Biology subjects

Wheelock, C.

Publications and source records attributed to Wheelock, C..

4 recordsLinked to original sources

bioRxiv2023

OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process.

bioinformatics↗

bioRxiv2022

Glutarate regulates T cell function and metabolism

T cell function is influenced by several metabolites; some acting through enzymatic inhibition of -KG-dependent dioxygenases (KGDDs), others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, with effects on T cell function and differentiation. Glutarate exerts those effects through KGDD inhibition and through direct regulation of T cell metabolism via post-translational modification of the pyruvate dehydrogenase E2 subunit. Diethyl-glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound reduces tumor growth and is correlated with increased levels of both peripheral and intratumoral cytotoxic CD8+ T cells. These results demonstrate that glutarate regulates both T cell metabolism and differentiation, with a potential role in the improvement of T cell immunotherapy.

immunology↗

bioRxiv2021

Spatiotemporal Determination of Metabolite Activities in Multiple Corneal Epithelium Barriers on a Chip

The corneal epithelial barrier maintains the metabolic activities of the ocular surface by regulating membrane transporters and metabolic enzymes responsible for the homeostasis of the eye as well as the pharmacokinetic behavior of drugs. Despite its importance, no established biomimetic in vitro methods are available to perform the spatiotemporal investigation of corneal metabolism and determine the transportation of endogenous and exogenous molecules. This study introduces multiple corneal epithelium barriers on a chip, namely, Cornea-Chip, which enables the spatiotemporal collection as well as analysis of micro-scaled extracellular metabolites from both the apical and basolateral sides of the barriers. Longitudinal samples collected during 48 h period were analyzed using untargeted liquid chromatography-mass spectrometry metabolomics method, and 104 metabolites were annotated. The shifts in extracellular metabolites and quantitative analysis of the mRNA associated with membrane transporters could allow the investigation of the correlation between the expression of and the secretion and transportation of metabolites across the polarized corneal epithelial barrier. The Cornea-Chip might provide a non-invasive, simple, and effectively informative method to determine pharmacokinetics and pharmacodynamics as well as to discover novel biomarkers for drug toxicological and safety tests as an alternative to animal experiments.

bioengineering↗

bioRxiv2020

Untargeted LC-MS metabolomics for the analysis of micro-scaled extracellular metabolites from hepatocytes

Metabolome analysis in micro physiological models is a challenge due to the low volume of cell culture medium (CCM). Here, we report a LC-MS-based untargeted metabolomics protocol for the detection of hepatocyte extracellular metabolites from micro-scale samples of CCM. Using a single LC-MS method we have detected 57 metabolites of which 27 showed >2-fold shifts after 72-hours incubation. We demonstrate that micro-scale CCM samples can be used for modelling micro-physiological temporal dynamics in metabolite intensities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/312520v3_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@1b307e3org.highwire.dtl.DTLVardef@cada64org.highwire.dtl.DTLVardef@1c7fb70org.highwire.dtl.DTLVardef@4cb37f_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

bioengineering↗