The catechol-O-methyltransferase (COMT) Val¹⁵⁸Met polymorphism has been associated with working memory (WM) in many studies, but the results have not been consistent. One plausible explanation is sex-specific effects of this polymorphism as reported in several studies. The current study aimed to explore the sex-specific effects of the COMT Val¹⁵⁸Met polymorphism on WM-related brain function in an elderly sample. We found that Val homozygotes outperformed Met allele carriers on the backward digit span subtest for both males and females. The triangular part of the left inferior frontal gyrus and the left inferior temporal gyrus exhibited higher activation in Met allele carriers compared with Val homozygotes during the n-back task, while the background functional connectivity (bFC) between the left angular gyrus (ANG) and the right ANG was enhanced in Val homozygotes as compared to Met allele carriers. Finally, the associations between brain activation, bFC (among various regions), and WM performance were identified only in specific genotype groups of the female participants. These findings provide new insights into the role of COMT Val¹⁵⁸Met gene polymorphism in brain function, particularly its female-specific nature.

MicroRNA sequences are now publicly available. Page 6270, last paragraph in Materials and Methods, line 1: "Microarray data accession number" should read "Accession numbers." Page 6270, last paragraph in Materials and Methods, line 4: The following sentence should be added. "MicroRNA sequencing data have been deposited in the NCBI BioProject database under accession no. PRJNA429684 and in the NCBI Sequence Read Archive under accession no. SRP128960.".

Unlabelled

Epithelial barrier dysfunction during human immunodeficiency virus (HIV) infection has largely been attributed to the rapid and severe depletion of CD4(+) T cells in the gastrointestinal (GI) tract. Although it is known that changes in mucosal gene expression contribute to intestinal enteropathy, the role of small noncoding RNAs, specifically microRNA (miRNA), has not been investigated. Using the simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV pathogenesis, we investigated the effect of viral infection on miRNA expression in intestinal mucosa. SIV infection led to a striking decrease in the expression of mucosal miRNA compared to that in uninfected controls. This decrease coincided with an increase in 5'-3'-exoribonuclease 2 protein and alterations in DICER1 and Argonaute 2 expression. Targets of depleted miRNA belonged to molecular pathways involved in epithelial proliferation, differentiation, and immune response. Decreased expression of several miRNA involved in maintaining epithelial homeostasis in the gut was localized to the proliferative crypt region of the intestinal epithelium. Our findings suggest that SIV-induced decreased expression of miRNA involved in epithelial homeostasis, disrupted expression of miRNA biogenesis machinery, and increased expression of XRN2 are involved in the development of epithelial barrier dysfunction and gastroenteropathy.

Importance

MicroRNA (miRNA) regulate the development and function of intestinal epithelial cells, and many viruses disrupt normal host miRNA expression. In this study, we demonstrate that SIV and HIV disrupt expression of miRNA in the small intestine during infection. The depletion of several key miRNA is localized to the proliferative crypt region of the gut epithelium. These miRNA are known to control expression of genes involved in inflammation, cell death, and epithelial maturation. Our data indicate that this disruption might be caused by altered expression of miRNA biogenesis machinery during infection. These findings suggest that the disruption of miRNA in the small intestine likely plays a role in intestinal enteropathy during HIV infection.