Biology subjects

Stephens, J. C.

Publications and source records attributed to Stephens, J. C..

5 recordsLinked to original sources

bioRxiv2025

Prex1 controls glucose homeostasis by limiting glucose uptake and mitochondrial metabolism in liver through GEF-independent regulation of Gpr21

We investigated the roles of Rac guanine-nucleotide factor (Rac-GEF) Prex1 in glucose homeostasis using Prex1-/- and catalytically-inactive Prex1GD mice. Prex1 maintains fasting blood glucose levels and insulin sensitivity through its Rac-GEF activity but limits glucose clearance independently of its catalytic activity, throughout ageing. Prex1-/-mice on high-fat diet are protected from developing diabetes. The increased glucose clearance in Prex1-/- mice stems from constitutively enhanced hepatic glucose uptake. Prex1 limits Glut2 surface levels, mitochondrial membrane potential and mitochondrial ATP production, and controls mitochondrial morphology in hepatocytes, independently of its catalytic activity. Prex1 limits GPCR trafficking through an adaptor function, and we identify here the inhibitory orphan GPCR Gpr21 as a Prex1 target. The Gpr21-mediated blockade of glucose uptake and mitochondrial ATP production in hepatocytes requires Prex1. We propose that Prex1 limits glucose clearance by maintaining Gpr21 at the hepatocyte surface, thus limiting hepatic glucose uptake and metabolism. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/648781v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@110e660org.highwire.dtl.DTLVardef@84c0c3org.highwire.dtl.DTLVardef@18b8319org.highwire.dtl.DTLVardef@4bfde0_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Characterization of the Y Chromosome in Newfoundland and Labrador: Evidence of a Founder Effect

The population of Newfoundland and Labrador (NL) is largely derived from settlers who migrated primarily from England and Ireland in the 1700-1800s. Previously described as an isolated founder population, based on historical and demographic studies, data on the genetic ancestry of this population remains fragmentary. Here we describe the largest investigation of patrilineal ancestry in NL. To determine the paternal genetic structure of the population, 1,110 Y chromosomes from an NL based cohort were analyzed using 5,761 Y-specific markers. We identified 160 distinct paternal haplotypes, the majority of which (71.4%) belong to the R1b haplogroup. When NL is compared with global reference populations, the haplotype composition and frequencies of the NL paternal lineages primarily resemble the English and Irish ancestral source populations. There is also evidence for genetic contributions from Basque, French, Portuguese, and Spanish fishermen and early settlers that frequented NL. The population structure shows geographical and religious clustering that can be associated with the settlement of ancestral source populations from England and Ireland. For example, the R1b-M222 haplotype, seen in people of Irish descent, is found clustered in the Irish-settled Southeast region of NL. The clustering and expansion of Y haplotypes in conjunction with the geographical and religious clusters illustrate that limited subsequent in-migration, geographic isolation and societal factors have contributed to the genetic substructure of the NL population and its designation as a founder population.

genomics↗

bioRxiv2022

Newfoundland and Labrador: A mosaic founder population of an Irish and British diaspora from 300 years ago.

The founder population of Newfoundland and Labrador (NL) is a unique genetic resource, in part due to geographic and cultural isolation, where historical records describe a migration of European settlers primarily from Ireland and England to NL in the 18th and 19th centuries. Whilst its historical isolation, and increase prevalence of certain monogenic disorders, have been appreciated, the fine-scale genetic structure and ancestry of the population has not been well described. Understanding the genetic background on which functional, disease causing, genetic variation resides on would aid informed genetic mapping efforts in the Province. Here, we leverage dense genome-wide SNP data on 1,807 NL individuals to reveal fine-scale genetic structure in NL that is clustered around coastal communities and correlated with Christian denomination. We show that the majority of NL European ancestry can be traced back to the south-east and south-west of Ireland and England, respectively. We date a substantial population size bottleneck approximately 10-15 generations ago in NL, associated with increased haplotype sharing and autozygosity. Our results elucidate novel insights into the population history of NL and demonstrate evidence of a population conducive to further genetic studies and biomarker discovery. Significance StatementNewfoundland and Labrador (NL) has been identified as a founder population, though evidence of its magnitude and subsequent isolation is unclear. Here, analysis of 1,807 NL individuals demonstrates population structure associated with geographical isolation in coastal communities and religious denomination (Catholic or Protestant Christian). Further, NL European ancestry primarily descends from settlers from south-east Ireland and south-west England. This history is associated with increased sharing of longer haplotypes in NL, and NL-specific drift in some communities more than others, providing strong evidence of a founder event occurring about 10-15 generations ago. This study elucidates the detailed population structure of NL and shows enrichment for otherwise low frequency functional variants due to genetic drift useful for potential future biomarker discovery studies.

genetics↗

bioRxiv2021

Synergistic Cytotoxicity Between Cold Atmospheric Plasma and Pyrazolopyrimidinones Against Glioblastoma Cells

Pyrazolopyrimidinone is a fused nitrogen-containing heterocyclic system, which acts as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. We have tested the synergistic anti-cancer effects of 15 pyrazolopyrimidinones, synthesised in a two-step process, combined with cold atmospheric plasma (CAP), a novel innovation generating reactive species with other unique chemical and physical effects. We identify two pyrazolopyrimidinones that act as prodrugs and display enhanced reactive-species dependent cytotoxicity when used in combination with cold atmospheric plasma. Synergistic activation was evident for both direct CAP treatment on prodrug loaded tumour cells and indirect CAP treatment of prodrug in media prior to adding to tumour cells. Our results demonstrate the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy against cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/429831v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@56c8aeorg.highwire.dtl.DTLVardef@1913ea9org.highwire.dtl.DTLVardef@a8f522org.highwire.dtl.DTLVardef@75a529_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

GRID - Genomics of Rare Immune Disorders: a highly sensitive and specific diagnostic gene panel for patients with primary immunodeficiencies

Primary Immune disorders affect 15,000 new patients every year in Europe. Genetic tests are usually performed on a single or very limited number of genes leaving the majority of patients without a genetic diagnosis. We designed, optimised and validated a new clinical diagnostic platform called GRID, Genomics of Rare Immune Disorders, to screen in parallel 279 genes, including 2015 IUIS genes, known to be causative of Primary Immune disorders (PID). Validation to clinical standard using more than 58,000 variants in 176 PID patients shows an excellent sensitivity, specificity. The customised and automated bioinformatics pipeline prioritises and reports pertinent Single Nucleotide Variants (SNVs), INsertions and DELetions (INDELs) as well as Copy Number Variants (CNVs). An example of the clinical utility of the GRID panel, is represented by a patient initially diagnosed with X-linked agammaglobulinemia due to a missense variant in the BTK gene with severe inflammatory bowel disease. GRID results identified two additional compound heterozygous variants in IL17RC, potentially driving the altered phenotype.

genomics↗