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The volume entropy of a compact metric measure space is known to be the exponential growth rate of the measure lifted to its universal cover at infinity. For a compact Riemannian n -manifold with a negative lower Ricci curvature bound and a upper diameter bound, it was known that it admits an almost maximal volume entropy if and only if it is diffeomorphic and Gromov-Hausdorff close to a hyperbolic space form. We prove the quantitative rigidity of almost maximal volume entropy for RCD ⁎ -spaces with a negative lower Ricci curvature bound and Riemannian manifolds with a negative L p -integral Ricci curvature lower bound. [ABSTRACT FROM AUTHOR]

Complex chronic diseases are caused by the effects of genetic and environmental factors. Single nucleotide polymorphisms (SNPs), one common type of genetic variations, played vital roles in diseases. We hypothesized that disease risk functional SNPs in coding regions and protein interaction network modules were more likely to contribute to the identification of disease susceptible genes for complex chronic diseases. This could help to further reveal the pathogenesis of complex chronic diseases. Disease risk SNPs were first recognized from public SNP data for coronary heart disease (CHD), hypertension (HT) and type 2 diabetes (T2D). SNPs in coding regions that were classified into nonsense and missense by integrating several SNP functional annotation databases were treated as functional SNPs. Then, regions significantly associated with each disease were screened using random permutations for disease risk functional SNPs. Corresponding to these regions, 155, 169 and 173 potential disease susceptible genes were identified for CHD, HT and T2D, respectively. A disease-related gene product interaction network in environmental context was constructed for interacting gene products of both disease genes and potential disease susceptible genes for these diseases. After functional enrichment analysis for disease associated modules, 5 CHD susceptible genes, 7 HT susceptible genes and 3 T2D susceptible genes were finally identified, some of which had pleiotropic effects. Most of these genes were verified to be related to these diseases in literature. This was similar for disease genes identified from another method proposed by Lee et al. from a different aspect. This research could provide novel perspectives for diagnosis and treatment of complex chronic diseases and susceptible genes identification for other diseases. [ABSTRACT FROM AUTHOR]

Exposure to diesel exhaust particles (DEP) increases the risk of ischemic heart disease, especially heart attacks and ischemic/thrombotic strokes. Shengmai Yin (SMY) is a traditional Chinese medicine used to treat coronary heart disease. The aim of this study was to determine the protective role of SMY and the mechanism by which SMY affects DEP-induced cardiovascular injury. This study is expected to provide the basis for the development of an adaptive signature of SMY in the prevention of atherosclerotic cardiovascular disease and premature death from global air pollution exposure. We developed animal models of myocardial ischemia and atherosclerosis (AS) in response to DEP exposure. After SMY treatment, serum lipids returned to normal. Aortic plaque area and MMP9 expression were significantly reduced and collagen fiber expression increased after SMY treatment compared to DEP exposure alone. Thus, the risk of plaque formation and vulnerability is reduced. In addition, SMY improved left ventricular structure, morphology, function, blood flow, infarct area, myocardial damage, and ROS accumulation to varying degrees in ApoE-/- mice. These results indicate that the use of SMY is effective, to varying degrees, for the treatment of dyslipidemia, atherosclerosis, myocardial ischemia, and oxidative stress in ApoE-/- mice. SMY has a potential protective effect in DEP-aggravated AS in people with myocardial ischemia. ● Animal models of myocardial ischemia and atherosclerosis (AS) in response to DEP exposure was developed. ● After SMY treatment, the risk of plaque formation and vulnerability is reduced. Treatment improved left ventricular structure, morphology, function, blood flow, infarct area, myocardial damage, and ROS accumulation in ApoE-/- mice. ● SMY has a potential protective effect in DEP-aggravated AS in people with myocardial ischemia. [ABSTRACT FROM AUTHOR]

Candidate gene prioritization for complex non-communicable diseases is essential to understanding the mechanism and developing better means for diagnosing and treating these diseases. Many methods have been developed to prioritize candidate genes in protein-protein interaction (PPI) networks. Integrating functional information/similarity into disease-related PPI networks could improve the performance of prioritization. In this study, a candidate gene prioritization method was proposed for non-communicable diseases considering disease risks transferred between genes in weighted disease PPI networks with weights for nodes and edges based on functional information. Here, three types of non-communicable diseases with pathobiological similarity, Type 2 diabetes (T2D), coronary artery disease (CAD) and dilated cardiomyopathy (DCM), were used as case studies. Literature review and pathway enrichment analysis of top-ranked genes demonstrated the effectiveness of our method. Better performance was achieved after comparing our method with other existing methods. Pathobiological similarity among these three diseases was further investigated for common top-ranked genes to reveal their pathogenesis. [ABSTRACT FROM AUTHOR]

Grain boundary enriched CuO nanobundle was reported to significantly increased the glucose diffusion as well as reduce the glucose oxidation barrier, thus displayed a lower onset potential of 94 mV, an extremely high sensitivity of 7474 μA mM−1 cm−2 in glucose detection and a high peak power density of 242 W m−2 in a glucose fuel cell. [Display omitted] • CuO nanobundle with high density and homogenous GBs was obtained by a facile and large-scale method. • A high sensitivity of 7474 μA mM−1 cm−2 in glucose detection and a high peak power density of 242 W m−2 in a glucose fuel cell are achieved. • CuO-NB possesses the faster glucose mass transfer due to the terraces in GBs dislocation surface. • Electrons accumulate on GBs interfaces promote glucose adsorption and decrease free energy of dehydrogenation step. Glucose oxidation reaction (GOR) plays a significant role in glucose fuel cells anode and glucose sensors. Therefore, optimizing the GOR catalyst nanostructure is auxiliary to their efficient operation. In this study, we present a cascade-assembled strategy to prepare CuO nanobundles (CuO-NB) with high-density and homogenous grain boundaries (GBs). The essence of activity in GOR that depended on GBs are thoroughly investigated. The increased glucose diffusion coefficient of CuO-NB means that GBs has a faster glucose mass transfer, which is attributed to the terraces in GBs dislocation surface. Furthermore, the accumulation of electrons on GBs makes the glucose adsorption increased and the free energy of dehydrogenation step decreased, leading to a lower glucose oxidation barrier. Therefore, CuO-NB is appropriate for non-invasive glucose detection and glucose fuel cells. This study sheds new light on the GBs effect in GOR and paves the way for developing high-efficiency electrocatalysts. [ABSTRACT FROM AUTHOR]

Evidence on the short-term effects of size-specific particulate matter with aerodynamic diameter ≤2.5 μm (PM 2.5), ≤10 μm (PM 10), and their difference (PM C) on children's Lower Respiratory Infections (LRI) is scare. This study aimed to estimate the differential effects of three size-specific PM on hospitalizations of children aged <18 years for pneumonia and bronchitis in 18 cities of southwestern China. The city-specific association was firstly estimated using the over-dispersed generalized additive model and then combined to obtain the regional average association. Further, to evaluate the robustness of the key findings, subgroup analyses and co-pollutant models were constructed. PM-related risks of LRI differed by PM fractions and cause-specific LRI. A 10 μg/m3 increment in PM 2.5 _lag03, PM 10 _lag06, and PM C _lag06 was associated with a 0.79% (95% CI: 0.29%, 1.29%), 0.77% (95% CI: 0.13%, 1.41%), and 2.33% (95% CI: 1.23%, 3.44%) increase in children's LRI hospitalizations, respectively. After adjustment for gaseous pollutants, adverse effects of the three types of size-specific PM on pneumonia hospitalizations were stable, ranging from 0.29% (95% CI: 0.05%, 0.54%) for PM 2.5 –2.50% (95% CI: 1.38%, 3.64%) for PM C. Additionally, PM C -related risk of bronchitis hospitalizations remained stable after adjustment for gaseous pollutants. Associations of pneumonia with PM C and PM 10 in infants, bronchitis with PM 2.5 in children aged 6–17 years, pneumonia and bronchitis with PM 2.5 , PM C , and PM 10 in children aged 1–5 years were all statistical significant. Specifically, the effects of PM 2.5 on LRI hospitalizations increased by age, with the highest effect of 1.72% (95%CI: 1.01%, 2.43%) in children aged 6–17 years. Our study provided evidence for short-term effects of different PM fractions on children LRI hospitalizations in Southwestern China, which will be useful for making and promoting policies on air quality standards in order to protect children's health. • PM-related risks of children's LRI hospitalizations differed by PM fractions. • PM 2.5 - and PM 10 -related risk of LRI was comparable, around one third of PM C. • Association of pneumonia with PM C was the strongest among three size-specific PM. • In particular, PM 2.5 -related risks of LRI hospitalizations increased by age. [ABSTRACT FROM AUTHOR]

The development of efficient electrode materials is essential to promote the performance of energy storage equipment. Nowadays, metal organic frameworks (MOFs) have been widely regarded as active materials for supercapacitors mainly thanks to their adjustable structure and outstanding porosity. Here, highly optimized Nickel and Cobalt MOF-derived N -doped porous carbon (Ni/Co-MOF-NPC) are considered the best choice for electrode materials due to their unique structural properties and excellent electrochemical performance. Pure cobalt oxide rarely reaches a specific capacitance of 104.3 F g−1 when the current density is 1 A g−1, but the optimized Ni/Co-MOF-NPC-2:1 offers an ultra-high specific capacitance of 1214 F g−1, which is much higher than that of pure cobalt oxide in a three-electrode test system. When the current density is 10 A g−1, after 6000 cycles, the capacitance can still maintain 98.8% of the initial capacitance. Asymmetric supercapacitors were assembled using the prepared Ni/Co-MOF-NPC-2:1 as the positive electrode material, corrugated paper activated carbon (CPAC) as the negative electrode material, the prepared Ni/Co-MOF-NPC-2:1//CPAC exhibits an outstanding energy density of 55.4 Wh kg−1 at 758.5 W kg−1, and has a significant cycle stability of 75.2% retention after 20,000 cycles. This excellent MOF synthesis strategy reduced the gap between the experimental synthesis and practical application of MOF in fast energy storage. [ABSTRACT FROM AUTHOR]

Complex diseases, such as obesity, type II diabetes and chronic obstructive pulmonary disease (COPD) as metabolic disorder-related diseases are major concern for worldwide public health in the 21st century. The identification of these disease risk genes has attracted increasing interest in computational systems biology. In this paper, a novel method was proposed to prioritize disease risk genes (PDRG) by integrating functional annotations, protein interactions and gene expression information to assess similarity between genes in a disease-related metabolic network. The gene prioritization method was successfully carried out for obesity and COPD, the effectiveness of which was superior to those of ToppGene and ToppNet in both literature validation and recall rate by LOOCV. Our method could be applied broadly to other metabolism-related diseases, helping to prioritize novel disease risk genes, and could shed light on diagnosis and effective therapies. • A novel method was proposed to prioritize disease risk genes (PDRG) by integrating multiple data to assess similarity between genes in disease-related metabolic network. • The PDRG method was superior to ToppGene and ToppNet in both literature validation and recall rate. • The PDRG method would be applied broadly to other metabolic related diseases helping in prioritizing novel disease risk genes. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis. • Erythropoietin mitigated cognitive dysfunction in T2DM mice. • Erythropoietin inhibits ferroptosis in high-glucose-treated PC12 cells. • Erythropoietin regulated ferroptosis-related proteins in vivo and in vitro. [ABSTRACT FROM AUTHOR]

[Display omitted] • The kinase inhibitory activity of the selected compound 10a with better neuroprotective effect was 2.7 fold than that of Tideglusib. • Similar to Tideglusib, the selected compound 10a showed GSK-3β selective inhibition among the whole tested kinases. • The selected compound 10a could significantly reduce the levels of APP and p-tau via increasing expression of p-GSK-3β. • The selected compound 10a could improve the learning and memory functions of AD mice induced by d -galactose combined with AlCl 3 , and reduce the damage of hippocampal neurons. • Compared to Tideglusib, the selected compound 10a has less hepatotoxicity. Tideglusib is a non-competitive GSK-3β inhibitor which contain 1,2,4-thiadiazolidine-3,5-dione moiety, and now mainly used for progressive supranuclear palsy due to the lack of some primary cognitive endpoints and secondary endpoints in a phase IIb trail for Alzheimer's disease. Additionally, insufficient evidence exists to support that there are obvious covalent bonds between Tideglusib and GSK-3β. Targeted covalent inhibition strategy could improve the binding efficiency, selectivity and duration of kinase inhibitors. Based on the above premise, two series of targeted compounds with acryloyl warheads were designed and synthesized. The kinase inhibitory activity of the selected compound 10a with better neuroprotective effect improved 2.7 fold than that of Tideglusib. After the preliminary screening of GSK-3β inhibition and neuroprotective activity, the mechanism action of the selected compound 10a was investigated in vitro and in vivo. The results confirmed that 10a with excellent selectivity among the whole tested kinases could significantly reduce the expressions of APP and p-Tau via increasing the level of p-GSK-3β. The pharmacodynamic assay in vivo showed that 10a could markedly improve the learning and memory functions in AD mice induced by AlCl 3 combined with d -galactose. At the same time, the damage of hippocampal neurons in AD mice was obviously reduced. Accordingly, the introduction of acryloyl warheads could increase the GSK-3β inhibitory activity of 1,2,4-thiadiazolidine-3,5-dione derivatives, and the selected compound 10a deserves further research as an effective GSK-3β inhibitor for the potential treatment of AD. [ABSTRACT FROM AUTHOR]

Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5–50.0 mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (I Kv1.5 ) were markedly inhibited by 12.5–50.0 mM ethanol in a concentration-dependent manner. Ethanol with 50.0 mM could inhibit rapid delayed rectifier potassium currents (I hERG ). Ethanol under 6.25–50.0 mM did not affect on inward rectifier potassium currents (I Kir2.1 ). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of I Kv1.5 and I hERG , which contributed to preventing the development and duration of AF. [ABSTRACT FROM AUTHOR]

Background Breast cancer stem cells (BCSCs) play essential roles in tumor metastasis and contribute to remarkably negative clinical outcomes. Recently, aldehyde dehydrogenase (ALDH) and CD44 positivity (ALDH + /CD44 + ) was identified as a marker of BCSCs in vitro/in vivo studies. The aim of this study was to evaluate the prevalence of ALDH + /CD44 + cells in breast cancer and the association of these two markers with clinicopathological features and clinical outcomes. Materials and methods We investigated the prevalence of ALDH1A3 + /CD44 + cells in a cohort of 144 formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues. The tissues were stained for ALDH1A3 and CD44 by single and dual immunohistochemistry (dIHC). The associations among the prevalence of ALDH1A3 + /CD44 + cells, the clinicopathological features and the clinical outcomes of the patients were also analyzed. Results ALDH1A3 + /CD44 + cells were present in 39 patients (27.1%). By the Mann–Whitney U test, the Pearson Chi-square test or Fisher's exact test, it was demonstrated that the prevalence of ALDH1A3 + /CD44 + cells was closely correlated with larger tumor size ( p = 0.001), nodal metastasis status ( p = 0.043), more advanced clinical stage ( p = 0.021) and distant metastasis after initial surgery ( p = 0.001). In a univariate survival analysis, the presence of ALDH1A3 + /CD44 + tumor cells had a significant negative association with both disease-free survival (DFS) and overall survival (OS) ( p DFS < 0.001; p OS < 0.001). The negative clinical outcomes in ALDH1A3 + /CD44 + tumors were further confirmed by a multivariate analysis using Cox proportional hazard models ( p DFS < 0.001, HR = 3.155; p OS = 0.001, HR = 3.193). This was also true with respect to the clinical treatment regimens of chemotherapy ( p DFS < 0.001; p OS = 0.001), radiotherapy ( p DFS = 0.004; p OS = 0.004), and endocrine therapy ( p DFS < 0.001; p OS < 0.001). Conclusion In summary, our results indicate that the prevalence of ALDH1A3 + /CD44 + tumor cells in breast cancer is significantly associated with worse prognostic factors and favors a poor prognosis. [ABSTRACT FROM AUTHOR]

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1 , Ngn2 and Pax6 , and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a , the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21. [ABSTRACT FROM AUTHOR]

The voltage-gated potassium (Kv) channel blockers tetraethylammonium (TEA) and 4-aminopyridine (4-AP) have shown beneficial effects on some neurological disorders. But their involvements in diabetes-associated cognitive dysfunction are still unknown. The present study aims to investigate whether the blockade of Kv channels by TEA and 4-AP alleviate cognitive decline in diabetes. In vivo, the effects of TEA and 4-AP (5 mg/kg body weight per day, 1 mg/kg body weight per day intraperitoneal injected for 4 weeks, respectively) were investigated in streptozotocin-induced C57BL/6 diabetic mice. In vitro study, we investigated the effects of TEA and 4-AP on the high glucose (HG) -stimulated primary cortical neurons. The results showed that TEA and 4-AP ameliorated the cognitive decline of diabetic mice in the Morris water maze test, improved the ultrastructure of pancreatic β cells, hippocampal neurons and synapses, decreased oxidative stress, modulated apoptosis-related proteins, and activated phosphatidylinositol 3-kinase (PI3K)/ Protein kinase-B (PKB or Akt) signaling pathway. In the HG-stimulated primary cultured cortical neurons, TEA and 4-AP increased the cell viability, decreased oxidative stress; prevented apoptosis and activated PI3K/Akt signaling pathway. Additionally, the PI3K inhibitor LY294002 partially abolished the effects of TEA and 4-AP. These findings indicate that the blockade of Kv channels by TEA and 4-AP ameliorates the diabetes-associated cognitive dysfunction via PI3K/Akt pathway, suggesting that targeting Kv channels could be a promising strategy for the treatments of cognitive impairments in diabetes. • TEA and 4-AP attenuated cognitive decline in STZ-induced diabetic mice. • TEA and 4-AP exerted neuroprotective effects in vivo and in vitro. • Blocking Kv channel alleviates diabetic cognitive dysfunction via PI3K/Akt pathway. • Kv channel blockers are promising therapeutics for diabetic cognitive impairment. [ABSTRACT FROM AUTHOR]