to wild-type plants. This result is consistent with the role of NRT1.1 as a key component of a nitrate signaling pathway that involves phosphoproteomic changes. Our integrative bioinformatics analysis highlights auxin transport as an important mechanism modulated by nitrate signaling at the post-translational level. We experimentally validated the role of PIN2 phosphorylation in both primary and lateral root growth responses to nitrate. Our data provide new insights into the phosphoproteome and identifies novel protein components that are regulated post-translationally, such as PIN2, in nitrate responses in Arabidopsis thaliana roots.

plant biology↗

bioRxiv2020

Modulation of root growth by nutrient-defined fine-tuning of polar auxin transport

Nitrogen is an essential macronutrient and its availability in soil plays a critical role in plant growth, development and impacts agricultural productivity. Plants have evolved different strategies to sense and respond to heterogeneous nitrogen distribution. Modulating root system architecture, including primary root growth and branching, is among the most essential plant adaptions to ensure adequate nitrogen acquisition. However, the immediate molecular pathways coordinating the adjustment of root growth in response to varying nitrogen sources are poorly understood. Here, using a combination of physiological, live in vivo high- and super resolution imaging, we describe a novel adaptation strategy of root growth on available nitrogen source. We show that growth, i.e. tissue-specific cell division and elongation rates are fine-tuned by modulating auxin flux within and between tissues. Changes in auxin redistribution are achieved by nitrogen source dependent post-translational modification of PIN2, a major auxin efflux carrier, at an uncharacterized, evolutionary conserved phosphosite. Further, we generate a computer model based on our results which successfully recapitulate our experimental observations and creates new predictions that could broaden our understanding of root growth mechanisms in the dynamic environment.

plant biology↗

bioRxiv2019

Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Microbiomes are vast communities of microbes and viruses that populate all natural ecosystems. Viruses have been considered the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared to other environments. Here we investigate the origin, evolution, and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboratory, we obtained DNA sequences of crAssphage from over one-third of the worlds countries, and showed that its phylogeography is locally clustered within countries, cities, and individuals. We also found colinear crAssphage-like genomes in both Old-World and New-World primates, challenging genomic mosaicism and suggesting that the association of crAssphage with primates may be millions of years old. We conclude that crAssphage is a benign globetrotter virus that may have co-evolved with the human lineage and an integral part of the normal human gut virome.

microbiology↗