Biology subjects

Artis, D.

Publications and source records attributed to Artis, D..

7 recordsLinked to original sources

bioRxiv2026

Omics-scale capture of electrophilic metabolites

The majority of metabolic pathways rely on the production of activated electrophilic intermediates, e.g., coenzyme-A esters, and their chemical structures and abundances are central to understanding enzyme function and biochemical mechanisms. However, most electrophilic metabolites are lost in traditional metabolomic analysis and thus remain poorly characterized. Here we introduce a biochemical probe, O-(trimethylammoniobutyl)-hydroxylamine (TAMOHA), that enables comprehensive profiling of electrophilic species such as coenzyme-A esters, ketones, and aldehydes. TAMOHA incorporates a highly nucleophilic hydroxyl amine that reacts quickly with electrophilic species upon tissue lysis, trapping them as stable derivatives that feature a tetraalkylammonium moiety whose constitutive charge and characteristic MS2 fragmentation fingerprint enable their highly sensitive detection. Using TAMOHA to survey the electrophilomes of E. coli, C. elegans, and mouse revealed several thousand electrophilic metabolites, most of which have not been characterized. We then demonstrate trapping of electrophilic metabolites with TAMOHA in the context of specific biochemical pathways, confirming previously proposed functions of two fatty acid metabolism enzymes, detecting formaldehyde production in mice, and providing new insights into the biosynthesis of ascaroside pheromones in C. elegans. We anticipate that use of TAMOHA for the profiling of electrophilic species will help clarify enzyme function and uncover previously elusive biochemical mechanisms in a wide range of biological systems. Table of Contents artwork O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/743530v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@79a416org.highwire.dtl.DTLVardef@3b937org.highwire.dtl.DTLVardef@74cae9org.highwire.dtl.DTLVardef@1b5a915_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Charting the small-molecule universe from mass spectra with neuro-symbolic AI

Mass spectrometry (MS) has revealed millions of small organic molecules across organisms, yet most remain uncharacterized, limiting progress in biology and medicine. Despite computational advances, MS workflows rely heavily on expert input and reference libraries that cover only a fraction of known chemical space. Here, we introduce AIMe (AI Molecule Explorer), a multi-agent neuro-symbolic AI framework that transforms the interpretation of unknown spectra into an omics-scale exploration across the known structural space, providing chemically interpretable annotations. At its core, AIMe combines chemical reasoning with structure- informed learning to predict MS2 spectra by modeling fragmentation as a sequence of actions, outperforming existing methods. AIMe dynamically constructs fragmentation pathways by assigning likelihoods to individual fragmentation actions, linking spectral peaks to explicit fragment molecular formulas and structures. At scale, AIMe predicted MS2 spectra for over 100 million small organic molecules in PubChem and organized them into MS2KOSMOS, a substructure-informed community resource comprising over 800 million predicted spectra that expands the searchable small-molecule universe by roughly three orders of magnitude relative to experimental libraries. Analogous to sequence homology-based searches in genomics and proteomics, AIMe maps unknown spectra to molecular neighborhoods in MS2KOSMOS. Exact- formula indexing enables ranked retrieval of candidates and related structures, with peak-level structural and fragmentation-pathway annotations. Applied to mouse microbiota-dependent metabolites, AIMe enabled putative annotation of knowns and guided structure elucidation of unknowns, revealing previously unreported types of microbiota-dependent polyamines that also occur in humans. At repository scale, AIMe enabled putative annotation of roughly a third of 7 million spectral clusters representing most of the unknowns in the GNPS database. By extending MS2 annotation beyond curated-library matching to interpretable search across the known small-molecule universe, AIMe accelerates discovery and large-scale exploration of small molecules across biomedicine, agriculture, and ecology.

biochemistry↗

bioRxiv2025

Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial-immune cell interactions

The distal small intestine plays vital roles in host physiology by regulating nutrient and fluid homeostasis. Despite being impacted in Crohns disease and a major target for a range of infections, we know relatively little about the complexity of cellular responses and cell-cell communication in the ileum during infection. Single cell and spatial transcriptomics have emerged as powerful technologies to study tissue heterogeneity in the gut, but these tools have focused on the large intestine, in part due to the accessibility of this tissue for biopsies and its importance in cancer. Here we present GutPath, an atlas of over 500,000 single cells with RNA and protein expression profiles for 91 cell states in the ileum across diverse infectious archetypes. We show that GutPath accurately captures established immune responses to infection while revealing pathogen-specific responses in enterocytes. To highlight the discovery potential of this atlas, we identify a novel enterocyte cell state present during Yersinia pseudotuberculosis infection that is spatially linked to bacterial load and tissue pathology. GutPath establishes a much-needed resource for the immunology community that will accelerate the study of the transcriptional diversity of cellular landscapes in the small intestine.

immunology↗

bioRxiv2025

Chlamydia muridarum Infection Impacts Murine Models of Intestinal Inflammation and Cancer

Chlamydia muridarum (Cm) has reemerged as a prevalent infectious agent in research mouse colonies. Despite its prevalence and ability to persistently colonize the murine gastrointestinal tract, few studies have evaluated the potential impact of Cm on experimental models of gastrointestinal disease. Studies were conducted to evaluate the impact of Cm on the Citrobacter rodentium (Cr), Trichuris muris (Tm) and Il10-/- mouse models of intestinal inflammation, as well as on tumorigenesis in the ApcMin/+ mouse following administration of DSS. Naive C57BL/6J (B6), B6.129P2-Il10tm1Cgn/J (Il10-/-) and C57BL/6J-ApcMin/J (ApcMin/+) mice were infected with Cm by cohousing with chronic Cm-shedding BALB/cJ mice for 2 weeks; controls were cohoused with Cm-free mice. After cohousing, B6 mice (n=8 Cm-infected and free) were infected with Citrobacter rodentium (Cr; 109 CFU orally) or Trichuris muris (Tm; 200 ova orally). Il10-/- mice (n=8/group with and without Helicobacter hepaticus [108 CFU/mouse] and with and without Cm) and ApcMin/+ mice (n=8/group) received 2% DSS for 7 days in drinking water after cohousing. Mice were sacrificed 14-days post-Cr infection, 18-days post-Tm infection, 70-days after cessation of cohousing with Il10-/- mice, and 28-days post-DSS administration to ApcMin/+ mice. The severity of the cecal and colonic lesions were evaluated and graded using a tiered, semi-quantitative scoring system. Cm infection attenuated colitis associated with Cr (p=0.03), had no effect on Tm associated pathology (p=0.22), worsened colitis in Il10-/- mice in the absence of H. hepaticus (p=0.007), and reduced chemically induced colonic tumorigenesis in ApcMin/+ mice (p=0.004). Thus, Cm colonization differentially impacts several models of intestinal inflammation and tumorigenesis, and the presence of this bacterium in mouse colonies should be considered as a variable in these experimental readouts.

microbiology↗

bioRxiv2024

Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation

The tuft cell-ILC2 circuit orchestrates rapid type 2 responses upon detecting microbe-derived succinate and luminal helminths. Our findings delineate key mechanistic steps, involving IP3R2 engagement and Ca2+ flux, governing IL-25 production by tuft cells triggered by succinate detection. While IL-17RB plays a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Suboptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb-deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.

immunology↗

bioRxiv2022

Gut bacteria-derived serotonin promotes immune tolerance in early life

The gut microbiome promotes immune system development in early life, but the neonatal gut metabolome remains undefined. Here, we demonstrate that, distinct from adults, the neonatal mouse gut is enriched with neurotransmitters, and specific bacteria produce serotonin directly while downregulating monoamine oxidase A to limit serotonin breakdown. Serotonin inhibits mTOR activation to promote regulatory T cells and suppress T cell responses both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice leads to long-term immune tolerance toward both dietary antigens and commensal bacteria as well as alterations of the gut microbiome. Together, our study has uncovered unique microbiome-dependent mechanisms to maximize serotonin in the neonatal gut and a novel role for intestinal serotonin to promote immune tolerance in early life.

immunology↗

bioRxiv2021

Simultaneous single cell measurements of intranuclear proteins and gene expression

Identifying gene regulatory targets of nuclear proteins in tissues remains a challenge. Here we describe intranuclear Cellular Indexing of Transcriptomes and Epitopes (inCITE-seq), a scalable method for measuring multiplexed intranuclear protein levels and the transcriptome in parallel in thousands of cells, enabling joint analysis of TF levels and gene expression in vivo. We apply inCITE-seq to characterize cell state-related changes upon pharmacological induction of neuronal activity in the mouse brain. Modeling gene expression as a linear combination of quantitative protein levels revealed the genome-wide effect of each TF and recovered known targets. Cell type-specific genes associated with each TF were co-expressed as distinct modules that each corresponded to positive or negative TF levels, showing that our approach can disentangle relative contributions of TFs to gene expression and add interpretability to gene networks. InCITE-seq can illuminate how combinations of nuclear proteins shape gene expression in native tissue contexts, with direct applications to solid or frozen tissues and clinical specimens.

genomics↗