Role of Circular RNAs in Atherosclerosis through Regulation of Inflammation, Cell Proliferation, Migration, and Apoptosis: Focus on Atherosclerotic Cerebrovascular Disease.

Atherosclerosis (AS) is a disease dangerous to human health and the main pathological cause of ischemic cardiovascular diseases. Although its pathogenesis is not fully understood, numerous basic and clinical studies have shown that AS is a chronic inflammatory disease existing in all stages of atherogenesis. It may be a common link or pathway in the pathogenesis of multiple atherogenic factors. Inflammation is associated with AS complications, such as plaque rupture and ischemic cerebral infarction. In addition to inflammation, apoptosis plays an important role in AS. Apoptosis is a type of programmed cell death, and different apoptotic cells have different or even opposite roles in the process of AS. Unlike linear RNA, circular RNA (circRNA) a covalently closed circular non-coding RNA, is stable and can sponge miRNA, which can affect the stages of AS by regulating downstream pathways. Ultimately, circRNAs play very important roles in AS by regulating inflammation, apoptosis, and some other mechanisms. The study of circular RNAs can provide new ideas for the prediction, prevention, and treatment of AS.

Opportunities and challenges of glioma organoids.

Glioma is the most common primary brain tumor and its prognosis is poor. Despite surgical removal, glioma is still prone to recurrence because it grows rapidly in the brain, is resistant to chemotherapy, and is highly aggressive. Therefore, there is an urgent need for a platform to study the cell dynamics of gliomas in order to discover the characteristics of the disease and develop more effective treatments. Although 2D cell models and animal models in previous studies have provided great help for our research, they also have many defects. Recently, scientific researchers have constructed a 3D structure called Organoids, which is similar to the structure of human tissues and organs. Organoids can perfectly compensate for the shortcomings of previous glioma models and are currently the most suitable research platform for glioma research. Therefore, we review the three methods currently used to establish glioma organoids. And introduced how they play a role in the diagnosis and treatment of glioma. Finally, we also summarized the current bottlenecks and difficulties encountered by glioma organoids, and the current efforts to solve these difficulties. Video Abstract.

[Mobilization of Bone Marrow Mesenchymal Stem Cells Inhibits TGF-ß Non-classical Pathway Against Myocardial Fibrosis in Rats].

OBJECTIVE: To observe the relationship between the mechanism of bone marrow stem cell mobilization mediated the myocardial fibrosis inhibition in rats and the non-classical pathway mediated by transforming growth factor-ß (TGF-ß). METHODS: Twenty two Wistar rats were subcutaneously injected with isoproterenol (Iso) to establish the model of myocardial fibrosis, and then were randomly divided into control group and granulocyte colony-stimulating factor (G-CSF)-treat group (GT group). The rats in GT group were subcutaneously injected with recombinant human granulocyte stimulating factor for 5 days, and the control group was injected with normal saline. After 4 weeks, the myocardial structure was observed by pathological staining, the content of serum B type natriuretic peptide (BNP) was detected by ELISA , the expression of type Ⅲ collagen was detected by immunohistochemistry staining and the protein expression level of typeⅠcollagen, TGF-ß, transforming growth factor kinase 1 (TAK1), mitogen-activated protein kinase kinase (MKK) and p38 mitogen-activated protein kinase (p38MAPK) was determined by Western blot. RESULTS: Compared with the control group, the serum BNP level, Masson staining collagen deposition, collagen area ratio and the expression of typeⅠcollagen, TGF- ß, TAK1, MKK3 and p38MAPK in the GT group were lower than those in the control group. CONCLUSION: Bone marrow stem cell mobilization can alleviate the degree of myocardial fibrosis in rats, which is related to the inhibition of TGF- ß/TAK1/MKK/p38MAPK pathway.

Decreased Spontaneous Brain Activity and Functional Connectivity in Type 1 Diabetic Patients Without Microvascular Complications.

BACKGROUND/AIMS: Type 1 diabetes mellitus (T1DM) has been proven to be associated with an increased risk of cognitive dysfunction. In this study, we aimed to investigate whether disrupted spontaneous activity and functional connectivity (FC) exist in T1DM patients using resting-state functional magnetic resonance imaging (rs-fMRI) and to detect the relationships of these parameters with cognitive impairment. METHODS: T1DM patients (n=35) were compared with age-, sex-, and education level-matched healthy controls (n=50) through rs-fMRI. Using rs-fMRI professional software, we calculated the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and seed-based FC in the posterior cingulate cortex (PCC) to measure the spontaneous neural activity in the groups. The relationship between rs-fMRI data and cognitive performance was further investigated. RESULTS: Compared with the healthy controls, T1DM patients showed significantly decreased ALFF values in the PCC and right inferior frontal gyrus (IFG), decreased ReHo values in the right middle frontal gyrus (MFG) and reduced FC between the PCC and the right MFG. Furthermore, a positive correlation was found between decreased ALFF values in the PCC and Rey-Osterrieth Complex Figure Test (CFT)-delay scores in T1DM patients (r=0.394, p=0.026). Moreover, the Trail Making Test-B (TMT-B) scores showed negative correlations with decreased ReHo values in the right MFG (r=-0.468, p=0.007) and reduced FC between the PCC and right MFG (r=-0.425, p=0.015). CONCLUSION: Our combined analyses revealed decreased spontaneous activity and FC mainly within the default mode network, which was correlated with specific impaired cognitive functioning in T1DM. This study thus elucidates the neurophysiological mechanisms underlying T1DM-related cognitive impairment and may serve as a reference for future clinical diagnosis.

Energy Efficient Pico Cell Range Expansion and Density Joint Optimization for Heterogeneous Networks with eICIC.

Heterogeneous networks, constituted by conventional macro cells and overlaying pico cells, have been deemed a promising paradigm to support the deluge of data traffic with higher spectral efficiency and Energy Efficiency (EE). In order to deploy pico cells in reality, the density of Pico Base Stations (PBSs) and the pico Cell Range Expansion (CRE) are two important factors for the network spectral efficiency as well as EE improvement. However, associated with the range and density evolution, the inter-tier interference within the heterogeneous architecture will be challenging, and the time domain Enhanced Inter-cell Interference Coordination (eICIC) technique becomes necessary. Aiming to improve the network EE, the above factors are jointly considered in this paper. More specifically, we first derive the closed-form expression of the network EE as a function of the density of PBSs and pico CRE bias based on stochastic geometry theory, followed by a linear search algorithm to optimize the pico CRE bias and PBS density, respectively. Moreover, in order to realize the pico CRE bias and PBS density joint optimization, a heuristic algorithm is proposed to achieve the network EE maximization. Numerical simulations show that our proposed pico CRE bias and PBS density joint optimization algorithm can improve the network EE significantly with low computational complexity.

Saitohin Q7R polymorphism is associated with late-onset Alzheimer's disease susceptibility among caucasian populations: a meta-analysis.

Saitohin (STH) Q7R polymorphism has been reported to influence the individual's susceptibility to Alzheimer's disease (AD); however, conclusions remain controversial. Therefore, we performed this meta-analysis to explore the association between STH Q7R polymorphism and AD risk. Systematic literature searches were performed in the PubMed, Embase, Cochrane Library and Web of Science for studies published before 31 August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association using a fixed- or random-effects model. Subgroup analyses, Galbraith plot and sensitivity analyses were also performed. All statistical analyses were performed with STATA Version 12.0. A total of 19 case-control studies from 17 publications with 4387 cases and 3972 controls were included in our meta-analysis. The results showed that the Q7R polymorphism was significantly associated with an increased risk of AD in a recessive model (RR versus QQ+QR, OR = 1.27, 95% CI = 1.01-1.60, P = 0.040). After excluding the four studies not carried out in caucasians, the overall association was unchanged in all comparison models. Further subgroup analyses stratified by the time of AD onset, and the quality of included studies provided statistical evidence of significant increased risk of AD in RR versus QQ+QR model only in late-onset subjects (OR = 1.56, 95% CI = 1.07-2.26, P = 0.021) and in studies with high quality (OR = 1.37, 95% CI = 1.01-1.86, P = 0.043). This meta-analysis suggests that the RR genotype in saitohin Q7R polymorphism may be a human-specific risk factor for AD, especially among late-onset AD subjects and caucasian populations.

Tinnitus distress is linked to enhanced resting-state functional connectivity from the limbic system to the auditory cortex.

The phantom sound of tinnitus is believed to be triggered by aberrant neural activity in the central auditory pathway, but since this debilitating condition is often associated with emotional distress and anxiety, these comorbidities likely arise from maladaptive functional connections to limbic structures such as the amygdala and hippocampus. To test this hypothesis, resting-state functional magnetic resonance imaging (fMRI) was used to identify aberrant effective connectivity of the amygdala and hippocampus in tinnitus patients and to determine the relationship with tinnitus characteristics. Chronic tinnitus patients (n = 26) and age-, sex-, and education-matched healthy controls (n = 23) were included. Both groups were comparable for hearing level. Granger causality analysis utilizing the amygdala and hippocampus as seed regions were used to investigate the directional connectivity and the relationship with tinnitus duration or distress. Relative to healthy controls, tinnitus patients demonstrated abnormal directional connectivity of the amygdala and hippocampus, including primary and association auditory cortex, and other non-auditory areas. Importantly, scores on the Tinnitus Handicap Questionnaires were positively correlated with increased connectivity from the left amygdala to left superior temporal gyrus (r = 0.570, P = 0.005), and from the right amygdala to right superior temporal gyrus (r = 0.487, P = 0.018). Moreover, enhanced effective connectivity from the right hippocampus to left transverse temporal gyrus was correlated with tinnitus duration (r = 0.452, P = 0.030). The results showed that tinnitus distress strongly correlates with enhanced effective connectivity that is directed from the amygdala to the auditory cortex. The longer the phantom sensation, the more likely acute tinnitus becomes permanently encoded by memory traces in the hippocampus. Hum Brain Mapp 38:2384-2397, 2017. © 2017 Wiley Periodicals, Inc.

Higher pre-pregnancy body mass index is associated with excessive gestational weight gain in normal weight Chinese mothers with gestational diabetes.

AIM: To assess how pre-pregnancy body mass index (BMI) affects pregnancy outcome and total gestational weight gain (GWG) in a cohort of women with gestational diabetes (GDM). METHODS: Pregnant women at 24-28 gestational weeks diagnosed with GDM were classified as normal weight (pre-pregnancy BMI, 18.5-24.9 kg/m(2) ) or overweight (pre-pregnancy BMI, 25.0-29.9 kg/m(2) ). GWG was derived from the self-reported pre-pregnancy and pre-delivery weights, and analyzed using 2009 Institute of Medicine categories. RESULTS: A total of 106 GDM women were categorized as normal weight (n = 79) or overweight (n = 27). No statistically significant differences were found between the groups in terms of various obstetrical and neonatal outcomes. Higher pre-pregnancy BMI, however, was associated with excessive GWG during pregnancy (difference between groups, P = 0.013). Furthermore, pre-pregnancy BMI (OR, 0.529; 95%CI: 0.377-0.742; P = 0.000) and pre-pregnancy overweight (OR, 3.825; 95%CI: 1.469-9.959; P = 0.006) were independent factors of GWG. CONCLUSIONS: Among Chinese GDM women, overweight GDM mothers gain excessive weight during pregnancy. Regulation of pre-pregnancy bodyweight might be an appropriate precaution against excessive GWG.

HbA1c below 7% as the goal of glucose control fails to maximize the cardiovascular benefits: a meta-analysis.

OBJECTIVE: Whether lowering glycosylated haemoglobin (HbA1c) level below 7.0% improves macro-vascular outcomes in diabetes remains unclear. Here, we aimed to assess the effect of relatively tight glucose control resulting in a follow-up HbA1c level of less or more than 7.0% on cardiovascular outcomes in diabetic patients. RESEARCH DESIGN AND METHODS: We systematically searched Medline, Web of science and Cochrane Library for prospective randomized controlled trials published between Jan 1, 1996 and July 1, 2015 that recorded cardiovascular outcome trials of glucose-lowering drugs or strategies in patients with type 2 diabetes mellitus. RESULTS: Data from 15 studies involving 88,266 diabetic patients with 4142 events of non-fatal myocardial infarction, 6997 of major cardiovascular events, 3517 of heart failure, 6849 of all-cause mortality, 2084 of non-fatal stroke, 3816 of cardiovascular death were included. A 7% reduction of major cardiovascular events was observed only when relatively tight glucose control resulted in a follow-up HbA1c level above 7.0% (OR 0.93, 95% CI 0.88-0.98; I(2) = 33%), however, the patients can benefit from reduction incidence of non-fatal myocardial infarction only when the follow-up HbA1c value below 7.0% (OR 0.85, 95% CI 0.74-0.96). Apart from the HbA1c value above 7.0% (OR 1.22, 95% CI 1.06-1.40), the application of thiazolidinediones (OR 1.39, 95% CI 1.14-1.69) also increased the risk of heart failure, while the gliptins shows neutral effects to heart failure (OR 1.14, 95% CI 0.97-1.34). CONCLUSIONS: Relatively tight glucose control has some cardiovascular benefits. HbA1c below 7.0% as the goal to maximize the cardiovascular benefits remains suspended.

Poorly controlled cholesterol is associated with cognitive impairment in T2DM: a resting-state fMRI study.

BACKGROUND: Debate remains on whether hypercholesterolemia is associated with cognitive impairment. Hence, we investigated whether poorly controlled cholesterol impairs functional connectivity among patients with type 2 diabetes mellitus (T2DM). METHODS: Resting-state functional connectivity infers to an interregional cooperation characterized by synchronous and low-frequency (<0.08 Hz) fluctuations on blood oxygen level-dependent functional magnetic resonance imaging (fMRI). We used resting-state fMRI to investigate the functional connectivity of 25 T2DM patients with poorly controlled cholesterol, 22 patients with target cholesterol and 26 healthy controls. Further correlation analysis was conducted between the functional connectivity and clinical data as well as neuropsychological tests. RESULTS: The three groups did not statistically differ in age, sex, education level, body mass index, blood pressure, fasting C-peptides, and triglyceride. Compared with target cholesterol patients, patients with poorly controlled cholesterol showed significantly increased levels of serum cholesterol, low-density lipoprotein (LDL), and LDL/high-density lipoproteins (HDL) ratio, as well as poor performance in Trail Making Test B (TMT-B) (p<0.05). Disordered functional connectivity of bilateral hippocampus-middle frontal gyrus (MFG) in the poorly controlled group consistently existed when compared with the two other groups. Moreover, the aberrant functional connectivity was associated with the TMT-B scores and the LDL/HDL index in T2DM patients with poorly controlled cholesterol. CONCLUSIONS: T2DM patients with poorly controlled cholesterol showed impaired attention and executive function. The resting-state connectivity disturbance of the hippocampus-MFG may be involved in this process. Decreasing the LDL/HDL ratio can be taken as precaution against cognitive decrements.

Intensified low-density lipoprotein-cholesterol target of statin therapy and cancer risk: a meta-analysis.

BACKGROUND: This study aimed to investigate the relationship between an intensified low-density lipoprotein-cholesterol (LDL-c) target of statin therapy and cancer risk. METHODS: Data from PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials as of September 2014 were searched for randomized controlled trials on statins. An intensified LDL-c target of <2.59 mmol/L (100 mg/dL) or a relative LDL-c reduction by at least 30% of the baseline was the primary criterion for all the trials that were included in this meta-analysis. The I(2) statistic was used to measure heterogeneity among the trials, and risk estimates were calculated for cancer incidence in this random-effect meta-analysis. RESULTS: Nine eligible studies were identified with 59,571 participants, of whom 5379 developed cancer during the follow-up period (2691 were given statins and 2688 were given control treatment). The intensified LDL-c target of statin therapy did not affect cancer incidence (odds ratio, 1.00; 95% confidence interval, 0.94 - 1.06; I(2) = 1.6%, p = 0.42), which included some common cancers. Subgroup analysis showed that neither the chemical properties nor the variety of the statins accounted for the residual variation in risk. CONCLUSIONS: The intensified LDL-c target of statin therapy had no effect on the overall incidence of cancer, including some common cancers. Therefore, intensified statin therapy does not need to be changed among adult clinical patients.

Thalamic resting-state functional connectivity: disruption in patients with type 2 diabetes.

To explore the disrupted thalamic functional connectivity and its relationships with cognitive dysfunction in type 2 diabetes mellitus (T2DM) by using resting-state functional magnetic resonance imaging (fMRI). A total of 38 T2DM patients and 39 well-matched healthy controls participated in the resting-state fMRI and T1-weighted imaging scans. The thalamic functional connectivity was characterized by using a seed-based whole-brain correlation method and compared T2DM patients with healthy controls. Pearson correlation analysis was performed between thalamic functional connectivity and clinical data. When compared with healthy controls, T2DM showed significantly decreased functional connectivity of the thalamus mainly in the right middle temporal gyrus (MTG), right precentral gyrus and bilateral occipital cortex; Increased functional connectivity of the thalamus was detected in the left cerebellum, bilateral middle frontal gyrus and middle cingulate gyrus (p < 0.05, corrected for AlphaSim). In T2DM patients, the decreased thalamic functional connectivity of the right MTG was positively associated with the Verbal Fluency Test score (r = 0.438, p = 0.006). Meanwhile, the decreased thalamic functional connectivity of the right cuneus was positively correlated with the Complex Figure Test-delayed score and negatively correlated with the Trail Making Test-B score, respectively (r = 0.492, p = 0.002; r = -0.504, p = 0.001). Moreover, there was no structural damage in the thalamus of T2DM patients. T2DM patients develop disrupted thalamocortical functional connectivity, which is associated with cognitive impairment in selected brain regions. Resting-state thalamocortical connectivity disturbance may play a central role in the underlying neuropathological process of T2DM-related cognitive dysfunction.

Altered intra- and interregional synchronization in resting-state cerebral networks associated with chronic tinnitus.

OBJECTIVE: Subjective tinnitus is hypothesized to arise from aberrant neural activity; however, its neural bases are poorly understood. To identify aberrant neural networks involved in chronic tinnitus, we compared the resting-state functional magnetic resonance imaging (fMRI) patterns of tinnitus patients and healthy controls. MATERIALS AND METHODS: Resting-state fMRI measurements were obtained from a group of chronic tinnitus patients (n = 29) with normal hearing and well-matched healthy controls (n = 30). Regional homogeneity (ReHo) analysis and functional connectivity analysis were used to identify abnormal brain activity; these abnormalities were compared to tinnitus distress. RESULTS: Relative to healthy controls, tinnitus patients had significant greater ReHo values in several brain regions including the bilateral anterior insula (AI), left inferior frontal gyrus, and right supramarginal gyrus. Furthermore, the left AI showed enhanced functional connectivity with the left middle frontal gyrus (MFG), while the right AI had enhanced functional connectivity with the right MFG; these measures were positively correlated with Tinnitus Handicap Questionnaires (r = 0.459, P = 0.012 and r = 0.479, P = 0.009, resp.). CONCLUSIONS: Chronic tinnitus patients showed abnormal intra- and interregional synchronization in several resting-state cerebral networks; these abnormalities were correlated with clinical tinnitus distress. These results suggest that tinnitus distress is exacerbated by attention networks that focus on internally generated phantom sounds.

Vulnerability for apoptosis in the hippocampal dentate gyrus of STZ-induced diabetic rats with cognitive impairment.

BACKGROUND: Hyperglycemia impaired hippocampal network via triggering suicide program of immanent neurons, this is regarded as an etiological factor for diabetic cognition deficits. AIM: To investigate the occurrence of apoptosis in the hippocampal dentate gyrus of streptozotocin (STZ)-induced diabetic rats with cognitive impairment and assess the gene and protein expression of the apoptotic proteins bax, bcl-2, and caspase-3. MATERIALS AND METHODS: Four weeks after the verification of STZ-induced diabetes, diabetic rats with and without cognitive decline subgroups were subsequently assigned according to Morris water maze test. The expression levels of apoptotic proteins were measured using real-time RT-PCR and western blotting, respectively. Neuronal apoptosis was detected by TUNEL staining and electron microscopy. RESULTS: In the dentate gyrus of the rats with cognitive decline, Bcl-2 exhibited lower gene and protein levels, whereas a higher expression of bax was detected contributing to a significant increase in their mean bax/bcl-2 ratio. However, caspase-3 was not activated. Statistically different numbers of TUNEL-staining cells and features of apoptosis were no found. CONCLUSIONS: The higher bax/bcl ratio probably represents neurons of dentate gyrus vulnerable to apoptosis in the diabetes with cognitive decline. However, the normal caspase-3 level suggests that apoptosis is not active in this illness phase.

LDL receptor knock-out mice show impaired spatial cognition with hippocampal vulnerability to apoptosis and deficits in synapses.

BACKGROUND: Evidence from clinical studies support the fact that abnormal cholesterol metabolism in the brain leads to progressive cognitive dysfunction. The low-density lipoprotein receptor (LDLR) is well-known for its role in regulating cholesterol metabolism. Whether LDLR involved in this impaired cognition and the potential mechanisms that underlie this impairment are unknown. METHODS: Twelve-month-old Ldlr-/- mice (n = 10) and wild-type littermates C57BL/6 J (n = 14) were subjected to the Morris water maze test. At 1 week after completion of the behavioural testing, all of the animals were sacrificed for analysis of synaptic and apoptotic markers. RESULTS: The plasma cholesterol concentration of Ldlr-/- mice was increased moderately when compared with C57BL/6 J mice (P < 0.05). Behavioural testing revealed that Ldlr-/- mice displayed impaired spatial memory, and moreover, the expression levels of synaptophysin and the number of synaptophysin-immunoreactive presynaptic boutons in the hippocampal CA1 and dentate gyrus were decreased (all P < 0.05). Ultrastructural changes in the dentate gyrus were observed using transmission electron microscopy. Furthermore, apoptosis in the hippocampus of Ldlr-/- mice was revealed based on elevation, at both the mRNA and protein levels, of the ratio of Bax/Bcl-2 expression (all P < 0.05)and an increase in activated-caspase3 protein level (P < 0.05). CONCLUSION: LDLR deficiency contributes to impaired spatial cognition. This most likely occurs via negative effects that promote apoptosis and synaptic deficits in the hippocampus.

Association Between Serum Zinc and Non-Alcoholic Fatty Liver Disease and Advanced Liver Fibrosis: NHANES 2011-2016.

Limited and inconclusive evidence exists regarding the correlation between serum zinc levels and non-alcoholic fatty liver disease (NAFLD) and advanced fibrosis. The objective of this cross-sectional study was to investigate the association between serum zinc concentration and both NAFLD and advanced liver fibrosis among the United States (US) adults. 3398 subjects from National Health and Nutrition Examination Survey (NHANES) 2011-2016 were included. Serum zinc concentration was measured by inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS). NAFLD was diagnosed with Hepatic Steatosis Index (HSI), and advanced fibrosis risk was assessed by NAFLD Fibrosis Score (NFS). Weighted logistic regression and restricted cubic splines (RCS) were used to examine the association between serum zinc concentration and NAFLD and advanced fibrosis. Linear trend tests were conducted by incorporating the median of serum zinc quartiles as a continuous variable in the models. We employed sensitivity analysis and subgroup analysis to enhance the robustness of our results. The results from the RCS regression revealed no evident nonlinear relationship between serum zinc concentration and the presence of NAFLD and advanced fibrosis (p-nonlinear > 0.05). Compared with those in the lowest quartile (Q1) of serum zinc concentrations, the odds ratios (95% confidence intervals) of NAFLD were 1.49 (0.89,2.49) in Q2, 0.99 (0.68,1.45) in Q3, and 2.00 (1.40,2.86) in Q4 (p-trend = 0.002). Similarly, the odds ratios (95% confidence intervals) for advanced fibrosis in Q2-4 compared to Q1 were 0.86 (0.50,1.47), 0.60 (0.26,1.39), and 0.41 (0.21,0.77), respectively (p-trend = 0.006). Subgroup analyses and sensitivity analyses reinforce the same conclusion. The investigation revealed a positive linear relationship between serum zinc concentrations and the probability of developing NAFLD. Conversely, an inverse correlation was observed between serum zinc concentrations and the incidence of advanced liver fibrosis among individuals diagnosed with NAFLD.

Aberrant Brain Triple-Network Effective Connectivity Patterns in Type 2 Diabetes Mellitus.

INTRODUCTION: Aberrant brain functional connectivity network is thought to be related to cognitive impairment in patients with type 2 diabetes mellitus (T2DM). This study aims to investigate the triple-network effective connectivity patterns in patients with T2DM within and between the default mode network (DMN), salience network (SN), and executive control network (ECN) and their associations with cognitive declines. METHODS: In total, 92 patients with T2DM and 98 matched healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Spectral dynamic causal modeling (spDCM) was used for effective connectivity analysis within the triple network. The posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), lateral prefrontal cortex (LPFC), supramarginal gyrus (SMG), and anterior insula (AINS) were selected as the regions of interest. Group comparisons were performed for effective connectivity calculated using the fully connected model, and the relationships between effective connectivity alterations and cognitive impairment as well as clinical parameters were detected. RESULTS: Compared to HCs, patients with T2DM exhibited increased or decreased effective connectivity patterns within the triple network. Furthermore, diabetes duration was significantly negatively correlated with increased effective connectivity from the r-LPFC to the mPFC, while body mass index (BMI) was significantly positively correlated with increased effective connectivity from the l-LPFC to the l-AINS (r = - 0.353, p = 0.001; r = 0.377, p = 0.004). CONCLUSION: These results indicate abnormal effective connectivity patterns within the triple network model in patients with T2DM and provide new insight into the neurological mechanisms of T2DM and related cognitive dysfunction.

A novel EGFR variant EGFRx maintains glioblastoma stem cells through STAT5.

BACKGROUND: Glioblastomas are universally lethal brain tumors containing tumor-propagating glioblastoma stem cells (GSCs). EGFR gene amplification or mutation is frequently detected in GBMs and is associated with poor prognosis. However, EGFR variants in GSCs and their role in the maintenance of GSCs and progression of GBM are unclear. METHODS: EGFR variants were detected through bioinformatic HISAT-StringTie-Ballgown pipeline and verified through 5' RACE, RT-PCR, ribonuclease protection, and northern blotting assays. EGFRx function was investigated through neurosphere, cell viability, intracranial xenograft and RNA-seq assays. EGFRx-STAT5 signaling was investigated through western blotting, coimmunoprecipitation, immunofluorescence, luciferase reporter, RT-PCR and CUT&Tag assays. RESULTS: We identified a novel EGFR variant (EGFRx), that is specifically expressed in GSCs. Unlike the EGFRvIII variant, which lacks exons 2-7, EGFRx is characterized by the absence of exons 2-14, and encodes an EGFR protein that does not possess the entire extracellular ligand-binding domain. We observed that EGFRx exhibits significant glycosylation, is required for GSC self-renewal, proliferation, and tumorigenesis, and highly active in glioblastomas compared to normal brain tissue. Mechanistically, EGFRx constitutively and specifically activates STAT5 in GSCs through spontaneous asymmetric dimerization of the kinase domain. CONCLUSIONS: EGFRx plays essential roles in the maintenance of the GSC phenotype through constitutive activation of STAT5 and promotes GBM progression, suggesting that EGFRx-STAT5 signaling represents a promising therapeutic target for GBM.

Advanced glycation end product-induced astrocytic differentiation of cultured neurospheres through inhibition of Notch-Hes1 pathway-mediated neurogenesis.

This study aims to investigate the roles of the Notch-Hes1 pathway in the advanced glycation end product (AGE)-mediated differentiation of neural stem cells (NSCs). We prepared pLentiLox3.7 lentiviral vectors that express short hairpin RNA (shRNA) against Notch1 and transfected it into NSCs. Cell differentiation was analyzed under confocal laser-scanning microscopy. The percentage of neurons and astrocytes was quantified by normalizing the total number of TUJ1+ (Neuron-specific class III ß-tubulin) and GFAP+ (Glial fibrillary acidic protein) cells to the total number of Hoechst 33342-labeled cell nuclei. The protein and gene expression of Notch-Hes1 pathway components was examined via western blot analysis and real-time PCR. After 1 week of incubation, we found that AGE-bovine serum albumin (BSA) (400 µg/mL) induced the astrocytic differentiation of cultured neurospheres and inhibited neuronal formation. The expression of Notch-Hes1 pathway components was upregulated in the cells in the AGE-BSA culture medium. Immunoblot analysis indicated that shRNA silencing of Notch1 expression in NSCs significantly increases neurogenesis and suppresses astrocytic differentiation in NSCs incubated with AGE-BSA. AGEs promote the astrocytic differentiation of cultured neurospheres by inhibiting neurogenesis through the Notch-Hes1 pathway, providing a potential therapeutic target for hyperglycemia-related cognitive deficits.

Aberrant brain functional network strength related to cognitive impairment in age-related hearing loss.

Purpose: Age-related hearing loss (ARHL) is a major public issue that affects elderly adults. However, the neural substrates for the cognitive deficits in patients with ARHL need to be elucidated. This study aimed to explore the brain regions that show aberrant brain functional network strength related to cognitive impairment in patients with ARHL. Methods: A total of 27 patients with ARHL and 23 well-matched healthy controls were recruited for the present study. Each subject underwent pure-tone audiometry (PTA), MRI scanning, and cognition evaluation. We analyzed the functional network strength by using degree centrality (DC) characteristics and tried to recognize key nodes that contribute significantly. Subsequent functional connectivity (FC) was analyzed using significant DC nodes as seeds. Results: Compared with controls, patients with ARHL showed a deceased DC in the bilateral supramarginal gyrus (SMG). In addition, patients with ARHL showed enhanced DC in the left fusiform gyrus (FG) and right parahippocampal gyrus (PHG). Then, the bilateral SMGs were used as seeds for FC analysis. With the seed set at the left SMG, patients with ARHL showed decreased connectivity with the right superior temporal gyrus (STG). Moreover, the right SMG showed reduced connectivity with the right middle temporal gyrus (MTG) and increased connection with the left middle frontal gyrus (MFG) in patients with ARHL. The reduced DC in the left and right SMGs showed significant negative correlations with poorer TMT-B scores (r = -0.596, p = 0.002; r = -0.503, p = 0.012, respectively). Conclusion: These findings enriched our understanding of the neural mechanisms underlying cognitive impairment associated with ARHL and may serve as a potential brain network biomarker for investigating and predicting cognitive difficulties.