SSH3 promotes pancreatic cancer proliferation and migration by activating the notch signaling pathway.

Recent studies have indicated that the dual-specificity phosphatases (DUSP) family may play a role in the advancement of pancreatic cancer. Exploring the role of the DUSP family in pancreatic cancer development and discovering novel therapeutic targets are crucial for pancreatic cancer therapy. A critical subset of 20 genes exhibiting differential expression was identified, with particular emphasis on four key genes: DUSP10, PTP4A2, SSH3, and CDKN3 by multivariate Cox proportional hazards analysis. These genes were integral to developing a novel risk model for PC, which has been independently validated as a prognostic factor for patients. To provide help for clinical treatment, we performed tumor immune analysis and predicted potential chemical drugs. Notably, our research unveiled elevated expression levels of SSH3 in human PC cells and tissues. Intriguingly, SSH3 expression correlates with the patient grade, staging, and T stage in PC. Additional studies reveal SSH3's role in enhancing PC cell proliferation and migration, intricately linked to the activation of the Notch signaling pathway. These insights provide a deeper understanding of PC pathophysiology and pave the way for novel therapeutic interventions.

Frequency-dependent alterations of global signal topography in patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated not only with disorders in multiple brain networks but also with frequency-specific brain activities. The abnormality of spatiotemporal networks in patients with MDD remains largely unclear. METHODS: We investigated the alterations of the global spatiotemporal network in MDD patients using a large-sample multicenter resting-state functional magnetic resonance imaging dataset. The spatiotemporal characteristics were measured by the variability of global signal (GS) and its correlation with local signals (GSCORR) at multiple frequency bands. The association between these indicators and clinical scores was further assessed. RESULTS: The GS fluctuations were reduced in patients with MDD across the full frequency range (0-0.1852 Hz). The GSCORR was also reduced in the MDD group, especially in the relatively higher frequency range (0.0728-0.1852 Hz). Interestingly, these indicators showed positive correlations with depressive scores in the MDD group and relative negative correlations in the control group. CONCLUSION: The GS and its spatiotemporal effects on local signals were weakened in patients with MDD, which may impair inter-regional synchronization and related functions. Patients with severe depression may use the compensatory mechanism to make up for the functional impairments.

Spatiotemporal dedifferentiation of the global brain signal topography along the adult lifespan.

Age-related variations in many regions and/or networks of the human brain have been uncovered using resting-state functional magnetic resonance imaging. However, these findings did not account for the dynamical effect the brain's global activity (global signal [GS]) causes on local characteristics, which is measured by GS topography. To address this gap, we tested GS topography including its correlation with age using a large-scale cross-sectional adult lifespan dataset (n = 492). Both GS topography and its variation with age showed frequency-specific patterns, reflecting the spatiotemporal characteristics of the dynamic change of GS topography with age. A general trend toward dedifferentiation of GS topography with age was observed in both spatial (i.e., less differences of GS between different regions) and temporal (i.e., less differences of GS between different frequencies) dimensions. Further, methodological control analyses suggested that although most age-related dedifferentiation effects remained across different preprocessing strategies, some were triggered by neuro-vascular coupling and physiological noises. Together, these results provide the first evidence for age-related effects on global brain activity and its topographic-dynamic representation in terms of spatiotemporal dedifferentiation.

Frequency-dependent effective connections between local signals and the global brain signal during resting-state.

The psychological and physiological meanings of resting-state global brain signal (GS) and GS topography have been well confirmed. However, the causal relationship between GS and local signals was largely unknown. Based on the Human Connectome Project dataset, we investigated the effective GS topography using the Granger causality (GC) method. In consistent with GS topography, both effective GS topographies from GS to local signals and from local signals to GS showed greater GC values in sensory and motor regions in most frequency bands, suggesting that the unimodal superiority is an intrinsic architecture of GS topography. However, the significant frequency effect for GC values from GS to local signals was primarily located in unimodal regions and dominated at slow 4 frequency band whereas that from local signals to GS was mainly located in transmodal regions and dominated at slow 6 frequency band, consisting with the opinion that the more integrated the function, the lower the frequency. These findings provided valuable insight for the frequency-dependent effective GS topography, improving the understanding of the underlying mechanism of GS topography. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09831-0.

The thalamus is the causal hub of intervention in patients with major depressive disorder: Evidence from the Granger causality analysis.

Major depressive disorder (MDD) is the leading mental disorder and afflicts more than 350 million people worldwide. The underlying neural mechanisms of MDD remain unclear, hindering the accurate treatment. Recent brain imaging studies have observed functional abnormalities in multiple brain regions in patients with MDD, identifying core brain regions is the key to locating potential therapeutic targets for MDD. The Granger causality analysis (GCA) measures directional effects between brain regions and, therefore, can track causal hubs as potential intervention targets for MDD. We reviewed literature employing GCA to investigate abnormal brain connections in patients with MDD. The total degree of effective connections in the thalamus (THA) is more than twice that in traditional targets such as the superior frontal gyrus and anterior cingulate cortex. Altered causal connections in patients with MDD mainly included enhanced bottom-up connections from the thalamus to various cortical and subcortical regions and reduced top-down connections from these regions to the THA, indicating excessive uplink sensory information and insufficient downlink suppression information for negative emotions. We suggest that the thalamus is the most crucial causal hub for MDD, which may serve as the downstream target for non-invasive brain stimulation and medication approaches in MDD treatment.

MJDs family members: Potential prognostic targets and immune-associated biomarkers in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal malignancies. It is not easy to be diagnosed in the early stage and is prone to relapse, with a very poor prognosis. And immune cell infiltration and tumor microenvironment play important roles in predicting therapeutic response and prognosis of HCC. Machado-Joseph domain-containing proteases (MJDs), as a gene family extensively involved in tumor progression, has pro-cancer and anti-cancer effects. However, the relationship between MJDs family members and immune cell infiltration and tumor microenvironment in HCC remains unclear. Therefore, cBio Cancer Genomics Portal (cBioPortal), The Cancer Genome Atlas (TCGA), UALCAN, Human Protein Atlas (HPA), MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were performed to investigate the mRNA expression, DNA methylation, clinicopathologic features, immune cell infiltration and other related functions of MJDs family members in HCC. The results indicated that the expression of ATXN3, JOSD1, and JOSD2 was dramatically increased in HCC tissues and cell lines, and was correlated with histological grade, specimen type, TP53 mutation, lymph node metastatic, gender, and age of patients with HCC. Meanwhile, these genes also showed clinical value in improving the overall survival (OS), disease-specific survival (DSS), progression free survival (PFS), and relapse-free survival (RFS) in patients with HCC. The prognostic model indicated that the worse survival was associated with overall high expression of MJDs members. Next, the results suggested that promotor methylation levels of the MJDs family were closely related to these family mRNA expression levels, clinicopathologic features, and prognostic values in HCC. Moreover, the MJDs family were significantly correlated with CD4+ T cells, CD8+ T cells, B cells, neutrophils, macrophages, and DCs. And MJDs family members' expression were substantially associated with the levels of several lymphocytes, immunomoinhibitors, immunomostimulators, chemokine ligands, and chemokine receptors. In addition, the expression levels of MJDs family were significantly correlated with cancer-related signaling pathways. Taken together, our results indicated that the aberrant expression of MJDs family in HCC played a critical role in clinical feature, prognosis, tumor microenvironment, immune-related molecules, mutation, gene copy number, and promoter methylation level. And MJDs family may be effective immunotherapeutic targets for patients with HCC and have the potential to be prognostic biomarkers.

The temporal dedifferentiation of global brain signal fluctuations during human brain ageing.

The variation of brain functions as healthy ageing has been discussed widely using resting-state brain imaging. Previous conclusions may be misinterpreted without considering the effects of global signal (GS) on local brain activities. Up to now, the variation of GS with ageing has not been estimated. To fill this gap, we defined the GS as the mean signal of all voxels in the gray matter and systematically investigated correlations between age and indices of GS fluctuations. What's more, these tests were replicated with data after hemodynamic response function (HRF) de-convolution and data without noise regression as well as head motion data to verify effects of non-neural information on age. The results indicated that GS fluctuations varied as ageing in three ways. First, GS fluctuations were reduced with age. Second, the GS power transferred from lower frequencies to higher frequencies with age. Third, the GS power was more evenly distributed across frequencies in ageing brain. These trends were partly influenced by HRF and physiological noise, indicating that the age effects of GS fluctuations are associated with a variety of physiological activities. These results may indicate the temporal dedifferentiation hypothesis of brain ageing from the global perspective.

Global Signal Topography of the Human Brain: A Novel Framework of Functional Connectivity for Psychological and Pathological Investigations.

The global signal (GS), which was once regarded as a nuisance of functional magnetic resonance imaging, has been proven to convey valuable neural information. This raised the following question: what is a GS represented in local brain regions? In order to answer this question, the GS topography was developed to measure the correlation between global and local signals. It was observed that the GS topography has an intrinsic structure characterized by higher GS correlation in sensory cortices and lower GS correlation in higher-order cortices. The GS topography could be modulated by individual factors, attention-demanding tasks, and conscious states. Furthermore, abnormal GS topography has been uncovered in patients with schizophrenia, major depressive disorder, bipolar disorder, and epilepsy. These findings provide a novel insight into understanding how the GS and local brain signals coactivate to organize information in the human brain under various brain states. Future directions were further discussed, including the local-global confusion embedded in the GS correlation, the integration of spatial information conveyed by the GS, and temporal information recruited by the connection analysis. Overall, a unified psychopathological framework is needed for understanding the GS topography.