14-3-3ε/YWHAE regulates the transcriptional expression of cardiac sodium channel NaV1.5.

BACKGROUND: Cardiac sodium channel NaV1.5 encoded by SCN5A is associated with arrhythmia disorders. However, the molecular mechanism underlying NaV1.5 expression remains to be fully elucidated. Previous studies have reported that 14-3-3 family acts as an adaptor involved in regulating kinetic characteristics of cardiac ion channels. OBJECTIVE: The purpose of this study was to establish 14-3-3ε/YWHAE, a member of 14-3-3 family, as a crucial regulator of NaV1.5 and explore the potential role of 14-3-3ε in the heart. METHODS: Western blotting, patch-clamping, real-time RT-PCR, RNA immunoprecipitation, electrocardiogram recording, echocardiography and histological analysis were performed. RESULTS: YWHAE overexpression significantly reduced the expression level of SCN5A mRNA and sodium current density, whereas YWHAE knockdown significantly increased SCN5A mRNA expression and sodium current density in HEK293/NaV1.5 and H9c2 cells. Similar results were observed in mice injected with adeno-associated virus serotype 9 (AAV9)-mediated YWHAE knockdown. The effect of 14-3-3ε on NaV1.5 expression was abrogated by knockdown of TBX5, a transcription factor of NaV1.5. An interaction between 14-3-3ε protein and TBX5 mRNA was identified, and YWHAE overexpression significantly decreased TBX5 mRNA stability without affecting SCN5A mRNA stability. Additionally, mice subjected to AAV9-mediated YWHAE knockdown exhibited shorter R-R intervals and higher prevalence of premature ventricular contractions. CONCLUSION: Our data unveil a novel regulatory mechanism of NaV1.5 by 14-3-3ε, and highlight the significance of 14-3-3ε in transcriptional regulation of NaV1.5 expression and cardiac arrhythmias.

Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. RESULTS: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. CONCLUSIONS: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Interleukin-6 classic and trans-signaling utilize glucose metabolism reprogramming to achieve anti- or pro-inflammatory effects.

Interleukin (IL)-6 has anti- and pro-inflammatory functions, controlled by IL-6 classic and trans-signaling, respectively. Differences in the downstream signaling mechanism between IL-6 classic and trans-signaling have not been identified. Here, we report that IL-6 activates glycolysis to regulate the inflammatory response. IL-6 regulates glucose metabolism by forming a complex containing signal-transducing activators of transcription 3 (STAT3), hexokinase 2 (HK2), and voltage-dependent anion channel 1 (VDAC1). The IL-6 classic signaling directs glucose flux to oxidative phosphorylation (OxPhos), while IL-6 trans-signaling directs glucose flux to anaerobic glycolysis. Classic IL-6 signaling promotes STAT3 translocation into mitochondria to interact with pyruvate dehydrogenase kinase-1 (PDK1), leading to pyruvate dehydrogenase α (PDHA) dissociation from PDK1. As a result, PDHA is dephosphorylated, and STAT3 is phosphorylated at Ser727. By contrast, IL-6 trans-signaling promotes the interaction of sirtuin 2 (SIRT2) and lactate dehydrogenase A (LDHA), leading to the dissociation of STAT3 from SIRT2. As a result, LDHA is deacetylated, and STAT3 is acetylated and phosphorylated at Tyr705. IL-6 classic signaling promotes the differentiation of regulatory T cells via the PDK1/STAT3/PDHA axis, whereas IL-6 trans-signaling promotes the differentiation of Th17 cells via the SIRT2/STAT3/LDHA axis. Conclusion: IL-6 classic signaling generates anti-inflammatory functions by shifting energy metabolism to OxPhos, while IL-6 trans-signaling generates pro-inflammatory functions by shifting energy metabolism to anaerobic glycolysis.

The protective effect of vitamin D supplementation as adjunctive therapy to antidepressants on brain structural and functional connectivity of patients with major depressive disorder: a randomized controlled trial.

BACKGROUND: Growing evidence points to the pivotal role of vitamin D in the pathophysiology and treatment of major depressive disorder (MDD). However, there is a paucity of longitudinal research investigating the effects of vitamin D supplementation on the brain of MDD patients. METHODS: We conducted a double-blind randomized controlled trial in 46 MDD patients, who were randomly allocated into either VD (antidepressant medication + vitamin D supplementation) or NVD (antidepressant medication + placebos) groups. Data from diffusion tensor imaging, resting-state functional MRI, serum vitamin D concentration, and clinical symptoms were obtained at baseline and after an average of 7 months of intervention. RESULTS: Both VD and NVD groups showed significant improvement in depression and anxiety symptoms but with no significant differences between the two groups. However, a greater increase in serum vitamin D concentration was found to be associated with greater improvement in depression and anxiety symptoms in VD group. More importantly, neuroimaging data demonstrated disrupted white matter integrity of right inferior fronto-occipital fasciculus along with decreased functional connectivity between right frontoparietal and medial visual networks after intervention in NVD group, but no changes in VD group. CONCLUSIONS: These findings suggest that vitamin D supplementation as adjunctive therapy to antidepressants may not only contribute to improvement in clinical symptoms but also help preserve brain structural and functional connectivity in MDD patients.

Transcriptomic analysis reveals the lipid metabolism-related gene regulatory characteristics and potential therapeutic agents for myocardial ischemia-reperfusion injury.

Background: Impaired energy balance caused by lipid metabolism dysregulation is an essential mechanism of myocardial ischemia-reperfusion injury (MI/RI). This study aims to explore the lipid metabolism-related gene (LMRG) expression patterns in MI/RI and to find potential therapeutic agents. Methods: Differential expression analysis was performed to screen the differentially expressed genes (DEGs) and LMRGs in the MI/RI-related dataset GSE61592. Enrichment and protein-protein interaction (PPI) analyses were performed to identify the key signaling pathways and genes. The expression trends of key LMRGs were validated by external datasets GSE160516 and GSE4105. The corresponding online databases predicted miRNAs, transcription factors (TFs), and potential therapeutic agents targeting key LMRGs. Finally, the identified LMRGs were confirmed in the H9C2 cell hypoxia-reoxygenation (H/R) model and the mouse MI/RI model. Results: Enrichment analysis suggested that the "lipid metabolic process" was one of the critical pathways in MI/RI. Further differential expression analysis and PPI analysis identified 120 differentially expressed LMRGs and 15 key LMRGs. 126 miRNAs, 55 TFs, and 51 therapeutic agents were identified targeting these key LMRGs. Lastly, the expression trends of Acadm, Acadvl, and Suclg1 were confirmed by the external datasets, the H/R model and the MI/RI model. Conclusion: Acadm, Acadvl, and Suclg1 may be the key genes involved in the MI/RI-related lipid metabolism dysregulation; and acting upon these factors may serve as a potential therapeutic strategy.

Network Localization of State and Trait of Auditory Verbal Hallucinations in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Neuroimaging studies investigating the neural substrates of auditory verbal hallucinations (AVH) in schizophrenia have yielded mixed results, which may be reconciled by network localization. We sought to examine whether AVH-state and AVH-trait brain alterations in schizophrenia localize to common or distinct networks. STUDY DESIGN: We initially identified AVH-state and AVH-trait brain alterations in schizophrenia reported in 48 previous studies. By integrating these affected brain locations with large-scale discovery and validation resting-state functional magnetic resonance imaging datasets, we then leveraged novel functional connectivity network mapping to construct AVH-state and AVH-trait dysfunctional networks. STUDY RESULTS: The neuroanatomically heterogeneous AVH-state and AVH-trait brain alterations in schizophrenia localized to distinct and specific networks. The AVH-state dysfunctional network comprised a broadly distributed set of brain regions mainly involving the auditory, salience, basal ganglia, language, and sensorimotor networks. Contrastingly, the AVH-trait dysfunctional network manifested as a pattern of circumscribed brain regions principally implicating the caudate and inferior frontal gyrus. Additionally, the AVH-state dysfunctional network aligned with the neuromodulation targets for effective treatment of AVH, indicating possible clinical relevance. CONCLUSIONS: Apart from unifying the seemingly irreproducible neuroimaging results across prior AVH studies, our findings suggest different neural mechanisms underlying AVH state and trait in schizophrenia from a network perspective and more broadly may inform future neuromodulation treatment for AVH.

N-Acetylcysteine Alleviates Phenylephrine-Induced Cardiomyocyte Dysfunction via Engaging PI3K/AKT Signaling Pathway.

BACKGROUND: Increased reactive oxygen species (ROS) and oxidative stress response lead to cardiomyocyte hypertrophy and apoptosis, which play crucial roles in the pathogenesis of heart failure. The purpose of current research was to explore the role of antioxidant N-acetylcysteine (NAC) on cardiomyocyte dysfunction and the underlying molecular mechanisms. METHODS AND RESULTS: Compared with control group without NAC treatment, NAC dramatically inhibited the cell size of primary cultured neonatal rat cardiomyocytes (NRCMs) tested by immunofluorescence staining and reduced the expression of representative markers associated with hypertrophic, fibrosis and apoptosis subjected to phenylephrine administration examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Moreover, enhanced ROS expression was attenuated, whereas activities of makers related to oxidative stress response examined by individual assay Kits, including total antioxidation capacity (T-AOC), glutathione peroxidase (GSH-Px), and primary antioxidant enzyme Superoxide dismutase (SOD) were induced by NAC treatment in NRCMs previously treated with phenylephrine. Mechanistically, we noticed that the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and AKT were increased by NAC stimulation. More importantly, we identified that the negative regulation of NAC in cardiomyocyte dysfunction was contributed by PI3K/AKT signaling pathway through further utilization of PI3K/AKT inhibitor (LY294002) or agonist (SC79). CONCLUSIONS: Collected, NAC could attenuate cardiomyocyte dysfunction subjected to phenylephrine, partially by regulating the ROS-induced PI3K/AKT-dependent signaling pathway.

Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI.

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapy targeting LMCG represented a promising strategy for the treatment of AMI.

Neural mechanism underlying the beneficial effect of Theory of Mind psychotherapy on early-onset schizophrenia: a randomized controlled trial.

BACKGROUND: Psychosocial interventions have emerged as an important component of a comprehensive therapeutic approach in early-onset schizophrenia, typically representing a more severe form of the disorder. Despite the feasibility and efficacy of Theory of Mind (ToM) psychotherapy for schizophrenia, relatively little is known regarding the neural mechanism underlying its effect on early-onset schizophrenia. METHODS: We performed a randomized, active controlled trial in patients with early-onset schizophrenia, who were randomly allocated into either an intervention (ToM psychotherapy) or an active control (health education) group. Diffusion tensor imaging data were collected to construct brain structural networks, with both global and regional topological properties measured using graph theory. RESULTS: We enrolled 28 patients with early-onset schizophrenia in our study. After 5 weeks of treatment, both the intervention and active control groups showed significant improvement in psychotic symptoms, yet the improvement was greater in the intervention group. Importantly, in contrast with no brain structural network change after treatment in the active control group, the intervention group showed increased nodal centrality of the left insula that was associated with psychotic symptom improvement. LIMITATIONS: We did not collect important information concerning the participants' cognitive abilities, particularly ToM performance. CONCLUSION: These findings suggest a potential neural mechanism by which ToM psychotherapy exerts a beneficial effect on early-onset schizophrenia via strengthening the coordination capacity of the insula in brain structural networks, which may provide a clinically translatable biomarker for monitoring or predicting responses to ToM psychotherapy.Clinical trial registration: NCT05577338; ClinicalTrials.gov.

Sintilimab-Induced Myocarditis in a Patient with Gastric Cancer: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) have emerged as a powerful and efficacious therapeutic approach for many cancer patients. Sintilimab is a fully human IgG4 monoclonal antibody that binds with programmed cell death receptor-1 (PD-1) to block its interaction with ligands, thereby enhancing the antitumor effects of T cells. However, ICIs may induce immune-related adverse events (irAEs) in various systems and organs, with fulminant myocarditis being the most severe one. We report the case of a 45-year-old female with gastric cancer who developed chest pain two weeks after chemotherapy with sintilimab; she was diagnosed with immune-associated fulminant myocarditis and experienced an Adams-Stokes syndrome attack in the hospital. Eventually, she was discharged after being treated with methylprednisolone, immunoglobulin, and an IABP.

Transcriptome analysis reveals the mechanism of pyroptosis-related genes in septic cardiomyopathy.

Background: Septic cardiomyopathy (SC) is characterized by myocardial dysfunction caused by sepsis and constitutes one of the serious complications of sepsis. Pyroptosis is a unique proinflammatory programmed cell death process. However, the role of pyroptosis in the development of SC remains unclear, and further study is required. The purpose of this study is to identify pyroptosis-related genes (PRGs) in SC and explore the mechanism of pyroptosis involved in the regulation of SC formation and progression. Methods: Differential expression analysis and enrichment analysis were performed on the SC-related dataset GSE79962 to identify differentially expressed genes (DEGs). PRGs were screened by intersecting genes associated with pyroptosis in previous studies with the DEGs obtained from GSE79962. The expression pattern of them was studied based on their raw expression data. Additionally, corresponding online databases were used to predict miRNAs, transcription factors (TFs) and therapeutic agents of PRGs. Lipopolysaccharide (LPS)-induced cell damage models in H9C2 and AC16 cell lines were constructed, cell activity was detected by CCK-8 and cell pyroptosis were detected by Hoechst33342/PI staining. Furthermore, these PRGs were verified in the external datasets (GSE53007 and GSE142615) and LPS-induced cell damage model. Finally, the effect of siRNA-mediated PRGs knockdown on the pyroptosis phenotype was examined. Results: A total of 1,206 DEGs were screened, consisting of 663 high-expressed genes and 543 low-expressed genes. Among them, ten PRGs (SOD2, GJA1, TIMP3, TAP1, TIMP1, NOD1, TP53, CPTP, CASP1 and SAT1) were identified, and they were mainly enriched in "Pyroptosis", "Ferroptosis", "Longevity regulating pathway", and "NOD-like receptor signaling pathway". A total of 147 miRNAs, 31 TFs and 13 therapeutic drugs were predicted targeting the PRGs. The expression trends of SOD2 were confirmed in both the external datasets and LPS-induced cell damage models. Knockdown of SOD2 induced increased pyroptosis in the AC16 LPS-induced cell damage model. Conclusions: In this study, we demonstrated that SOD2 is highly expressed in both the SC and LPS-induced cell damage models. Knockdown of SOD2 led to a significant increase in pyroptosis in the AC16 LPS-induced cell damage model. These findings suggest that SOD2 may serve as a potential target for the diagnosis and treatment of SC.

Molecular mechanisms underlying resting-state brain functional correlates of behavioral inhibition.

Previous literature has established the presence of sex differences in behavioral inhibition as well as its neural substrates and related disease risk. However, there is limited evidence that speaks directly to the question of whether or not there are sex-dependent associations between behavioral inhibition and resting-state brain function and, if so, how they are modulated by the underlying molecular mechanisms. We computed functional connectivity density (FCD) using resting-state functional MRI data to examine their associations with behavioral inhibition ability measured using a Go/No-Go task across a large cohort of 510 healthy young adults. Then, we examined the spatial relationships of the FCD correlates of behavioral inhibition with gene expression and neurotransmitter atlases to explore their potential genetic architecture and neurochemical basis. A significant negative correlation between behavioral inhibition and FCD in the left superior parietal lobule was found in females but not males. Further spatial correlation analyses demonstrated that the identified neural correlates of behavioral inhibition were associated with expression of gene categories predominantly implicating essential components of the cerebral cortex (glial cell, neuron, axon, dendrite, and synapse) and ion channel activity, as well as were linked to the serotonergic system. Our findings may not only yield important insights into the molecular mechanisms underlying the female-specific neural substrates of behavioral inhibition, but also provide a critical context for understanding how biological sex might contribute to variation in behavioral inhibition and its related disease risk.

Protein O-GlcNAcylation in multiple immune cells and its therapeutic potential.

O-GlcNAcylation is a post-translational modification of proteins that involves the addition of O-GlcNAc to serine or threonine residues of nuclear or cytoplasmic proteins, catalyzed by O-GlcNAc transferase (OGT). This modification is highly dynamic and can be reversed by O-GlcNAcase (OGA). O-GlcNAcylation is widespread in the immune system, which engages in multiple physiologic and pathophysiologic processes. There is substantial evidence indicating that both the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation are critically involved in regulating immune cell function. However, the precise role of O-GlcNAcylation in the immune system needs to be adequately elucidated. This review offers a thorough synopsis of the present research on protein O-GlcNAcylation, accentuating the molecular mechanisms that control immune cells' growth, maturation, and performance via this PTM.

MAVS integrates glucose metabolism and RIG-I-like receptor signaling.

MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling in mitochondria, peroxisomes, and mitochondria-associated ER membranes (MAMs). However, the role of MAVS in glucose metabolism and RLR signaling cross-regulation and how these signaling pathways are coordinated among these organelles have not been defined. This study reports that RLR action drives a switch from glycolysis to the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP) through MAVS. We show that peroxisomal MAVS is responsible for glucose flux shift into PPP and type III interferon (IFN) expression, whereas MAMs-located MAVS is responsible for glucose flux shift into HBP and type I IFN expression. Mechanistically, peroxisomal MAVS interacts with G6PD and the MAVS signalosome forms at peroxisomes by recruiting TNF receptor-associated factor 6 (TRAF6) and interferon regulatory factor 1 (IRF1). By contrast, MAMs-located MAVS interact with glutamine-fructose-6-phosphate transaminase, and the MAVS signalosome forms at MAMs by recruiting TRAF6 and TRAF2. Our findings suggest that MAVS mediates the interaction of RLR signaling and glucose metabolism.

Immune Cell Infiltration Analysis Based on Bioinformatics Reveals Novel Biomarkers of Coronary Artery Disease.

Background: Coronary artery disease (CAD) is a multifactorial immune disease, but research into the specific immune mechanism is still needed. The present study aimed to identify novel immune-related markers of CAD. Methods: Three CAD-related datasets (GSE12288, GSE98583, GSE113079) were downloaded from the Gene Expression Integrated Database. Gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and weighted gene co-expression network analysis were performed on the common significantly differentially expressed genes (DEGs) of these three data sets, and the most relevant module genes for CAD obtained. The immune cell infiltration of module genes was evaluated with the CIBERSORT algorithm, and characteristic genes accompanied by their diagnostic effectiveness were screened by the machine-learning algorithm least absolute shrinkage and selection operator (LASSO) regression analysis. The expression levels of characteristic genes were evaluated in the peripheral blood mononuclear cells of CAD patients and healthy controls for verification. Results: A total of 204 upregulated and 339 downregulated DEGs were identified, which were mainly enriched in the following pathways: "Apoptosis", "Th17 cell differentiation", "Th1 and Th2 cell differentiation", "Glycerolipid metabolism", and "Fat digestion and absorption". Five characteristic genes, LMAN1L, DOK4, CHFR, CEL and CCDC28A, were identified by LASSO analysis, and the results of the immune cell infiltration analysis indicated that the proportion of immune infiltrating cells (activated CD8 T cells and CD56 DIM natural killer cells) in the CAD group was lower than that in the control group. The expressions of CHFR, CEL and CCDC28A in the peripheral blood of the healthy controls and CAD patients were significantly different. Conclusion: We identified CHFR, CEL and CCDC28A as potential biomarkers related to immune infiltration in CAD based on public data sets and clinical samples. This finding will contribute to providing a potential target for early noninvasive diagnosis and immunotherapy of CAD.

Nek6 knockdown polarized macrophages into a pro-inflammatory phenotype via inhibiting STAT3 expression.

Recently macrophage polarization has emerged as playing an essential role in the oathogenesis of atherosclerosis, which is the most important underlying process in many types of cardiovascular diseases. Although Nek6 has been reported to be involved in various cellular processes, the effect of Nek6 on macrophage polarization remains unknown. Macrophages exposed to lipopolysaccharide (LPS) or IL-4 were used to establish an in vitro model for the study of regulation of classically (M1) or alternatively (M2) activated macrophage. Bone marrow-derived macrophages (BMDMs) transfected with short hairpin RNA-targeting Nek6 were then in functional studies. We observed that Nek6 expression was decreased in both peritoneal macrophages (PMs) and BMDMs stimulated by LPS. This effect was seen at both mRNA and protein level. The opposite results were obtained after administration of IL-4. Macrophage-specific Nek6 knockdown significantly exacerbated pro-inflammatory M1 polarized macrophage gene expression in response to LPS challenge, but the anti-inflammatory response gene expression that is related to M2 macrophages was attenuated by Nek6 silencing followed by treatment with IL-4. Mechanistic studies exhibited that Nek6 knockdown inhibited the phosphorylated STAT3 expression that mediated the effect on macrophage polarization regulated by AdshNek6. Moreover, decreased Nek6 expression was also observed in atherosclerotic plaques. Collectively, these evidences suggested that Nek6 acts as a crucial site in macrophage polarization, and that this operates in a STAT3-dependent manner.

Functional connectivity gradients of the cingulate cortex.

Heterogeneity of the cingulate cortex is evident in multiple dimensions including anatomy, function, connectivity, and involvement in networks and diseases. Using the recently developed functional connectivity gradient approach and resting-state functional MRI data, we found three functional connectivity gradients that captured distinct dimensions of cingulate hierarchical organization. The principal gradient exhibited a radiating organization with transitions from the middle toward both anterior and posterior parts of the cingulate cortex and was related to canonical functional networks and corresponding behavioral domains. The second gradient showed an anterior-posterior axis across the cingulate cortex and had prominent geometric distance dependence. The third gradient displayed a marked differentiation of subgenual and caudal middle with other parts of the cingulate cortex and was associated with cortical morphology. Aside from providing an updated framework for understanding the multifaceted nature of cingulate heterogeneity, the observed hierarchical organization of the cingulate cortex may constitute a novel research agenda with potential applications in basic and clinical neuroscience.

The hierarchical organization of the precuneus captured by functional gradients.

The precuneus shows considerable heterogeneity in multiple dimensions including anatomy, function, and involvement in brain disorders. Leveraging the state-of-the-art functional gradient approach, we aimed to investigate the hierarchical organization of the precuneus, which may hold promise for a unified understanding of precuneus heterogeneity. Resting-state functional MRI data from 793 healthy individuals were used to discover and validate functional gradients of the precuneus, which were calculated based on the voxel-wise precuneus-to-cerebrum functional connectivity patterns. Then, we further explored the potential relationships of the precuneus functional gradients with cortical morphology, intrinsic geometry, canonical functional networks, and behavioral domains. We found that the precuneus principal and secondary gradients showed dorsoanterior-ventral and ventroposterior-dorsal organizations, respectively. Concurrently, the principal gradient was associated with cortical morphology, and both the principal and secondary gradients showed geometric distance dependence. Importantly, precuneus functional subdivisions corresponding to canonical functional networks (behavioral domains) were distributed along both gradients in a hierarchical manner, i.e., from the sensorimotor network (somatic movement and sensation) at one extreme to the default mode network (abstract cognitive functions) at the other extreme for the principal gradient and from the visual network (vision) at one end to the dorsal attention network (top-down control of attention) at the other end for the secondary gradient. These findings suggest that the precuneus functional gradients may provide mechanistic insights into the multifaceted nature of precuneus heterogeneity.

Dopamine D2 receptor on CD4+ T cells is protective against inflammatory responses and signs in a mouse model of rheumatoid arthritis.

BACKGROUND: Dopamine is a neurotransmitter and has been found to regulate lymphocytes by acting on dopamine receptors (DRs). CD4+ T cells express all the five subtypes of DRs, D1R to D5R. Although CD4+ T cells have been involved in pathogenesis of rheumatoid arthritis (RA), roles of DRs expressed on these cells in RA are poorly understood. This study determined whether D2R expressed on CD4+ T cells regulates inflammatory responses and signs in collagen type II (CII)-induced arthritis (CIA), a mouse model of RA. METHODS: DBA/1 mice and C57BL/6 mice with global D1r or D2r deficiency (D1r-/- or D2r-/-) or CD4+ T cell-specific D2r deletion (D2rfl/fl/CD4Cre) were used to prepare CIA model by intradermal injection of CII. D2R agonist sumanirole was intraperitoneally administered in CIA mice. CD4+ T cells obtained from CIA mice were exposed to sumanirole or/and D2R antagonist L-741,626 in vitro. Arthritic symptoms were assessed by clinical arthritis scores. Flow cytometric assay measured frequencies of CD4+ T cell subsets (Th1, Th2, Th17 and Treg cells). Expression of specific transcription factors for the CD4+ T cell subsets was tested by Western blot. Cytokine production was estimated by quantitative PCR and ELISA. RESULTS: CIA mice manifested a bias of CD4+ T cells towards Th1 and Th17 cells. D2r-/- CIA mice showed a stronger bias towards Th1 and Th17 phenotypes than CIA mice, while D1r-/- CIA mice did not show the changes. CD4+ T cell-specific D2r deletion exacerbated both the polarization towards Th1 and Th17 cells and the symptoms of arthritis. Sumanirole administration in CIA mice ameliorated the bias of CD4+ T cells towards Th1 and Th17 phenotypes as well as arthritic symptoms. Sumanirole treatment of in vitro CD4+ T cells obtained from CIA mice promoted the shift to Treg cells, and the effect of sumanirole was blocked by L-741,626. CONCLUSIONS: D2R expressed on CD4+ T cells is protective against imbalance between pro-inflammatory and anti-inflammatory T cells and arthritic symptoms in CIA.