Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed–protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation. Loss of Gcn5 functions impaired T cell proliferation, IL-2 production, and Th1/Th17, but not Th2 and regulatory T cell differentiation. Gcn5 is recruited onto the il-2 promoter by interacting with the NFAT in T cells upon TCR stimulation. Interestingly, instead of directly acetylating NFAT, Gcn5 catalyzes histone H3 lysine H9 acetylation to promote IL-2 production. T cell–specific suppression of Gcn5 partially protected mice from myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis, an experimental model for human multiple sclerosis. Our study reveals previously unknown physiological functions for Gcn5 and a molecular mechanism underlying these functions in regulating T cell immunity. Hence Gcn5 may be an important new target for autoimmune disease therapy.

Accumulating evidence indicates that the actin regulator cofilin is overactivated in Alzheimer’s Disease (AD), but whether this abnormality contributes to synaptic and cognitive impairments in AD is unclear. In addition, the brain region and cell types involved remain unknown. In this study, we specifically manipulate LIMK1, the key protein kinase that phosphorylates and inactivates cofilin, in the hippocampus of APP/PS1 transgenic mice. Using local injections of the AAV virus containing LIMK1 under the control of the CaMKIIα promoter, we show that expression of LIMK1 in hippocampal excitatory neurons increases cofilin phosphorylation (i.e., decreases cofilin activity), rescues impairments in long-term potentiation, and improves social memory in APP/PS1 mice. Our results suggest that deficits in LIMK1/cofilin signaling in the hippocampal excitatory neurons contribute to AD pathology and that manipulations of LIMK1/cofilin activity provide a potential therapeutic strategy to treat AD.

Previous task-related functional magnetic resonance imaging (task-fMRI) investigations have documented abnormal brain activation associated with subclinical depression (SD), defined as a clinically relevant level of depressive symptoms that does not meet the diagnostic criteria for major depressive disorder. However, these task-fMRI studies have not reported consistent conclusions. Performing a voxel-based meta-analysis of task-fMRI studies may yield reliable findings. We extracted the peak coordinates and t values of included studies and analyzed brain activation between individuals with SD and healthy controls (HCs) using anisotropic effect-size signed differential mapping (AES-SDM). A systematic literature search identified eight studies, including 266 individuals with SD and 281 HCs (aged 14 to 25). The meta-analysis showed that individuals with SD exhibited significantly greater activation in the right lenticular nucleus and putamen according to task-fMRI. The meta-regression analysis revealed a negative correlation between the proportion of females in a group and activation in the right striatum. The recruitment criteria for individuals with SD, type of tasks and MRI acquisition parameters of included studies were heterogeneous. The results should be interpreted cautiously due to insufficient included studies. Our findings suggest that individuals with SD exhibit increased activation in the right lenticular nucleus, putamen and striatum, which may indicate a compensatory increase in response to an impairment of insular and striatal function caused by depression. These results provide valuable insights into the potential pathophysiology of brain dysfunction in SD.

Background. Recent studies suggest a correlation between the reduced Sirt‐1 expression with Alzheimer’s diseases (AD) and depression, respectively, suggesting a possible pathogenic role of the altered Sirt‐1 expression in neuronal degenerative diseases, such as AD and depression. However, the molecular mechanisms underlying how Sirt‐1 reduction impairs neuronal functions remain unknown. Methods. We used the SK‐N‐SH neuroblastoma cells to study the role of Sirt‐1 expression on physiological roles in neuronal cells. Gain of Sirt‐1 was achieved by transiently transfecting Sirt‐1 expression plasmid. Sirt‐1‐specific shRNA was used to elucidate the role of Sirt‐1 loss of function. CCK‐8 (Cell Counting Kit‐8) assay and flow cytometry were used to evaluate cell proliferation. Semiquantitative western blotting was used to detect relative protein levels. A further luciferase reporter gene assay was employed to examine the effect of Sirt‐1 expression on the transcriptional activity of p53. RT‐qPCR was used to determine the mRNA levels of p21, Bax, and Bcl‐2, which were the downstream target genes of p53. Results. Sirt‐1 suppressed the p53 downstream gene p21 transcription, while shRNA‐mediated Sirt‐1 knockdown resulted in a significant increase in p21 expression, implying a possibility that Sirt‐1 promotes neuron proliferation through suppressing p53 transcriptional activity. The mRNA and protein levels of p53 were not affected by the altered Sirt‐1 expression, suggesting that Sirt‐1 regulates the transcriptional regulatory activity of p53 rather than p53 expression. Indeed, we further confirmed that Sirt‐1 appeared to inhibit p53 transcriptional activity by attenuating its acetylation and resulted in a decrease of p53’s binding to the p21 promoter. Overexpressed Sirt‐1 scavenged reactive oxygen species (ROS) production in SK‐N‐SH with H₂O₂. Knockdown of Sirt‐1 presented opposite effect; the addition of EX527 (Sirt‐1 inhibitor) increased ROS accumulation. Conclusions. Oxidative stress induces Sirt‐1 in neuron cells, and Sirt‐1 promotes proliferation in SK‐N‐SH cells, which protects them from oxidative stress‐induced cell death, potentially via suppressing the transcriptional activity of p53. These results provide a molecular explanation underlying how the reduced Sirt‐1 potentially causes the AD and depression‐related diseases, supporting the idea that Sirt‐1 can possibly be used as a diagnostic biomarker and/or therapeutic drug target for the AD and depression‐related diseases.

Objective. This paper aimed to probe changes in the default mode network (DMN) functional connectivity (DMNFC) of the brain of patients with insomnia disorder (ID) under the resting state. Methods. A total of 67 patients with ID and 67 graphically matched healthy controls were selected. Then, their general information was collected, followed by a psychological scale valuation. Resting state functional magnetic resonance imaging (rs‐fMRI) scanning was conducted. Subsequently, collected statistics were processed, bilateral precuneus and medial superior frontal gyrus were defined as regions of interest (ROI), and the difference in intensity between these two groups was compared. Results. Compared with the healthy control group, the patients in the ID group were observed with abnormalities of DMNFC. Specifically, a significant increase in the functional connectivity (FC) could be observed between the left medial superior frontal gyrus and left central anterior gyrus, the left medial superior frontal gyrus and anterior cingulate gyrus, the right medial superior frontal gyrus and left central anterior gyrus, the left anterior cuneiform and left central anterior/posterior gyrus, the left anterior cuneiform and left superior occipital gyrus, as well as the right anterior cuneiform and left central posterior gyrus. However, the FC between the left anterior cuneiform and the right middle frontal gyrus was weakened, as well as between the left anterior cuneiform and the right angle gyrus and between the right precuneus and the left inferior temporal gyrus. Conclusion. ID patients may suffer changes in FC. The decline of FC in DMN may be one of the underlying causes of ID; the enhancement of FC between DMN and the visual‐spatial attention network may play a key role in the mechanisms of impaired brain functional networks of ID.