Causal association between genetically predicted circulating immune cell counts and frailty: a two-sample Mendelian randomization study.

Background: Despite the recognized link between immune responses and frailty, the association between immune cell counts and frailty based on previous observational studies remains disputed, with uncertain causal nexus. This study aimed to elucidate causal association between genetically predicted circulating immune cell counts and frailty. Methods: We conducted the two-sample Mendelian randomization (MR) study with independent genetic variants associated with six immune cell subtype counts from genome-wide association studies in 563,946 European individuals. Frailty summary data, assessed via frailty index (FI), was obtained from study comprising 175,226 subjects. Univariate MR, reverse MR and multivariate MR were conducted to comprehensive investigate the association between immune cell counts and FI, with two-step MR analysis for mediation analysis. Results: Univariate MR evidence indicated that among six leukocyte subtype counts, only elevated eosinophil count was significantly correlated with higher FI (ß = 0.059, 95% confidence interval [CI], 0.042-0.078, P=5.63E-11), with no reverse causal relationship identified in reverse MR. In multivariate MR, the causal effect of eosinophil count retained statistical significance (ß = 0.063, 95% CI, 0.021-0.104, P = 0.003). Ultimately, the two-step MR analysis demonstrated two mediators in this causal pathway: asthma (ß= 0.019, 95% CI, 0.013-0.025, P = 35.84E-10, mediated proportion, 31.732%) and rheumatoid arthritis (ß= 0.004, 95% CI, 0.001-0.006, P=1.75E-03, mediated proportion, 6.411%). Conclusions: Within immune cell subtypes, MR evidence indicated only genetically predicted circulating eosinophil count had irreversible and independent causal effect on frailty, with asthma and rheumatoid arthritis possibly serving as partial mediators. The finding stressed the need for further exploring physiological functions of eosinophils in order to develop effective strategies against frailty.

The Role of Format Familiarity and Word Frequency in Chinese Reading.

For Chinese readers, reading from left to right is the norm, while reading from right to left is unfamiliar. This study comprises two experiments investigating how format familiarity and word frequency affect reading by Chinese people. Experiment 1 examines the roles of format familiarity (reading from left to right is the familiar Chinese format, and reading from right to left is the unfamiliar Chinese format) and word frequency in vocabulary recognition. Forty students read the same Chinese sentences from left to right and from right to left. Target words were divided into high and low frequency words. In Experiment 2, participants engaged in right-to-left reading training for 10 days to test whether their right-to-left reading performance could be improved. The study yields several main findings. First, format familiarity affects vocabulary recognition. Participants reading from left to right had shorter fixation times, higher skipping rates, and viewing positions closer to word center.. Second, word frequency affects vocabulary recognition in Chinese reading. Third, right-to-left reading training could improve reading performance. In the early indexes, the interaction effect of format familiarity and word frequency was significant. There was also a significant word-frequency effect from left to right but not from right to left. Therefore, word segmentation and vocabulary recognition may be sequential in Chinese reading.

Protective effects of GPR120 agonist-programmed macrophages on renal interstitial fibrosis in unilateral ureteral obstruction (UUO) rats.

Macrophages in the kidney play different roles in renal interstitial fibrosis (RIF) depending on their phenotypes. M2 phenotype macrophages are believed to protect the kidney against RIF. Free fatty acid receptor GPR120 is expressed in macrophages, and its activation induces macrophage transition to M2 phenotype. In this study, the effects of GPR120 agonist-programmed macrophages on RIF were investigated. The peritoneal macrophages collected from rats were incubated with GPR120 agonist TUG891 in vitro for 24 h, and then they were transplanted autologously to the kidney with ureteral obstruction by intrarenal injection for 7 days on the same day following unilateral ureteral obstruction (UUO) operation. RIF was identified by Masson trichrome histological staining, and the expression of RIF-related proteins was analyzed by immunohistochemistry and western blot. It was observed that TUG891-programmed macrophages up-regulated the expression of CD206 and arginase-1 while the expression of interleukin-6 and tumor necrosis factor-α were down-regulated. RIF in rats was significantly increased following UUO, which was markedly alleviated by TUG891-programmed macrophages but not untreated macrophages. TUG891-programmed macrophages inhibited the abnormal expression of TGF-ß1 and SMAD2. The abnormal expression of epithelial-mesenchymal transition (EMT)-related proteins including vimentin, α-SMA and ß-catenin was also significantly decreased in rats with transplantation of TUG891-programmed macrophages as compared to UUO rats. This study suggests that autologous administration of peritoneal macrophages programmed in vitro by GPR120 agonist to kidney has a protective effect against RIF following UUO.

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma.

AIM: Rosiglitazone is one of the specific PPARγ agonists showing potential therapeutic effects in asthma. Though PPARγ activation was considered protective in inhibiting airway inflammation and remodeling in asthma, the specific mechanisms are still unclear. This study was aimed to investigate whether heme oxygenase-1 (HO-1) related pathways were involved in rosiglitazone-activated PPARγ signaling in asthma treatment. METHODS: Asthma was induced in mice by multiple exposures to ovalbumin (OVA) in 8 weeks. Prior to every OVA challenge, the mice received rosiglitazone (5 mg/kg, p.o.). After the mice were sacrificed, the bronchoalveolar lavage fluid (BALF), blood samples and lungs were collected for analyses. The activities of HO-1, MMP-2 and MMP-9 in airway tissue were assessed, and the expression of PPARγ, HO-1 and p21 proteins was also examined. RESULTS: Rosiglitazone administration significantly attenuated airway inflammation and remodeling in mice with OVA-induced asthma, which were evidenced by decreased counts of total cells, eosinophils and neutrophils, and decreased levels of IL-5 and IL-13 in BALF, and by decreased airway smooth muscle layer thickness and reduced airway collagen deposition. Furthermore, rosiglitazone administration significantly increased PPARγ, HO-1 and p21 expression and HO-1 activity, decreased MMP-2 and MMP-9 activities in airway tissue. All the therapeutic effects of rosiglitazone were significantly impaired by co-administration of the HO-1 inhibitor ZnPP. CONCLUSION: Rosiglitazone effectively attenuates airway inflammation and remodeling in OVA-induced asthma of mice by activating PPARγ/HO-1 signaling pathway.