bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal Distribution and Genotyping of Antibiotic Resistant Strains of Listeria Innocua Isolated from A River Basin Categorized by ERIC-PCR
Authors: Tsai Hsin-Chi , Chou Ming-Yuan , Wu Cheng-Chun , Wan Min-Tao , Kuo Yi-Jie , Chen Jung-Sheng , Huang Tung-Yi , Hsu Bing-Mu
Published: July 2018

Listeria innocua retains many conserved homologous domains with Listeria monocytogenes, which is a food-borne and water-borne diarrhea-causing bacterium. Studies of antimicrobial resistance in L. innocua showed that this microbe is more prone to acquire resistance than other bacteria in the genus Listeria. However, little is known about the seasonal population distribution and antimicrobial resistance patterns of L. innocua in natural water environments. The aims of the study were: (1) to investigate the occurrence of L. innocua isolates in a subtropical watershed and reconstruct the population structure and (2) to analyze the antibacterial resistance patterns of the identified L. innocua isolates according to ERIC type. A total of 288 water samples was collected from the Puzi River basin (23°28’ N, 120°13’ E) between March 2014 and March 2015, and 36 L. innocua isolates were recovered from 15 positive water samples. With regard to seasonal variation, L. innocua was only detected in the spring and summer. Eighteen enterobacterial repetitive intergenic consensus (ERIC)-PCR types were identified, and two genogroups with four subgroups were reconstructed in a minimum spanning tree. Isolates from different sampling areas that were located near each other were genetically different. All L. innocua isolates (including 41.7% of the multidrug-resistant (MDR) isolates) were resistant to oxacillin and showed high minimum inhibitory concentrations of tetracycline. These findings demonstrate the seasonal variations and differing geographical distributions of L. innocua in this subtropical water environment, as well as the existence of strong population structures and MDR and antimicrobial resistance patterns. Phylogenetic analysis based on ERIC-type showed that the Cluster A isolates were resistant to more antibiotics, and two types, ERIC8 and ERIC15 were multidrug resistant. The more commonly detected types, such as ERIC1 and ERIC12, were also more likely to be resistant to two or more antibiotics. Close monitoring of drug resistance in environmental L. innocua is warranted due to its potential for transferring antimicrobial resistance determinants to pathogenic Listeria.
Relations between Objective and Perceived Built Environments and the Modifying Role of Individual Socioeconomic Position. A Cross-Sectional Study on Traffic Noise and Urban Green Space in a Large German City
Authors: Schüle Steffen Andreas , Nanninga Sarah , Dreger Stefanie , Bolte Gabriele
Published: July 2018

Perceived annoyance due to traffic noise and lack of urban green space is mostly determined using data from self-administered questionnaires. However, there is still no clear evidence to what extent such perceived measures are related to objectively assessed environmental data and whether socioeconomic dimensions modify such relationships. In a cross-sectional study in Dortmund, Germany, georeferenced home addresses from parents with preschool aged children were used to analyse relations between exposures to objectively measured green space and traffic noise and subjective annoyance due to noise and lack of green space with the additional consideration of socioeconomic characteristics as effect modifiers. Higher perceived annoyance correlated with higher objectively measured traffic noise and lower objectively measured green, respectively. Stratified logistic regression models indicated a modifying role of socioeconomic characteristics. The strengths of associations between objectively measured environmental exposures and perceived annoyance differed by socioeconomic strata. Especially for noise, odds ratios were higher in low socioeconomic strata than in high socioeconomic strata. Therefore, using objective measures of the built environment as a proxy for individual perception should be made with caution as negative relations between objectively assessed built environments and health could be underestimated when considering individual socioeconomic position only as a confounder.
Nonadult Supervision of Children in Low- and Middle-Income Countries: Results from 61 National Population-Based Surveys
Authors: Ruiz-Casares Mónica , Nazif-Muñoz José Ignacio , Iwo René , Oulhote Youssef
Published: July 2018

Despite scarce empirical research in most countries, evidence has shown that young children are unsupervised or under the supervision of another young child while their adult caregivers attend work or engage in other activities outside the home. Lack of quality supervision has been linked to unintentional childhood injuries and other negative outcomes. Nationally representative, population-based data from rounds four and five of the Multiple Indicator Cluster Surveys (MICS) and four to eight of the Demographic and Health Surveys (DHS) from 61 low- and middle-income countries were used to estimate prevalence and socio-economic factors associated with leaving children under five years old home alone or under the care of another child younger than 10 years of age. Socio-economic factors included age and sex of the child, rurality, wealth, maternal education, and household composition. Large variations in the prevalence rates (0.1–35.3% for children home alone and 0.2–50.6% for children supervised by another child) and associated factors have been recorded within and across regions and countries. Understanding why and under what conditions children are home alone or under the supervision of another child is crucial to the development of suitable policies and interventions to protect young children, promote healthy growth, and support caregivers.
Quality Assurance and Patient Safety Measures: A Comparative Longitudinal Analysis
Authors: Manzanera Rafael , Moya Diego , Guilabert Mercedes , Plana Manel , Gálvez Gloria , Ortner Jordi , Mira José Joaquín
Published: July 2018

Objective: To analyze whether the results on quality assurance and safety culture in a healthcare organization are related to and affected by the actions implemented. Setting: Health Insurance of Work-related Accidents and Occupational Diseases. Methods: The study was conducted as a longitudinal observational study that analyzed the relationship of the Safety Culture and Quality Assurance measurements. Participants who were involved came from small centers with less than eight workers (N = 52), big centers (eight and more workers) (N = 707), and those centers with quality coordinators (N = 91). Data were collected during the years 2015 and 2016. Results: A total of 595 healthcare professionals responded in 2015 and 491 in 2016. The scores showed a positive progression both in Quality Assurance (T-test = 3.5, p = 0.001) and in Safety Culture (T-test = 5.6, p < 0.0001). Hence, the gradient of improvement in quality (average 5.5%) was greater compared to that of the safety culture (2.1%). Conclusions: The assessments of the quality assurance goals were consistent with the safety culture assessment. Hence, the results on Safety Culture were observed to be more stable over time.
Using Geospatial Analysis and Hydrologic Modeling to Estimate Climate Change Impacts on Nitrogen Export: Case Study for a Forest and Pasture Dominated Watershed in North Carolina
Authors: Alam Md Jahangir , Ercan Mehmet B. , Zahura Faria Tuz , Goodall Jonathan L.
Published: July 2018

Many watersheds are currently experiencing streamflow and water quality related problems that are caused by excess nitrogen. Given that weather is a major driver of nitrogen transport through watersheds, the objective of this study was to predict climate change impacts on streamflow and nitrogen export. A forest and pasture dominated watershed in North Carolina Piedmont region was used as the study area. A physically-based Soil and Water Assessment Tool (SWAT) model parameterized using geospatial data layers and spatially downscaled temperature and precipitation estimates from eight different General Circulation Models (GCMs) were used for this study. While temperature change predictions are fairly consistent across the GCMs for the study watershed, there is significant variability in precipitation change predictions across the GCMs, and this leads to uncertainty in the future conditions within the watershed. However, when the downscaled GCM projections were taken as a model ensemble, the results suggest that both high and low emission scenarios would result in an average increase in streamflow of 14.1% and 12.5%, respectively, and a decrease in the inorganic nitrogen export by 12.1% and 8.5%, respectively, by the end of the century. The results also show clear seasonal patterns with streamflow and nitrogen loading both increasing in fall and winter months by 97.8% and 50.8%, respectively, and decreasing by 20.2% and 35.5%, respectively, in spring and summer months by the end of the century.
Using Eye Tracking to Evaluate the Usability of Flow Maps
Authors: Dong Weihua , Wang Shengkai , Chen Yizhou , Meng Liqiu
Published: July 2018

Flow maps allow users to perceive not only the location where interactions take place, but also the direction and volume of events. Previous studies have proposed numerous methods to produce flow maps. However, how to evaluate the usability of flow maps has not been well documented. In this study, we combined eye-tracking and questionnaire methods to evaluate the usability of flow maps through comparisons between (a) straight lines and curves and (b) line thicknesses and color gradients. The results show that curved flows are more effective than straight flows. Maps with curved flows have more correct answers, fixations, and percentages of fixations in areas of interest. Furthermore, we find that the curved flows require longer finish times but exhibit smaller times to first fixation than straight flows. In addition, we find that using color gradients to indicate the flow volume is significantly more effective than the application of different line thicknesses, which is mainly reflected by the presence of more correct answers in the color-gradient group. These empirical studies could help improve the usability of flow maps employed to visualize geo-data.
Shape Similarity Assessment Method for Coastline Generalization
Authors: Li Zhaoxing , Zhai Jingsheng , Wu Fang
Published: July 2018

Although shape similarity is one fundamental element in coastline generalization quality, its related research is still inadequate. Consistent with the hierarchical pattern of shape recognition, the Dual-side Bend Forest Shape Representation Model is presented by reorganizing the coastline into bilateral bend forests, which are made of continuous root-bends based on Constrained Delaunay Triangulation and Convex Hull. Subsequently, the shape contribution ratio of each level in the model is expressed by its area distribution in the model. Then, the shape similarity assessment is conducted on the model in a top–down layer by layer pattern. Contrast experiments are conducted among the presented method and the Length Ratio, Hausdorff Distance and Turning Function, showing the improvements of the presented method over the others, including (1) the hierarchical shape representation model can distinguish shape features of different layers on dual-side effectively, which is consistent with shape recognition, (2) its usability and stability among coastlines and scales, and (3) it is sensitive to changes in main shape features caused by coastline generalization.
Semi-Supervised Classification for Hyperspectral Images Based on Multiple Classifiers and Relaxation Strategy
Authors: Xie Fuding , Hu Dongcui , Li Fangfei , Yang Jun , Liu Deshan
Published: July 2018

Hyperspectral image (HSI) classification is a fundamental and challenging problem in remote sensing and its various applications. However, it is difficult to perfectly classify remotely sensed hyperspectral data by directly using classification techniques developed in pattern recognition. This is partially owing to a multitude of noise points and the limited training samples. Based on multinomial logistic regression (MLR), the local mean-based pseudo nearest neighbor (LMPNN) rule, and the discontinuity preserving relaxation (DPR) method, in this paper, a semi-supervised method for HSI classification is proposed. In pre-processing and post-processing, the DPR strategy is adopted to denoise the original hyperspectral data and improve the classification accuracy, respectively. The application of two classifiers, MLR and LMPNN, can automatically acquire more labeled samples in terms of a few labeled instances per class. This is termed the pre-classification procedure. The final classification result of the HSI is obtained by employing the MLRsub approach. The effectiveness of the proposal is experimentally evaluated by two real hyperspectral datasets, which are widely used to test the performance of the HSI classification algorithm. The comparison results using several competing methods confirm that the proposed method is effective, even for limited training samples.
Water Level Reconstruction Based on Satellite Gravimetry in the Yangtze River Basin
Authors: Fok Hok Sum , He Qing
Published: July 2018

The monitoring of hydrological extremes requires water level measurement. Owing to the decreasing number of continuous operating hydrological stations globally, remote sensing indices have been advocated for water level reconstruction recently. Nevertheless, the feasibility of gravimetrically derived terrestrial water storage (TWS) and its corresponding index for water level reconstruction have not been investigated. This paper aims to construct a correlative relationship between observed water level and basin-averaged Gravity Recovery and Climate Experiment (GRACE) TWS and its Drought Severity Index (GRACE-DSI), for the Yangtze river basin on a monthly temporal scale. The results are subsequently compared against traditional remote sensing, Palmer’s Drought Severity Index (PDSI), and El Niño Southern Oscillation (ENSO) indices. Comparison of the water level reconstructed from GRACE TWS and its index, and that of remote sensing against observed water level reveals a Pearson Correlation Coefficient (PCC) above 0.90 and below 0.84, with a Root-Mean-Squares Error (RMSE) of 0.88–1.46 m, and 1.41–1.88 m and a Nash-Sutcliffe model efficiency coefficient (NSE) above 0.81 and below 0.70, respectively. The ENSO-reconstructed water levels are comparable to those based on remote sensing, whereas the PDSI-reconstructed water level shows a similar performance to that of GRACE TWS. The water level predicted at the location of another station also exhibits a similar performance. It is anticipated that the basin-averaged, remotely-sensed hydrological variables and their standardized forms (e.g., GRACE TWS and GRACE-DSI) are viable alternatives for reconstructing water levels for large river basins affected by the hydrological extremes under ENSO influence.
Task-Oriented Visualization Approaches for Landscape and Urban Change Analysis
Authors: Schiewe Jochen
Published: July 2018

Approaches to landscape and urban change analysis are still far away from being fully automatic or operational. For this reason, the concept of Geovisual Analytics is proposed, combining computational and visual/manual processing steps. This contribution concentrates on the latter part with the overall goal of improving its usability. For this purpose, a classification of tasks is created, which often occur in the context of change analysis. This serves as the basis for the assignment of suitable map types to change processing results. Beyond this, it is pointed out that in many cases an appropriate pre-processing of data is imperative to preserve or enhance certain spatial relationships or characteristics for visualization. This is demonstrated using the example of data classification prior to choropleth mapping. Methods are described which allow the preservation of local extreme values, large value differences between adjacent polygons, clusters, and hot/cold spots. Finally, discussing future research and developments, it will be stressed that the importance of visual methods in the context of big data change analysis will continue to increase, which is due to the particular ability of maps to generalize and reduce complex data to a minimum.
The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture
Authors: Brown Geoffrey , Ceredig Rhodri , Tsapogas Panagiotis
Published: July 2018

Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the many different types of blood and immune cells. The new scenario abandons the classical view of a rigidly demarcated lineage tree and replaces it with a much more continuum-like view of the spectrum of fate options open to hematopoietic stem cells and their progeny. This is in contrast to previous lineage diagrams, which envisaged stem cells progressing stepwise through a series of fairly-precisely described intermediate progenitors in order to close down alternative developmental options. Instead, stem and progenitor cells retain some capacity to step sideways and adopt alternative, closely related, fates, even after they have “made a lineage choice.” The stem and progenitor cells are more inherently versatile than previously thought and perhaps sensitive to lineage guidance by environmental cues. Here we examine the evidence that supports these views and reconsider the meaning of cell lineages in the context of a continuum model of stem cell fate determination and environmental modulation.
Characterization of a Long Non-Coding RNA, the Antisense RNA of Na/K-ATPase α1 in Human Kidney Cells
Authors: Fan Xiaoming , Ashraf Usman M. , Drummond Christopher A. , Shi Huilin , Zhang Xiaolu , Kumarasamy Sivarajan , Tian Jiang
Published: July 2018

Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, ATP1A1-AS1, which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult kidney cells (HK2 cells) and embryonic kidney cells (HEK293 cells). These variants can be detected in both cytosol and nuclear fractions. We also found that the inhibition of DNA methylation has a differential effect on the expression of ATP1A1-AS1 and its sense gene. To investigate the physiological role of this antisense gene, we overexpressed the ATP1A1-AS1 transcripts, and examined their effect on Na/K-ATPase expression and related signaling function in human kidney cells. The results showed that overexpression of the ATP1A1-AS1-203 transcript in HK2 cells reduced the Na/K-ATPase α1 (ATP1A1) gene expression by approximately 20% (p < 0.05), while reducing the Na/K-ATPase α1 protein synthesis by approximately 22% (p < 0.05). Importantly, overexpression of the antisense RNA transcript attenuated ouabain-induced Src activation in HK2 cells. It also inhibited the cell proliferation and potentiated ouabain-induced cell death. These results demonstrate that the ATP1A1-AS1 gene is a moderate negative regulator of Na/K-ATPase α1, and can modulate Na/K-ATPase-related signaling pathways in human kidney cells.
PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity
Authors: Corrales Patricia , Vidal-Puig Antonio , Medina-Gómez Gema
Published: July 2018

Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions.
Comparison of the Anion Inhibition Profiles of the α-CA Isoforms (SpiCA1, SpiCA2 and SpiCA3) from the Scleractinian Coral Stylophora pistillata
Authors: Del Prete Sonia , Bua Silvia , Zoccola Didier , Alasmary Fatmah , AlOthman Zeid , Alqahtani Linah , Techer Nathalie , Supuran Claudiu , Tambutté Sylvie , Capasso Clemente
Published: July 2018

Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes used by living organisms to accelerate the CO2 hydration/dehydration reaction at rates dramatically high compared to the uncatalyzed reaction. These enzymes have different isoforms and homologues and can be found in the form of cytoplasmic, secreted or membrane-bound proteins. CAs play a role in numerous physiological processes including biomineralization and symbiosis, as is the case in reef-building corals. Previously, molecular and biochemical data have been obtained at the molecular level in the branching coral Stylophora pistillata for two coral isoforms which differ significantly in their catalytic activity and susceptibility to inhibition with anions and sulfonamides. More recently it has been determined that the genome of S. pistillata encodes for 16 CAs. Here, we cloned, expressed, purified and characterized a novel α-CA, named SpiCA3, which is cytoplasmic and ubiquitously expressed in all the cell layers including the calcifying cells. SpiCA3 is the most effective CA among the coral isoforms investigated and the most efficient catalyst known up to date in Metazoa. We also investigated the inhibition profiles of SpiCA3 and compared it with those obtained for the two other isoforms in the presence of inorganic anions and other small molecules known to interfere with metalloenzymes. These results suggest that S. pistillata has adapted its CA isoforms to achieve the physiological functions in different physicochemical microenvironments.
High-Content Screening of a Taiwanese Indigenous Plant Extract Library Identifies Syzygium simile leaf Extract as an Inhibitor of Fatty Acid Uptake
Authors: Yen Chia-Hung , Chang Hsun-Shuo , Yang Tsai-Hsun , Wang Sheng-Fan , Wu Ho-Cheng , Chen Yu-Chang , Lin Kai-Jay , Wang Sheena
Published: July 2018

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the recent decades in both developed and developing countries, and is predicted to be the major etiology for liver transplantation in the next decade. Thus, pharmacological strategies to treat NAFLD are urgently needed. Natural products are considered an excellent source for drug discovery. By utilizing an image-based high-throughput screening with a library containing 3000 Taiwanese indigenous plant extracts, we discovered that the extract of Syzygium simile leaves (SSLE) has an anti-lipid droplet (LD) accumulation effect in hepatic cell lines. Analyses of the expression profile of genes involved in lipid metabolism revealed that SSLE suppressed the mRNA expression of CD36, fatty acid translocase. In agreement with this observation, we showed that SSLE inhibited CD36 protein expression and fatty acid uptake and has only limited effects on pre-formed LDs. Moreover, SSLE reduced LD accumulation and CD36 expression in enterocyte and macrophage cell lines. In conclusion, our findings suggest that SSLE could serve as a potential source for the discovery of novel therapeutic modalities for NAFLD and that the suppression of CD36 expression and fatty acid uptake could contribute to the lipid-lowering effect of SSLE.
Identification of Two Auxin-Regulated Potassium Transporters Involved in Seed Maturation
Authors: Tenorio-Berrío Rubén , Pérez-Alonso Marta-Marina , Vicente-Carbajosa Jesús , Martín-Torres Leticia , Dreyer Ingo , Pollmann Stephan
Published: July 2018

The seed is the most important plant reproductive unit responsible for the evolutionary success of flowering plants. Aside from its essential function in the sexual reproduction of plants, the seed also represents the most economically important agricultural product worldwide, providing energy, nutrients, and raw materials for human nutrition, livestock feed, and countless manufactured goods. Hence, improvements in seed quality or size are highly valuable, due to their economic potential in agriculture. Recently, the importance of indolic compounds in regulating these traits has been reported for Arabidopsis thaliana. The transcriptional and physiological mechanisms involved, however, remain largely undisclosed. Potassium transporters have been suggested as possible mediators of embryo cell size, controlling turgor pressure during seed maturation. In addition, it has been demonstrated that the expression of K+ transporters is effectively regulated by auxin. Here, we provide evidence for the identification of two Arabidopsis K+ transporters, HAK/KT12 (At1g60160) and KUP4 (At4g23640), that are likely to be implicated in determining seed size during seed maturation and, at the same time, show a differential regulation by indole-3-acetic acid and indole-3-acetamide.
Neuroglobin Regulates Wnt/β-Catenin and NFκB Signaling Pathway through Dvl1
Authors: Xun Yu , Li Zhen , Tang Yingxin , Yang Manjun , Long Shengwen , Shu Pan , Li Jiabing , Xiao Ye , Tang Fen , Wei Chenxi , Liu Ning , Xiang Shuanglin
Published: July 2018

Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/β-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined the role of Neuroglobin in regulating Dishevelled-1 and the downstream Wnt/β-Catenin and NFκB signaling pathway. We found that Neuroglobin directly interacts with Dishevelled-1 by co-immunoprecipitation, and the two proteins are co-localized in both cytoplasma and nucleus of SK-N-SH cells. Moreover, the ectopic expression of Neuroglobin promotes the degradation of exogenous and endogenous Dishevelled-1 through the proteasomal degradation pathway. Furthermore, our results showed that Neuroglobin significantly inhibits the luciferase activity of Topflash reporter and the expression of β-Catenin mediated by Dishevelled-1 in SK-N-SH cells. In addition, we also documented that Neuroglobin enhances TNF-α-induced NFκB activation via down-regulating Dishevelled-1. Finally, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assays showed that Neuroglobin is an important neuroprotectant that protects SK-N-SH cells from TNF-α-induced decrease in cell viability. Taken together, these findings demonstrated that Neuroglobin functions as an important modulator of the Wnt/β-Catenin and NFκB signaling pathway through regulating Dishevelled-1.
Intrinsic Oncogenic Function of Intracellular Connexin26 Protein in Head and Neck Squamous Cell Carcinoma Cells
Authors: Iikawa Nobuko , Yamamoto Yohei , Kawasaki Yohei , Nishijima-Matsunobu Aki , Suzuki Maya , Yamada Takechiyo , Omori Yasufumi
Published: July 2018

It has long been known that the gap junction is down-regulated in many tumours. One of the downregulation mechanisms is the translocation of connexin, a gap junction protein, from cell membrane into cytoplasm, nucleus, or Golgi apparatus. Interestingly, as tumours progress and reinforce their malignant phenotype, the amount of aberrantly-localised connexin increases in different malignant tumours including oesophageal squamous cell carcinoma, thus suggesting that such an aberrantly-localised connexin should be oncogenic, although gap junctional connexins are often tumour-suppressive. To define the dual roles of connexin in head and neck squamous cell carcinoma (HNSCC), we introduced the wild-type connexin26 (wtCx26) or the mutant Cx26 (icCx26) gene, the product of which carries the amino acid sequence AKKFF, an endoplasmic reticulum-Golgi retention signal, at the C-terminus and is not sorted to cell membrane, into the human FaDu hypopharyngeal cancer cell line that had severely impaired the expression of connexin during carcinogenesis. wtCx26 protein was trafficked to the cell membrane and formed gap junction, which successfully exerted cell-cell communication. On the other hand, the icCx26 protein was co-localised with a Golgi marker, as revealed by immunofluorescence, and thus was retained on the way to the cell membrane. While the forced expression of wtCx26 suppressed both cell proliferation in vitro and tumorigenicity in mice in vivo, icCx26 significantly enhanced both cell proliferation and tumorigenicity compared with the mock control clones, indicating that an excessive accumulation of connexin protein in intracellular domains should be involved in cancer progression and that restoration of proper subcellular sorting of connexin might be a therapeutic strategy to control HNSCC.
In Planta Preliminary Screening of ER Glycoprotein Folding Quality Control (ERQC) Modulators
Authors: Marti Lucia , Lia Andrea , Reca Ida-Barbara , Roversi Pietro , Santino Angelo , Zitzmann Nicole
Published: July 2018

Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate inhibitors in mammals are expensive and cannot be afforded at the preliminary stages of drug development programs. The strong conservation of the ERQC machinery across eukaryotes makes transgenic plants an attractive system for low-cost, easy and fast proof-of-concept screening of candidate ERQC inhibitors. The Arabidopsis thaliana immune response is mediated by glycoproteins, the folding of which is controlled by ERQC. We have used the plant response to bacterial peptides as a means of assaying an ERQC inhibitor in vivo. We show that the treatment of the plant with the iminosugar NB-DNJ, which is a known ER α-glucosidase inhibitor in mammals, influences the immune response of the plant to the bacterial peptide elf18 but not to the flagellin-derived flg22 peptide. In the NB-DNJ-treated plant, the responses to elf18 and flg22 treatments closely follow the ones observed for the ER α-glucosidase II impaired plant, At psl5-1. We propose Arabidopsis thaliana as a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation.
Development of Convenient System for Detecting Yeast Cell Stress, Including That of Amyloid Beta
Authors: Luu Yen Nhi , Macreadie Ian
Published: July 2018

(1) Background: As a model eukaryote, the study of stress responses in yeast can be employed for studying human health and disease, and the effects of various drugs that may impact health. “Reporting” of stress in yeast has frequently utilised enzymes like β-galactosidase that require laborious assays for quantitative results. The use of a stress reporter that can be measured quantitatively and with high sensitivity in living cells in a multi-well plate reader is a more desirable approach; (2) Methods: A multi-copy yeast-Escherichia coli shuttle plasmid containing the HSP42 promoter upstream of the mCherry reporter, along with the URA3 selectable marker was constructed and tested; (3) Results: Under certain stress conditions inducing the heat shock response, transformants containing the plasmid produced red fluorescence that could be readily quantitated in a microtitre plate reader. Stresses that produced red fluorescence included exposure to heat shock, copper ions, oligomeric amyloid beta (Aβ42) and fibrillar Aβ42; (4) Conclusions: Being able to conveniently and quantitatively monitor stresses in whole live populations of yeast offers great opportunities to screen compounds and conditions that cause stress, as well as conditions that alleviate stress. While freshly prepared oligomeric amyloid beta has previously been shown to exhibit high toxicity, fibrils have been generally considered to be non-toxic or of low toxicity. In this study, fibrillar amyloid beta has also been shown to induce stress.
The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Aging: Implications in Obesity and Cardiovascular Disease
Authors: Bartlett David E. , Miller Richard B. , Thiesfeldt Scott , Lakhani Hari Vishal , Shapiro Joseph I. , Sodhi Komal
Published: July 2018

Aging has been associated with a series of pathophysiological processes causing general decline in the overall health of the afflicted population. The cumulative line of evidence suggests an important role of oxidative stress in the development and progression of the aging process and metabolic abnormalities, exacerbating adipocyte dysfunction, cardiovascular diseases, and associated complications at the same time. In recent years, robust have established the implication of Na/K-ATPase signaling in causing oxidative stress and alterations in cellular mechanisms, in addition to its distinct pumping function. Understanding the underlying molecular mechanisms and exploring the possible sources of pro-oxidants may allow for developing therapeutic targets in these processes and formulate novel intervention strategies for patients susceptible to aging and associated complications, such as obesity and cardiovascular disease. The attenuation of oxidative stress with targeted treatment options can improve patient outcomes and significantly reduce economic burden.
Effects and Mechanism of Nano-Copper Exposure on Hepatic Cytochrome P450 Enzymes in Rats
Authors: Tang Huaqiao , Xu Min , Shi Fei , Ye Gang , Lv Cheng , Luo Jie , Zhao Ling , Li Yinglun
Published: July 2018

Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals.
Colletotrichum higginsianum as a Model for Understanding Host–Pathogen Interactions: A Review
Authors: Yan Yaqin , Yuan Qinfeng , Tang Jintian , Huang Junbin , Hsiang Tom , Wei Yangdou , Zheng Lu
Published: July 2018

Colletotrichum higginsianum is a hemibiotrophic ascomycetous fungus that causes economically important anthracnose diseases on numerous monocot and dicot crops worldwide. As a model pathosystem, the Colletotrichum–Arabidopsis interaction has the significant advantage that both organisms can be manipulated genetically. The goal of this review is to provide an overview of the system and to point out recent significant studies that update our understanding of the pathogenesis of C. higginsianum and resistance mechanisms of Arabidopsis against this hemibiotrophic fungus. The genome sequence of C. higginsianum has provided insights into how genome structure and pathogen genetic variability has been shaped by transposable elements, and allows systematic approaches to longstanding areas of investigation, including infection structure differentiation and fungal–plant interactions. The Arabidopsis-Colletotrichum pathosystem provides an integrated system, with extensive information on the host plant and availability of genomes for both partners, to illustrate many of the important concepts governing fungal–plant interactions, and to serve as an excellent starting point for broad perspectives into issues in plant pathology.
A History of the Pharmacological Treatment of Bipolar Disorder
Authors: López-Muñoz Francisco , Shen Winston W. , D’Ocon Pilar , Romero Alejandro , Álamo Cecilio
Published: July 2018

In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and the beginning of the so-called “Psychopharmacological Revolution” in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed.
Cartilage Regeneration in Humans with Adipose Tissue-Derived Stem Cells and Adipose Stromal Vascular Fraction Cells: Updated Status
Authors: Pak Jaewoo , Lee Jung Hun , Pak Natalie , Pak Yoon , Park Kwang Seung , Jeon Jeong Ho , Jeong Byeong Chul , Lee Sang Hee
Published: July 2018

Adipose tissue-derived stem cells (ASCs) in the form of stromal vascular fraction (SVF) and cultured expansion have been applied in clinical settings in some countries to treat osteoarthritis (OA) of knees, one of the most common debilitating, incurable disorders. Since the first report of successful cartilage-like tissue regeneration with autologous adipose SVF containing ASCs, there has been a gradual increase in the number of publications confirming such results. Thus far, most of the reports have been limited to treatments of OA of knees. Recently, successful applications of adipose SVF in treating OA of ankles and hips have been reported. In addition, several groups have reported modified methods of applying adipose SVF, such as combining bone marrow stimulation with adipose SVF or adding additional extracellular matrix (ECM) in treating OA. Here, we present an updated, systematic review of clinical effectiveness and safety in treating OA of knees, ankles, and one hip since 2016 using ASCs in the form of adipose SVF or in cultured expansion, along with a description and suggestion of potential biological mechanisms of cartilage regeneration.
The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice
Authors: Araki Masaya , Nakagawa Yoshimi , Oishi Asayo , Han Song-iee , Wang Yunong , Kumagai Kae , Ohno Hiroshi , Mizunoe Yuhei , Iwasaki Hitoshi , Sekiya Motohiro , Matsuzaka Takashi , Shimano Hitoshi
Published: July 2018

Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities.
Tailored Biodegradable and Electroactive Poly(Hydroxybutyrate-Co-Hydroxyvalerate) Based Morphologies for Tissue Engineering Applications
Authors: Amaro Luís , Correia Daniela M. , Marques-Almeida Teresa , Martins Pedro M. , Pérez Leyre , Vilas José L. , Botelho Gabriela , Lanceros-Mendez Senentxu , Ribeiro Clarisse
Published: July 2018

Polymer-based piezoelectric biomaterials have already proven their relevance for tissue engineering applications. Furthermore, the morphology of the scaffolds plays also an important role in cell proliferation and differentiation. The present work reports on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV), a biocompatible, biodegradable, and piezoelectric biopolymer that has been processed in different morphologies, including films, fibers, microspheres, and 3D scaffolds. The corresponding magnetically active PHBV-based composites were also produced. The effect of the morphology on physico-chemical, thermal, magnetic, and mechanical properties of pristine and composite samples was evaluated, as well as their cytotoxicity. It was observed that the morphology does not strongly affect the properties of the pristine samples but the introduction of cobalt ferrites induces changes in the degree of crystallinity that could affect the applicability of prepared biomaterials. Young’s modulus is dependent of the morphology and also increases with the addition of cobalt ferrites. Both pristine and PHBV/cobalt ferrite composite samples are not cytotoxic, indicating their suitability for tissue engineering applications.
A Naturally-Occurring Dominant-Negative Inhibitor of Keap1 Competitively against Its Negative Regulation of Nrf2
Authors: Qiu Lu , Wang Meng , Zhu Yuping , Xiang Yuancai , Zhang Yiguo
Published: July 2018

Transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) is a master regulator of antioxidant and/or electrophile response elements (AREs/EpREs)-driven genes involved in homeostasis, detoxification, and adaptation to various stresses. The cytoprotective activity of Nrf2, though being oppositely involved in both cancer prevention and progression, is critically controlled by Keap1 (Kelch-like ECH-associated protein 1), which is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase and also is a key sensor for oxidative and electrophilic stresses. Here, we first report a novel naturally-occurring mutant of Keap1, designated Keap1ΔC, which lacks most of its C-terminal Nrf2-interacting domain essential for inhibition of the cap’n’collar (CNC) basic-region leucine zipper (bZIP) factor. This mutant Keap1ΔC is yielded by translation from an alternatively mRNA-spliced variant lacking the fourth and fifth exons, but their coding sequences are retained in the wild-type Keap1 locus (with no genomic deletions). Although this variant was found primarily in the human highly-metastatic hepatoma (MHCC97H) cells, it was widely expressed at very lower levels in all other cell lines examined. Such Keap1ΔC retains no or less ability to inhibit Nrf2, so that it functions as a dominant-negative competitor of Keap1 against its inhibition of Nrf2 due to its antagonist effect on Keap1-mediated turnover of Nrf2 protein.
Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol
Authors: Visentin Cristina , Navarro Susanna , Grasso Gianvito , Regonesi Maria Elena , Deriu Marco Agostino , Tortora Paolo , Ventura Salvador
Published: July 2018

The protein ataxin-3 contains a polyglutamine stretch that triggers amyloid aggregation when it is expanded beyond a critical threshold. This results in the onset of the spinocerebellar ataxia type 3. The protein consists of the globular N-terminal Josephin domain and a disordered C-terminal tail where the polyglutamine stretch is located. Expanded ataxin-3 aggregates via a two-stage mechanism: first, Josephin domain self-association, then polyQ fibrillation. This highlights the intrinsic amyloidogenic potential of Josephin domain. Therefore, much effort has been put into investigating its aggregation mechanism(s). A key issue regards the conformational requirements for triggering amyloid aggregation, as it is believed that, generally, misfolding should precede aggregation. Here, we have assayed the effect of 2,2,2-trifluoroethanol, a co-solvent capable of stabilizing secondary structures, especially α-helices. By combining biophysical methods and molecular dynamics, we demonstrated that both secondary and tertiary JD structures are virtually unchanged in the presence of up to 5% 2,2,2-trifluoroethanol. Despite the preservation of JD structure, 1% of 2,2,2-trifluoroethanol suffices to exacerbate the intrinsic aggregation propensity of this domain, by slightly decreasing its conformational stability. These results indicate that in the case of JD, conformational fluctuations might suffice to promote a transition towards an aggregated state without the need for extensive unfolding, and highlights the important role played by the environment on the aggregation of this globular domain.