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Sex as a physiologic factor has a strong association with the features of metabolic syndrome. Our previous study showed that loss of the voltage-gated proton channel Hv1 inhibits insulin secretion and leads to hyperglycemia and glucose intolerance in male mice. However, there are significant differences in blood glucose between male and female Hv1-knockout (KO) mice. Here, we investigated the differences in glucose metabolism and insulin sensitivity between male and female KO mice and how sex steroids contribute to these differences. We found that the fasting blood glucose in female KO mice was visibly lower than that in male KO mice, which was accompanied by hypotestosteronemia. KO mice in both sexes exhibited higher expression of gluconeogenesis-related genes in liver compared with WT mice. Also, the livers from KO males displayed a decrease in glycolysis-related gene expression and an increase in gluconeogenesis-related gene expression compared with KO females. Furthermore, exogenous testosterone supplementation decreased blood glucose levels in male KO mice, as well as enhancing insulin signaling. Taken together, our data demonstrate that knockout of Hv1 results in higher blood glucose levels in male than female mice, despite a decreased insulin secretion in both sexes. This sex-related difference in glucose homeostasis is associated with the glucose metabolism in liver tissue, likely due to the physiological levels of testosterone in KO male mice.

Starch is the most important component in endosperm of sorghum grain. Usually, two types of starch are present: amylose (AM) and amylopectin (AP). The levels of AM and AP contents play a significant role in the appearance, structure, and quality of sorghum grains and in marketing applications. In the present study, a panel of 634 sorghum (Sorghum bicolor (L.) Moench) accessions were evaluated for starch, AM, and AP contents of grain, which included a mini core collection of 242 accessions from the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT) in India, and 252 landraces and 140 cultivars from China. The average starch content was 67.64% and the average AM and AP contents were 20.19 and 79.81%, respectively. We developed a total of 260 000 high-confidence single nucleotide polymorphism (SNP) markers in the panel of 634 accessions of S. bicolor using specific locus amplified fragment sequencing (SLAF-seq). We performed genome-wide association studies (GWAS) of starch, AM, and AM/AP of grain and SNP markers based on a mixed linear model (MLM). In total, 70 significant association signals were detected for starch, AM, and AM/AP ratio of grain with P

Hepatitis is a severe liver disease with worldwide distribution. This study explored the anti-inflammatory influence of Emodin on LPS-triggered liver injury in vitro and in vivo. In vitro, we discovered that LPS treatment triggered L-02 cell and primary hepatocyte inflammatory injury. Emodin weakened the LPS-triggered cell inflammatory injury and NF-κB pathway activation. Emodin alleviated LPS-stimulated decrease of miR-145 expression. Moreover, miR-145 participated in the regulation of pro-inflammatory factors expression and negatively regulated IRAK1. Besides, IRAK1 exert regulatory roles in the activation of NF-κB pathway. In vivo, we found that Emodin pre-treatment weakened the LPS-triggered increases of pro-inflammatory factors expression, up-regulations of AST and ALT level, liver cell apoptosis, reduction of miR-145 and enhancement of IRAK1. Our research verified that Emodin weakened LPS-triggered liver cell inflammatory injury in vitro and in vivo might be achieved by elevating miR-145, decreasing IRAK1 and then suppressing NF-κB pathway.

Graphical abstract, The ability of SARS-CoV-2 to replicate in host cells is dependent on its main protease (Mpro, also called 3CLpro) that cut the viral precursor polyproteins and is a major target for antiviral drug design. Here, we showed that heparin interacts with the Mpro of SARS-CoV-2 and inhibits its activity. Protein fluorescence quenching showed that heparin strongly binds to the Mpro protein with dissociation constants KD of 16.66 and 31.60 μM at 25 and 35 oC, respectively. From thermodynamic parameters of the interaction, there are hydrophobic and hydrogen bond interactions between them. Fluorescence resonance energy transfer (FRET) assay demonstrated that heparin inhibits the proteolytic activity of Mpro with an inhibition constant Ki of 6.9 nM and a half maximal inhibitory concentrations (IC50) of 7.8±2.6 nM. Furthermore, molecular docking analysis revealed that the recognition and binding groups of heparin within the active site of SARS-CoV-2 Mpro provide important new information for the characteristics of the interactions of heparin with the protease. Our finding suggested that heparin might have a potential role in inhibiting SARS-CoV-2 infection through inhibiting Mpro activity of SARS-CoV-2.

An exponential multigrid framework is developed and assessed with a modal high-order discontinuous Galerkin method in space. The algorithm based on a global coupling, exponential time integration scheme provides strong damping effects to accelerate the convergence towards the steady-state, while high-frequency, high-order spatial error modes are smoothed out with a s-stage preconditioned Runge-Kutta method. Numerical studies show that the exponential time integration substantially improves the damping and propagative efficiency of Runge-Kutta time-stepping for use with the p-multigrid method, yielding rapid and p-independent convergences to steady flows in both two and three dimensions.

Asthma is a chronic airway inflammation that caused by many factors. The voltage-gated proton channel Hv1 has been proposed to extrude excessive protons produced by NADPH oxidase (NOX) from cytosol to maintain its activity during respiratory bursts. Here, we showed that loss of Hv1 aggravates ovalbumin (OVA)-induced allergic lung asthma in mice. The numbers of total cells, eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) of Hv1-deficiency (KO) mice are obviously increased after OVA challenge compared with that of wild-type (WT) mice. Histopathological staining reveals that Hv1-deficiency aggravates OVA-induced inflammatory cell infiltration and goblet cell hyperplasia in lung tissues. The expression of IL-4, IL-5 and IL-13 are markedly increased in lung tissues of OVA-challenged KO mice compared with that of WT mice. Furthermore, the expression levels of NOX2, NOX4 and DUOX1 are dramatically increased, while the expression levels of SOD2 and catalase are significantly reduced in lung tissues of OVA-challenged KO mice compared with that of WT mice. The production of ROS in lung tissues of KO mice is significantly higher than that of WT mice after OVA challenge. Our data suggest that Hv1-deficiency might aggravate the development of allergic asthma through increasing ROS production.

Diabetes is characterized by an absolutely inadequate insulin secretion (type 1 diabetes mellitus) or a relative deficit in insulin secretion due to insulin resistance (type 2 diabetes mellitus), both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. The voltage-gated proton channel Hv1 is an ion channel with specific selectivity for protons, which is regulated by membrane potential and intracellular pH. Recently, our studies showed that Hv1 is expressed in β cells of the endocrine pancreas. Knockout of Hv1 reduces insulin secretion and results in hyperglycemia and glucose intolerance, but not insulin resistance. Furthermore, knockout of Hv1 leads to diet-induced obesity due to inflammation and hepatic steatosis. Increasing evidence suggests that Hv1 plays a pivotal role in glucose homeostasis and lipid metabolism. This review aims to summarize advances made so far in our understanding of the roles of Hv1 in the regulation of insulin secretion in β cells, glucose homeostasis, and obesity.

An exponential time-integrator scheme of second-order accuracy based on the predictor-corrector methodology, denoted PCEXP, is developed to solve multi-dimensional nonlinear partial differential equations pertaining to fluid dynamics. The effective and efficient implementation of PCEXP is realized by means of the Krylov method. The linear stability and truncation error are analyzed through a one-dimensional model equation. The proposed PCEXP scheme is applied to the Euler equations discretized with a discontinuous Galerkin method in both two and three dimensions. The effectiveness and efficiency of the PCEXP scheme are demonstrated for both steady and unsteady inviscid flows. The accuracy and efficiency of the PCEXP scheme are verified and validated through comparisons with the explicit third-order total variation diminishing Runge-Kutta scheme (TVDRK3), the implicit backward Euler (BE) and the implicit second-order backward difference formula (BDF2). For unsteady flows, the PCEXP scheme generates a temporal error much smaller than the BDF2 scheme does, while maintaining the expected acceleration at the same time. Moreover, the PCEXP scheme is also shown to achieve the computational efficiency comparable to the implicit schemes for steady flows., Comment: Exponential scheme for Computational Fluid Dynamics (CFD). 37 pages, 11 figures

Reactive oxygen species (ROS) impairs pancreatic β-cells and plays an important role in development of diabetes. Streptozotocin (STZ) can lead to β-cell dysfunction via inducing ROS production. The voltage-gated proton channel Hv1 contributes a majority of the charge compensation required for ROS production. Here, we investigated the effects of Hv1 on STZ-induced β-cell damage. We found that deficiency of Hv1 obviously inhibits STZ-induced glucose intolerance in mice, and prevents the decrease in β-cell mass and pancreatic insulin content from STZ-treatment. Further studies showed that loss of Hv1 significantly attenuates STZ-induced β-cell damage and ROS production in pancreatic β-cells. Our results suggest that Hv1 might contribute to development of diabetes through producing ROS.

Xanthine oxidase (XO) is a purine catabolic enzyme related to hyperuricemia and gout. Porphyra polysaccharide (PP) is a kind of sulfated polysaccharide with potent biological activity. Herein, the interaction mechanism between PP and XO was studied by enzyme kinetics and multi-spectroscopy methods for the first time. Inhibition kinetics assay showed that PP reversibly inhibited XO activity in a mixed competitive manner with an IC50 of 10.53 ± 0.69 mg/ml. Fluorescence titration studies and thermodynamic parameter calculations revealed that PP could spontaneously bind to XO through hydrophobic interactions, with a class of binding site. Circular dichroism analysis demonstrated that PP induced secondary structure rearrangement and conformational change of XO. Molecular docking further revealed that PP inserted into the hydrophobic cavity of XO, occupying the catalytic center, leading to the inhibition of XO activity. This study may provide new insights into the inhibitory mechanism of PP as a promising XO inhibitor.

Background/Aims: Inflammatory skin diseases are the most common problems in dermatology. Schizandrin A (SchA) has been reported to have anti-inflammatory properties. Herein, we aimed to investigate the protective effects of SchA on lipopolysaccharide (LPS)-induced injury in keratinocyte HaCaT cells. Methods: Inflammation injury in HaCaT cells was induced by LPS treatment. Cell viability, apoptotic cell rate, and apoptosis-related proteins were analyzed by cell counting kit-8 (CCK-8) assay, Annexin V-(fluorescein isothiocyanate (FITC)/ Propidium Iodide (PI) double staining method, and western blot, respectively. The pro-inflammatory factors were analyzed by western blot and quantified by enzyme linked immunosorbent assay (ELISA). Expression of miR-127 in SchA-treated cells was analyzed by qRT-PCR. The effects of SchA on activations of p38MAPK/ERK and JNK pathways were analyzed by western blot. Results: SchA protected HaCaT cells from LPS-induced inflammation damage via promoting cell viability, suppressing apoptosis. Meanwhile, SchA inhibited IL-1β, IL-6, and TNF-α expression. miR-127 expression was up-regulated in LPS-treated HaCaT cells but down-regulated after SchA treatment. Overexpression of miR-127 inhibited cell growth and induced expression of IL-1β, IL-6 and TNF-α. Additionally, miR-127 overexpression impaired the protective effects of SchA, implying miR-127 might be correlated to the anti-inflammation property of SchA and also involved in inactivation of p38MAPK/ERK and JNK pathways by SchA. Conclusion: miR-127 is involved in the protective functions of SchA on LPS-induced inflammation injury in human keratinocyte cell HaCaT, which might inactivates of p38MAPK/ERK and JNK signaling pathways in HaCaT cells.

Some 3D computer vision techniques such as structure from motion (SFM) and augmented reality (AR) depend on a specific perspective-n-point (PnP) algorithm to estimate the absolute camera pose. However, existing PnP algorithms are difficult to achieve a good balance between accuracy and efficiency, and most of them do not make full use of the internal camera information such as focal length. In order to attack these drawbacks, we propose a fast and robust PnP (FRPnP) method to calculate the absolute camera pose for 3D compute vision. In the proposed FRPnP method, we firstly formulate the PnP problem as the optimization problem in the null space that can avoid the effects of the depth of each 3D point. Secondly, we can easily get the solution by the direct manner using singular value decomposition. Finally, the accurate information of camera pose can be obtained by optimization strategy. We explore four ways to evaluate the proposed FRPnP algorithm with synthetic dataset, real images, and apply it in the AR and SFM system. Experimental results show that the proposed FRPnP method can obtain the best balance between computational cost and precision, and clearly outperforms the state-of-the-art PnP methods.

High glucose (HG)-induced oxidative stress contributes to the dysfunction of pancreatic β cells in diabetes. The voltage-gated proton channel Hv1 has been proposed to support reactive oxygen species (ROS) production during respiratory bursts. However, the effect of Hv1 on glucotoxicity in pancreatic β cells is not clear yet. In this study, we examined the protective effects of Hv1-deficiency in HG cultured β cells. Following 48 h of treatment with 30 mM high glucose, Hv1 KO β cells showed higher cell viability, lower cell apoptosis and a more stable insulin gene expression level compared to WT β cells. In both control and HG cultured β cells, deficiency of Hv1 decreased the glucose- and PMA-induced ROS production. Finally, HG incubation led to NOX4 upregulation in WT β cells, which could be inhibited by HV1 deficiency. In conclusion, Hv1-deficiency prevents the HG treatment-induced NOX4 upregulation and protects β cells from glucotoxicity.

The preprotein translocase of the inner membrane of mitochondria (TIM23 complex) is the main entry gate for proteins of the matrix and the inner membrane. Tim23p, the core component of TIM23 complex, forms the import pore across the inner membrane and exerts a key function in the protein import. However, the interaction of divalent metal ions with Tim23p and the contribution in the interaction of presequence peptide with Tim23p are still unknown. Herein, we investigated the interaction of divalent metal ions with the intermembrane space domain of Tim23p (Tim23 IMS ) and the interaction of presequence peptides with Tim23 IMS in presence of Ca 2+ ion by fluorescence spectroscopy in vitro . The static fluorescence quenching indicates the existence of strong binding between divalent metal ions and Tim23 IMS . The order of the binding strength is Ca 2+ , Mg 2+ , Cu 2+ , Mn 2+ , and Co 2+ (from strong to weak). Moreover, the interaction of presequence peptides with Tim23 IMS is weakened in presence of Ca 2+ ion, which implicates that Ca 2+ ion may play an important role in the protein import by TIM23 complex.

We report an approach of high-pressure hydrogenation to improve the performance of crystalline Si (c-Si) solar cells. As-received p-type c-Si wafer-based PN junctions were subjected to high-pressure (2.5 MPa) hydrogen atmosphere at 200 °C, followed by evaporating antireflection layers, passivation layers, and front and rear electrodes. The efficiency of the so prepared c-Si solar cell was found to increase evidently after high-pressure hydrogenation, with a maximal enhancement of 10%. The incorporation of hydrogen by Si solar cells was identified, and hydrogen passivation of dangling bonds in Si was confirmed. Compared to the regular approach of hydrogen plasma passivation, the approach of high-pressure hydrogenation reported here needs no post-hydrogenation treatment, and can be more convenient and efficient to use in improving the performances of the c-Si and other solar cells.

DNA-encoded peptide libraries are ideal functional peptide discovery platforms for their extremely large capacity. However, it’s still difficult to build high content peptide library in intact mammalian cells, which offer advantages associated with appropriate protein modification, proper protein folding, and natural status of membrane protein. Our previous work established linear-double-stranded DNAs (ldsDNAs) as innovative biological parts to implement AND gate genetic circuits in mammalian cell line. In the current study, we employ ldsDNA with terminal NNK degenerate codons as AND gate input to build highly diverse peptide library in mammalian cells. This ldsDNA-based AND gate (LBAG) peptide strategy is easy to conduct, only PCR reaction and cell transfection experiments are needed. High-throughput sequencing (HTS) results reveal that our new LBAG strategy could generate peptide library with both amino acid sequence and peptide length diversities. Moreover, by a mammalian cell two-hybrid system, we pan an MDM2 protein interacting peptide through the LBAG peptide library. Our work establishes ldsDNA as biological parts for building highly diverse peptide library in mammalian cells.

Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator of glucose and lipid, which is safe, effective and independent on insulin. FGF21 is considered as a prospective anti-diabetic drug. The aim of this study was to express recombinant h-FGF21 in periplasmic space of Escherichia coli. The pET27b plasmid was used to create the expression vectors of h-FGF21 with a PelB secretion signal. The ph-FGF21 (periplasmic expression of h-FGF21) was successfully expressed in the periplasm of E. coli BL21 (DE3), and soluble ph-FGF21 was isolated by disruption of the outer membrane. After twice of ion exchange chromatography, the purity of ph-FGF21 was above 95% in an analysis with a gray analysis software. The molecular weight of ph-FGF21 was about 20 kDa in SDS-PAGE and Western blotting analysis. The activity of ph-FGF21 and ih-FGF21 (intracellular expression of h-FGF21) was observed in vitro in the glucose uptake assay in HepG2 cells. The activity was observed in type 2 diabetic db/db mice after short or long-term treatments. The results suggest that the ph-FGF21 has a consistent activity with ih-FGF21 in vitro and in vivo.

The voltage-gated proton channel Hv1 is a potent acid extruder that participates in the extrusion of the intracellular acid. Here, we showed for the first time, Hv1 is highly expressed in mouse and human pancreatic islet β-cells, as well as β-cell lines. Imaging studies demonstrated that Hv1 resides in insulin-containing granules in β-cells. Knockdown of Hv1 with RNA interference significantly reduces glucose- and K(+)-induced insulin secretion in isolated islets and INS-1 (832/13) β-cells and has an impairment on glucose- and K(+)-induced intracellular Ca(2+) homeostasis. Our data demonstrated that the expression of Hv1 in pancreatic islet β-cells regulates insulin secretion through regulating Ca(2+) homeostasis.

Objectives The aim of this meta-analysis was to evaluate the efficacy and safety of duloxetine for management of osteoarthritis knee (OAK) pain. Methods A systematic literature search of articles for management of OAK using duloxetine were performed in PubMed, EBSCO, EMBASE, ScienceDirect, MEDLINE, [ClinicalTrials.gov][1], Google Scholar, and Cochrane Central Register of Controlled Trials from the available date of inception until the latest issue (October 2013). Potentially relevant randomized controlled trials (RCTs) regarding to comparison of efficacy and safety of duloxetine with placebo for managing OAK pain were included. Also, studies with specific data regarding to pain reductions and response rate, Patient Global Impression of Improvement (PGI-I), functional improvement, Western Ontario and McMaster Osteoarthritis Index (WOMAC), adverse events (AEs), treatment-emergent AEs (TEAEs), mortality were included and analyzed, and those with confounding conditions were excluded. Studies were assessed for quality using the Jadad five-point score for RCTs. Finally, a meta-analysis of all RCTs eligible for inclusion criteria was performed using Review Manager 5.1 meta-analysis software. Results. Three RCTs that enrolled 1,011 patients were included in our meta-analysis. There were statistically significant differences between patients taking duloxetine and those taking placebo with regard to the reductions in pain intensity (992 patients, mean difference [MD] = −0.88, 95% confidence interval [CI] −1.11–−0.65, P = 30% response rate; 989 patients, risk ratio [RR] = 1.49, 95% CI 1.31–1.70, P =50% response rate; 989 patients, RR = 1.69, 95% CI 1.27–2.25, P = 0.0004). Statistically significant differences in PGI-I (976 patients, MD = −0.47, 95% CI −0.63 to −0.30, P < 0.0001) and WOMAC—physical function subscale (977 patients, MD = −4.25, 95% CI −5.82 to −2.68, P < 0.0001) were observed. Similarly, more AEs, TEAEs, and discontinuations for any reason were associated with the use of duloxetine than with placebo (1,011 patients, RR = 2.15, 95% CI 1.48–3.11, P < 0.0001; 1,011 patients, RR = 1.32, 95% CI 1.16–1.49, P < 0.0001; 1,011 patients, RR = 1.43, 95% CI 1.14–1.78, P = 0.002, respectively). However, differences in serious AEs were not significantly statistically different. Moreover, no deaths occurred during these three studies. Conclusion. This analysis suggests duloxetine (60/120 mg quaque die (QD)), compared with placebo control, resulted in a greater reduction in pain, improved function and patient-rated impression of improvement, and acceptable adverse effects for the treatment of OAK pain after approximately 10 −13 weeks of treatment. [1]: http://ClinicalTrials.gov

Four kinds of granular activated carbon GAC were treated by water taken from surface drinking-water sources in Ji’nan. Five adsorption performance indicators of granular activated carbon (GAC) were investigated. The correlation between the indicators and the removal rate of organic matter in raw water was analysed and the results showed that the removal rates of CODMn and DOC were well correlated with iodine value, the coefficient correlations, R2 were 0.8745 and 0.8474 respectively, the removal rates of UV254 was well correlated with methylene blue value (R2 = 0.9454), indicating the capability as indicator for GAC selection. Additionally, one original GAC was used to adsorb organic matter in raw water, as well as the GAC samples treated with four different saturation time in raw water, to investigate the residue rate of adsorption ability. Of all five adsorption performance indicators, it was found that the iodine value, methylene blue value, and tannic acid were negatively related to the residual rate of the GAC absorption ability (R2 was over 0.9). Based on the research, the activated carbon filters in Quehua Water plant in Ji’nan was evaluated and the replacement of them was suggested.

The voltage-gated proton channel Hv1 is strongly sensitive to Zn(2+). The H(+) conduction is decreased at a high concentration of Zn(2+) and Hv1 channel closing is slowed by the internal application of Zn(2+). Although the recent studies demonstrated that Zn(2+) interacts with the intracellular C-terminal domain, the binding sites and details of the interaction remain unknown. Here, we studied the pH-dependent structural stability of the intracellular C-terminal domain of human Hv1 and showed that Zn(2+) binds to His(244) and His(266) residues. The thermodynamics signature of Zn(2+) binding to the two sites was investigated by isothermal titration calorimetry. The binding of Zn(2+) to His(244) (mutant H266A) and His(266) (mutant H244A) were an endothermic heat reaction and an exothermic heat reaction, respectively.

Objective: This paper aims to look at the impact of arts-based knowledge translation (ABKT) methods in raising awareness among nursing students and the public about the sex differences and behavioral and psychological symptoms of dementia (BPSD), implemented through a creative new media arts-exhibit at Toronto Rehabilitation Institute.Methods: Through surveys, interviews, and pre- and post-exhibit questionnaires, this project evaluated the use and efficacy of multi-modal media in translating data from a study on the BPSD. The research team categorized and conceptualized artwork and narratives based on data collected from previous phases; no confidential or identifying information related to study participants were used or displayed in the final exhibit.Results: The use of photographs, paintings, abstract data visualizations, augmented reality and virtual reality had various levels of effectiveness in engaging nursing students and the public on the topic of dementia. 360º videos, photographs, and paintings provided the highest level of engagement and discussion among nursing students. The majority of the students reported a better understanding and empathy towards people living with dementia after the viewing of the exhibit and all students perceived the exhibit as an effective method in portraying dementia experience and contributed to their overall understanding of the BPSD.Conclusions: This knowledge mobilization project overall provided a more informed perspective on BPSD among nursing students and the public, and effectively sparked discussion among viewers. The exhibit was able to raise awareness for dementia, its symptoms, and experiences of patients living with dementia. For the scholarly community, our project presents new ways to mobilize knowledge among a broad audience and demonstrates unique, innovative, and engaging forms of ABKT.

ObjectiveThe voltage-gated proton channel Hv1 has been proposed to mediate NADPH oxidase (NOX) function by regulating intracellular pH during respiratory bursts. In our previous work, we showed that Hv1 is expressed in pancreatic β cells and positively regulates insulin secretion. Here, we investigated the role of Hv1 in adipose tissue differentiation, metabolic homeostasis and insulin sensitivity using Hv1 knockout (KO) mice.DesignMice with genetic deletion of Hv1 are treated with high-fat diet (HFD) similar to wild-type (WT) mice. Body weight gain, adiposity, insulin sensitivity and gene expressions in both adipose tissue and liver were analyzed.ResultsMice with genetic deletion of Hv1 display overt obesity with higher body weight gain and accumulation of adipose tissue compared with similarly HFD-treated WT. Hv1-deficient mice develop more glucose intolerance than WT, but no significant difference in insulin resistance, after fed with HFD. Deficiency of Hv1 results in a remarkable increase in epididymal adipocyte weight and size, while the gene expressions of proinflammatory factors and cytokines are obviously enhanced in the HFD-fed mice. Furthermore, the gene expression of Hv1 is increased in the HFD-fed mice, which is accompanied by the increase of NOX2 and NOX4. In addition, there is more severely diet-induced steatosis and inflammation in liver in KO mice.ConclusionOur data demonstrated that lacking of Hv1 results in diet-induced obesity in mice through inflammation and hepatic steatosis. This study suggested that Hv1 acts as a positive regulator of metabolic homeostasis and a potential target for antiobesity drugs in therapy and may serve as an adaptive mechanism in cooperating with NOX to mediate reactive oxygen species for adipogenesis and insulin sensitivity.

The increased glycolysis and proton secretion in tumors is proposed to contribute to the proliferation and invasion of cancer cells during the process of tumorigenesis and metastasis. Here, treatment of human breast cancer cells with proton pump inhibitor (PPI) lansoprazole (LPZ) induces cell apoptosis in a dose-dependent manner. In the implantation of the MDA-MB-231 xenografts in nude mice, administration of LPZ significantly inhibits tumorigenesis and induces large-scale apopotosis of tumor cells. LPZ markedly inhibits intracellular proton extrusion, induces an increase in intracellular ATP level, lysosomal alkalinization and accumulation of reactive oxygen species (ROS) in breast cancer cells. The ROS scavenger N-acetyl-l-cysteine (NAC) and diphenyleneiodonium (DPI), a specific pharmacological inhibitor of NADPH oxidases (NOX), significantly abolish LPZ-induced ROS accumulation in breast cancer cells. Our results suggested that LPZ may be used as a new therapeutic drug for breast tumor.

TiC/TiB2-FeNiCr composite reinforced by TiC and TiB2 composite ceramic particles was successfully in-situ synthesized using thermite reaction. The effects of Ti content in the raw material on the microstructure and properties of the composite were studied. The microstructure was investigated using X-ray diffraction (XRD), scanning electron microscopy (SEM) and electron probe microanalysis (EPMA). The hardness, compressive strength and wear resistance were tested using the Vickers indentation method (HXZ-1000), mechanical testing machine (SANS5105) and the high temperature wear tester (HT-600), respectively. The results show that the composite is mainly consisted of TiC, TiB2, Cr7C3, α-FeNiCr and NiAl. The content of TiC and TiB2 is increased with the Ti content. The hardness and compressive strength of the composite is increased first and then decreased. They attain the maximum value at about 8.0wt%Ti. The hardness and the compressive strength of the composite are 1313.25HV and 2725.57MPa at 8.0% Ti. Also the wear resistance of the composite is good, and the weight wear loss at 8.0% Ti is nearly fifth of the mass loss of steel.

Highlights: •Hv1 is expressed in highly metastatic glioma cell. •Zn{sup 2+} ions induces apoptosis in highly metastatic glioma cells. •Zn{sup 2+} ions markedly inhibit proton secretion. •Zn{sup 2+} ions reduce the gelatinase activity. •Inhibition of Hv1 activity via Zn{sup 2+} ions can effectively retard the cancer growth. -- Abstract: In contrast to the voltage-gated K{sup +} channels, the voltage-gated proton channel Hv1 contains a voltage-sensor domain but lacks a pore domain. Here, we showed that Hv1 is expressed in the highly metastatic glioma cell SHG-44, but lowly in the poorly metastatic glioma cell U-251. Inhibition of Hv1 activity by 140 μM zinc chloride induces apoptosis in the human highly metastatic glioma cells. Zn{sup 2+} ions markedly inhibit proton secretion, and reduce the gelatinase activity in the highly metastatic glioma cells. In vivo, the glioma tumor sizes of the implantation of the SHG-44 xenografts in nude mice that were injected zinc chloride solution, were dramatically smaller than that in the controlled groups. The results demonstrated that the inhibition of Hv1 activity via Zn{sup 2+} ions can effectively retard the cancer growth and suppress the cancer metastasis by the decrease of proton extrusion and the down-regulation of gelatinase activity. Our results suggestmore » that Zn{sup 2+} ions may be used as a potential anti-glioma drug for glioma therapy.« less

Here, we demonstrate that the voltage-gated proton channel Hv1 represents a regulatory mechanism for insulin secretion of pancreatic isletβcell.In vivo, Hv1-deficient mice display hyperglycemia and glucose intolerance due to reduced insulin secretion, but normal peripheral insulin sensitivity.In vitro, islets of Hv1-deficient and heterozygous mice, INS-1 (832/13) cells with siRNA-mediated knockdown of Hv1 exhibit a marked defect in glucose- and K+-induced insulin secretion. Hv1 deficiency decreases both insulin and proinsulin contents, and limits glucose-induced Ca2+entry and membrane depolarization. Furthermore, loss of Hv1 increases insulin-containing granular pH and decreases cytosolic pH. In addition, histologic studies show a decrease inβcell mass in islets of Hv1-deficient mice. Collectively, our results indicate that Hv1 supports insulin secretion in theβcell by calcium entry, membrane depolarization and intracellular pH regulation.SIGNIFICANCE STATEMENTThe voltage-gated proton channel Hv1 is highly expressed in insulin-containing granules in pancreatic β cells. Hv1 supports insulin secretion in theβcell by calcium entry, membrane depolarization and regulation of intragranular and cytosolic pH, which represents a regulatory mechanism for insulin secretion of pancreatic isletβcell. Our research demonstrates that Hv1 expressed inβcell is required for insulin secretion and maintains glucose homeostasis, and reveals a significant role for the proton channel in the modulation of pancreaticβcell function.

To quickly get the global optimum by genetic algorithm, calculated the average and standard deviation of the adaptabilities of chromosomes of one generation, designed the selection operator and the mutation operator by the average and the standard deviation, dynamically adjusted the probability of selection operator and mutation operator and decreased the blindness of genetic algorithm, increased the multiplicity of chromosomes by multiple-point crossover and repetitiveness check. The test shows that the algorithm offered in the article is feasible and effective.

In our previous work, we showed for the first time that the voltage-gated proton channel Hv1 is specifically expressed in highly metastatic human breast tumor tissues and cell lines. However, the contribution of Hv1 to breast carcinogenesis is not well known. In this study, we showed that Hv1 expression was significantly correlated with the tumor size (p = 0.001), tumor classification (p = 0.000), lymph node status (p = 0.000), clinical stage (p = 0.000), and Her-2 status (p = 0.045). High Hv1 expression was associated significantly with shorter overall (p = 0.000) and recurrence-free survival (p = 0.000). In vitro, knockdown of Hv1 expression in the highly metastatic MDA-MB-231 cells decreased the cell proliferation and invasiveness, inhibited the cell proton secretion and intracellular pH recovery, and blocked the cell capacity of acidifying extracellular milieu. Furthermore, the gelatinase activity in MDA-MB-231 cells that suppressed Hv1 was reduced. In vivo, the breast tumor size of the implantation of the MDA-MB-231 xenografts in nude mice that were knocked down by Hv1 was dramatically smaller than that in the control groups. The results demonstrated that the inhibition of Hv1 function via knockdown of Hv1 expression can effectively retard the cancer growth and suppress the cancer metastasis by the decrease of proton extrusion and the down-regulation of gelatinase activity. Based on these results, we came to the conclusion that Hv1 is a potential biomarker for prognosis of breast cancer and a potential target for anticancer drugs in breast cancer therapy.

The preprotein translocase of the inner mitochondrial membrane (TIM23 complex) is the main entry gate for proteins of the matrix and the inner membrane. Tim23 forms a pore for preprotein transportation in TIM23 complex, which spans the inner membrane with transmembrane segments and exposes a hydrophilic domain in the intermembrane space. In this study, we expressed and purified the intermembrane space (IMS) domain of human Tim23 (Tim23 IMS ). The far-UV CD spectra of Tim23 IMS in native and denatured states revealed that the protein has a limited secondary structure and a not well-defined tertiary packing. Its Stokes radius was larger than both its expected size as a folded globular protein and the size determined by size exclusion chromatography. A large increase in 8-anilino-1-naphthalene-sulfonate (ANS) fluorescence (>50-fold) was observed, indicating that hydrophobic clusters are exposed at its surface. And GlobPlot/DisEMBL program predicted that the protein is in a loose folding state. We therefore conclude that, the non-bound hydrophilic domain of the human Tim23 is in a molten globule configuration with marginal stability. Furthermore, size exclusion chromatography and sedimentation equilibrium analysis showed that Tim23 IMS exists as a dimer. And the results, showed by ANS binding and fluorescence quenching, indicated that a pH-dependent conformational change of Tim23 IMS occurs, and at pH 4 and 3, it forms a compact structure.

With the frequency converter for driving belt conveyor, the synchronous control of torque and speed for the belt-drive unit can be achieved and the start-up characteristics of belt conveyor can also be improved. This paper uses two methods for achieving synchronous drive of belt conveyor, one is synchronization through master-slave control of frequency converter itself, the second is adding external algorithm implemented by PLC systems. This article describes a variable-frequency adjustable-speed drive system used for long distance belt conveyor in mine main inclined shaft or ground. This frequency conversion device and system can be applied to the adjustable-speed drive process of constant torque load for conveyor.

According to the demand of gas schedule management in the steel plant, Kirchhoff law in the power grid is used to build virtual network model for gas pipe network. Applying Newton-lafusen method, by solving nonlinear equations, the gas flow and pressure drop on the measurement points in the network are calculated. These data are compared with the real-time data in the database to monitor the operation status of entire network. When the production plans are changed, the schedule instruction are input to simulation calculation module. By analysing the operation status of entire network, after forecast instructions are issued, to adjust the forecast scheduling instructions.

The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT-PCR and immunocytochemistry showed that the expression levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells.

With the development of computer science, the finite element method has been used widely. The paper used the ABAQUS finite element analysis software to carry out the finite element analysis on the middle long columns of high-strength concrete filled square steel tube with inner CFRP circular tube under compressive load. The results of finite element analysis were obtained, which agreed well with theoretical data. This conclusion proved the correctness and feasibility of finite element model.

The voltage-gated proton channel Hv1 has a voltage sensor domain but lacks a pore domain. Although the C-terminal domain of Hv1 is known to be responsible for dimeric architecture of the channel, its role and structure are not known. We report that the full-length Hv1 is mainly localized in intracellular compartment membranes rather than the plasma membrane. Truncation of either the N or C terminus alone or both together revealed that the N-terminal deletion did not alter localization, but deletion of the C terminus either alone or together with the N terminus resulted in expression throughout the cell. These results indicate that the C terminus is essential for Hv1 localization but not the N terminus. In the 2.0 A structure of the C-terminal domain, the two monomers form a dimer via a parallel alpha-helical coiled-coil, in which one chloride ion binds with the Neta atom of Arg(264). A pH-dependent structural change of the protein has been observed, but it remains a dimer irrespective of pH value.

Objectives: This study investigated the levels of macrophage migration inhibitory factor (MIF) in adult-onset Still's disease (AOSD) and explored the role of this pro-inflammatory cytokine in the systemic inflammation of AOSD. Design and methods: Serum MIF levels were measured by ELISA in patients with AOSD and controls. Intracellular MIF production by peripheral blood leukocytes was detected by three-color flow cytometry. Results: Serum MIF levels were significantly increased in patients with AOSD. Serum MIF levels were significantly higher in AOSD patients with sore throat, myalgias, splenomegaly, or pleuritis, and were closely correlated with clinical disease severity and activity. Examined by flow cytometry, the intracellular MIF levels in monocytes and T-lymphocytes from AOSD patients were significantly higher than those from healthy subjects. Conclusion: These data represent the first demonstration of increased MIF expression in AOSD, and suggest that MIF may be an important marker for disease evaluation and monitoring.

Carbon fiber reinforced CMCs (ceramic matrix composites) are promising high temperature structural materials for aeronautical and astronautical industries. But the engineering application of the materials strongly depends on the joining technique. As a fundamental research, high strength graphite can be used to simulate carbon fiber. The study of wettability of graphite by liquid metals contributes to the development of joining technique of carbon fiber reinforced CMCs. The wettability of graphite/Ni plus Cr system was investigated using the sessile drop method. The contact angle was determined by high temperature photography. The microstructure and composition of the interfacial zone were analyzed by SEM, EDX and XRD. The contact angle of graphite/Ni plus Cr system decreases with increasing the Cr content. It becomes zero, when the Cr content reaches 50wt%. The wetting of graphite/Ni plus Cr system is chemical wetting. The contact angle of the system decreases with increasing the wetting temperature or prolonging the holding time. The higher the Cr content, the more remarkable the effects of the temperature and the holding time on the contact angle are. Microstructure and phase analysis reveals that inter-diffusions and interfacial reactions take place in the wetting process. The reaction products include Cr3C2. The formation of Cr3C2 contributes to the interfacial bonding and results in the accumulation of Cr in the interfacial zone.

In order to contribute to the development of the joining technique of Cf/SiC, joining of SiC ceramic to high strength graphite was investigated. This joining has been successfully realized by reaction joining process using a preceramic polymer, polysiloxane, mixed with the active additive Al-Si powder as joining material. The weld strength is strongly affected by the technological parameters and the ingredient ratio (polysiloxane:Al-Si powder). The optimized factors have been obtained by orthogonal experiments, under which the achieved three-point bending strength of the joints is 96.8% of the strength of the welding base material graphite. The microstructure and composition of the weld zone were analyzed by SEM, EDX and XRD. The results show that the joining material has transformed into a densified interlayer with the thickness of about 15μm. Also, diffusion takes place in the interfacial area, which contributes to a sound interfacial bonding. The interlayer is composed of SiC, Al2O3 and Si.

L-Lactate oxidase (LOX) from Aerococcus viridans catalyzes the oxidation of L-lactate to pyruvate by the molecular oxygen and belongs to a large family of 2-hydroxy acid-dependent flavoenzymes. To investigate the interaction of LOX with pyruvate in structural details and understand the chemical mechanism of flavin-dependent L-lactate dehydrogenation, the LOX-pyruvate complex was crystallized and the crystal structure of the complex has been solved at a resolution of 1.90 Angstrom. One pyruvate molecule bound to the active site and located near N5 position of FMN for subunits, A, B, and D in the asymmetric unit, were identified. The pyruvate molecule is stabilized by the interaction of its carboxylate group with the side-chain atoms of Tyr40, Arg181, His265, and Arg268, and of its keto-oxygen atom with the side-chain atoms of Tyr146, Tyr215, and His265. The alpha-carbon of pyruvate is found to be 3.13 Angstrom from the N5 atom of FMN at an angle of 105.4 degrees from the flavin N5-N10 axis.

The combined presence of anti-phospholipid Ab (aPL), thrombosis, and/or fetal loss is recognized as the antiphospholipid syndrome (APS). aPL include anti-cardiolipin Ab (aCL) and/or lupus anticoagulants (LAC, detected as Ig that prolong certain in vitro phospholipid (PL)-restricted blood clotting tests); both aCL and LAC are the diagnostic Ab for APS. Studies show that aPL represent a heterogeneous group of Ab, which recognize various PL, PL-binding plasma proteins, and/or PL-protein complexes. Recently, we found that five of seven patient-derived IgG monoclonal aCL react with thrombin, activated protein C, and plasmin. All three proteins are trypsin-like serine proteases (SP), and are highly homologous in their catalytic domains. Importantly, among these SP autoantigens, the reactive aCL bind to plasmin with the highest affinity, suggesting that plasmin may serve as a major driving autoantigen for some aCL in ∼30% of APS patients who are positive for IgG anti-plasmin Ab. To test this hypothesis, we immunized BALB/c mice with human plasmin and analyzed immune sera for aCL activity and reactivity with relevant SP. We found that some immune sera displayed aCL activity and/or bound to test SP. Subsequently, eight mAb were obtained and studied. The results revealed that one mAb displayed the aCL and the LAC activities and induced fetal loss when injected into pregnant mice. Immunohistological analyses of placentas revealed extensive deposits of activated C3 components. Combined, these data demonstrate that plasmin may serve as a driving Ag for some pathogenic aPL.