Neuroanatomical Correlates of Creativity: Evidence From Voxel-Based Morphometry

Creativity was a special cognitive capacity which was crucial to human survival and prosperity. Remote associates test (RAT), identifying the relationships among remote ideas, was one of the most frequently used methods of measuring creativity. However, the structural characteristics associated with RAT remains unclear. In the present study, the relationship between gray matter density (GMD)/white matter density (WMD) and RAT was explored using voxel-based morphometry (VBM) in a larger healthy college student sample (144 women and 117 men). Results showed that the score of RAT was significantly positively related with the GMD in the right anterior superior temporal gyrus (aSTG) and negatively correlated with the GMD in the right dorsal anterior cingulate cortex (dACC). Meanwhile, results also showed that the score of RAT was significantly positively related with the WMD in the right dACC and negatively correlated with the WMD in the left inferior frontal gyrus (IFG). These findings indicate that individual creativity, as measured by the RAT, was mainly related to the regional gray /white matter density of brain regions in the aSTG, dACC and IFG, which might have been involved in the forming of novel combinations, breaking of mental set, monitoring of conflict and semantic integration

Individual phosphorylation sites at the C-terminus of the apelin receptor play different roles in signal transduction

The apelin and Elabela proteins constitute a spatiotemporal double-ligand system that controls apelin receptor (APJ) signal transduction. Phosphorylation of multiple sites within the C-terminus of APJ is essential for the recruitment of β-arrestins. We sought to determine the precise mechanisms by which apelin and Elabela promote APJ phosphorylation, and to elucidate the influence of β-arrestin phosphorylation on G-protein-coupled receptor (GPCR)/β-arrestin-dependent signaling. We used techniques including mass spectrometry (MS), mutation analysis, and bioluminescence resonance energy transfer (BRET) to evaluate the role of phosphorylation sites in APJ-mediated G-protein-dependent and β-dependent signaling. Phosphorylation of APJ occurred at five serine residues in the C-terminal region (Ser335, Ser339, Ser345, Ser348 and Ser369). We also identified two phosphorylation sites in β-arrestin1 and three in β-arrestin2, including three previously identified residues (Ser412, Ser361, and Thr383) and two new sites, Tyr47 in β-arrestin1 and Tyr48 in β-arrestin2. APJ mutations did not affect the phosphorylation of β-arrestins, but it affects the β-arrestin signaling pathway, specifically Ser335 and Ser339. Mutation of Ser335 decreased the ability of the receptor to interact with β-arrestin1/2 and AP2, indicating that APJ affects the β-arrestin signaling pathway by stimulating Elabela. Mutation of Ser339 abolished the capability of the receptor to interact with GRK2 and β-arrestin1/2 upon stimulation with apelin-36, and disrupted receptor internalization and β-arrestin-dependent ERK1/2 activation. Five peptides act on distinct phosphorylation sites at the APJ C-terminus, differentially regulating APJ signal transduction and causing different biological effects. These findings may facilitate screening for drugs to treat cardiovascular and metabolic diseases

A predictive model for early death in elderly colorectal cancer patients: a population-based study

PurposeThe purpose of this study is to determine what variables contribute to the early death of elderly colorectal cancer patients (ECRC) and to generate predictive nomograms for this population.MethodsThis retrospective cohort analysis included elderly individuals (≥75 years old) diagnosed with colorectal cancer (CRC) from 2010-2015 in the Surveillance, Epidemiology, and End Result databases (SEER) databases. The external validation was conducted using a sample of the Chinese population obtained from the China-Japan Union Hospital of Jilin University. Logistic regression analyses were used to ascertain variables associated with early death and to develop nomograms. The nomograms were internally and externally validated with the help of the receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA).ResultsThe SEER cohort consisted of 28,111 individuals, while the Chinese cohort contained 315 cases. Logistic regression analyses shown that race, marital status, tumor size, Grade, T stage, N stage, M stage, brain metastasis, liver metastasis, bone metastasis, surgery, chemotherapy, and radiotherapy were independent prognostic factors for all-cause and cancer-specific early death in ECRC patients; The variable of sex was only related to an increased risk of all-cause early death, whereas the factor of insurance status was solely associated with an increased risk of cancer-specific early death. Subsequently, two nomograms were devised to estimate the likelihood of all-cause and cancer-specific early death among individuals with ECRC. The nomograms exhibited robust predictive accuracy for predicting early death of ECRC patients, as evidenced by both internal and external validation.ConclusionWe developed two easy-to-use nomograms to predicting the likelihood of early death in ECRC patients, which would contribute significantly to the improvement of clinical decision-making and the formulation of personalized treatment approaches for this particular population

Male Patients With Dilated Cardiomyopathy Exhibiting a Higher Heart Rate Acceleration Capacity or a Lower Deceleration Capacity Are at Higher Risk of Cardiac Death

The effects of dilated cardiomyopathy (DCM) on cardiac autonomic regulation and electrophysiology, and the consequences of such changes, remain unclear. We evaluated the associations between heart rate acceleration capacity (AC) and deceleration capacity (DC), heart structural and functional changes, and cardiac death in 202 healthy controls and 100 DCM patients. The DC was lower and the AC was higher in DCM patients (both males and females). Multivariable, linear, logistic regression analyses revealed that in males, age was positively associated with AC in healthy controls (N = 85); the left atrial diameter (LAD) was positively and the left ventricular ejection fraction (LVEF) was negatively associated with AC in DCM patients (N = 65); age was negatively associated with DC in healthy controls (N = 85); and the LAD was negatively and the LVEF was positively associated with DC in DCM patients (N = 65). In females, only age was associated with either AC or DC in healthy controls (N = 117). Kaplan–Meier analysis revealed that male DCM patients with greater LADs (≥46.5 mm) (long-rank chi-squared value = 11.1, P = 0.001), an elevated AC (≥-4.75 ms) (log-rank chi-squared value = 6.8, P = 0.009), and a lower DC (≤4.72 ms) (log-rank chi-squared value = 9.1, P = 0.003) were at higher risk of cardiac death within 60 months of follow-up. In conclusion, in males, DCM significantly affected both the AC and DC; a higher AC or a lower DC increased the risk of cardiac death

EGFR deficiency leads to impaired self-renewal and pluripotency of mouse embryonic stem cells

Background Self-renewal and pluripotency are considered as unwavering features of embryonic stem cells (ESCs). How ESCs regulate the self-renewal and differentiation is a central question in development and regenerative medicine research. Epidermal growth factor receptor (EGFR) was identified as a critical regulator in embryonic development, but its role in the maintenance of ESCs is poorly understood. Methods Here, EGFR was disrupted by its specific inhibitor AG1478 in mouse ESCs (mESCs), and its self-renewal and pluripotency were characterized according to their proliferation, expression of pluripotency markers, embryoid body (EB) formation, and mRNA expression patterns. We also used another EGFR inhibitor (gefitinib) and RNA interference assay to rule out the possibility of non-specific effects of AG1478. Results EGFR inhibition by AG1478 treatment in mESCs markedly reduced cell proliferation, caused cell cycle arrest at G0/G1 phase, and altered protein expressions of the cell cycle regulatory genes (CDK2 (decreased 11.3%) and proliferating cell nuclear antigen (decreased 25.2%)). The immunoreactivities and protein expression of pluripotency factors (OCT4 (decreased 26.9%)) also dramatically decreased, while the differentiation related genes (GATA4 (increased 1.6-fold)) were up-regulated in mESCs after EGFR inhibition. Meanwhile, EGFR inhibition in mESCs disrupted EB formation, indicating its impaired pluripotency. Additionally, the effects observed by EGFR inhibition with another inhibitor gefitinib and siRNA were consistent with those observed by AG1478 treatment in mESCs. These effects were manifested in the decreased expression of proliferative and pluripotency-related genes and the increased expression of genes involved in differentiation. Moreover, RNA-seq analysis displayed that transcript profiling was changed significantly after EGFR inhibition by AG1478. A large number of differentially expressed genes were involved in cell cycle, apoptotic process, epigenetic modification, and metabolic process, which were related to self-renewal and pluripotency, confirming that EGFR deficiency impaired self-renewal and pluripotency in mESCs. Conclusions Taken together, our results demonstrated the importance of EGFR in guarding the stemness of mESCs

Disruption of 5-hydroxytryptamine 1A receptor and orexin receptor 1 heterodimer formation affects novel G protein-dependent signaling pathways and has antidepressant effects in vivo

G protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of depression. Increasing evidence supports the importance of serotonergic and orexin-producing neurons in numerous physiological processes, possibly via a crucial interaction between 5-hydroxytryptamine 1A receptor (5-HT1AR) and orexin receptor 1 (OX1R). However, little is known about the function of 5-HT1AR/OX1R heterodimers. It is unclear how the transmembrane domains (TMs) of the dimer affect its function and whether its modulation mediates antidepressant-like effects. Here, we examined the mechanism of 5-HT1AR/OX1R dimerization and downstream G protein-dependent signaling. We found that 5-HT1AR and OX1R form constitutive heterodimers that induce novel G protein-dependent signaling, and that this heterodimerization does not affect recruitment of β-arrestins to the complex. In addition, we found that the structural interface of the active 5-HT1AR/OX1R dimer transforms from TM4/TM5 in the basal state to TM6 in the active conformation. We also used mutation analyses to identify key residues at the interface (5-HT1AR R1514.40, 5-HT1AR Y1985.41, and OX1R L2305.54). Injection of chronic unpredictable mild stress (CUMS) rats with TM4/TM5 peptides improved their depression-like emotional status and decreased the number of endogenous 5-HT1AR/OX1R heterodimers in the rat brain. These antidepressant effects may be mediated by upregulation of BDNF levels and enhanced phosphorylation and activation of CREB in the hippocampus and medial prefrontal cortex. This study provides evidence that 5-HT1AR/OX1R heterodimers are involved in the pathological process of depression. Peptides including TMs of the 5-HT1AR/OX1R heterodimer interface are candidates for the development of compounds with fast-acting antidepressant-like effects

Mucosal-Associated Invariant T Cells Improve Nonalcoholic Fatty Liver Disease Through Regulating Macrophage Polarization

Mucosal-associated invariant T (MAIT) cells, a novel population of innate-like lymphocytes, have been involved in various inflammatory and autoimmune diseases. However, their role in the development of nonalcoholic fatty liver disease (NAFLD) remains unclear. In this study, we investigated the alterations of phenotype and immunological function of MAIT cells in NAFLD. Analysis of PBMCs in 60 patients with NAFLD and 48 healthy controls (HC) revealed that circulating MAIT cell frequency decreased in NAFLD, especially in the patients with higher serum levels of γ-glutamyl transferase or total triglyceride. Functional alterations of circulating MAIT cells were also detected in NAFLD patients, such as the increased production of IL-4 whereas the decreased production of IFN-γ and TNF-α. Furthermore, elevated expression of CXCR6 was observed in circulating MAIT cells of patients. Meanwhile, we found an increased number of MAIT cells in the livers of NAFLD, and the number was even greater in patients with higher NAFLD activity score. Moreover, activated MAIT cells induced monocytes/macrophages differentiation into M2 phenotype in vitro. Additionally, MAIT cells were enriched and displayed Th2 type cytokines profile in livers of wild type mice fed with methionine and choline deficient diet (MCD). Notably, mice deficient of MAIT cells exhibited more severe hepatic steatosis and inflammation upon MCD, accompanied with more CD11c+ proinflammatory macrophages (M1) and less CD206+ anti-inflammatory macrophages (M2) in livers. Our results indicate that MAIT cells protect against inflammation in NAFLD through producing regulatory cytokines and inducing anti-inflammatory macrophage polarization, which may provide novel therapeutic strategies for NAFLD

The Immune Self-adjusting Contour Error Coupled Control in Machining Based on Grating Ruler Sensors

The actual dynamic performance of each feed axis can’t match well usually, which will destroy machine tool contour accuracy seriously. The immune self-adjusting contour error coupled control method based on grating ruler sensors is developed to improve machine tool contour accuracy in the paper. Firstly, measure and convert the feed axis actual displacement into pulse signals with grating ruler sensors on each sampling period; then calculate the contour error and contour error compensation control quantity. The method combines the advantages of immune mechanism and classical Proportion Integration Differentiation (PID) control algorithm. The introduced method is testified on the three-axis computer numerical control (CNC) milling machine with three high precision grating ruler sensors. And the experimental results show that the proposed immune self-adjusting contour error coupled control method can improve machine tool contour accuracy remarkably