bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive and Immersive Learning Using 360° Virtual Reality Contents on Mobile Platforms
Authors: Choi Kanghyun , Yoon Yeo-Jin , Song Oh-Young , Choi Soo-Mi
Published: October 2018

Recent advances in mobile virtual reality (VR) devices have paved the way for various VR applications in education. This paper presents a novel authoring framework for mobile VR contents and a play-based learning model for marine biology education. For interactive and immersive mobile VR contents, we develop a multilayer 360° VR representation with image-based interactions such as mesh deformation and water simulation, which enable users to realistically interact with 360° panoramic contents without consuming excessive computational resources. On the basis of this representation, we design and implement play-based learning scenarios to increase the interactivity and immersion of users. Then, we verify the effectiveness of our educational scenarios using a user study in terms of user-created VR contents, interactivity, and immersion. The results show that more experienced elements in VR contents improve the immersion of users and make them more actively involved.
The Economic Impact of Cutaneous Leishmaniasis in Sri Lanka
Authors: Wijerathna Tharaka , Gunathilaka Nayana , Gunawardena Kithsiri
Published: October 2018

Cutaneous leishmaniasis (CL) is a neglected tropical disease which affects mainly the poorest communities in developing countries. Considering the limited published information on economic impact of CL in Sri Lanka, the current study was conducted with the objective of revealing the nature and magnitude of the economic impact of CL in three selected disease endemic regions in Kurunegala District, Sri Lanka. The patient records of CL notified of relevant Medical Officer of Health (MOH) office during 2013- 2016 were obtained. Patient households were visited and data collection was done using an interviewed administered questionnaire. The majority of patients (57%) were economically active at the time of infection. Of them, 65% were the only contributors to household economy. Total median costs including both direct and indirect costs were 66.85 USD (Rs. 10,831) (IQR = 57.26 - 86.78 USD), while total median economic loss to households was 61.27 USD (Rs. 9,927) (IQR= 49.61- 75.04 USD). From provider perspective, total median cost per patient was 22.83 USD (Rs. 3,696). The mean total economic loss was denoted as 65.26 USD (Rs. 10,572) which is about 5.4% of the annual household income and 20.9% of the mean annual per capita income of the study population. Although economic impact of CL infection is not catastrophic according to current interpretation, the infection may have significant economic impacts on households when considering the mean economic loss to household as a percentage of the mean annual per capita income of the population.
Efficient Quantization with Linear Index Coding for Deep‐Space Images
Authors: Mahmood Rehan , Wang Zulin , Huang Qin
Published: October 2018

Due to inevitable propagation delay involved in deep‐space communication systems, very high cost is associated with the retransmission of erroneous segments. Quantization with linear index coding (QLIC) scheme is known to provide compression along with robust transmission of deep‐space images, and thus the likelihood of retransmissions is significantly reduced. This paper aims to improve its spectral efficiency as well as robustness. First, multiple quantization refinement levels per transmitted source block of QLIC are proposed to increase spectral efficiency. Then, iterative multipass decoding is introduced to jointly decode the subsource symbol‐planes. It achieves better PSNR of the reconstructed image as compared to the baseline one‐pass decoding approach of QLIC.
Anti‐Inflammatory Activity of Rg3‐Enriched Korean Red Ginseng Extract in Murine Model of Sepsis
Authors: Saba Evelyn , Jeong Dahye , Irfan Muhammad , Lee Yuan Yee , Park Sang-Joon , Park Chae-Kyu , Rhee Man Hee
Published: October 2018

Ginseng has therapeutic effects on various bodily disorders ranging from minor inflammation to major cardiovascular diseases. In our study, we explored the anti‐inflammatory effects of Rg3‐enriched red ginseng extract (Rg3‐RGE), a ginsenoside belonging to the panaxadiol group. We employed nitric oxide assay (NO) and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, quantitative reverse transcriptase‐polymerase chain reaction (qRT‐PCR), western blot, and hematoxylin and eosin staining (H&E) to elucidate the anti‐inflammatory activity of Rg3‐RGE. Rg3‐RGE potently suppressed NO production in the murine macrophage cell line, RAW 264.7 cells, without any cytotoxicity across dosages. Additionally, it inhibited the mRNA expression of proinflammatory mediators and cytokines like iNOS, COX‐2, IL‐1β, IL‐6, and TNF‐α. Moreover it also inhibited the levels of malondialdehyde levels in serum of septic shock mice. Immunoblot analysis showed that Rg3‐RGE induced anti‐inflammatory signal transduction via the NF‐κB and MAPK pathways. A remarkable attenuation of inflammation by oral treatment with Rg3‐RGE in mice was observed in the survival study. The in vivo study using a septic shock mouse model also showed similar results as the in vitro study. Our findings suggest that Rg3‐RGE can potentially be a potent anti‐inflammatory agent that likely mediates its anti‐inflammatory effects via the NF‐κB and MAPK pathways.
Positive Periodic Solutions for an Generalized SIS Epidemic Model with Time-Varying Coefficients and Delays
Authors: Long Zhiwen
Published: October 2018

This paper mainly explores a generalized SIS epidemic model with time-varying coefficients and delays. By employing Lyapunov function method and differential inequality approach, a sufficient criterion to guarantee the existence and exponential stability of positive periodic solutions for the addressed model is obtained, which complements the earlier publications. Particularly, an example and its numerical simulations are given to demonstrate our theoretical results.
Differentiation Potential of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells and Paracrine Signaling Interaction Contribute to Improve the In Vitro Maturation of Mouse Cumulus Oocyte Complexes
Authors: Maldonado Martin , Huang Tianhua , Chen Jianying , Zhong Ying
Published: October 2018

In vitro maturation (IVM) in cumulus oocyte complexes (COCs) can be improved by the presence of human Wharton’s jelly-derived MSCs (hWJ-MSCs), under specific culture conditions. COCs were cultured in twelve different culture systems, composed of four stock media, stock media conditioned with hWJ-MSCs, and stock media in which the oocytes were indirectly cocultured with the hWJ-MSCs. The rates of maturation to meiosis II were compared among the groups. G2-PLUS and coculture with DMEM-F12 were the most efficient systems for the maturation of COCs. The fertilization rate and rate of development to the blastocyst stage were compared between these two groups. Moreover, hWJ-MSC-conditioned media showed no benefits for the COC-IVM. The analysis of OCT4 expression of hWJ-MSCs in G1-PLUS, TYH, and G2-PLUS showed a downregulation of OCT4 by 25.9, 24.7, and 6.6%, respectively, compared to that in hWJ-MSCs cultured in DMEM-F12. Finally, we have demonstrated that two prerequisites appeared to be necessary for the hWJ-MSCs to improve the IVM of COCs: hWJ-MSCs’ differentiation potential and the presence of coordinated paracrine interaction between the stem cells and COCs. Under the appropriate conditions, the paracrine factors produced in the coculture system with DMEM-F12 may help to develop synthetic media for successful in vitro culture of COCs.
Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis
Authors: Shastri Madhur D. , Shukla Shakti Dhar , Chong Wai Chin , Dua Kamal , Peterson Gregory M. , Patel Rahul P. , Hansbro Philip M. , Eri Rajaraman , O’Toole Ronan F.
Published: October 2018

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR‐TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first‐/second‐line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S‐oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD+ ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug‐susceptible and drug‐resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host’s OS response.
First Case of Pleural Empyema Caused byStaphylococcus simulans: Review of the Literature
Authors: Lal Amos , Akhtar Jamal , Ullah Ashfaq , Abraham George M.
Published: October 2018

Staphylococcus simulansis a coagulase-negative organism, mainly an animal pathogen. Reports of human infection have been infrequent, mainly in patients with repeated animal contact. We report the first case of pleural empyema in an elderly woman.S. simulanstends to cause more severe infection because of a biofilm layer which helps in adherence and colonization of smooth surfaces, especially prosthetic devices, shunts, and catheters. The challenging problem even after CoNS isolation and identification is the assessment of their clinical relevance. Major factors that inhibit the penetration of antibiotics is the large-sized effusions/empyema, thickness of pleura, and the nature of antibiotic itself. Source control for septic patients remains the cornerstone of treatment along with optimal antimicrobial coverage.Staphylococcus simulans, a coagulase-negative staphylococcus, is emerging as an important cause of virulent infections with high mortality in humans. Given its propensity for multidrug resistance, including vancomycin, there is an imperative for early and accurate identification of the isolate. Despite aggressive treatment, the patient succumbed to her illness.
Pitch Controller Design of Wind Turbine Based on Nonlinear PI/PD Control
Authors: Zhou Feihang , Liu Jun
Published: October 2018

This paper analyzed and discussed the nonlinear PI/PD control for wind energy conversion system (WECS) pitch controller design. The nonlinear PI/PD controller consists of a classical PI/PD controller and a nonlinear gain table. In this paper, the detailed design procedures of the controller including not only the selection of control parameters but also the formulation of nonlinear gain table were given. In order to verify the effectiveness and correctness of the algorithm, a detailed 2 MW simulation test platform based on MATLAB/SIMULINK environment was established. Meanwhile, some valuable conclusions were also obtained. The presented contents of this article have the reference value and guiding significance for practical engineering application.
Limbal Stem Cell Transplantation: Clinical Results, Limits, and Perspectives
Authors: Sacchetti Marta , Rama Paolo , Bruscolini Alice , Lambiase Alessandro
Published: October 2018

Limbal stem cell deficiency (LSCD) is a clinical condition characterized by damage of cornea limbal stem cells, which results in an impairment of corneal epithelium turnover and in an invasion of the cornea by the conjunctival epithelium. In these patients, the conjunctivalization of the cornea is associated with visual impairment and cornea transplantation has poor prognosis for recurrence of the conjunctivalization. Current treatments of LSCD are aimed at replacing the damaged corneal stem cells in order to restore a healthy corneal epithelium. The autotransplantation of limbal tissue from the healthy, fellow eye is effective in unilateral LSCD but leads to depauperation of the stem cell reservoir. In the last decades, novel techniques such as cultivated limbal epithelial transplantation (CLET) have been proposed in order to reduce the damage of the healthy fellow eye. Clinical and experimental evidence showed that CLET is effective in inducing long-term regeneration of a healthy corneal epithelium in patients with LSCD with a success rate of 70%–80%. Current limitations for the treatment of LSCD are represented by the lack of a marker able to unequivocally identify limbal stem cells and the treatment of total, bilateral LSCD which requires other sources of stem cells for ocular surface reconstruction.
Total Flavone of Rhododendron Improves Cerebral Ischemia Injury by Activating Vascular TRPV4 to Induce Endothelium‐Derived Hyperpolarizing Factor‐Mediated Responses
Authors: Han Jun , Xu Hang-Hang , Chen Xiao-Long , Hu Hao-Ran , Hu Kun-Mei , Chen Zhi-Wu , He Guo-Wei
Published: October 2018

Background. Total flavonoids of Rhododendron (TFR) is extracted from Rhododendron, a herbal medicine widely used in China. The main components are flavone compounds such as warfarin, rutin, quercetin, and hyperoside. We investigated the role of TRPV4 channel in the TFR induced endothelium‐dependent hyperpolarizing factor‐ (EDHF‐) mediated responses against ischemia/reperfusion injury (IR) in cerebral IR (CIR) rats. Methods. The morphological changes of cerebral cortex, the relaxation of cerebral basal artery (CBA), and cell membrane potential recording were studied in CIR rats. The outward potassium current in smooth muscle cell was recorded by whole‐cell patch clamp recording. The protein expression of TRPV4, SKca, and IKca was determined. Confocal laser was used to measure the Ca2+ fluorescence intensity. Results. After treatment with TFR, the number of pyramidal cells in brain tissue increased and the number of empty or lightly stained cells decreased and these effects were eliminated by using HC‐067047, Apamin, or TRAM‐34. TFR induced and EDHF‐mediated dilatation and hyperpolarization in CBA were also attenuated by using these inhibitors. The increased outward current density elicited by TFR in acutely isolated CBA smooth muscle cells was abolished by using TRAM‐34 and Apamin. TFR upregulated the protein expression of TRPV4, SKca, and IKca that was also eliminated by these inhibitors. Laser scanning showed that the increased mean fluorescence intensity of Ca2+ by CIR was decreased by using TFR and that this effect was again eliminated by the above inhibitors. Conclusions. We conclude that in the CBA of the CIR rats the protective effect of TFR on ischemic cerebrovascular injury may be related to the activation of the TRPV4 in both endothelium and smooth muscle by increasing its expression and activity. The activation of TRPV4 channel in the endothelium may be linked to the opening of endothelial IKca/SKca channels that induces EDHF‐mediated relaxation and hyperpolarization in the smooth muscle cell. In addition, the activation of TRPV4 in the smooth muscle cell in CBA may be linked with the activation of BKCa channel through a TRPV4‐dependent pathway, reduce Ca2+ concentration in the cell, and relaxes the vessel. These findings may form a new therapeutic target for protection of ischemic brain injury and facilitate the use of Chinese medicine in brain protection.
Identification of Six Potentially Long Noncoding RNAs as Biomarkers Involved Competitive Endogenous RNA in Clear Cell Renal Cell Carcinoma
Authors: Yang Kang , Lu Xiao-fan , Luo Peng-cheng , Zhang Jie
Published: October 2018

Background. Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), usually is representative of metastatic heterogeneous neoplasm that links with poor prognosis, but the pathogenesis of ccRCC remains unclear. Currently, numerous evidences prove that long noncoding RNAs (lncRNAs) are considered as competing endogenous RNA (ceRNA) to participate in cellular processes of tumors. Therefore, to investigate the underlying mechanisms of ccRCC, the expression profiles of lncRNAs, miRNAs, and mRNAs were downloaded from the Cancer Genome Atlas (TCGA) database. A total of 1526 differentially expressed lncRNAs (DElncRNAs), 54 DEmiRNAs, and 2352 DEmRNAs were identified. To determine the connection of them, all DElncRNAs were input to the miRcode database. The results indicated that 85 DElncRNAs could connect with 9 DEmiRNAs in relation to our study. Then, databases of TargetScan and miRDB were used to search for targeted genes with reference to DEmiRNAs. The results showed that 203 out of 2352 targeted genes were identified in our TCGA set. Subsequently, ceRNA network was constructed according to Cytoscape and the targeted genes were functionally analyzed to elucidate the mechanisms of DEmRNAs. The results of survival analysis and regression analysis indicated that 6 DElncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were significantly correlative with the clinical traits of ccRCC patients and could be served as predictors for ccRCC. Finally, these findings were validated by quantitative RT-PCR (qRT-PCR). Based on these discoveries, we believe that this identified ceRNA network will provide a novel perspective to elucidate ccRCC pathogenesis.
Analysis of the Magnetic Anomalies of Buried Archaeological Ovens of Aïn Kerouach (Morocco)
Authors: Ayad Abderrahim , Bakkali Saâd
Published: October 2018

Aïn Kerouach is one of the most important archaeological sites in the northern part of Morocco. The main buried archaeological ruins in this area were surveyed in 1977 using magnetic prospecting. This survey highlights the mean anomalies that are related to potteries ovens built to the Marinid dynasty that governed Morocco from the 13th to the 15th century. In order to find the maximum depth of the sources, we computed the enhanced downward continuation filter in order to highlight the magnetization contrasts in high detail, depending on the depth downward included in the computation. The main goal is providing a reliable mapping to observe the ovens in depth by shifting the data below the plane of measurement. The results showed an important depth variation of the main ovens given by the original magnetic map and revealed others. Indeed, the downward continuation process applied to analyze the magnetic data shows its efficiency to highlight the buried archaeological structures.
A Case of Multiple Myeloma Misdiagnosed as Seronegative Rheumatoid Arthritis and Review of Relevant Literature
Authors: Schoninger Scott , Homsi Yamen , Kreps Alexandra , Milojkvovic Natasa
Published: October 2018

Multiple myeloma (MM) is a malignant plasma cell proliferation producing large numbers of monoclonal immunoglobulins. Typical MM symptoms include anemia, renal failure, hypercalcemia, and bone pain. Atypical symptoms have rarely been reported in the literature. We report a case of a 58-year-old male who presented with symmetrical inflammatory polyarthritis and was misdiagnosed with seronegative rheumatoid arthritis (RA). After failing many RA treatments and with further workup, the diagnosis of MM was made. This rare manifestation of MM carries a diagnostic challenge and causes a significant delay in treating such patients. Here, we report this unusual initial presentation with review of several cases in the English literature describing similar presentations.
Cervical and Amniotic Fluid Matrix Metalloproteinase-8 and Interleukin-6 Concentrations in Preterm Pregnancies with or without Preterm Premature Rupture of Membranes
Authors: Holmström Emilia , Myntti Tarja , Sorsa Timo , Kruit Heidi , Juhila Juuso , Paavonen Jorma , Rahkonen Leena , Stefanovic Vedran
Published: October 2018

Introduction: Intra-amniotic inflammation is defined by elevated inflammatory biomarkers in the amniotic fluid (AF), either due to microbial invasion of the amniotic cavity (MIAC) or sterile inflammation. Amniocentesis being an invasive procedure, we wanted to investigate whether elevated matrix metalloproteinase-8 (MMP-8) or interleukin-6 (IL-6) concentrations could be detected from cervical fluid samples. Materials and Methods: This prospective study included 67 women with singleton nondiabetic pregnancies with or without preterm premature rupture of membranes (PPROM) between 22+0 and 37+0 weeks of gestation. Simultaneous AF and cervical samples were obtained. Results: In women without PPROM, cervical MMP-8 concentrations correlated with AF MMP-8 concentrations (rS = 0.466, p = 0.002), but cervical IL-6 did not correlate with AF IL-6 (rS = 0.277, p = 0.076). In PPROM cases no correlations were found. Women with MIAC had higher concentrations of AF MMP-8 and AF IL-6 compared to women without MIAC regardless of membrane status. However, only women without PPROM had higher concentrations of cervical MMP-8 in proven MIAC. Conclusion: In women without PPROM, cervical MMP-8 concentration reflects the magnitude of AF MMP-8, thus potentially guiding the selection of patients benefitting from amniocentesis.
Plasma MicroRNA-29c Levels Are Associated with Carotid Intima-Media Thickness and is a Potential Biomarker for the Early Detection of Atherosclerosis
Authors: Huang Yu-Qing , Li Jie , Huang Cheng , Feng Ying-Qing
Published: October 2018

Background/Aims: Atherosclerosis is a serious disease that increases the risk of myocardial infarction and ischemic stroke. Previous studies have demonstrated that microRNA (miR)-29c could play significant roles in atherosclerosis via regulating inflammatory processes. However, the relationship between miR-29c and carotid intima-media thickness (CIMT) remains unknown. This study investigated associations between miR-29c and atherosclerosis and tested whether plasma miR-29c levels could be used to detect atherosclerosis. Methods: Plasma miR-29c levels were estimated by quantitative real-time PCR, and CIMT was measured by carotid ultrasound. Associations between miR-29c and CIMT were assessed by Spearman’s correlation coefficient and multiple linear regression analyses. Results: In total, 170 participants were divided into the study (CIMT ≥0.9 mm) and control (CIMT < 0.9 mm) groups. The study group showed higher C-reactive protein (CRP) and miR-29c relative expression levels compared with the control group. CIMT was positively correlated with miR-29c (r=0.659, p< 0.001) and CRP (r=0.447, p< 0.001), and miR-29c levels were also correlated with CRP (r=0.512, p< 0.001). Furthermore, multiple linear regression analysis showed that CIMT was significantly correlated with miR-29c (β=0.573, 95% confidence interval [CI]: 0.315-0.839; p< 0.001) and CRP (β=0.439, 95%CI: 0.186–0.825; p< 0.001). After age, body mass index, systolic blood pressure, total cholesterol and fasting blood-glucose were adjusted for, CIMT was still closely associated with miR-29c (β=0.529, 95%CI: 0.354–0.812; p< 0.001) and CRP (β=0.417, 95%CI: 0.198–0.724; p< 0.001). Evaluating CRP and miR-29c together (AUC=0.900, p< 0.001) achieved a better prognostic value for atherosclerosis than miR-29c (AUC=0.870, p< 0.001) or CRP (AUC=0.722, p< 0.001) alone. Conclusion: Increased miR-29c was closely associated with CIMT and may serve as a biomarker for identifying atherosclerotic patients.
Comprehensive Analysis of Differentially Expressed Profiles of lncRNAs/mRNAs and miRNAs with Associated ceRNA Networks in Triple-Negative Breast Cancer
Authors: Yang Rui , Xing Lei , Wang Min , Chi Hong , Zhang Luyu , Chen Junxia
Published: October 2018

Background/Aims: Triple-negative breast cancer (TNBC) is a subtype of highly malignant breast cancer with poor prognosis. Growing evidence indicates that Long noncoding RNAs (lncRNAs) play important regulatory roles in the development and progression of a variety of cancers including breast cancer. However, the underlying mechanisms remain largely unknown. Methods: Here, we compared the expression profiles of mRNAs, lncRNAs and miRNAs between 111 TNBC tissues and 104 non-cancerous tissues utilizing RNA-Seq Data from The Cancer Genome Atlas (TCGA). Gene Ontology and KEGG pathway enrichment analyses were executed to investigate the principal functions of the significantly dysregulated mRNAs. Moreover, Kaplan-Meier survival analyses were performed to determine the effects of differentially expressed lncRNAs/mRNAs/miRNAs on overall survival. Subsequently, we constructed a competing endogenous RNA (ceRNA) network, which included 66 dysregulated lncRNAs, 24 miRNAs and 55 mRNAs. The four dysregulated lncRNAs, three aberrantly expressed miRNAs and four mRNAs were confirmed in the ceRNA network by qRT-PCR in 30 pairs of samples, respectively. Results: A total of 1441 lncRNAs, 114 miRNA and 2501 mRNAs were found to be differentially expressed in TNBC tissues compared with controls. 109 lncRNAs and 124 mRNAs might serve as prognostic signature for patients with TNBC according to the survival analysis. Functional analysis revealed that 19 mRNAs in the ceRNA network were enriched in 17 cancer-related pathways. Conclusion: Taken together, we identified novel lncRNAs/miRNAs which may serve as potential biomarkers to predict the survival and therapeutic targets for TNBC patients based on a large-scale sample. More importantly, we constructed the ceRNA network of TNBC, which provides valuable information to further explore the molecular mechanism underlying tumorigenesis and development of TNBC.
SMARCAD1 in Breast Cancer Progression
Authors: Arafat Kholoud , Al Kubaisy Elham , Sulaiman Shahrazad , Karam Sherif M. , Al Natour Zeina , Hassan Ahmed H. , Attoub Samir 
Published: October 2018

Background/Aims: Breast cancer is the most common cancer in women worldwide, and within this cancer type, triple-negative breast cancers have the worst prognosis. The identification of new genes associated with triple-negative breast cancer progression is crucial for developing more specific anti-cancer targeted therapies, which could lead to a better management of these patients. In this context, we have recently demonstrated that SMARCAD1, a DEAD/H box-containing helicase, is involved in breast cancer cell migration, invasion, and metastasis. The aim of this study was to investigate the impact of the stable knockdown of SMARCAD1 on human breast cancer cell progression. Methods: Using two different designs of shRNA targeting SMARCAD1, we investigated the impact of the stable knockdown of SMARCAD1 on human breast cancer cell proliferation and colony growth in vitro and on tumour growth in chick embryo and nude mouse xenograft models in vivo using MDA-MB-231 (ER-/PR-/ HER2-) and T47D (ER+/PR+/-/HER2-) human breast cancer cell lines. Results: We found that SMARCAD1 knockdown resulted in a significant decrease in breast cancer cell proliferation and colony formation, leading to the significant inhibition of tumour growth in both the chick embryo and nude mouse xenograft models. This inhibition was due, at least in part, to a decrease in IKKβ expression. Conclusion: These results indicate that SMARCAD1 is involved in breast cancer progression and can be a promising target for breast cancer therapy.
Psoriasis Treatment Changes the Expression Profile of Selected Caspases and their Regulatory MicroRNAs
Authors: Wcisło-Dziadecka Dominika , Simka Klaudia , Kaźmierczak Agata , Kruszniewska-Rajs Celina , Gola Joanna , Grabarek Beniamin , Hybiak Jolanta , Grillon Catherine , Mazurek Urszula , Łos Marek J.
Published: October 2018

Background/Aims: Psoriasis, an autoimmune diseases of the skin, characterized by patches of abnormal/inflammed skin, although not usually life-threatening, it causes severe discomfort, esthetic impairments, and may lead to impaired social functions and social withdrawal. Besides UV-phototherapy, various anti-inflammatory treatments are applied, depending on the severity of symptoms. In 2008, adalimumab (fully humanized human anti-TNF antibody) was launched for the treatment of psoriasis. In the quest to better understand the pathomechanism of adalimumab’s therapeutic effects, and the acquired resistance to the drug, we have investigated how its administration affect the regulation of the expression of selected caspases, including those activated by inflammosome. Methods: The research was initially carried out on normal human dermal fibroblasts (NHDF) treated with adalimumab for 2, 8 and 24 hours in vitro. Then, expression profile of genes encoding caspases and their regulatory micro-RNAs was determined with the use of oligonucleotide microarray. The validation of the microarray results was carried out by qRT-PCR. The in vitro study was followed by ex-vivo investigation of adalimumab’s effects on the expression of caspase-6 in blood of the psoriatic patients. The samples were collected before, and 2 hours after adalimumab’s administration and the analysis was determined by qRT-PCR. Results: The result of the analysis indicated that introduction of adalimumab to the NHDF culture resulted in the change of the transcription activity of genes encoding caspases and genes encoding miRNAs. The analysis revealed 5 different miRNA molecules regulating the expression of: CASP2, CASP3 and CASP6. There were no statistically significant differences in the expression of gene encoding caspase-6 in the patients’ blood before and 2 hours after the anti-TNF drug administration. Conclusion: We have found that adalimumab administration affects caspases expression, thus they may be used as molecular markers for monitoring the therapy with the use of an anti-TNF drugs, including adalimumab. It is likely that the mechanisms responsible for changed expression profiles of genes encoding caspase-2,-3, and -6, may be caused by the upregulation of the respective microRNA molecules. Increased expression of genes encoding specific caspases may induce inflammatory processes, as well as trigger apoptosis. Furthermore, the proapoptotic activity of caspases may be enhanced by miRNA molecules, which exhibit proapoptotic function. The overexpression of such miRNAs was observed in our study.
Gentiopicroside Ameliorates Diabetic Peripheral Neuropathy by Modulating PPAR- Γ/AMPK/ACC Signaling Pathway
Authors: Lu Yi , Yao Jiayin , Gong Chulian , Wang Bao , Zhou Piao , Zhou Shaoli , Yao Xinhua
Published: October 2018

Background/Aims: Gentiopicroside is promising as an important secoiridoid compound against pain. The present study aimed to investigate the analgesic effect and the probable mechanism of Gentiopicroside on Diabetic Peripheral Neuropathy (DPN), and to figure out the association among Gentiopicroside, dyslipidemia and PPAR- γ/AMPK/ACC signaling pathway. Methods: DPN rat models were established by streptozotocin and RSC96 cells were cultured. Hot, cold and mechanical tactile allodynia were conducted. Blood lipids, nerve blood flow, Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity (SNCV) were detected. Gene and protein expression of PPAR- γ/AMPK/ACC pathway was analyzed by reverse transcription-quan titative polymerase chain reaction (RT-qPCR) and Westernblot. Besides, PPAR-γ antagonist GW9662 and agonist rosiglitazone, AMPK antagonist compound C and activator AICAR as well as ACC inhibitor TOFA were used to further confirm the relationship between PPAR-γ and AMPK. Results: The results demonstrated that Gentiopicroside markedly ameliorated hyperalgesia with prolonged paw withdrawal latency to heat and cold stimuli and fewer responses to mechanical allodynia compared with DPN model group. Gentiopicroside regulated dyslipidemia, enhanced nerve blood flow and improved MNCV as well as SNCV. Gentiopicroside suppressed ACC expression through the activation of AMPK and PPAR-γ mediated the activation of AMPK and subsequent inhibition of ACC expression. Conclusion: In conclusion, the present study demon strated that Gentiopicroside exerted nerve-protective effect and attenuated experimental DPN by restoring dyslipidmia and improved nerve blood flow through regulating PPAR-γ/AMPK/ACC signal pathway. These results provided a promising potential treatment of DPN.
Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo
Authors: Xing Zhao-yu , Wang Yin , Cheng Long , Chen Jie , He Xiao-zhou , Xing Wei 
Published: October 2018

Background/Aims: Mammalian target of rapamycin (mTOR) is a valuable treatment target of renal cell carcinoma (RCC). Palomid 529 is a novel mTORC1/2 dual inhibitor. Methods: RCC cells were treated with different concentrations of Palomid 529. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by BrdU ELISA assay. Cell apoptosis was tested by the Hoechst-33342 nuclei staining assay and Histone DNA ELISA assay. mTOR signaling was tested by Western blotting assay and co-immunoprecipitation (IP) assay. The SCID mouse 786-O xenograft model was established to test RCC cell growth in vivo. Results: Palomid 529 exerted cytotoxic, anti-proliferative and pro-apoptotic activities in 786-O RCC cells. Palomid 529 disassembled mTORC1/2, causing de-phosphorylation of mTORC1/2 substrates. Bromodomain-containing protein 4 (BRD4) is a primary resistant factor of Palomid 529. Palomid 529-induced 786-O cell apoptosis was sensitized by BRD4 inhibitors or BRD4 silencing, but inhibited with BRD4 over-expression. Palomid 529-induced cytotoxicity in the primary human RCC cells was negatively correlated with BRD4 expression level. In vivo, Palomid 529 i.p. administration inhibited 786-O xenograft tumor growth in SCID mice. Its anti-tumor activity was further sensitized by co-administration of the BRD4 inhibitor JQ1. Cconclusion: Palomid 529 inhibits RCC cell growth in vitro and in vivo. BRD4 inhibition could further sensitize Palomid 529 against RCC cells.
La comunicación interna y el desarrollo humano en el sector restaurantero regional en Yucatán, México
Authors: Martínez Rebeca Illiana Arévalo , Várguez Carlos Gaspar Pérez
Published: October 2018

La gastronomía yucateca es uno de los bienes culturales distintivos de México. Por ello, se realizó un estudio cuantitativo con tres restaurantes de comida regional de Mérida, Yucatán, en los cuales se entrevistó a sus colaboradores para determinar si la comunicación está relacionada con la conformación de una cultura organizacional que genere representaciones sociales vinculadas a las tradiciones regionales y al crecimiento de los colaboradores en términos de bienestar para el desarrollo humano. Se eligió este giro ya que en Yucatán el sector restaurantero regional tiene un lugar preponderante en la economía local.
Ética, um bem essencial para uma vida feliz
Authors: Videira Denise Pragana
Published: October 2018

Resenha da obra Fundamentos de ética empresarial e econômica de Maria Cecilia Coutinho de Arruda, Maria do Carmo Whitaker e José Maria Rodriguez Ramos.
Um olhar prático para compliance e outros temas ainda obscuros
Authors: Pinheiro Fabiana Pereira , Rangel Ronaldo
Published: October 2018

Resenha da obra Compliance, ética, responsabilidade social e empresarial: uma visão prática de Luis Roberto Antonik.
Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species
Authors: Varshneya Meera , Devenyi Ryan A. , Sobie Eric A.
Published: October 2018

Background:

The slow and rapid delayed rectifier K
+
currents (I
Ks
and I
Kr
, respectively) are responsible for repolarizing the ventricular action potential (AP) and preventing abnormally long APs that may lead to arrhythmias. Although differences in biophysical properties of the 2 currents have been carefully documented, the respective physiological roles of I
Kr
and I
Ks
are less established. In this study, we sought to understand the individual roles of these currents and quantify how effectively each stabilizes the AP and protects cells against arrhythmias across multiple species.

Methods:

We compared 10 mathematical models describing ventricular myocytes from human, rabbit, dog, and guinea pig. We examined variability within heterogeneous cell populations, tested the susceptibility of cells to proarrhythmic behavior, and studied how I
Ks
and I
Kr
responded to changes in the AP.

Results:

We found that (1) models with higher baseline I
Ks
exhibited less cell-to-cell variability in AP duration; (2) models with higher baseline I
Ks
were less susceptible to early afterdepolarizations induced by depolarizing perturbations; (3) as AP duration is lengthened, I
Ks
increases more profoundly than I
Kr
, thereby providing negative feedback that resists excessive AP prolongation; and (4) the increase in I
Ks
that occurs during β-adrenergic stimulation is critical for protecting cardiac myocytes from early afterdepolarizations under these conditions.

Conclusions:

Slow delayed rectifier current is uniformly protective across a variety of cell types. These results suggest that I
Ks
enhancement could potentially be an effective antiarrhythmic strategy.
Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure
Authors: Li Jie , Yue Guihua , Ma Wenxia , Zhang Aizhen , Zou Jianqiu , Cai Yafei , Tang Xiaoli , Wang Jun , Liu Jinbao , Li Honglin , Su Huabo
Published: October 2018

Background:

Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)—a novel ubiquitin-like protein—has not been explored in either the normal or stressed heart.

Methods and Results:

Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)—an enzyme essential for Ufm1 modification—was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction.

Conclusions:

Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.
Outcomes Among Patients Undergoing Distal Left Main Percutaneous Coronary Intervention
Authors: Kandzari David E. , Gershlick Anthony H. , Serruys Patrick W. , Leon Martin B. , Morice Marie-Claude , Simonton Charles A. , Lembo Nicholas J. , Banning Adrian P. , Merkely Béla , van Boven Ad J. , Ungi Imre , Kappetein Arie Pieter , Sabik Joseph F. , Généreux Philippe , Dressler Ovidiu , Stone Gregg W.
Published: October 2018

Background:

Distal left main (LM) coronary artery bifurcation disease increases percutaneous coronary intervention (PCI) procedural complexity and is associated with worse outcomes than isolated ostial/shaft disease. The optimal treatment strategy for distal LM disease is undetermined. We sought to determine whether outcomes after PCI of LM distal bifurcation lesions are influenced by treatment with a provisional 1-stent versus planned 2-stent technique, and if so, whether such differences are conditioned by the complexity of the LM bifurcation lesion.

Methods and Results:

The clinical and angiographic characteristics, procedural methods and outcomes, and clinical events through 3-year follow-up were compared in patients undergoing distal LM PCI with a 1-stent provisional versus planned 2-stent technique in the EXCEL trial (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization). Among 529 patients undergoing planned distal LM PCI, 344 (65.0%) and 185 (35.0%) were treated with intended 1-stent provisional and planned 2-stent techniques, respectively. The primary composite end point rate of death, myocardial infarction, or stroke at 3 years was significantly lower in patients treated with the provisional 1-stent versus planned 2-stent method (14.1% versus 20.7%; adjusted hazard ratio, 0.55; 95% CI, 0.35–0.88;
P
=0.01), driven by differences in cardiovascular death (3.3% versus 8.3%,
P
=0.01) and myocardial infarction (7.7% versus 12.8%,
P
=0.06). The 3-year rate of ischemia-driven revascularization of the LM complex was also lower in the provisional group (7.2% versus 16.3%,
P
=0.001). In 342 patients with distal LM bifurcation disease that did not involve both major side branch vessels, the 3-year primary end point was lower with a provisional 1-stent versus planned 2-stent technique (13.8% versus 23.3%,
P
=0.04), whereas no significant difference was present in 182 patients with distal LM bifurcation disease that did involve both side branch vessels (14.3% versus 19.2%,
P
=0.36).

Conclusions:

Among patients with distal LM bifurcation disease in the EXCEL trial randomized to PCI, 3-year adverse outcomes were worse with planned 2-stent treatment compared with a provisional 1-stent approach, a difference that was confined to patients without major involvement of both LM side branch vessels.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01205776.
Validating Publicly Available Crosswalks for Translating
ICD-9
to
ICD-10
Diagnosis Codes for Cardiovascular Outcomes Research
Authors: Columbo Jesse A. , Kang Ravinder , Trooboff Spencer W. , Jahn Kristen S. , Martinez Camilo J. , Moore Kayla O. , Austin Andrea M. , Morden Nancy E. , Brooks Corinne G. , Skinner Jonathan S. , Goodney Philip P.
Published: October 2018

Background

On October 1, 2015, the Center for Medicare and Medicaid Services transitioned from the
International Classification of Diseases
,
Ninth Revision
(
ICD-9
) to the
ICD
,
Tenth Revision
(
ICD-10
) compendium of codes for diagnosis and billing in health care, but translation between the two is often inexact. Here we describe a validated crosswalk to translate
ICD-9
codes into
ICD-10
codes, with a focus on complications after carotid revascularization and endovascular aortic aneurysm repair.

Methods and Results

We devised an 8-step process to derive and validate
ICD-10
codes from existing
ICD-9
codes. We used publicly available sources, including the General Equivalence Mapping database, to translate
ICD-9
codes used in prior work to
ICD-10
codes. We defined
ICD-10
codes as validated if they were concordant with the initial
ICD-9
codes after manual comparison by two physicians. Our primary validation measure was the percent of valid
ICD-10
codes out of the total
ICD-10
codes obtained during translation. We began with 126
ICD-9
diagnosis codes used for complication identification after carotid revascularization procedures, and 97
ICD-9
codes for complications after endovascular aortic aneurysm procedures. Translation generated 143
ICD-10
codes for carotid revascularization, a 14% increase from the initial 126 codes. Manual comparison demonstrated 98% concordance, with 99% agreement between the reviewers. Similarly, we identified 108
ICD-10
codes for endovascular aortic aneurysm repair, an 11% increase from the initial 97
ICD-9
codes. We again noted excellent concordance and agreement (98% and 100%, respectively). Manual review identified 4
ICD-10
codes incorrectly translated from
ICD-9
codes for carotid revascularization, and 3 codes incorrectly translated for endovascular aortic aneurysm repair.

Conclusions

Algorithms to crosswalk lists of
ICD-9
codes to
ICD-10
codes can leverage electronic resources to minimize the burden of code translation. However, manual review for code validation may be necessary, with collaboration across institutions for researchers to share their efforts.
Midbody Positioning and Distance Between Daughter Nuclei Enable Unequivocal Identification of Cardiomyocyte Cell Division in Mice
Authors: Hesse Michael , Doengi Michael , Becker Alexandra , Kimura Kenichi , Voeltz Nadine , Stein Valentin , Fleischmann Bernd K.
Published: October 2018

Rationale:

New strategies in the field of cardiac regeneration are directed at identifying proliferation-inducing substances to induce regrowth of myocardium. Current screening assays utilize neonatal cardiomyocytes and markers for cytokinesis, such as Aurora B-kinase. However, detection of cardiomyocyte division is complicated because of cell cycle variants, in particular, binucleation.

Objective:

To analyze the process of cardiomyocyte binucleation to identify definitive discriminators for cell cycle variants and authentic cardiomyocyte division.

Methods and Results:

Herein, we demonstrate by direct visualization of the contractile ring and midbody in Myh6 (myosin, heavy chain 6)-eGFP (enhanced green fluorescent protein)-anillin transgenic mice that cardiomyocyte binucleation starts by formation of a contractile ring. This is followed by irregular positioning of the midbody and movement of the 2 nuclei into close proximity to each other. In addition, the widespread used marker Aurora B-kinase was found to also label binucleating cardiomyocytes, complicating the interpretation of existing screening assays. Instead, atypical midbody positioning and the distance of daughter nuclei on karyokinesis are bona fide markers for cardiomyocyte binucleation enabling to unequivocally discern such events from cardiomyocyte division in vitro and in vivo.

Conclusions:

The 2 criteria provide a new method for identifying cardiomyocyte division and should be considered in future studies investigating cardiomyocyte turnover and regeneration after injury, in particular in the postnatal heart to prevent the assignment of false positive proliferation events.