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ObjectiveAccumulating evidence shows that cognitive impairment (CI) in chronic heart failure (CHF) patients is related to brain network dysfunction. This study investigated brain network structure and rich-club organization in chronic heart failure patients with cognitive impairment based on graph analysis of diffusion tensor imaging data.MethodsThe brain structure networks of 30 CHF patients without CI and 30 CHF patients with CI were constructed. Using graph theory analysis and rich-club analysis, changes in global and local characteristics of the subjects’ brain network and rich-club organization were quantitatively calculated, and the correlation with cognitive function was analyzed.ResultsCompared to the CHF patients in the group without CI group, the CHF patients in the group with CI group had lower global efficiency, local efficiency, clustering coefficient, the small-world attribute, and increased shortest path length. The CHF patients with CI group showed lower nodal degree centrality in the fusiform gyrus on the right (FFG.R) and nodal efficiency in the orbital superior frontal gyrus on the left (ORB sup. L), the orbital inferior frontal gyrus on the left (ORB inf. L), and the posterior cingulate gyrus on the right (PCG.R) compared with CHF patients without CI group. The CHF patients with CI group showed a smaller fiber number of edges in specific regions. In CHF patients with CI, global efficiency, local efficiency and the connected edge of the orbital superior frontal gyrus on the right (ORB sup. R) to the orbital middle frontal gyrus on the right (ORB mid. R) were positively correlated with Visuospatial/Executive function. The connected edge of the orbital superior frontal gyrus on the right to the orbital inferior frontal gyrus on the right (ORB inf. R) is positively correlated to attention/calculation. Compared with the CHF patients without CI group, the connection strength of feeder connection and local connection in CHF patients with CI group was significantly reduced, although the strength of rich-club connection in CHF patients complicated with CI group was decreased compared with the control, there was no statistical difference. In addition, the rich-club connection strength was related to the orientation (direction force) of the Montreal cognitive assessment (MoCA) scale, and the feeder and local connection strength was related to Visuospatial/Executive function of MoCA scale in the CHF patients with CI.ConclusionChronic heart failure patients with CI exhibited lower global and local brain network properties, reduced white matter fiber connectivity, as well as a decreased strength in local and feeder connections in key brain regions. The disrupted brain network characteristics and connectivity was associated with cognitive impairment in CHF patients. Our findings suggest that impaired brain network properties and decreased connectivity, a feature of progressive disruption of brain networks, predict the development of cognitive impairment in patients with chronic heart failure.

ObjectiveTo investigate the changes of brain network in epilepsy patients without intracranial lesions under resting conditions.MethodsTwenty-six non-lesional epileptic patients and 42 normal controls were enrolled for BOLD-fMRI examination. The differences in brain network topological characteristics and functional network connectivity between the epilepsy group and the healthy controls were compared using graph theory analysis and independent component analysis.ResultsThe area under the curve for local efficiency was significantly lower in the epilepsy patients compared with healthy controls, while there were no differences in global indicators. Patients with epilepsy had higher functional connectivity in 4 connected components than healthy controls (orbital superior frontal gyrus and medial superior frontal gyrus, medial superior frontal gyrus and angular gyrus, superior parietal gyrus and paracentral lobule, lingual gyrus, and thalamus). In addition, functional connectivity was enhanced in the default mode network, frontoparietal network, dorsal attention network, sensorimotor network, and auditory network in the epilepsy group.ConclusionThe topological characteristics and functional connectivity of brain networks are changed in in non-lesional epilepsy patients. Abnormal functional connectivity may suggest reduced brain efficiency in epilepsy patients and also may be a compensatory response to brain function early at earlier stages of the disease.

Objective To investigate the changes of cerebral white matter diffusion tensor in epilepsy patients based on the method of tract-based spatial statistics (TBSS). Methods Twenty-six patients with epilepsy and 42 healthy volunteers matched for sex, age and handedness were examined for diffusion tensor imaging (DTI). TBSS was used to analyze the changes of each relevant parameter index of DTI in white matter of the brain in all subjects, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Results Compared to healthy controls, patients with epilepsy had decreased FA and elevated MD, AD, and RD in the anterior thalamic radiation, corticospinal tract, forceps major, forceps minor, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus and uncinate fasciculus. (P < 0.05). Conclusion Widespread white matter integrity was found in epilepsy patients, which may be the structural basis for the development of affective disorders, impaired cognition, and motor abnormalities.

BACKGROUNDSpinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of a CAG repeat in Ataxin-2 (ATXN2) gene. The mutant ATXN2 protein with a polyglutamine tract is known to be toxic and contributes to the SCA2 pathogenesis.OBJECTIVEHere we tested the hypothesis that the mutant ATXN2 transcript with an expanded CAG repeat (expATXN2) is also toxic and contributes to SCA2 pathogenesis.METHODSThe toxic effect of expATXN2 transcripts on SK-N-MC neuroblastoma cells and primary mouse cortical neurons was evaluated by caspase 3/7 activity and nuclear condensation assay, respectively. RNA immunoprecipitation assay was performed to identify RNA binding proteins (RBPs) that bind to expATXN2 RNA. Quantitative PCR was used to examine if rRNA processing is disrupted in SCA2 and Huntington disease (HD) human brain tissue.RESULTSexpATXN2 RNA induces neuronal cell death, and aberrantly interacts with RBPs involved in RNA metabolism. One of the RBPs, transducin β-like protein 3 (TBL3), involved in rRNA processing, binds to both expATXN2 and expanded huntingtin (expHTT) RNA in vitro. rRNA processing is disrupted in both SCA2 and HD human brain tissue.CONCLUSIONThese findings provide the first evidence of a contributory role of expATXN2 transcripts in SCA2 pathogenesis, and further support the role expHTT transcripts in HD pathogenesis. The disruption of rRNA processing, mediated by aberrant interaction of RBPs with expATXN2 and expHTT transcripts, suggest a point of convergence in the pathogeneses of repeat expansion diseases with potential therapeutic implications.

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of huntingtin (HTT). While there are currently no disease-modifying treatments for HD, recent efforts have focused on the development of nucleotide-based therapeutics to lower HTT expression. As an alternative to siRNA or oligonucleotide methods, we hypothesized that suppression of HTT expression might be accomplished by small molecules that either (1) directly decrease HTT expression by suppressing HTT promoter activity or (2) indirectly decrease HTT expression by increasing the promoter activity of HTT-AS, the gene antisense to HTT that appears to inhibit expression of HTT. We developed and employed a high-throughput screen for modifiers of HTT and HTT-AS promoter activity using luminescent reporter HEK293 cells; of the 52,041 compounds tested, we identified 898 replicable hits. We used a rigorous stepwise approach to assess compound toxicity and the capacity of the compounds to specifically lower huntingtin protein in 5 different cell lines, including HEK293 cells, HD lymphoblastoid cells, mouse primary neurons, HD iPSCs differentiated into cortical-like neurons, and HD hESCs. We found no compounds which were able to lower huntingtin without lowering cell viability in all assays, though the potential efficacy of a few compounds at non-toxic doses could not be excluded. Our results suggest that more specific targets may facilitate a small molecule approach to HTT suppression.

Epilepsy is one of the most common neurological diseases with spontaneous recurrent seizures. Long noncoding RNAs (lncRNAs) are crucial modulators in numerous diseases, including epilepsy. However, the functional role and potential mechanism of lncRNA Nespas in epilepsy remain unknown. Our study clarified that Nespas was underexpressed in epileptiform hippocampal tissues and neurons. Furthermore, Nespas promoted hippocampal neuron viability and proliferation, and inhibited hippocampal neuron apoptosis. Mechanistically, Nespas interacted with microRNA 615-3p (miR-615-3p) in epileptiform hippocampal neurons. 26S proteasome non-ATPase regulatory subunit 11 (Psmd11) was a downstream target of miR-615-3p, and Nespas elevated Psmd11 expression via competitively binding to miR-615-3p in epileptiform hippocampal neurons. In addition, rescue assays suggested that Nespas promoted hippocampal neuron viability and proliferation, and suppressed hippocampal neuron apoptosis by upregulation of Psmd11. Furthermore, Nespas suppressed the PI3K/Akt/mTOR pathway via upregulating Psmd11 in epileptiform hippocampal neurons. This report explored the function and regulatory mechanism of Nespas in epileptiform hippocampal neurons for the first time. Our findings revealed that Nespas suppressed the apoptosis of epileptiform hippocampal neurons by inhibiting the PI3K/Akt/mTOR pathway via upregulation of Psmd11 at a miR-615-3p dependent way, indicating that Nespas may offer a new direction for the treatment of epilepsy.

Background: Eosinopenia has been shown to be a predicative factor for the infection and mortality in ischemic stroke patients which mainly focused on static eosinophil count. This study aimed to explore the relationship between dynamic change of eosinophil count and short-term prognosis of acute ischemic stroke (AIS).Methods: A total of 174 patients with AIS were respectively enrolled. Blood samples for blood routine examination were obtained at admission before any treatments and the next day. Eosinopenia was defined as the continuous decrease of the count of eosinophil from the first day to the second. Infarct volume was measured by diffusion-weighted MR imaging volume. 90-day modified Rankin Scale scores were collected to assess the prognosis of patients with AIS.Results: Patients were divided into two groups according to whether they have eosinopenia. Patients with eosinopenia were more likely to have large infarct volume (3.2 [0.6-39.9] cm3 vs 1.1 [0.3-6.0] cm3, P =.004). Receiver operating characteristic analysis demonstrated that the eosinophil count on the second day was more accurate than the time of admission to identify the large cerebral infarction (LCI) (0.866 vs 0.603, P ＜.001). Logistic regression analysis revealed that eosinopenia was independently associated with LCI (P =.015) and poor outcome (P =.011), and patients with eosinopenia had a 4.05-fold greater risk for LCL (95% CI 1.31-12.51) and a 4.29-fold greater risk for worse clinical outcomes (95% CI 1.27-14.51) than patients without.Conclusion： Eosinophil is a dynamic variable, and its variation is associated with poor outcome in acute ischemic stroke patients.

Our previous study had identified ciclopirox (CPX) as a promising lead compound for treatment of ischemic stroke. To find better neuroprotective agents, a series of

Spinocerebellar ataxia type 12 (SCA12) is caused by a CAG expansion mutation in PPP2R2B, a gene encoding a brain-specific regulatory unit of protein phosphatase 2A (PP2A); while normal alleles carry 4 to 31 triplets, the disease alleles carry 43 to 78 triplets. Here, by CRISPR/Cas9 genome editing, we have generated a human homozygous SCA12 iPSC line with 69 and 72 triplets for each allele. The homozygous SCA12 iPSCs have normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

Vertebral artery dominance (VAD), which is a common congenital variation of vertebral artery, may be associated with an increased risk of cerebral posterior circulation infarction (PCI). The aims of this study were to investigate the correlation of VAD with incidence and laterality of PCI, and oblige the correlation of VAD and basilar artery (BA) curvature. Incidence of separate territory infarction in posterior circulation and incidence of BA curvature were compared between 78 VAD patients and 68 controls. VA dominance, laterality of BA curvature and separate territory infarction, and their directional relationships were observed in VAD group. The incidence of BA curvature in VAD group was significantly higher than that in controls (P = 0.000). 89.7 % (35/39) of patients had an opposite directional relationship between dominant VA and BA curvature. The total incidence of PCI in VAD group was significantly higher than that in controls (P = 0.001). The incidences of posterior inferior cerebellar artery (PICA) and BA territory infarction were both significantly higher than those in controls [11.5 % (9/78) vs. 1.5 % (1/68), P = 0.016; 20.5 % (16/78) vs. 7.4 % (5/68), P = 0.024]. No differences were found in superior cerebellar artery and posterior cerebral artery territory infarction between two groups. 77.8 % (7/9) of PICA infarction were on the opposite side of dominant VA. 75.0 % (12/16) of BA infarction were on the side of dominant VA. The incidence of PCI in BA curvature patients was significantly higher than that in BA straight patients. The incidence of BA curvature is higher in VAD patients, and BA usually bends to the opposite side of dominant VA. The incidence of PCI is higher in VAD patients, especially in PICA infarction and BA infarction patients.

Cerebral infarction is usually associated with arteriosclerosis, vascular endothelial cell injury and blood flow through the vascular system. The diagnostic value of markers, including von Willebrand factor antigen (vWF:Ag), D-dimer (D-D) and fibrinogen/fibrin degradation product (FDP), have not been studied in patients with acute cerebral infarction. Thus, the aim of the present study was to use receiver operating characteristic (ROC) curves to evaluate the diagnostic significance of vWF:Ag, D-D and FDP in 94 cases of acute cerebral infarction. The results revealed that vWF:Ag and D-D concentrations were significantly higher in acute cerebral infarction patients as compared with the normal controls (P0.01). Plasma vWF:Ag and D-D concentrations significantly correlated with the National Institute of Health Stroke Scale (NIHSS) scores (r=0.625 and 0.582, respectively; P0.05). The area under the ROC curve using vWF:Ag as a diagnostic marker in patients with acute cerebral infarction was 0.900, while for D-D the area was 0.795 and for FDP the area was 0.465. Logistic regression analysis revealed that the odds ratios of vWF:Ag and D-D were 16.727 and 2.324, respectively, which were statistically significant (P

Pulmonary arterial hypertension is a life-threatening disease lacking effective therapies. Osthole is a natural coumarin compound isolated from Angelica pubescens Maxim., which possesses hypotensive effect. Although its effects on isolated thoracic aorta (systemic circulating system) are clarified, it remains unclear whether Osthole relaxes isolated pulmonary arteries (PAs) (pulmonary circulating system). The aim of this study was to investigate the effects of Osthole on isolated PAs and the underlying mechanisms. We examined PA relaxation induced by Osthole in isolated human and rat PA rings with force-electricity transducers, the expression and activity of endothelial nitric oxide synthase (eNOS) and protein kinase B (Akt) with western blot, and nitric oxide (NO) production using DAF-FM DA fluorescent indicator. The results showed that Osthole elicited a dose-dependent vasorelaxation activity with phenylephrine-precontracted human and rat PA rings, which can be diminished by endothelium denudation and inhibition of eNOS, while having no effect on rat mesenteric arteries. Osthole increased NO release as well as activation of Akt and eNOS, indicated with increased phosphorylations of Akt at Ser-473 and eNOS at Ser-1177 in endothelial cells. PI3K inhibitor LY294002 also blocked Osthole induced vasodilation. In summary, dilative effect of Osthole was dependent on endothelial integrity and NO production, and was mediated by endothelial PI3K/Akt-eNOS-NO pathway. These may provide a new pulmonary vasodilator for the therapy of pulmonary arterial hypertension.