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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]

Abstract: Integration of genetic and metabolic network holds promise for providing insight into human disease. Coronary artery disease (CAD) is strongly heritable, but the heritability of metabolic compounds has not been evaluated in human metabolic context. Here we performed a genetic-based computational approach within eight sub-cellular networks from Edinburgh Human Metabolic Network to identify significant genetic risk compounds (SGRCs) of CAD. Our results provide the evidence that the high heritabilities of SGRCs played an important role in CAD pathogenesis. Besides, SGRCs were discovered to be strongly associated with lipid metabolism. We also established a possible disease-causing reference table to decipher genetic associations of SGRCs with CAD. Comparing with traditional method, RCM experienced better performance in CAD genetic risk compounds'' identification. These findings provided novel insights into CAD pathogenesis from a genetic perspective. [Copyright &y& Elsevier]

Abstract: Rem2 belongs to the RGK family of small GTPases whose members are known to interact with the voltage gated calcium channel β subunit, and to inhibit or abolish calcium currents. To identify the underlying functional domains of Rem2, we created several N- or C-terminally truncated Rem2 proteins and examined their abilities to interact with the Cav β subunit and to regulate the activities of Cav2.2 N-type calcium channels. Confocal imaging of Rem2 in tsA-201 cells revealed that it contains a membrane-targeting signal in its C-terminus, consistent with previous studies. Co-precipitation assays showed that Cav β3 interaction depends on Rem2 residues 1–123. Only Rem2 proteins that targeted the cell membrane as well as bound the β subunit were able to reduce whole cell calcium currents. [Copyright &y& Elsevier]

Abstract: We have identified a novel interaction between huntingtin (htt) and N-type calcium channels, a channel key in coupling calcium influx with synaptic vesicle exocytosis. Htt is a widely expressed 350-kDa cytosolic protein bearing an N-terminal polyglutamine tract. Htt is proteolytically cleaved by calpains and caspases and the resultant htt N-terminal fragments have been proposed to be biologically active; however, the cellular function of htt and/or the htt fragments remains enigmatic. We show that N-terminal fragments of htt (consisting of exon1) and full-length htt associate with the synaptic protein interaction (synprint) region of the N-type calcium channel. Given that synprint has previously been shown to bind syntaxin 1A and that this association elicits inhibition of N-type calcium channels, we tested whether httexon1 affects the modulation of these channels. Our data indicate that httexon1 enhances calcium influx by blocking syntaxin 1A inhibition of N-type calcium channels and attributes a key role for htt N-terminal fragments in the fine tuning of neurotransmission. [Copyright &y& Elsevier]

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]

Abstract: Establishing stable cropping systems was vital in antiquity, assuring certain yields and enabling ancient people to settle, thus possibly causing various modern food habits and culture to form around the world, especially in cereal-cultivation-dominated countries. China, one of the most famous ancient agricultural countries, has a long history of rice planting, and the fire-irrigation paddy cultivation system is prevalent in the lower Yangtze region, which is considered a rice domestication center. However, its origin and cultivation pattern remain unclear. We studied a famous agricultural vestige, the Chuodun site, involved in rice planting in the lower Yangtze River Delta in eastern China, during the Neolithic Age. Clear evidence from archaeology, paleobiology, pedology and biogeochemistry suggest both that the rice fire-irrigation cultivation system formed during the Neolithic Age and that ancient peoples lived there steadily. Under this extensive cultivation system, soil structures and properties changed significantly; in particular, it left more black carbon in the soil and increased the organic carbon soil stability, which can be used to reconstruct prehistoric environments. Meanwhile, the prevalent fire-irrigation paddy cultivation system used by farmers in this area, though for a different purpose than ancient people, may be inherited from the Neolithic Age. [Copyright &y& Elsevier]

Abstract: We have generated a syntaxin 1A knockout mouse by deletion of exons 3 through 6 and a concomitant insertion of a stop codon in exon 2. Heterozygous knockout animals were viable with no apparent phenotype. In contrast, the vast majority of homozygous animals died in utero, with embryos examined at day E15 showing a drastic reduction in body size and development when compared to WT and heterozygous littermates. Surprisingly, out of a total of 204 offspring from heterozygous breeding pairs only four homozygous animals were born alive and viable. These animals exhibited reduced body weight, but showed only mild behavioral deficiencies. Taken together, our data indicate that syntaxin 1A is an important regulator of normal in utero development, but may not be essential for normal brain function later in life. [Copyright &y& Elsevier]

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]