Search bioRxiv⌕ Search

Biology subjects

Jarmusch, A. K.

Publications and source records attributed to Jarmusch, A. K..

16 recordsLinked to original sources

The Everything Bagel Feature Finder: Ultra-fast automated feature finding for untargeted metabolomics

Metabolomics studies are increasingly being applied with hundreds to thousands, even tens of thousands of samples that demand rapid, automated data processing while maintaining analytical sensitivity or quantitative accuracy. A major computational bottleneck is feature finding, which is the transformation of LC-MS and LC-MS/MS data into a set of analyte signals aligned and quantified across samples. Feature finding can be computationally intensive and often requires manual iterative parameter optimization. To accelerate this process, we present the Everything Bagel (EB) feature finder, an ultra-fast automated feature finding tool that integrates feature detection, retention-time alignment, and gap filling designed for run-time and memory efficiency. We benchmarked EB against two automated feature finding methods on eight benchmarking datasets. Specifically, we evaluated these three feature finding methods by measuring spike-in standard detection coverage, dilution series quantification accuracy, and yeast 12C/13C credentialed features. In this evaluation, the EB feature finder achieved performance comparable to, and often exceeding, existing methods while requiring up to 150-fold lower CPU hours and up to 113-fold lower wall time. We further demonstrated the bioanalytical validity of EB by reanalyzing published datasets used for biomarker discovery and reproduced biologically significant features that matched the published findings using manually tuned feature finding settings. Taken along with the speed improvements, we anticipate EB will enhance the ability to automatically analyze datasets with thousands to tens of thousands of samples for the community.

bioinformatics↗

Discovery of BilV reveals a multienzymatic basis for bilirubin reduction across vertebrate gut microbiomes

Gut bacteria reduce bilirubin to urobilinogen, allowing it to be excreted through feces and urine, but studies have long noted a heterogeneous mixture of partially reduced bilirubin-derived intermediates, suggesting that multiple enzymes are involved. Here we identify bilirubin vinyl reductase (BilV), a novel Old Yellow Enzyme family reductase encoded in the genomic neighborhood of the known bilirubin reductase (bilR). Using heterologous expression and LC-MS/MS, we show that BilR acts on the methine bridges in the bilirubin reduction pathway; co-expression with BilV enables vinyl-group reduction and complete conversion to urobilinogen. In bacterial genomes, bilV co-occurs primarily with the bilR-insertion subtype and is largely absent alongside bilR-short. Analysis of 1,197 gut metagenomes across 14 vertebrate species reveals that this differential co-occurrence shapes pathway availability across hosts: carnivores and omnivores carry balanced bilR and bilV, whereas avian microbiomes, dominated by bilR-short, are depleted for bilV. These findings establish that bilirubin reduction to urobilinogen involves two enzymes with complementary regioselectivity, and that their distribution across vertebrate gut microbiomes varies in concert with host bile pigment chemistry.

microbiology↗

Community Curation of Microbial Metabolites Enables Biological Insights of Metabolomics Data

Microbial metabolites play a critical role in regulating ecosystems, including the human body and its microbiota. However, understanding the physiologically relevant role of these molecules, especially through liquid chromatography tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomics, poses significant challenges and often requires manual parsing of a large amount of literature, databases, and webpages. To address this gap, we established the Collaborative Microbial Metabolite Center knowledgebase (CMMC-KB), a platform that fosters collaborative efforts within the scientific community to curate knowledge about microbial metabolites. The CMMC-KB aims to collect comprehensive information about microbial molecules originating from microbial biosynthesis, drug metabolism, exposure-related molecules, food, host-derived molecules, and, whenever available, their known activities. Molecules from other sources, including host-produced, dietary, and pharmaceutical compounds, are also included. By enabling direct integration of this knowledgebase with downstream analytical tools, including molecular networking, we can deepen insights into microbiota and their metabolites, ultimately advancing our understanding of microbial ecosystems.

bioinformatics↗

Pericyte-tumor crosstalk facilitates metastatic tumor cell latency through PIEZO1-activated lysophospholipid transfer.

Tumor dissemination is increasingly recognized to begin early in tumor development. Although most of these early disseminated cells are cleared, some survive and persist below clinical detection, acting as reservoirs for metastatic relapse. Metastatic tumor cells often rely on interactions with local stromal cells to support their colonization. In this study, we propose that pericyte-tumor cell interactions promote dormancy induction in the early metastatic lung, enhancing disseminated tumor cell (DTC) persistence. Extravital imaging demonstrated that DTCs interact with pericytes upon extravasation into the lung. Co-culture experiments were used to assess DTC fate after pericyte contact and revealed that transient contact with pericytes reduced the proliferation of metastatic 4T1 breast cancer cells but had no effect on non-metastatic 67NR cells. In vivo, transient pericyte contact resulted in higher lung metastatic burden, driven by small, non-proliferative lesions (<6 cells), 10 days after intracardiac injection. These lesions exhibited reduced KI67 staining and EdU incorporation compared to those from monocultured cells. We further observed that primary lung pericytes transferred lyso-phospholipids (lyso-PLs) specifically to metastatic 4T1 cells through direct contact. Gene expression analysis indicated that transient pericyte contact activated pathways related to syncytium formation in metastatic cells. In normal physiology, pericytes act in a syncytium to regulate blood flow via mechanosensitive channels in response to blood pressure changes. We hypothesize that tumor cells exploit these mechanosensitive responses to trigger lyso-PL transfer from pericytes. Supporting this, calcium imaging showed higher calcium activity in pericytes co-cultured with 4T1 cells, and calcium channel inhibitors significantly reduced lyso-PL transfer. Pharmacological activation of pericyte calcium channels induced lyso-PL release, which was subsequently taken up by tumor cells. Conditioned medium from activated pericytes, containing free lyso-PLs, recapitulated the reduced proliferation observed in transient co-culture. Finally, we found our pericyte-induced dormancy signature to be associated with tumor dormancy and distant metastasis free survival latency in breast cancer patients. Together, these findings suggest that early DTCs may exploit pericyte signaling mechanisms to enter dormancy, facilitating their persistence at metastatic sites and contributing to future relapse.

cancer biology↗

Empirically establishing drug exposure records directly from untargeted metabolomics data

Despite extensive efforts, extracting information on medication exposure from clinical records remains challenging. To complement this approach, we developed the tandem mass spectrometry (MS/MS) based GNPS Drug Library. This resource integrates MS/MS data for drugs and their metabolites/analogs with controlled vocabularies on exposure sources, pharmacologic classes, therapeutic indications, and mechanisms of action. It enables direct analysis of drug exposure and metabolism from untargeted metabolomics data independent of clinical records. Our library facilitates stratification of individuals in clinical studies based on the empirically detected medications, exemplified by drug-dependent microbiota-derived N-acyl lipid changes in a cohort with human immunodeficiency virus. The GNPS Drug Library holds potential for broader applications in drug discovery and precision medicine.

bioinformatics↗

A Universal Language for Finding Mass Spectrometry Data Patterns

Even though raw mass spectrometry data is information rich, the vast majority of the data is underutilized. The ability to interrogate these rich datasets is handicapped by the limited capability and flexibility of existing software. We introduce the Mass Spec Query Language (MassQL) that addresses these issues by enabling an expressive set of mass spectrometry patterns to be queried directly from raw data. MassQL is an open-source mass spectrometry query language for flexible and mass spectrometer manufacturer-independent mining of MS data. We envision the flexibility, scalability, and ease of use of MassQL will empower the mass spectrometry community to take fuller advantage of their mass spectrometry data and accelerate discoveries.

bioinformatics↗

Open Access Repository-Scale Propagated Nearest Neighbor Suspect Spectral Library for Untargeted Metabolomics

Despite the increasing availability of tandem mass spectrometry (MS/MS) community spectral libraries for untargeted metabolomics over the past decade, the majority of acquired MS/MS spectra remain uninterpreted. To further aid in interpreting unannotated spectra, we created a nearest neighbor suspect spectral library, consisting of 87,916 annotated MS/MS spectra derived from hundreds of millions of public MS/MS spectra. Annotations were propagated based on structural relationships to reference molecules using MS/MS-based spectrum alignment. We demonstrate the broad relevance of the nearest neighbor suspect spectral library through representative examples of propagation-based annotation of acylcarnitines, bacterial and plant natural products, and drug metabolism. Our results also highlight how the library can help to better understand an Alzheimers brain phenotype. The nearest neighbor suspect spectral library is openly available through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.

bioinformatics↗

Non-Invasive Skin Sampling Detects Systemically Administered Drugs in Humans

Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n=10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mechanism of the drug and metabolites pathway to the skins surface remains unknown.

pharmacology and toxicology↗

Physicochemical and Pharmacokinetic Properties Determining Drug Detection in Skin

Chemicals, including some systemically administered xenobiotics and their biotransformations, can be detected noninvasively using skin swabs and untargeted metabolomics analysis. We sought to understand the principal drivers that determine whether a drug taken orally or systemically is likely to be observed on the epidermis by using a random forest classifier to predict which drugs would be detected on the skin. A variety of molecular descriptors describing calculated properties of drugs, such as measures of volume, electronegativity, bond energy, and electrotopology, were used to train the classifier. The mean area under the ROC curve was 0.71 for predicting drug detection on the epidermis, and the SHapley Additive exPlanations model interpretation technique was used to determine the most relevant molecular descriptors. Based on the analysis of 2,561 FDA approved drugs, we predict that therapeutic drug classes such as nervous system drugs are more likely to be detected on the skin. Detecting drugs and other chemicals noninvasively on the skin using untargeted metabolomics could be a useful clinical advancement in therapeutic drug monitoring, adherence, and health status.

bioinformatics↗

GNPS Dashboard: Collaborative Analysis of Mass Spectrometry Data in the Web Browser

Access to web-based platforms has enabled scientists to perform research remotely. A critical aspect of mass spectrometry data analysis is the inspection, analysis, and visualization of the raw data to validate data quality and confirm statistical observations. We developed the GNPS Dashboard, a web-based data visualization tool, to facilitate synchronous collaborative inspection, visualization, and analysis of private and public mass spectrometry data remotely.

bioinformatics↗

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↗

Feature-based Molecular Networking in the GNPS Analysis Environment

Molecular networking has become a key method used to visualize and annotate the chemical space in non-targeted mass spectrometry-based experiments. However, distinguishing isomeric compounds and quantitative interpretation are currently limited. Therefore, we created Feature-based Molecular Networking (FBMN) as a new analysis method in the Global Natural Products Social Molecular Networking (GNPS) infrastructure. FBMN leverages feature detection and alignment tools to enhance quantitative analyses and isomer distinction, including from ion-mobility spectrometry experiments, in molecular networks.

bioinformatics↗

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↗

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↗

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↗

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↗