Biology subjects

O'Connell, T.

Publications and source records attributed to O'Connell, T..

5 recordsLinked to original sources

bioRxiv2024

A Cell Autonomous Free fatty acid receptor 4 - ChemR23 Signaling Cascade Protects Cardiac Myocytes from Ischemic Injury

Acute myocardial infarction (AMI) causes ischemic damage and cardiac remodeling that ultimately progresses into ischemic cardiomyopathy (ICM). Coronary revascularization reduces morbidity and mortality from an MI, however, reperfusion also induces oxidative stress that drives cardiac myocyte (CM) dysfunction and ICM. Oxidative stress in CMs leads to reactive oxygen species (ROS) production and mitochondrial damage. Free fatty acid receptor 4 (Ffar4) is a GPCR for long chain fatty acids (FA) that is expressed in multiple cell types including CMs. We have recently shown that CM-specific overexpression of Ffar4 protects the heart from systolic dysfunction in the context of ischemic injury. Mechanistically, in CMs, Ffar4 increases the levels of 18-hydroxyeicosapentaenoic acid (18-HEPE), an eicosapentaenoic acid (EPA)-derived, cardioprotective oxylipin (oxidatively modified FA). 18-HEPE is the precursor for resolvin E1 (RvE1), a cardioprotective, specialized pro-resolving mediator (SPM) that activates the GPCR ChemR23. We hypothesize Ffar4 in CMs protects the heart from oxidative stress and ischemic injury through activation of a CM-autonomous, Ffar4-ChemR23 cardioprotective signaling pathway. Here, we developed an in vitro hypoxia reoxygenation (H/R) model (3 hours of hypoxia, 17 hours of reoxygenation) in adult CMs as a model for ischemic injury. In adult CMs subjected to H/R, TUG-891, an Ffar4 agonist, attenuated ROS generation and TUG-891, 18-HEPE, and RvE1 protected CMs from H/R-induced cell death. More importantly, we found that the ChemR23 antagonist -NETA prevented TUG-891 cytoprotection in adult CMs subjected to H/R, demonstrating that ChemR23 is required for Ffar4 cardioprotection. In summary, our data demonstrate co-expression of Ffar4 and ChemR23 in the same CM, that Ffar4, 18-HEPE, and RvE1 attenuate H/R-induced CM death, and that ChemR23 is required for Ffar4 cardioprotection in H/R support a CM-autonomous Ffar4-ChemR23 cardioprotective signaling pathway.

physiology↗

bioRxiv2023

Somatic small-variant calling methods in Illumina DRAGEN™ Secondary Analysis

We present the DRAGEN somatic pipeline for calling small somatic variants from tumor samples, with or without paired normal samples. The DRAGEN somatic variant caller offers 1) a flexible architecture that can be used on a wide array of somatic use cases; 2) built-in noise models enabling robustness against various sources of noise artifacts (mapping, genome context, or sample specific); 3) performance of joint analysis of tumor and normal samples in the case of a tumor-normal workflow yielding improved accuracy; 4) benefits from FPGA acceleration for efficient run time. We demonstrate the speed and accuracy of the DRAGEN tumor-normal pipeline across a range of whole genome sequencing (WGS) datasets and compare against third party tools such as Mutect2/GATK4 [1] and Strelka2 [2]. DRAGEN secondary analysis outperforms all other tools with its ability to complete a 110x/40x T/N whole-genome analysis in less than two hours. It offers exceptional accuracy, with higher sensitivity and precision than third party tools. We also show that the DRAGEN T/N workflow supports analysis of liquid and late-stage solid tumors by tolerating tumor-in-normal (TiN) contamination.

bioinformatics↗

bioRxiv2022

Free fatty acid receptor 4 (FFAR4) regulates cardiac oxylipin balance to promote inflammation resolution in a model of heart failure preserved ejection fraction secondary to metabolic syndrome

Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor for long-chain fatty acids that improves metabolism and attenuates inflammation. Heart failure preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of patients has meta-bolic syndrome (MetS). Mechanistically, systemic, non-resolving inflammation associated with MetS might promote HFpEF. Interestingly, we recently demonstrated that Ffar4 is cardioprotective in pressure overload. The beneficial effects of Ffar4 on metabolism/inflammation, the high incidence of MetS in HFpEF patients, and the cardioprotective effects of Ffar4 led us to hypothesize that loss of Ffar4 would worsen remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water (HFpEF-MetS diet) to induce HFpEF-MetS. In male Ffar4KO mice, the HFpEF-MetS diet induced similar metabolic deficits, but worsened diastolic function and microvascular rarefaction compared to wild-type mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsening of HFpEF. Loss of Ffar4 in males altered the balance of inflammatory oxylipins in the heart, decreasing the eicosapentaenoic acid derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachadonic acid derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio, reflecting a more proinflammatory state, was associated with increased macrophage numbers, which in turn correlated with worsened ventricular remodeling in male Ffar4KO hearts. In summary, our data suggest that Ffar4 controls the pro/anti-inflammatory oxylipin balance in the heart to modulate macrophage function and attenuate HFpEF remodeling.

physiology↗

bioRxiv2019

Zero-shot neural decoding of visual categories withoutprior exemplars

Decoding information from neural responses in visual cortex demonstrates interpolation across repetitions or exemplars. Is it possible to decode novel categories from neural activity without any prior training on activity from those categories? We built zero-shot neural decoders by mapping responses from macaque inferior temporal cortex onto a deep neural network. The resulting models correctly interpreted responses to novel categories, even extrapolating from a single category.

neuroscience↗

bioRxiv2018

Anacapa Toolkit: an environmental DNA toolkit for processing multilocus metabarcode datasets

1. Environmental DNA (eDNA) metabarcoding is a promising method to monitor species and community diversity that is rapid, affordable, and non-invasive. Longstanding needs of the eDNA community are modular informatics tools, comprehensive and customizable reference databases, flexibility across high-throughput sequencing platforms, fast multilocus metabarcode processing, and accurate taxonomic assignment. As bioinformatics tools continue to improve, addressing each of these demands within a single bioinformatics toolkit is becoming a reality.\n\n2. We present the modular metabarcode sequence toolkit Anacapa (https://github.com/limey-bean/Anacapa/), which addresses the above needs, allowing users to build comprehensive reference databases and assign taxonomy to raw multilocus metabarcode sequence data A novel aspect of Anacapa is our database building module, Creating Reference libraries Using eXisting tools (CRUX), which generates comprehensive reference databases for specific user-defined metabarcode loci. The Quality Control and Dereplication module sorts and processes multiple metabarcode loci and processes merged, unmerged and unpaired reads maximizing recovered diversity. Followed by amplicon sequence variants (ASVs) detection using DADA2. The Anacapa Classifier module aligns these ASVs to CRUX-generated reference databases using Bowtie2. Taxonomy is assigned to ASVs with confidence scores using a Bayesian Lowest Common Ancestor (BLCA) method. The Anacapa Toolkit also includes an R package, ranacapa, for automated results exploration through standard biodiversity statistical analysis.\n\n3. We performed a series of benchmarking tests to verify that the Anacapa Toolkit generates comprehensive reference databases that capture wide taxonomic diversity and that it can assign high-quality taxonomy to both MiSeq-length and Hi-Seq length sequence data. We demonstrate the value of the Anacapa Toolkit to assigning taxonomy to eDNA sequences from seawater samples from southern California including capability of this tool kit to process multilocus metabarcoding data.\n\n4. The Anacapa Toolkit broadens the exploration of eDNA and assists in biodiversity assessment and management by generating metabarcode specific databases, processing multilocus data, retaining all read types, and expanding non-traditional eDNA targets. Anacapa software and source code are open and available in a virtual container to ease installation.

bioinformatics↗