Sleep quality mediates the relationship between systemic inflammation and neurocognitive performance.

Background: Systemic inflammation is a significant mechanism underpinning adverse cognitive changes. Sleep quality is a crucial factor associated with systemic inflammation and neurocognitive health. Elevated levels of pro-inflammatory cytokines in the periphery help mark inflammation. With this background, we examined the relationship between systemic inflammation, subjective sleep quality, and neurocognitive performance in adults. Method & Results: In 252 healthy adults, we measured the systemic inflammation reflected by serum levels of IL-6, IL-12, IL-18, TNF-α and IFN-γ, subjective sleep quality reflected by the global scores of the Pittsburgh Sleep Quality Index, and their neurocognitive performance measured by the Hong Kong Montreal Cognitive Assessment. We observed that neurocognitive performance was negatively related to IL-18 (p = 0.046) and positively related to sleep quality (p = 0.006). We did not observe significant associations between other cytokines and neurocognitive performance. Furthermore, we found that sleep quality as a mediator explained the relationship between IL-18 and neurocognitive performance depending on the levels of IL-12 (index of moderated mediation: 95% CI = [0.0047, 0.0664]). Better subjective sleep quality buffered the negative effect of IL-18 on neurocognitive performance when IL-12 was low (bootstrapping 95% CI: [- 0.0824, - 0.0018]). On the contrary, poor subjective sleep quality mediated the association between higher IL-18 and poorer neurocognitive performance when IL-12 was elevated (bootstrapping 95% CI: [0.0004, 0.0608]). Conclusion & Implications: Our findings indicate that systemic inflammation was negatively associated with neurocognitive performance. Sleep quality regulated by IL-18/IL-12 axis activation could be a potential mechanism underpinning neurocognitive changes. Our results illustrate the intricate relationships between immune functioning, sleep quality and neurocognitive performance. These insights are essential to understand the potential mechanisms underpinning neurocognitive changes, paving the way for the development of preventive interventions for the risk of cognitive impairment.

Sex Differences in Association Between Gut Microbiome and Essential Hypertension Based on Ambulatory Blood Pressure Monitoring.

BACKGROUND: Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association between GM and hypertension. METHODS: We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years). RESULTS: The hypertensive group was associated with GM alterations; however, significant differences in ß-diversity and GM composition in hypertensive versus normotensive groups were only observed in women and not in men under various statistical models adjusting for the following covariates: age, sex, body mass index, sodium intake estimated by spot urine analysis, blood glucose, triglycerides, low- and high-density lipoprotein cholesterol, smoking, menopause, and fatty liver status. Specifically, Ruminococcus gnavus, Clostridium bolteae, and Bacteroides ovatus were significantly more abundant in the hypertensive women, whereas Dorea formicigenerans was more abundant in the normotensive women. No bacterial species were found to be significantly associated with hypertension in men. Furthermore, total plasma short-chain fatty acids and propionic acid were independent predictors of systolic and diastolic blood pressure in women but not men. CONCLUSIONS: GM dysregulation was strongly associated with 24-hour ambulatory blood pressure in women but not men, which may be mediated through propionic acid. Our work suggests that sex differences may be an important consideration while assessing the role of GM in the development and treatment of hypertension.

An unfolded protein-induced conformational switch activates mammalian IRE1.

The unfolded protein response (UPR) adjusts the cell's protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α's ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD's MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1's activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization.