Biology subjects

Riley, K.

Publications and source records attributed to Riley, K..

6 recordsLinked to original sources

bioRxiv2022

Enteroendocrine cells protect the stem cell niche by regulating crypt metabolism in response to nutrients

Background and aimsThe intestinal stem cell niche is exquisitely sensitive to changes in diet, with high fat diet, caloric restriction, and fasting resulting in altered crypt metabolism and intestinal stem cell function. Unlike cells on the villus, cells in the crypt are not immediately exposed to the dynamically changing contents of the lumen. We hypothesized that enteroendocrine cells (EECs), which sense environmental cues and in response release hormones and metabolites, are essential for relaying the nutrient status of the animal to cells deep in the crypt. MethodsWe used the tamoxifen-inducible VillinCreERT2 mouse model to deplete EECs (Neurog3fl/fl) from adult intestinal epithelium and we generated human intestinal organoids from wild-type and NEUROG3-null human pluripotent stem cells. We used indirect calorimetry, 1H-NMR metabolomics, mitochondrial live imaging, and the Seahorse bioanalyzer to assess metabolism. Intestinal stem cell activity was measured by proliferation and enteroid-forming capacity. Transcriptional changes were assessed using 10X Genomics single-cell sequencing. ResultsLoss of EECs resulted in increased energy expenditure in mice, an abundance of active mitochondria, and a shift of crypt metabolism to fatty acid oxidation. Crypts from mouse and human intestinal organoids lacking EECs displayed increased intestinal stem cell activity and failed to activate phospho-S6 ribosomal protein, a marker for activity of the master metabolic regulator mammalian target of rapamycin (mTOR). These phenotypes were similar to those observed when wild-type mice were deprived of nutrients. ConclusionsDeletion of EECs recapitulated a fasting phenotype despite normal levels of ingested nutrients. These data suggest that EECs are required to relay nutritional information to the stem cell niche and are essential regulators of intestinal metabolism.

cell biology↗

bioRxiv2021

The CXCR6/CXCL16 axis links inflamm-aging to disease severity in COVID-19 patients

Advancing age and chronic health conditions, significant risk factors for severe COVID-19, are associated with a pro-inflammatory state, termed inflamm-aging. CXCR6+ T cells are known to traffic to the lung and have been reported to increase with age. The ligand of CXCR6, CXCL16, is constitutively expressed in the lung and upregulated during inflammatory responses and the CXCR6/CXCL16 axis is associated with severe lung disease and pneumonia. Genome-wide association studies have also recently identified 3p21.31, encompassing the CXCR6 gene, as a susceptibility locus for severe COVID-19. We assessed numbers T cells expressing the chemokine receptor CXCR6 and plasma levels of CXCL16, in control and COVID-19 patients. Results demonstrated that circulating CD8+CXCR6+ T cells were significantly elevated with advancing age, yet virtually absent in patients with severe COVID-19. Peripheral levels of CXCL16 were significantly upregulated in severe COVID-19 patients compared to either mild COVID-19 patients or SARS-CoV-2 negative controls. This study supports a significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19.

immunology↗

bioRxiv2020

Anterior Nucleus of Thalamus Gates Progression of Mesial Temporal Seizures by Modulating Thalamocortical Synchrony

The anterior nucleus of the thalamus (ANT) mediates cortical-subcortical interactions between the limbic system and is hypothesized to facilitate the early organization of temporal lobe seizures. We set out to investigate the dynamic changes in synchronization parameters between the seizure onset zone (SOZ) and ANT during seizure stages (pre-onset to post-termination) in seven patients (n=26 seizures) with drug-resistant nonlesional temporal lobe epilepsy. Using local field potentials recorded directly from the limbic system and the ANT during stereoelectroencephalography, we confirm that the onset of mesial temporal lobe seizure is associated with increased thalamocortical network excitability and phase-amplitude coupling. The increase in thalamocortical phase synchronization preceded seizure onset, thereby suggesting that the early organization of temporal lobe seizures involves the integration of the ANT within the epileptic network. Towards seizure termination, there is a significant decrease in thalamic excitability, thalamocortical synchronization, and decoupling, thereby suggesting a breakdown in thalamocortical connectivity. A higher disease burden is significantly correlated with increased synchronization between the ANT and epileptic networks. Collectively, the results elucidate mechanistic insights and provide the temporal architecture of thalamocortical interactions that can be targeted in the rational designing of closed-loop seizure abortive interventions. HighlightsO_LIAnterior nucleus of thalamus is coactivated at the onset of temporal lobe seizures C_LIO_LIIncrease thalamocortical synchronization and excitability is observed at seizure onset C_LIO_LISeizure termination is characterized by a breakdown in thalamocortical connectivity C_LIO_LIIncreased seizure burden affects thalamocortical synchronization C_LI

neuroscience↗

bioRxiv2019

Early Ictal Recruitment of Midline Thalamus in Mesial Temporal Lobe Epilepsy

The causal role of midline thalamus in the initiation and early organization of mesial temporal lobe seizures is studied. Three patients undergoing stereoelectroencephalography were enrolled for the placement of an additional depth electrode targeting the midline thalamus. The midline thalamus was recruited in all three patients at varying points of seizure initiation (0-13 seconds) and early propagation (9-60 seconds). Stimulation of either thalamus or hippocampus induced similar habitual seizures. Seizure-induced in the hippocampus rapidly recruited the thalamus. Evoked potentials demonstrated stronger connectivity from the hippocampus to the thalamus than in the opposite direction. The midline thalamus can be within the seizure initiation and symptomatogenic circuits.

neuroscience↗

bioRxiv2018

Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GlcNAc Homeostasis that can be Reversed to Dampen Epileptiform Activity

Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-{beta}-N-acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that integrate energy supply with demand. The enzymes O-GlcNActransferase (OGT) and O-GlcNAcase (OGA) mediate the addition and removal, respectively, of the O-GlcNAc modification. The goal of this study was to determine whether changes in OGT/OGA cycling and disruptions in protein O-GlcNAcylation occur in the epileptic hippocampus. We observed reduced global and protein specific O-GlcNAcylation and OGT expression in the kainate rat model of TLE and in human TLE hippocampal tissue. Inhibiting OGA with Thiamet-G elevated protein O-GlcNAcylation, and decreased both seizure duration and epileptic spike events, suggesting that OGA may be a therapeutic target for seizure control. These findings suggest that loss of O-GlcNAc homeostasis in the kainate model and in human TLE can be reversed via targeting of O-GlcNAc related pathways.

neuroscience↗

bioRxiv2018

Loss-of-function in IRF2BPL is associated with neurological phenotypes

The Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

genetics↗