Biology subjects

Vargas, F.

Publications and source records attributed to Vargas, F..

12 recordsLinked to original sources

bioRxiv2025

New insights into the metabolomic signatures of spontaneously hypertensive rats

BACKGROUNDHypertension is a major risk factor associated with cardiovascular diseases and one of the leading causes of premature death. Hypertension has no obvious clinical signs; therefore, the identification of new biomarkers for the early detection of people at risk is needed to prevent hypertension and its further complications. Metabolomics is a useful tool for studying in vivo metabolic profiles that better understand the pathogenesis of diseases such as hypertension. This work aimed to explore the plasma and urinary non-targeted metabolic profile of 16-week-old spontaneously hypertensive rats (SHR) to identify new metabolomic profiles associated with hypertensive phenotypical characteristics that allow early diagnosis of patients at risk. METHODSPlasma and 24-hours urine samples were collected from 10 SHR and 10 age-matched normotensive Wistar-Kyoto 16-week-old male rats. Plasma and urinary metabolic profiles were investigated using high-performance liquid chromatography quadrupole time of flight coupled to mass spectroscopy followed by multivariate statistical analysis. The mummichog pathway enrichment analysis was used to integrate metabolomics data into biological contexts. RESULTSA total of 16 differential metabolites were found in plasma and 13 differential metabolites in urine from SHR compared to normotensive rats. Differences in some microbiota-derived metabolites suggest changes in the gut microbiota associated with hypertension in our experimental model. The mummichog algorithm has recognized that hypertensive metabolism is associated with the altered metabolism of steroid hormones, bile acid and purines. CONCLUSIONSThis work highlights the importance of metabolomics as a tool for the identification of biomarkers in the early detection of hypertension, a condition that represents a significant risk to cardiovascular health. The findings suggest that hypertension is associated with alterations in the metabolism of steroid hormones, bile acids and purines, as well as metabolites derived from the intestinal microbiota. These results not only contribute to a better understanding of the pathogenesis of hypertension but also open the door to future research in humans that could facilitate more accurate and earlier diagnoses, thus helping to prevent serious complications associated with this disease.

biochemistry↗

bioRxiv2024

Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection

Chronic infections drive a CD8 T cell program termed T cell exhaustion, characterized by reduced effector functions. While cell-intrinsic mechanisms underlying CD8 T cell exhaustion have been extensively studied, the impact of the metabolic environment in which exhausted CD8 T cells (Tex) operate remains less clear. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model we investigated systemic metabolite changes early and late following acute versus chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the acute phase of the sustained infection. This included nutrient changes that were independent of viral loads and partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acid (FA) and acylcarnitines during the early phase after chronic infection. During this time, virus-specific CD8 T cells from chronically infected mice exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly stem-like Tex (TexSTEM), a subset that generates effector-like TexINT which directly limit viral replication. Notably, only TexSTEM increased oxidative metabolism and ATP production upon FA exposure. Consistently, short-term reintroduction of FA during late chronic infection exclusively improved TexSTEM mitochondrial fitness, percentages and numbers. This treatment, however, also reduced TexINT, resulting in compromised viral control. Our study offers a valuable resource for investigating the role of specific metabolites in regulating immune responses during acute and chronic viral infections and highlights the potential of long-chain FA to influence TexSTEM and viral control during a protracted infection. SignificanceThis study examines systemic metabolite changes during acute and chronic viral infections. Notably, we identified an early, transient nutrient shift in chronic infection, marked by an increase in medium- and long-chain fatty acid related species. Concomitantly, a virus-specific stem-like T cell population, essential for maintaining other T cells, displayed high lipid avidity and was capable of metabolizing exogenous fatty acids. Administering fatty acids late in chronic infection, when endogenous lipid levels had normalized, expanded this stem-like T cell population and enhanced their mitochondrial fitness. These findings highlight the potential role of fatty acids in regulating stem-like T cells in chronic settings and offer a valuable resource for studying other metabolic signatures in both acute and persistent infections.

immunology↗

bioRxiv2022

An untargeted metabolomics analysis of exogenous chemicals in human milk and transfer to the infant

Human milk is the optimal infant nutrition. However, while human-derived metabolites such as lipids and oligosaccharides in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n=996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules such as medications and their metabolites, food, industrial sources such as plasticizers, cosmetics, microbial molecules, and other personal care products are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborns stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent.

pharmacology and toxicology↗

bioRxiv2021

Probiotic bacteria and bile acid profile are modulated by prebiotic diet and associate with facilitated diurnal clock/sleep realignment after chronic disruption of rhythms

Chronic disruption of rhythms (CDR) impacts sleep and can result in circadian misalignment of physiological systems, which in turn is associated with increased disease risk. Exposure to repeated or severe stressors also disturbs sleep and diurnal rhythms. Prebiotic nutrients produce favorable changes in gut microbial ecology, the gut metabolome, and reduce several negative impacts of acute severe stressor exposure, including disturbed sleep, core body temperature rhythmicity, and gut microbial dysbiosis. This study tested the hypothesis whether prebiotics can also reduce the negative impacts of CDR by facilitating light/dark realignment of sleep/wake, core body temperature, and locomotor activity; and whether prebiotic-induced changes in bacteria and bile acid profiles are associated with these effects. Male, Sprague Dawley rats were fed diets enriched in prebiotic substrates or calorically matched control chow. After 5 weeks on diet, rats were exposed to CDR (12h light/dark reversal, weekly for 8 weeks) or remained on undisturbed normal light/dark cycles (NLD). Sleep EEG, core body temperature, and locomotor activity were recorded via biotelemetry in freely moving rats. Fecal samples were collected on experimental days -33, 0 (day of onset of CDR), and 42. Taxonomic identification and relative abundances of gut microbes were measured in fecal samples using 16S rRNA gene sequencing and shotgun metagenomics. Fecal primary, bacterially-modified secondary, and conjugated bile acids were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Prebiotic diet produced rapid and stable increases in the relative abundances of Parabacteroides distasonis and Ruminiclostridium 5. Shotgun metagenomics analyses confirmed reliable increases in relative abundances of Parabacteroides distasonis and Clostridium leptum, a member of the Ruminiclostridium genus. Prebiotic diet also modified fecal bile acid profiles; and based on correlational and step-wise regression analyses, Parabacteroides distasonis and Ruminiclostridium 5 were positively associated with each other and negatively associated with secondary and conjugated bile acids. Prebiotic diet, but not CDR, impacted beta diversity. Measures of alpha diversity evenness were decreased by CDR and prebiotic diet prevented that effect. Rats exposed to CDR while eating prebiotic, compared to control diet, more quickly realigned NREM sleep and core body temperature (ClockLab) diurnal rhythms to the altered light/dark cycle. Finally, both cholic acid and Ruminiclostridium 5 prior to CDR were associated with time to realign CBT rhythms to the new light/dark cycle after CDR; whereas both Ruminiclostridium 5 and taurocholic acid prior to CDR were associated with NREM sleep recovery after CDR. These results suggest that ingestion of prebiotic substrates is an effective strategy to increase the relative abundance of health promoting microbes, alter the fecal bile acid profile, and facilitate the recovery and realignment of sleep and diurnal rhythms after circadian disruption.

physiology↗

bioRxiv2020

Ion Identity Molecular Networking in the GNPS Environment

Molecular networking connects tandem mass spectra of molecules based on the similarity of their fragmentation patterns. However, during ionization, molecules commonly form multiple ion species with different fragmentation behavior. To connect ion species of the same molecule, we developed Ion Identity Molecular Networking. These new relationships improve network connectivity, are shown to reveal novel ion-ligand complexes, enhance annotation within molecular networks, and facilitate the expansion of spectral libraries.

bioinformatics↗

bioRxiv2019

ZODIAC: database-independent molecular formula annotation using Gibbs sampling reveals unknown small molecules

1The confident high-throughput identification of small molecules remains one of the most challenging tasks in mass spectrometry-based metabolomics. SIRIUS has become a powerful tool for the interpretation of tandem mass spectra, and shows outstanding performance for identifying the molecular formula of a query compound, being the first step of structure identification. Nevertheless, the identification of both molecular formulas for large compounds above 500 Daltons and novel molecular formulas remains highly challenging. Here, we present ZODIAC, a network-based algorithm for the de novo estimation of molecular formulas. ZODIAC reranks SIRIUS molecular formula candidates, combining fragmentation tree computation with Bayesian statistics using Gibbs sampling. Through careful algorithm engineering, ZODIACs Gibbs sampling is very swift in practice. ZODIAC decreases incorrect annotations 16.2-fold on a challenging plant extract dataset with most compounds above 700 Dalton; we then show improvements on four additional, diverse datasets. Our analysis led to the discovery of compounds with novel molecular formulas such as C24H47BrNO8P which, as of today, is not present in any publicly available molecular structure databases.

bioinformatics↗

bioRxiv2019

Protocol for Community-created Public MS/MS Reference Library Within the GNPS Infrastructure

RationaleA major hurdle in identifying chemicals in mass spectrometry experiments is the availability of MS/MS reference spectra in public databases. Currently, scientists purchase databases or use public databases such as GNPS. The MSMS-Chooser workflow empowers the creation of MS/MS reference spectra directly in the GNPS infrastructure.\n\nMethodsAn MSMS-Chooser sample template was completed with the required information and sequence tables were generated programmatically. Standards in methanol-water (1:1) solution (1 M) were placed into wells individually. An LC-MS/MS system using data-dependent acquisition in positive and negative modes was used. Species that may be generated under typical ESI conditions are chosen. The MS/MS spectra and MSMS-Chooser sample template were subsequently uploaded to MSMS-Chooser in GNPS for automatic MS/MS spectral annotation.\n\nResultsData acquisition quickly and effectively collected MS/MS spectra. MSMS-Chooser was able to accurately annotate 99.2% of the manually validated MS/MS scans that were generated from the chemical standards. The output of MSMS-Chooser includes a table ready for inclusion in the GNPS library (after inspection) as well as the ability to directly launch searches via MASST. Altogether, the data acquisition, processing, and upload to GNPS took ~2 hours for our proof-of-concept results.\n\nConclusionsThe MSMS-Chooser workflow enables the rapid data acquisition, analysis, and annotation of chemical standards, and uploads the MS/MS spectra to community-driven GNPS. MSMS-Chooser democratizes the creation of MS/MS reference spectra in GNPS which will improve annotation and strengthen the tools which use the annotation information.

bioinformatics↗

bioRxiv2019

Repository-scale Co- and Re-analysis of Tandem Mass Spectrometry Data

Metabolomics data are difficult to find and reuse, even in public repositories. We, therefore, developed the Reanalysis of Data User (ReDU) interface (https://redu.ucsd.edu/), a community- and data-driven approach that solves this problem at the repository scale. ReDU enables public data discovery and co- or re-analysis via uniformly formatted, publicly available MS/MS data and metadata in the Global Natural Product Social Molecular Networking Platform (GNPS), consistent with findable, accessible, interoperable, and reusable (FAIR) principles.1

bioinformatics↗

bioRxiv2019

Chemical Impacts of the Microbiome Across Scales Reveal Novel Conjugated Bile Acids

A mosaic of cross-phyla chemical interactions occurs between all metazoans and their microbiomes. In humans, the gut harbors the heaviest microbial load, but many organs, particularly those with a mucosal surface, associate with highly adapted and evolved microbial consortia1. The microbial residents within these organ systems are increasingly well characterized, yielding a good understanding of human microbiome composition, but we have yet to elucidate the full chemical impact the microbiome exerts on an animal and the breadth of the chemical diversity it contributes2. A number of molecular families are known to be shaped by the microbiome including short-chain fatty acids, indoles, aromatic amino acid metabolites, complex polysaccharides, and host lipids; such as sphingolipids and bile acids3-11. These metabolites profoundly affect host physiology and are being explored for their roles in both health and disease. Considering the diversity of the human microbiome, numbering over 40,000 operational taxonomic units12, a plethora of molecular diversity remains to be discovered. Here, we use unique mass spectrometry informatics approaches and data mapping onto a murine 3D-model13-15 to provide an untargeted assessment of the chemical diversity between germ-free (GF) and colonized mice (specific-pathogen free, SPF), and report the finding of novel bile acids produced by the microbiome in both mice and humans that have evaded characterization despite 170 years of research on bile acid chemistry16.

microbiology↗

bioRxiv2019

MASST: A Web-based Basic Mass Spectrometry Search Tool for Molecules to Search Public Data.

CorrespondenceWe introduce a web-enabled small-molecule mass spectrometry (MS) search engine. To date, no tool can query all the public small-molecule tandem MS data in metabolomics repositories, greatly limiting the utility of these resources in clinical, environmental and natural product applications. Therefore, we introduce a Mass Spectrometry Search Tool (MASST) (https://proteosafe-extensions.ucsd.edu/masst/), that enables the discovery of molecular relationships among accessible public metabolomics and natural product tandem mass spectrometry data (MS/MS).

bioinformatics↗

bioRxiv2018

Untargeted Mass Spectrometry-Based Metabolomics Tracks Molecular Changes in Raw and Processed Foods and Beverages

A major aspect of our daily lives is the need to acquire, store and prepare our food. Storage and preparation can have drastic effects on the compositional chemistry of our foods, but we have a limited understanding of the temporal nature of processes such as storage, spoilage, fermentation and brewing on the chemistry of the foods we eat. Here, we performed a temporal analysis of the chemical changes in foods during common household preparations using untargeted mass spectrometry and novel data analysis approaches. Common treatments of foods such as home fermentation of yogurt, brewing of tea, spoilage of meats and ripening of tomatoes altered the chemical makeup through time, through both chemical and biological processes. For example, brewing tea altered its composition by increasing the diversity of molecules, but this change was halted after 4 min of brewing. The results indicate that this is largely due to differential extraction of the material from the tea and not modification of the molecules during the brewing process. This is in contrast to the preparation of yogurt from milk, spoilage of meat and the ripening of tomatoes where biological transformations directly altered the foods molecular composition. Comprehensive assessment of chemical changes using multivariate statistics showed the varied impacts of the different food treatments, while analysis of individual chemical changes show specific alterations of chemical families in the different food types. The methods developed here represent novel approaches to studying the changes in food chemistry that can reveal global alterations in chemical profiles and specific transformations at the chemical level.\n\nO_LSTHighlightsC_LSTO_LIWe created a reference data set for tomato, milk to yogurt, tea, coffee, turkey and beef.\nC_LIO_LIWe show that normal preparation and handling affects the molecular make-up.\nC_LIO_LITea preparation is largely driven by differential extraction.\nC_LIO_LIFormation of yogurt involves chemical transformations.\nC_LIO_LIThe majority of meat molecules are not altered in 5 days at room temperature.\nC_LI

biochemistry↗

bioRxiv2017

MetaRiPPquest: A Peptidogenomics Approach for the Discovery of Ribosomally Synthesized and Post-translationally Modified Peptides

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an important class of natural products that include many antibiotics and a variety of other bioactive compounds. While recent breakthroughs in RiPP discovery raised the challenge of developing new algorithms for their analysis, peptidogenomic-based identification of RiPPs by combining genome/metagenome mining with analysis of tandem mass spectra remains an open problem. We present here MetaRiPPquest, a software tool for addressing this challenge that is compatible with large-scale screening platforms for natural product discovery. After searching millions of spectra in the Global Natural Products Social (GNPS) molecular networking infrastructure against just six genomic and metagenomic datasets, MetaRiPPquest identified 27 known and discovered 5 novel RiPP natural products.

bioinformatics↗