Biology subjects

Devine, K.

Publications and source records attributed to Devine, K..

3 recordsLinked to original sources

bioRxiv2026

Replication-coupled maturation of readthrough late transcripts by a polyomavirus small T antigen

Productive polyomavirus gene expression requires the maturation of long, non-polyadenylated "wraparound" transcripts generated by late-strand readthrough of the polyadenylation signal on the circular genome, giving rise to structural protein mRNAs and microRNAs. In Merkel cell polyomavirus (MCV), small T (sT) antigen, along with large T (LT) antigen-mediated DNA replication, drives this process. Deletion of sT (MCV{Delta}sT) attenuates late gene transcription, abolishes splicing, eliminates VP1 expression, and traps unspliced transcripts in the nucleus. Exogenous sT restored transcription and splicing in an aphidicolin-sensitive manner, requiring domains that activate DNA replication and bind chromatin. RNA sequencing revealed that sT promotes splicing and polyadenylation of wraparound transcripts, thereby increasing cytoplasmic VP1 and VP2 mRNA levels. A dual-fluorescence reporter confirmed that the leaky late poly(A) signal (LpA) was used more efficiently upon sT expression, indicating enhanced polyadenylation. Co-expression with LT abolished this effect, likely by overwhelming the capacity of the polyadenylation machinery. sT from HPyV7 and HPyV9 could similarly rescue this defect, indicating that this regulatory activity is conserved in a subset of sT proteins. Together, these findings define sT as a replication-coupled regulator of late transcript expression, splicing, and polyadenylation, revealing how a compact DNA virus converts readthrough transcription into productive gene expression.

microbiology↗

bioRxiv2026

Rapid turnover of corticosterone in humans: the role of a second glucocorticoid hormone

BACKGROUNDAdrenal insufficiency is primarily treated with replacement of cortisol, which is the predominant circulating glucocorticoid. Human adrenals also secrete corticosterone and emerging evidence suggests this may be a safer glucocorticoid replacement therapy. However, little is known about corticosterone in humans, particularly related to its metabolism. METHODSTo investigate the secretion and metabolism of corticosterone in comparison with cortisol, we: 1) investigated the diurnal rhythm of circulating cortisol/ corticosterone in 7 healthy volunteers; 2) quantified A-ring reduction of both hormones in human hepatic cytosol and 3) measured glucocorticoid metabolites in vivo in 24 healthy men; 4) determined the pharmacokinetics of corticosterone via intravenous infusion of 2,2,4,6,6,17,21,21-[2H]8-corticosterone; 5) assessed the response of corticosterone and cortisol to 1mcg ACTH in 279 healthy volunteers. RESULTSThe natural diurnal rhythm of corticosterone closely mirrored that of cortisol, and accounted for [~]3% of total circulating glucocorticoid concentrations. Daily corticosterone production, as measured through urinary steroid profiling, was approximately 10-fold lower than cortisol, and corticosterone demonstrated substantially greater metabolism by both 5- and 5{beta}-reductase than cortisol. In keeping with greater metabolism, the half-life of corticosterone was 28.5 {+/-} 3.3 minutes. Finally, corticosterone demonstrated a greater relative rise in response to ACTH than cortisol, particularly in men, revealing sex-specific differences. CONCLUSIONSCorticosterone is a dynamic glucocorticoid with faster metabolism and greater response to stimulation than cortisol in humans. These data raise the possibility of distinct roles for these two glucocorticoids and highlight important pharmacokinetic differences with implications for the therapeutic potential of corticosterone replacement in humans.

pharmacology and toxicology↗

bioRxiv2019

Tumor cell phenotype and heterogeneity differences in IDH1 mutant vs wild-type gliomas

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated multiplexed immunofluorescence single cell data for 43 protein markers across cancer hallmarks, in addition to cell spatial metrics, genomic sequencing and magnetic resonance imaging (MRI) quantitative features. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion differ between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. Longer overall survival for IDH1mt glioma patients may reflect generalized altered cellular, molecular, spatial heterogeneity which manifest in discernable radiological manifestations.

genomics↗