Diabetes mellitus induces a pathophysiological disorder known as diabetic cardiomyopathy and may eventually cause heart failure. Diabetic cardiomyopathy is manifested with systolic and diastolic contractile dysfunction along with alterations in unique cardiomyocyte proteins and diminished cardiomyocyte contraction. Multiple mechanisms contribute to the pathology of diabetic cardiomyopathy, mainly including abnormal insulin metabolism, hyperglycemia, glycotoxicity, cardiac lipotoxicity, endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, calcium treatment damage, programmed myocardial cell death, improper Renin-Angiotensin-Aldosterone System activation, maladaptive immune modulation, coronary artery endothelial dysfunction, exocrine dysfunction, etc. There is an urgent need to investigate the exact pathogenesis of diabetic cardiomyopathy and improve the diagnosis and treatment of this disease. The nuclear receptor superfamily comprises a group of transcription factors, such as liver X receptor, retinoid X receptor, retinoic acid-related orphan receptor-α, retinoid receptor, vitamin D receptor, mineralocorticoid receptor, estrogen-related receptor, peroxisome proliferatoractivated receptor, nuclear receptor subfamily 4 group A 1(NR4A1), etc. Various studies have reported that nuclear receptors play a crucial role in cardiovascular diseases. A recently conducted work highlighted the function of the nuclear receptor superfamily in the realm of metabolic diseases and their associated complications. This review summarized the available information on several important nuclear receptors in the pathophysiology of diabetic cardiomyopathy and discussed future perspectives on the application of nuclear receptors as targets for diabetic cardiomyopathy treatment.

Attention is often viewed as a mental spotlight, which can be scaled like a zoom lens at specific spatial locations and features a center-surround gradient. Here, we demonstrate a neural signature of attention spotlight in signal transmission along the visual hierarchy. fMRI background connectivity analysis was performed between retinotopic V1 and downstream areas to characterize the spatial distribution of inter-areal interaction under two attentional states. We found that, compared to diffused attention, focal attention sharpened the spatial gradient in the strength of the background connectivity. Dynamic causal modeling analysis further revealed the effect of attention in both the feedback and feedforward connectivity between V1 and extrastriate cortex. In a context which induced a strong effect of crowding, the effect of attention in the background connectivity profile diminished. Our findings reveal a context-dependent attention prioritization in information transmission via modulating the recurrent processing across the early stages in human visual cortex.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism.
RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα).
CONCLUSIONS: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

UNASSIGNED: The involvement of specific basal ganglia-thalamocortical circuits in response inhibition has been extensively mapped in animal models. However, the pivotal nodes and directed causal regulation within this inhibitory circuit in humans remains controversial.
UNASSIGNED: The main aim of the present study was to determine the causal information flow and critical nodes in the basal ganglia-thalamocortical inhibitory circuits and also to examine whether these are modulated by biological factors (i.e. sex) and behavioral performance.
UNASSIGNED: Here, we capitalize on the recent progress in robust and biologically plausible directed causal modeling (DCM-PEB) and a large response inhibition dataset (n = 250) acquired with concomitant functional magnetic resonance imaging to determine key nodes, their causal regulation and modulation via biological variables (sex) and inhibitory performance in the inhibitory circuit encompassing the right inferior frontal gyrus (rIFG), caudate nucleus (rCau), globus pallidum (rGP), and thalamus (rThal).
UNASSIGNED: The entire neural circuit exhibited high intrinsic connectivity and response inhibition critically increased causal projections from the rIFG to both rCau and rThal. Direct comparison further demonstrated that response inhibition induced an increasing rIFG inflow and increased the causal regulation of this region over the rCau and rThal. In addition, sex and performance influenced the functional architecture of the regulatory circuits such that women displayed increased rThal self-inhibition and decreased rThal to GP modulation, while better inhibitory performance was associated with stronger rThal to rIFG communication. Furthermore, control analyses did not reveal a similar key communication in a left lateralized model.
UNASSIGNED: Together, these findings indicate a pivotal role of the rIFG as input and causal regulator of subcortical response inhibition nodes.

BACKGROUND: Diabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM\'s unique cell states and molecular landscape for targeted therapeutic interventions.
METHODS: Single-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings.
RESULTS: This study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation.
CONCLUSIONS: Our integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.

Background: Dysfunction in myocardial energy metabolism plays a vital role in the pathological process of Dilated Cardiomyopathy (DCM). However, the precise mechanisms remain unclear. This study aims to investigate the key molecular mechanisms of energy metabolism and potential therapeutic agents in the progression of dilated cardiomyopathy with heart failure. Methods: Gene expression profiles and clinical data for patients with dilated cardiomyopathy complicated by heart failure, as well as healthy controls, were sourced from the Gene Expression Omnibus (GEO) database. Gene sets associated with energy metabolism were downloaded from the Molecular Signatures Database (MSigDB) for subsequent analysis. Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis were employed to identify key modules and genes related to heart failure. Potential biological mechanisms were investigated through Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the construction of a competing endogenous RNA (ceRNA) network. Molecular docking simulations were then conducted to explore the binding affinity and conformation of potential therapeutic drugs with hub genes. Results: Analysis of the left ventricular tissue expression profiles revealed that, compared to healthy controls, patients with dilated cardiomyopathy exhibited 234 differentially expressed genes and 2 genes related to myocardial energy metabolism. Additionally, Benzoylaconine may serve as a potential therapeutic agent for the treatment of dilated cardiomyopathy. Conclusion: The study findings highlight the crucial role of myocardial energy metabolism in the progression of Dilated Cardiomyopathy. Notably, Benzoylaconine emerges as a potential candidate for treating Dilated Cardiomyopathy, potentially exerting its therapeutic effects by targeted modulation of myocardial energy metabolism through NRK and NT5.

UNASSIGNED: Cognitive deficits are common in rheumatoid arthritis (RA) patients, but the mechanisms remain unclear. We investigated the effective connectivity and structural alterations of the core brain regions in RA patients with cognitive impairment.
UNASSIGNED: Twenty-four female patients with RA and twenty-four healthy controls were enrolled. We analyzed abnormal brain activity patterns using functional MRI during the Iowa gambling task (IGT) and core regions effective connectivity using dynamic causal model (DCM). Structural alterations of white matter volume (WMV) and gray matter volume (GMV) were detected using voxel-based morphometry (VBM).
UNASSIGNED: RA patients showed altered activation patterns of the cortico-thalamo-cortical network, increased coupling strength from the left ventromedial prefrontal gyrus to the anterior cingulate cortex (ACC), the ACC to the right thalamus, and decreased connectivity from the thalamus to left hippocampus. VBM structural analysis showed increased GMV in the bilateral orbital frontal gyrus, bilateral hippocampus and right putamen, and reduced GMV and WMV in the bilateral thalamus in RA patients. Right thalamic GMV and WMV were positively correlated with the right thalamus-to-hippocampus connective strength. Additionally, the bold signal, GMV and WMV of the right thalamus were positively correlated with cognitive performance (IGT score) in RA patients.
UNASSIGNED: Results suggest a structural and functional deficiency in the cortico-thalamo-cortical network, which is characterized by increased ACC-to-thalamus strength and reduced thalamus-to-hippocampus coupling in RA patients. The cognitive dysfunction may be the result of compensatory measures against imbalanced cortico-thalamic-cortical coupling.

A target circle surrounded by small circles looks larger than an identical circle surrounded by large circles (termed as the Ebbinghaus illusion). While previous research has shown that both early and high-level visual regions are involved in the generation of the illusion, it remains unclear how these regions work together to modulate the illusion effect. Here, we used functional MRI and dynamic causal modelling to investigate the neural networks underlying the illusion in conditions where the focus of attention was manipulated via participants directing their attention to and maintain fixation on only one of the two illusory configurations at a time. Behavioural findings confirmed the presence of the illusion. Accordingly, functional MRI activity in the extrastriate cortex accounted for the illusory effects: apparently larger circles elicited greater activation than apparently smaller circles. Interestingly, this spread of activity for size overestimation was accompanied by a decrease in the inhibitory self-connection in the extrastriate region, and an increase in the feedback connectivity from the precuneus to the extrastriate region. These findings demonstrate that the representation of apparent object size relies on feedback projections from higher- to lower-level visual areas, highlighting the crucial role of top-down signals in conscious visual perception.

Effective visual search is essential for daily life, and attention orientation as well as inhibition of return play a significant role in visual search. Researches have established the involvement of dorsolateral prefrontal cortex in cognitive control during selective attention. However, neural evidence regarding dorsolateral prefrontal cortex modulates inhibition of return in visual search is still insufficient. In this study, we employed event-related functional magnetic resonance imaging and dynamic causal modeling to develop modulation models for two types of visual search tasks. In the region of interest analyses, we found that the right dorsolateral prefrontal cortex and temporoparietal junction were selectively activated in the main effect of search type. Dynamic causal modeling results indicated that temporoparietal junction received sensory inputs and only dorsolateral prefrontal cortex →temporoparietal junction connection was modulated in serial search. Such neural modulation presents a significant positive correlation with behavioral reaction time. Furthermore, theta burst stimulation via transcranial magnetic stimulation was utilized to modulate the dorsolateral prefrontal cortex region, resulting in the disappearance of the inhibition of return effect during serial search after receiving continuous theta burst stimulation. Our findings provide a new line of causal evidence that the top-down modulation by dorsolateral prefrontal cortex influences the inhibition of return effect during serial search possibly through the retention of inhibitory tagging via working memory storage.

Dilated cardiomyopathy (DCM) is one of the most common primary myocardial diseases. However, to this day, it remains an enigmatic cardiovascular disease (CVD) characterized by ventricular dilatation, which leads to myocardial contractile dysfunction. It is the most common cause of chronic congestive heart failure and the most frequent indication for heart transplantation in young individuals. Genetics and various other factors play significant roles in the progression of dilated cardiomyopathy, and variants in more than 50 genes have been associated with the disease. However, the etiology of a large number of cases remains elusive. Numerous studies have been conducted on the genetic causes of dilated cardiomyopathy. These genetic studies suggest that mutations in genes for fibronectin, cytoskeletal proteins, and myosin in cardiomyocytes play a key role in the development of DCM. In this review, we provide a comprehensive description of the genetic basis, mechanisms, and research advances in genes that have been strongly associated with DCM based on evidence-based medicine. We also emphasize the important role of gene sequencing in therapy for potential early diagnosis and improved clinical management of DCM.