Search results for: target gene database

Authors: Christelle E. Chua, Alicia L. Ho

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The development of a panel of differential gene expression signatures has been of interest in the field of biomarker discovery for radiation exposure. In the absence of the availability of exposed human subjects, lymphocyte cell lines have often been used as a surrogate to human whole blood, when performing ex vivo irradiation studies. The extent of variation between different lymphocyte cell lines is currently unclear, especially with regard to the expression of extracellular miRNA. This study compares the expression profile of extracellular miRNA isolated from different lymphocyte cell lines. It also compares the profile of miRNA obtained when different exosome isolation kits are used. Lymphocyte cell lines were created using lymphocytes isolated from healthy adult males of similar racial descent (Chinese American and Chinese Singaporean) and immortalised with Epstein-Barr virus. The cell lines were cultured in exosome-free cell culture media for 72h and the cell culture supernatant was removed for exosome isolation. Two exosome isolation kits were used. Total exosome isolation reagent (TEIR, ThermoFisher) is a polyethylene glycol (PEG)-based exosome precipitation kit, while ExoSpin (ES, Cell Guidance Systems) is a PEG-based exosome precipitation kit that includes an additional size exclusion chromatography step. miRNA from the isolated exosomes were isolated using miRNEASY minikit (Qiagen) and analysed using nCounter miRNA assay (Nanostring). Principal component analysis (PCA) results suggested that the overall extracellular miRNA expression profile differed between the lymphocyte cell line originating from the Chinese American donor and the cell line originating from the Chinese Singaporean donor. As the gender, age and racial origins of both donors are similar, this may suggest that there are other genetic or epigenetic differences that account for the variation in extracellular miRNA gene expression in lymphocyte cell lines. However, statistical analysis showed that only 3 miRNA genes had a fold difference > 2 at p < 0.05, suggesting that the differences may not be of that great a significance as to impact overall conclusions drawn from different cell lines. Subsequent analysis using cell lines from other donors will give further insight into the reproducibility of results when difference cell lines are used. PCA results also suggested that the method of exosome isolation impacted the expression profile. 107 miRNA had a fold difference > 2 at p < 0.05. This suggests that the inclusion of an additional size exclusion chromatography step altered the subset of the extracellular vesicles that were isolated. In conclusion, these results suggest that extracellular miRNA can be isolated and analysed from exosomes derived from lymphocyte cell lines. However, care must be taken in the choice of cell line and method of exosome isolation used.

Keywords: biomarker, extracellular miRNA, isolation methods, lymphocyte cell line

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Authors: Abu Salim Mustafa

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Polymerase chain reaction (PCR) assays targeting genomic DNA segments have been established for the detection of Helicobacter pylori in clinical specimens. However, the data on comparative evaluations of various targets in detection of H. pylori are limited. Furthermore, the frequencies of vacA (s1 and s2) and cagA genotypes, which are suggested to be involved in the pathogenesis of H. pylori in other parts of the world, are not well studied in Kuwait. The aim of this study was to evaluate PCR assays for the detection and genotyping of H. pylori by targeting the amplification of DNA targets from four genomic segments. The genomic DNA were isolated from 72 clinical isolates of H. pylori and tested in PCR with four pairs of oligonucleotides primers, i.e. ECH-U/ECH-L, ET-5U/ET-5L, CagAF/CagAR and Vac1F/Vac1XR, which were expected to amplify targets of various sizes (471 bp, 230 bp, 183 bp and 176/203 bp, respectively) from the genomic DNA of H. pylori. The PCR-amplified DNA were analyzed by agarose gel electrophoresis. PCR products of expected size were obtained with all primer pairs by using genomic DNA isolated from H. pylori. DNA dilution experiments showed that the most sensitive PCR target was 471 bp DNA amplified by the primers ECH-U/ECH-L, followed by the targets of Vac1F/Vac1XR (176 bp/203 DNA), CagAF/CagAR (183 bp DNA) and ET-5U/ET-5L (230 bp DNA). However, when tested with undiluted genomic DNA isolated from single colonies of all isolates, the Vac1F/Vac1XR target provided the maximum positive results (71/72 (99% positives)), followed by ECH-U/ECH-L (69/72 (93% positives)), ET-5U/ET-5L (51/72 (71% positives)) and CagAF/CagAR (26/72 (46% positives)). The results of genotyping experiments showed that vacA s1 (46% positive) and vacA s2 (54% positive) genotypes were almost equally associated with VaCA+/CagA- isolates (P > 0.05), but with VacA+/CagA+ isolates, S1 genotype (92% positive) was more frequently detected than S2 genotype (8% positive) (P< 0.0001). In conclusion, among the primer pairs tested, Vac1F/Vac1XR provided the best results for detection of H. pylori. The genotyping experiments showed that vacA s1 and vacA s2 genotypes were almost equally associated with vaCA⁺/cagA^- isolates, but vacA s1 genotype had a significantly increased association with vacA⁺/cagA⁺ isolates.

Keywords: H. pylori, PCR, detection, genotyping

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Authors: Shahnam Behnam Malekzadeh, Ian Kerr, Tyson Kaempffer, Teague Harper, Andrew Watson

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The Site C Hydroelectric dam is currently being constructed in north-eastern British Columbia on sub-horizontal sedimentary strata that dip approximately 15 meters from one bank of the Peace River to the other. More than 615 pressure sensors (Vibrating Wire Piezometers) have been installed on bedding planes (BPs) since construction began, with over 80 more planned before project completion. These pressure measurements are essential to monitor the stability of the rock foundation during and after construction and for dam safety purposes. BPs are identified by their clay gouge infilling, which varies in thickness from less than 1 to 20 mm and can be challenging to identify as the core drilling process often disturbs or washes away the gouge material. Without the use of depth predictions from nearby boreholes, stratigraphic markers, and downhole geophysical data, it is difficult to confidently identify BP targets for the sensors. In this paper, a Case-Based Reasoning (CBR) method was used to develop an empirical model called the Bedding Plane Elevation Prediction (BPEP) to help geologists and geotechnical engineers to predict geological features and bedding planes at new locations in a fast and accurate manner. To develop CBR, a database was developed based on 64 pressure sensors already installed on key bedding planes BP25, BP28, and BP31 on the Right Bank, including bedding plane elevations and coordinates. Thirteen (20%) of the most recent cases were selected to validate and evaluate the accuracy of the developed model, while the similarity was defined as the distance between previous cases and recent cases to predict the depth of significant BPs. The average difference between actual BP elevations and predicted elevations for above BPs was ±55cm, while the actual results showed that 69% of predicted elevations were within ±79 cm of actual BP elevations while 100% of predicted elevations for new cases were within ±99cm range. Eventually, the actual results will be used to develop the database and improve BPEP to perform as a learning machine to predict more accurate BP elevations for future sensor installations.

Keywords: case-based reasoning, geological feature, geology, piezometer, pressure sensor, core logging, dam construction

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Authors: Sidra Shaw, Sarenna Shaw, Chae Joon Lee, Irimpan Mathews, Eric Koehn

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One of the biggest public health concerns of our time is increasing antimicrobial resistance. As of 2019, the CDC has documented more than 2.8 million serious antibiotic resistant infections in the United States. Currently, antibiotic resistant infections are directly implicated in over 750,000 deaths per year globally. On our current trajectory, British economist Jim O’Neill predicts that by 2050, an additional 10 million people (about half the population of New York) will die annually due to drug resistant infections. As a result, new biochemical pathways must be targeted to generate next generation antibiotic drugs that will be effective against drug resistant bacteria. One enticing target is the biosynthesis of DNA within bacteria, as few drugs interrupt this essential life process. Thymidylate synthase enzymes are essential for life as they catalyze the synthesis of a DNA building block, 2′-deoxythymidine-5′-monophosphate (dTMP). In humans, the thymidylate synthase enzyme (TSase) has been shown to be distinct from the flavin-dependent thymidylate synthase (FDTS) produced by many pathogenic bacteria. TSase and FDTS have distinct structures and mechanisms of catalysis, which should allow selective inhibition of FDTS over human TSase. Currently, C. diff is one of the most antibiotic resistant bacteria, and no drugs that target thymine biosynthesis exist for C. diff. Here we present the initial biochemical characterization of FDTS from C. diff. Specifically, we examine enzyme kinetics and binding features of this enzyme to determine the nature of interaction with ligands/inhibitors and understand the molecular mechanism of catalysis. This research will provide more insight into the targetability of the C. diff FDTS enzyme for novel antibiotic drugs.

Keywords: flavin-dependent thymidylate synthase, FDTS, clostridioides difficile, C. diff, antibiotic resistance, DNA synthesis, enzyme kinetics, binding features

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Authors: Fakhrosadat Sajjadian

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The majority of deaths in cancer patients are caused by distant metastasis. Breast cancer shows a unique spread pattern, often affecting bone, liver, lung, and brain. Breast cancer can be categorized into various subtypes according to gene expression patterns, and these subtypes exhibit specific preferences for organs where metastasis occurs. Breast tumors with luminal characteristics have a preference for spreading to the bone, whereas basal-like breast cancer (BLBC) shows a tendency to metastasize to the lungs. Still, the mechanisms behind this particular pattern of metastasis in organs have yet to be fully understood. In this evaluation, we will outline the latest progress in molecular signaling pathways and treatment methods for breast cancer lung metastasis.

Keywords: lung cancer, liver cancer, diagnosis, BLBC, metastasis

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Authors: Abdelhadi Elharfi

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A problem of boundary feedback (exponential) stabilization of an overhead crane model represented by a PDE is considered. For any $r>0$, the exponential stability at the desired decay rate $r$ is solved in semi group setting by a collocated-type stabiliser of a target system combined with a term involving the solution of an appropriate PDE.

Keywords: feedback stabilization, semi group and generator, overhead crane system

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Authors: Alsu F. Saifitdinova, Alexey S. Komissarov, Svetlana A. Galkina, Elena I. Koshel, Maria M. Kulak, Stephen J. O'Brien, Elena R. Gaginskaya

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The mystery of sex determination is one of the most ancient and still not solved until the end so far. In many species, sex determination is genetic and often accompanied by the presence of dimorphic sex chromosomes in the karyotype. Genomic sequencing gave the information about the gene content of sex chromosomes which allowed to reveal their origin from ordinary autosomes and to trace their evolutionary history. Female-specific W chromosome in birds as well as mammalian male-specific Y chromosome is characterized by the degeneration of gene content and the accumulation of repetitive DNA. Tandem repeats complicate the analysis of genomic data. Despite the best efforts chicken W chromosome assembly includes only 1.2 Mb from expected 55 Mb. Supplementing the information on the sex chromosome composition not only helps to complete the assembly of genomes but also moves us in the direction of understanding of the sex-determination systems evolution. A whole-genome survey to the assembly Gallus_gallus WASHUC 2.60 was applied for repeats search in assembled genome and performed search and assembly of high copy number repeats in unassembled reads of SRR867748 short reads datasets. For cytogenetic analysis conventional methods of fluorescent in situ hybridization was used for previously cloned W specific satellites and specifically designed directly labeled synthetic oligonucleotide DNA probe was used for bioinformatically identified repetitive sequence. Hybridization was performed with mitotic chicken chromosomes and manually isolated giant meiotic lampbrush chromosomes from growing oocytes. A novel chicken W specific satellite (GGAAA)n which is not co-localizes with any previously described classes of W specific repeats was identified and mapped with high resolution. In the composition of autosomes this repeat units was found as a part of upstream regions of gonad specific protein coding sequences. These findings may contribute to the understanding of the role of tandem repeats in sex specific differentiation regulation in birds and sex chromosome evolution. This work was supported by the postdoctoral fellowships from St. Petersburg State University (#1.50.1623.2013 and #1.50.1043.2014), the grant for Leading Scientific Schools (#3553.2014.4) and the grant from Russian foundation for basic researches (#15-04-05684). The equipment and software of Research Resource Center “Chromas” and Theodosius Dobzhansky Center for Genome Bioinformatics of Saint Petersburg State University were used.

Keywords: birds, lampbrush chromosomes, sex chromosomes, tandem repeats

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Authors: Ji Su Kim, Bo Ram Choi, Ju Yeon Cho, Hyukjin Lee

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Epidermal growth factor receptor (EGFR) 19 deletion mutation gene is over-expressed in carcinoma patient. EGFR 19 deletion mutation is known as typical biomarker of non-small cell lung cancer (NSCLC), which one section in the coding exon 19 of EGFR is deleted. Therefore, there have been many attempts over the years to detect EGFR 19 deletion mutation for replacing conventional diagnostic method such as PCR and tissue biopsy. We developed a simple and facile detection platform based on Rolling Circle Amplification (RCA), which provides highly amplified products in isothermal amplification of the ligated DNA template. Limit of detection (~50 nM) and a faster detection time (~30 min) could be achieved by introducing RCA.

Keywords: EGFR19, cancer, diagnosis, rolling circle amplification (RCA), hydrogel

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Authors: Khaled A. Alsaif, Mosaad A. Foda

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The present work aims at development of traffic noise maps for Riyadh City using the software Lima. Road traffic data were estimated or measured as accurate as possible in order to obtain consistent noise maps. The predicted noise levels at some selected sites are validated by actual field measurements, which are obtained by a system that consists of a sound level meter, a GPS receiver and a database to manage the measured data. The maps show that noise levels remain over 50 dBA and can exceed 70 dBA at the nearside of major roads and highways.

Keywords: noise pollution, road traffic noise, LimA predictor, GPS

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Authors: Nazish Badar

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In early 2009, Pandemic type A (H1N1) Influenza virus emerged globally. Since then, it has continued circulation causing considerable morbidity and mortality. The purpose of this study was to evaluate the evolutionary changes in Influenza A (H1N1) pdm09 viruses from 2009-15 and their relevance with the current vaccine viruses. Methods: Respiratory specimens were collected with influenza-like illness and Severe Acute Respiratory Illness. Samples were processed according to CDC protocol. Sequencing and phylogenetic analysis of Haemagglutinin (HA) and neuraminidase (NA) genes was carried out comparing representative isolates from Pakistan viruses. Results: Between Jan2009 - Feb 2016, 1870 (13.2%) samples were positive for influenza A out of 14086. During the pandemic period (2009–10), Influenza A/ H1N1pdm 09 was the dominant strain with 366 (45%) of total influenza positives. In the post-pandemic period (2011–2016), a total of 1066 (59.6%) cases were positive Influenza A/ H1N1pdm 09 with co-circulation of different Influenza A subtypes. Overall, the Pakistan A(H1N1) pdm09 viruses grouped in two genetic clades. Influenza A(H1N1)pdm09 viruses only ascribed to Clade 7 during the pandemic period whereas viruses belong to clade 7 (2011) and clade 6B (2015) during the post-pandemic years. Amino acid analysis of the HA gene revealed mutations at positions S220T, I338V and P100S specially associated with outbreaks in all the analyzed strains. Sequence analyses of post-pandemic A(H1N1)pdm09 viruses showed additional substitutions at antigenic sites; S179N,K180Q (SA), D185N, D239G (CA), S202A (SB) and at receptor binding sites; A13T, S200P when compared with pandemic period. Substitution at Genetic markers; A273T (69%), S200P/T (15%) and D239G (7.6%) associated with severity and E391K (69%) associated with virulence was identified in viruses isolated during 2015. Analysis of NA gene revealed outbreak markers; V106I (23%) among pandemic and N248D (100%) during post-pandemic Pakistan viruses. Additional N-Glycosylation site; HA S179N (23%), NA I23T(7.6%) and N44S (77%) in place of N386K(77%) were only found in post-pandemic viruses. All isolates showed histidine (H) at position 275 in NA indicating sensitivity to neuraminidase inhibitors. Conclusion: This study shows that the Influenza A(H1N1)pdm09 viruses from Pakistan clustered into two genetic clades, with co-circulation of some variants. Certain key substitutions in the receptor binding site and few changes indicative of virulence were also detected in post-pandemic strains. Therefore, it is imperative to continue monitoring of the viruses for early identification of potential variants of high virulence or emergence of drug-resistant variants.

Keywords: Influenza A (H1N1) pdm09, evolutionary analysis, post pandemic period, Pakistan

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Authors: Antonello Durante, James Duff, Kevin Kelly

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The visual needs of people in modern work based buildings are changing. Self-illuminated screens of computers, televisions, tablets and smart phones have changed the relationship between people and the lit environment. In the past, lighting design practice was primarily based on providing uniform horizontal illuminance on the working plane, but this has failed to ensure good quality lit environments. Lighting standards of today continue to be set based upon a 100 year old approach that at its core, considers the task illuminance of the utmost importance, with this task typically being located on a horizontal plane. An alternative method focused on appearance has been proposed, as opposed to the traditional performance based approach. Mean Room Surface Exitance (MRSE) and Target-Ambient Illuminance Ratio (TAIR) are two new metrics proposed to assess illumination adequacy in interiors. The hypothesis is that these factors will be superior to the existing metrics used, which are horizontal illuminance led. For the six past years, research has examined this, within the Dublin Institute of Technology, with a view to determining the suitability of this approach for application to general lighting practice. Since the start of this research, a number of key findings have been produced that centered on how occupants will react to various levels of MRSE. This paper provides a broad update on how this research has progressed. More specifically, this paper will: i) Demonstrate how MRSE can be measured using HDR images technology, ii) Illustrate how MRSE can be calculated using scripting and an open source lighting computation engine, iii) Describe experimental results that demonstrate how occupants have reacted to various levels of MRSE within experimental office environments.

Keywords: illumination hierarchy (IH), mean room surface exitance (MRSE), perceived adequacy of illumination (PAI), target-ambient illumination ratio (TAIR)

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Authors: László L. Lippai

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In addition to the fact that mental health bears great significance to a particular individual, it can also be regarded as an organizational, community and societal resource. Within the Szeged Health Promotion Research Group, we conducted mental health surveys on two levels: The inhabitants of a medium-sized Hungarian town and students of a Hungarian university with a relatively big headcount were requested to participate in surveys whose goals were to define local government priorities and organization-level health promotion programmes, respectively. To facilitate professional decision-making, we defined three, pragmatically relevant, groups of the target population: the mentally healthy, the vulnerable and the endangered. In order to determine which group a person actually belongs to, we designed a simple and quick measurement tool, which could even be utilised as a smoothing method, the Mental State Questionnaire validity of the above three categories was verified by analysis of variance against psychological quality of life variables. We demonstrate the pragmatic significance of our method via the analyses of the scores of our two mental health surveys. On town level, during our representative survey in Hódmezővásárhely (N=1839), we found that 38.7% of the participants was mentally healthy, 35.3% was vulnerable, while 16.3% was considered as endangered. We were able to identify groups that were in a dramatic state in terms of mental health. For example, such a group consisted of men aged 45 to 64 with only primary education qualification and the ratios of the mentally healthy, vulnerable and endangered were 4.5, 45.5 and 50%, respectively. It was also astonishing to see to what a little extent qualification prevailed as a protective factor in the case of women. Based on our data, the female group aged 18 to 44 with primary education—of whom 20.3% was mentally healthy, 42.4% vulnerable and 37.3% was endangered—as well as the female group aged 45 to 64 with university or college degree—of whom 25% was mentally healthy, 51.3 vulnerable and 23.8% endangered—are to be handled as priority intervention target groups in a similarly difficult position. On organizational level, our survey involving the students of the University of Szeged, N=1565, provided data to prepare a strategy of mental health promotion for a university with a headcount exceeding 20,000. When developing an organizational strategy, it was important to gather information to estimate the proportions of target groups in which mental health promotion methods; for example, life management skills development, detection, psychological consultancy, psychotherapy, would be applied. Our scores show that 46.8% of the student participants were mentally healthy, 42.1% were vulnerable and 11.1% were endangered. These data convey relevant information as to the allocation of organizational resources within a university with a considerable headcount. In conclusion, The Mental State Questionnaire, as a valid smoothing method, is adequate to describe a community in a plain and informative way in the terms of mental health. The application of the method can promote the preparation, design and implementation of mental health promotion interventions. 

Keywords: health promotion, mental health promotion, mental state questionnaire, psychological well-being

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Authors: Mary Rose Eunice S. Gundayao, Manolo M. Fernandez

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Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder with an autosomal recessive inheritance pattern. Lysosomal storage disorders are often severe, follow a progressively neurodegenerative path, and may result in multi-organ failure, potentially leading to death within 5 to 6 years in cases of early-onset forms. There are limited data regarding cases of MLD in Filipino children. This is the case of a 2-year-old Filipino girl who presented with progressive neurological deterioration and was diagnosed with metachromatic leukodystrophy by molecular genetic testing. This case report aims to present this patient’s clinical history, neurological findings, diagnosis and novel genetic mutations causing MLD. A concise review of updated literature on MLD will be discussed.

Keywords: metachromatic leukodystrophy, ARSA gene, peripheral neuropathy, case report, demyelinating disease

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Authors: Yogesh Dalvi, Ruby Varghese, Nibu Varghese, C. K. Krishnan Nair

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Introduction: The Genus Phellinus, locally known as Phansomba is a well-known traditional folk medicine. Especially, in Western Ghats of India, many tribes use several species of Phellinus for various ailments related to teeth, throat, tongue, stomach and even wound healing. It is one of the few mushrooms which play a pivotal role in Ayurvedic Dravyaguna. Aim: The present study focuses on to investigate phytochemical analysis, antioxidant, and antitumor (in vitro and in vivo) potential of Phellinus robinae from South India, Kerala Material and Methods: The present study explores the following: 1. Phellinus samples were collected from Ranni, Pathanamthitta district of Kerala state, India from Artocarpus heterophyllus Lam. and species were identified using rDNA region. 2. The fruiting body was shadow dried, powdered and extracted with 50% alcohol using water bath at 60°C which was further condensed by rotary evaporator and lyophilized at minus 40°C temperature. 3. Secondary metabolites were analyzed by using various phytochemical screening assay (Hager’s Test, Wagner’s Test, Sodium hydroxide Test, Lead acetate Test, Ferric chloride Test, Folin-ciocalteu Test, Foaming Test, Benedict’s test, Fehling’s Test and Lowry’s Test). 4. Antioxidant and free radical scavenging activity were analyzed by DPPH, FRAP and Iron chelating assay. 5. The antitumor potential of Water alcohol extract of Phellinus (PAWE) is evaluated through In vitro condition by Trypan blue dye exclusion method in DLA cell line and In vivo by murine model. Result and Discussion: Preliminary phytochemical screening by various biochemical tests revealed presence of a variety of active secondary molecules like alkaloids, flavanoids, saponins, carbohydrate, protein and phenol. In DPPH and FRAP assay PAWE showed significantly higher antioxidant activity as compared to standard Ascorbic acid. While, in Iron chelating assay, PAWE exhibits similar antioxidant activity that of Butylated Hydroxytoluene (BHT) as standard. Further, in the in vitro study, PAWE showed significant inhibition on DLA cell proliferation in dose dependent manner and showed no toxicity on mice splenocytes, when compared to standard chemotherapy drug doxorubicin. In vivo study, oral administration of PAWE showed dose dependent tumor regression in mice and also raised the immunogenicity by restoring levels of antioxidant enzymes in liver and kidney tissue. In both in vitro and in vivo gene expression studies PAWE up-regulates pro-apoptotic genes (Bax, Caspases 3, 8 and 9) and down- regulates anti-apoptotic genes (Bcl2). PAWE also down regulates inflammatory gene (Cox-2) and angiogenic gene (VEGF). Conclusion: Preliminary phytochemical screening revealed that PAWE contains various secondary metabolites which contribute to its antioxidant and free radical scavenging property as evaluated by DPPH, FRAP and Iron chelating assay. PAWE exhibits anti-proliferative activity by the induction of apoptosis through a signaling cascade of death receptor-mediated extrinsic (Caspase8 and Tnf-α), as well as mitochondria-mediated intrinsic (caspase9) and caspase pathways (Caspase3, 8 and 9) and also by regressing angiogenic factor (VEGF) without any inflammation or adverse side effects. Hence, PAWE serve as a potential antioxidant and antitumor agent.

Keywords: antioxidant, antitumor, Dalton lymphoma ascites (DLA), fungi, Phellinus robinae

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Authors: Jean Berger, Mohamed Barkaoui

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Discrete search path planning in time-constrained uncertain environment relying upon imperfect sensors is known to be hard, and current problem-solving techniques proposed so far to compute near real-time efficient path plans are mainly bounded to provide a few move solutions. A new information-theoretic –based open-loop decision model explicitly incorporating false alarm sensor readings, to solve a single agent military logistics search-and-delivery path planning problem with anticipated feedback is presented. The decision model consists in minimizing expected entropy considering anticipated possible observation outcomes over a given time horizon. The model captures uncertainty associated with observation events for all possible scenarios. Entropy represents a measure of uncertainty about the searched target location. Feedback information resulting from possible sensor observations outcomes along the projected path plan is exploited to update anticipated unit target occupancy beliefs. For the first time, a compact belief update formulation is generalized to explicitly include false positive observation events that may occur during plan execution. A novel genetic algorithm is then proposed to efficiently solve search path planning, providing near-optimal solutions for practical realistic problem instances. Given the run-time performance of the algorithm, natural extension to a closed-loop environment to progressively integrate real visit outcomes on a rolling time horizon can be easily envisioned. Computational results show the value of the approach in comparison to alternate heuristics.

Keywords: search path planning, false alarm, search-and-delivery, entropy, genetic algorithm

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Authors: Li Chun Zhao, Zhi Chao Hu, Xi Qiang Liu, Man Lai Lee, Chak Shing Yeung, Man Fei Xu, Yuen Yee Kwan, Alan H. M. Ho, Nickie W. K. Chan, Bin Deng, Zhong Zhen Zhao, Min Xu

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Background: Chuangxiong Rhizoma (Chuangxion, CX) is one of the most frequently used herbs in Chinese medicine because of its wide therapeutic effects such as vasorelaxation and anti-inflammation. Aim: The purposes of this study are (1) to perform non-targeted / targeted analyses of CX methanol extract and water extract, and compare the present data with previously LC-MS or GC-MS fingerprints; (2) to examine the difference between CX methanol extract and water extract for preliminarily evaluating whether current compound markers of methanol extract from crude CX materials could be suitable for quality control of CX water extract. Method: CX methanol extract was prepared according to the Hong Kong Chinese Materia Medica Standards. DG water extract was prepared by boiling with pure water for three times (one hour each). UHPLC-Q-TOF-MS/MS fingerprint analysis was performed by C18 column (1.7 µm, 2.1 × 100 mm) with Agilent 1290 Infinity system. Experimental data were analyzed by Agilent MassHunter Software. A database was established based on 13 published LC-MS and GC-MS CX fingerprint analyses. Total 18 targeted compounds in database were selected as markers to compare present data with previous data, and these markers also used to compare CX methanol extract and water extract. Result: (1) Non-targeted analysis indicated that there were 133 compounds identified in CX methanol extract, while 325 compounds in CX water extract that was more than double of CX methanol extract. (2) Targeted analysis further indicated that 9 in 18 targeted compounds were identified in CX methanol extract, while 12 in 18 targeted compounds in CX water extract that showed a lower lose-rate of water extract when compared with methanol extract. (3) By comparing CX methanol extract and water extract, Senkyunolide A (+1578%), Ferulic acid (+529%) and Senkyunolide H (+169%) were significantly higher in water extract when compared with methanol extract. (4) Other bioactive compounds such as Tetramethylpyrazine were only found in CX water extract. Conclusion: Many new compounds in both CX methanol and water extracts were found by using UHPLC Q-TOF MS/MS analysis when compared with previous published reports. A new standard reference including non-targeted compound profiling and targeted markers functioned especially for quality control of CX water extract (herbal decoction) should be established in future. (This project was supported by Hong Kong Baptist University (FRG2/14-15/109) & Natural Science Foundation of Guangdong Province (2014A030313414)).

Keywords: Chuanxiong rhizoma, fingerprint analysis, targeted analysis, quality control

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Authors: Abdullah Bal

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This paper presents a one-class classification (OCC) technique based on Fukunaga-Koontz Transform (FKT) for binary classification problems. The FKT is originally a powerful tool to feature selection and ordering for two-class problems. To utilize the standard FKT for data domain description problem (i.e., one-class classification), in this paper, a set of non-class samples which exist outside of positive class (target class) describing boundary formed with limited training data has been constructed synthetically. The tunnel-like decision boundary around upper and lower border of target class samples has been designed using statistical properties of feature vectors belonging to the training data. To capture higher order of statistics of data and increase discrimination ability, the proposed method, termed one-class FKT (OC-FKT), has been extended to its nonlinear version via kernel machines and referred as OC-KFKT for short. Multiple kernel learning (MKL) is a favorable family of machine learning such that tries to find an optimal combination of a set of sub-kernels to achieve a better result. However, the discriminative ability of some of the base kernels may be low and the OC-KFKT designed by this type of kernels leads to unsatisfactory classification performance. To address this problem, the quality of sub-kernels should be evaluated, and the weak kernels must be discarded before the final decision making process. MKL/OC-FKT and selective MKL/OC-FKT frameworks have been designed stimulated by ensemble learning (EL) to weight and then select the sub-classifiers using the discriminability and diversities measured by eigenvalue ratios. The eigenvalue ratios have been assessed based on their regions on the FKT subspaces. The comparative experiments, performed on various low and high dimensional data, against state-of-the-art algorithms confirm the effectiveness of our techniques, especially in case of small sample size (SSS) conditions.

Keywords: ensemble methods, fukunaga-koontz transform, kernel-based methods, multiple kernel learning, one-class classification

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Authors: Suzan Sayegh, Izzeldin Ibrahim, Mercia Van Der Walt, Mohamed Al-Kuwari

Abstract:

Background: Walking is the most common form of physical activity which can promote a healthy well-being among people of different age groups. In this regard, pedometers are becoming more popular within research and are considered useful tools in monitoring physical activity levels based on individuals’ daily steps. A value of ˂5,000 steps/day is identified as a sedentary lifestyle index where individuals are physically inactive. Those achieving 5,000-7,499 steps/day have a low active lifestyle as they do not meet the moderate-to-vigorous physical activity (MVPA) recommendations. Moreover, individuals achieving ≥7,500 steps/day are classified as physically active. The objective of this study is to assess the physical activity levels of adult population in Qatar through a pedometer-based program over a one-year period. Methods: A cross-sectional analysis, as part of a longitudinal study, was carried out over one year to assess the daily step count. “Step into Health” is a community-based program launched by Aspire as an approach for the purpose of improving physical activity across the population of Qatar. The program involves distribution of pedometers to registered members which is supported by a self-monitoring online account and linked to a web database. Daily habitual physical activity (daily total step count) was assessed through Omron HJ-324U pedometer. Analyses were done on data extracted from the web database. Results: A total of 1,988 members were included in this study (males: n=1,143, 57%; females: n=845, 43%). Average age was 37.8±10.9 years distributed as 60% of age between age 25-54 (n=1,186), 27% of age 45-64 (n=546), and 13% of age 18-24 years (n=256). Majority were non-Qataris, 81% (n=1,609) compared with 19% of the Qatari nationality (n=379). Average body mass index (BMI) was 27.8±6.1 (kg/m2) where most of them (41%, n=809) were found to be overweight, between 25-30 kg/m2. Total average step count was 5,469±3,884. Majority were found to be sedentary (n=1110, 55.8%). Middle aged individuals were more active than the other two age groups. Males were seen as more active than females. Those who were less active had a higher BMI. Older individuals were more active. There was a variation in the physical activity level throughout the year period. Conclusion: It is essential to further develop the available intervention programs and increase their physical activity behavior. Planning such physical activity interventions for female population should involve aspects such as time, environmental variables and aerobic steps.

Keywords: adults, pedometer, physical activity, step-count

Procedia PDF Downloads 361

Authors: Ashimolowo Olubunmi

Abstract:

Contraception use helps prevent pregnancy as well as health-related challenges, most especially among youths and girls. Our communities are bedeviled with many problems, including rape, defilement, neglect by the spouse, and intimate partner violence. Current interventions target only adults, with most facilities having youth and unfriendly adolescent services. To further support the need for this research, especially with our target beneficiaries, the partnership embarked on qualitative evidence-finding research through focus group discussions and in-depth-interview in Abeokuta and Ibadan (the capital cities of Ogun). The Focus Group Discussion (FGD) sessions were held in the state with adolescents (10-18 years) and young women (18-30 years). The result revealed that teenagers and youths who receive formal and sexual education on abstinence, and birth control methods, are likely to have healthier sexual behaviours through the promotion of abstinence and the use of condoms and other forms of contraceptives at their first intercourse, thereby protecting themselves against HIV/AIDs (Human Immunodeficiency Virus/Acquired immunodeficiency syndrome. The result further revealed that parents do not discuss issues around Adolescent and Sexual Reproductive Health (ASRH) with their adolescent girls, leading to gaps in knowledge of ASRH. Stakeholders’ involvement and trust are low. Respondents noted that there were few outreaches on ASRH and that youth-friendly adolescent centres are not common in the community. Respondents noted that there were few outreaches on ASRH organised within the community. Also, youth-friendly services were not common. There is a need to work with all stakeholders to promote those foundational life skills on pubertal changes, menstruation, and sexual life to prepare youths and girls for challenges ahead through sex education; we should work to institutionalize youth and adolescent-friendly Sexual and Reproductive Health (SRH) in our communities.

Keywords: contraception, family planning, focus group discussion, adolescents

Procedia PDF Downloads 70

Authors: Abdelhadi Lotfi, Abdelkader Benyettou

Abstract:

In this work, a training algorithm for probabilistic neural networks (PNN) is presented. The algorithm addresses one of the major drawbacks of PNN, which is the size of the hidden layer in the network. By using a cross-validation training algorithm, the number of hidden neurons is shrunk to a smaller number consisting of the most representative samples of the training set. This is done without affecting the overall architecture of the network. Performance of the network is compared against performance of standard PNN for different databases from the UCI database repository. Results show an important gain in network size and performance.

Keywords: classification, probabilistic neural networks, network optimization, pattern recognition

Procedia PDF Downloads 262

Authors: Muamar Salameh, Rania Sinno

Abstract:

Non-governmental organizations in Saudi Arabia play a vital role in promoting humanitarian development. Though this paper will emphasize this role and will provide a specific case study on the role of Prince Mohammad Bin Fahd Foundation for Humanitarian Development, yet many organizations do not provide transparent information for the accomplishments of the NGOs. This study will provide answers to the main research question regarding this role that NGOs play in promoting humanitarian development. The recent law regulating associations and foundations in Saudi Arabia was issued in December 2015 and went into effect March 2016. Any new association or foundation will need to follow these regulations. Though the registration, implementation, and workflow of the organizations still need major improvement and development, yet, the currently-registered organizations have several notable achievements. Most of these organizations adopt a centralized administration approach which in many cases still hinders progress and may be an obstacle in achieving and reaching a larger population of beneficiaries. A large portion of the existing organizations are charities, some of which have some sort of government affiliation. The laws and regulations limit registration of new organizations. Any violations to Islamic Sharia, contradictions to public order, breach to national unity, foreign and foreign-affiliation organizations prohibits any organization from registration. The lack of transparency in the operations and inner-working of NGOs in Saudi Arabia is apparent for the public. However, the regulations invoke full transparency with the governing ministry. This transparency should be available to the public and in specific to the target population that are eligible to benefit from the NGOs services. In this study, we will provide an extensive review of all related laws, regulations, policies and procedures related to all NGOs in the Eastern Province of Saudi Arabia. This review will include some examples of current NGOs, services and target population. The study will determine the main accomplishments of reputable NGOs that have impacted positively the Saudi communities. The results will highlight and concentrate on actions, services and accomplishments that achieve sustainable assistance in promoting humanitarian development and advance living conditions of target populations of the Saudi community. In particular, we will concentrate on a case study related to PMFHD; one of the largest foundations in the Eastern Province of Saudi Arabia. The authors have access to the data related to this foundation and have access to the foundation administration to gather, analyze and conclude the findings of this group. The study will also analyze whether the practices, budgets, services and annual accomplishments of the foundation have fulfilled the humanitarian role of the foundation while meeting the governmental requirements, with an analysis in the light of the new laws. The findings of the study show that great accomplishments for advancing and promoting humanitarian development in Saudi community and international communities have been achieved. Several examples will be included from several NGOs, with specific examples from PMFHD.

Keywords: development, foundation, humanitarian, non-governmental organization, Saudi Arabia

Procedia PDF Downloads 296

Authors: Fanous Mohammadi, Majid H. Tangestani, Mohammad H. Tayebi

Abstract:

This research aims to evaluate and compare Geographical Information Systems (GIS)-based fuzzy models for producing orogenic gold prospectivity maps in the Saqqez area, NW of Iran. Gold occurrences are hosted in sericite schist and mafic to felsic meta-volcanic rocks in this area and are associated with hydrothermal alterations that extend over ductile to brittle shear zones. The predictor maps, which represent the Pre-(Source/Trigger/Pathway), syn-(deposition/physical/chemical traps) and post-mineralization (preservation/distribution of indicator minerals) subsystems for gold mineralization, were generated using empirical understandings of the specifications of known orogenic gold deposits and gold mineral systems and were then pre-processed and integrated to produce mineral prospectivity maps. Five fuzzy logic operators, including AND, OR, Fuzzy Algebraic Product (FAP), Fuzzy Algebraic Sum (FAS), and GAMMA, were applied to the predictor maps in order to find the most efficient prediction model. Prediction-Area (P-A) plots and field observations were used to assess and evaluate the accuracy of prediction models. Mineral prospectivity maps generated by AND, OR, FAP, and FAS operators were inaccurate and, therefore, unable to pinpoint the exact location of discovered gold occurrences. The GAMMA operator, on the other hand, produced acceptable results and identified potentially economic target sites. The P-A plot revealed that 68 percent of known orogenic gold deposits are found in high and very high potential regions. The GAMMA operator was shown to be useful in predicting and defining cost-effective target sites for orogenic gold deposits, as well as optimizing mineral deposit exploitation.

Keywords: mineral prospectivity mapping, fuzzy logic, GIS, orogenic gold deposit, Saqqez, Iran

Procedia PDF Downloads 121

Authors: Surekha Tony, Roshan Mevada

Abstract:

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema, and microthrombocytopenia. In its classical form, significant combined immune deficiency, autoimmune complications, and risk of hematological malignancy necessitate early correction, preferably before 2 years of age, with hematopoietic stem cell transplant (HSCT) or gene therapy. Clinical features and severity are varied, making the diagnosis difficult in milder cases. We report an Omani boy diagnosed in early infancy with WAS based on clinical presentation and confirmed by genetic diagnosis with cure by HSCT from an HLA-identical sibling donor.

Keywords: genetic diagnosis, hematopoietic stem cell transplant, infant, Wiskott-Aldrich syndrome

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Authors: Yosef Ferede Bogale

Abstract:

The purpose of this study was to evaluate the degree of customer satisfaction and the variables influencing it in the instance of the Bank of Abyssinia branches in the districts of Arada and Bole in Addis Ababa. The study was carried out utilizing a mixed research approach and a descriptive and explanatory research design in Addis Ababa, the capital city of Ethiopia. Both primary and secondary data were employed in this investigation. The study's target population consisted of 1000 of the bank's most prestigious clients. With a 93% response rate, 265 respondents from both genders in the active age group had higher levels of education and work experience and were in the active age group. Customers of the case bank under consideration comprised the study's target audience. The respondents, who belonged to both gender groups, were in the active age bracket with superior levels of education and work experience. As a result, this investigation discovered that the degree of client satisfaction was assigned a medium rating. Additionally given a middling rating were the company's image practices, employee competency, technology, and service quality. Further, the results also demonstrate that corporate image, employees’ competency, technology, and service quality all positively and significantly affect customer happiness. This study found that, to varying degrees, company image, technology, competence, and high-quality financial services will all improve consumer happiness. According to this report, banks should monitor customer satisfaction and service quality at least twice a year. This is because there is a growing movement among bank service providers for accountability, and measuring these factors is crucial. This study also recommends that banks make every effort to satisfy consumers' expectations to the highest level.

Keywords: customer satisfaction, corporate image, quality service risk, banks

Procedia PDF Downloads 123

Authors: Souzan Al Sayegh, Izzeldin Ibrahim, Mercia Van Der Walt, Mohamed Al-Kuwari

Abstract:

Background: Walking is the most common form of physical activity which can promote a healthy well-being among people of different age groups. In this regard, pedometers are becoming more popular within research and are considered useful tools in monitoring physical activity levels based on individuals’ daily steps. A value of ˂5,000 steps/day is identified as a sedentary lifestyle index where individuals are physically inactive. Those achieving 5,000-7,499 steps/day have a low active lifestyle as they do not meet the moderate-to-vigorous physical activity (MVPA) recommendations. Moreover, individuals achieving ≥7,500 steps/day are classified as physically active. The objective of this study is to assess the physical activity levels of adult population in Qatar through a pedometer-based program over a one-year period. Methods: A cross-sectional analysis, as part of a longitudinal study, was carried out over one year to assess the daily step count. 'Step into Health' is a community-based program launched by Aspire as an approach for the purpose of improving physical activity across the population of Qatar. The program involves the distribution of pedometers to registered members which is supported by a self-monitoring online account and linked to a web database. Daily habitual physical activity (daily total step count) was assessed through Omron HJ-324U pedometer. Analyses were done on data extracted from the web database. Results: A total of 1,988 members were included in this study (males: n=1,143, 57%; females: n=845, 43%). Average age was 37.8±10.9 years distributed as 60% of age between age 25-54 (n=1,186), 27% of age 45-64 (n=546), and 13% of age 18-24 years (n=256). Majority were non-Qataris, 81% (n=1,609) compared with 19% of the Qatari nationality (n=379). Average body mass index (BMI) was 27.8±6.1 (kg/m2) where most of them (41%, n=809) were found to be overweight, between 25-30 kg/m2. Total average step count was 5,469±3,884. Majority were found to be sedentary (n=1110, 55.8%). Middle aged individuals were more active than the other two age groups. Males were seen as more active than females. Those who were less active had a higher BMI. Older individuals were more active. There was a variation in the physical activity level throughout the year period. Conclusion: It is essential to further develop the available intervention programs and increase their physical activity behavior. Planning such physical activity interventions for female population should involve aspects such as time, environmental variables and aerobic steps.

Keywords: adults, pedometer, physical activity, step-count

Procedia PDF Downloads 305

Authors: Sakshi Piplani, Ajit Kumar

Abstract:

Valproic acid (VPA) is the first synthetic therapeutic agent used to treat epileptic disorders, which account for affecting nearly 1% world population. Teratogenicity caused by VPA has prompted the search for next generation drug with better efficacy and lower side effects. Recent studies have posed HDAC8 as direct target of VPA that causes the teratogenic effect in foetus. We have employed molecular dynamics (MD) and docking simulations to understand the binding mode of VPA and their analogues onto HDAC8. A total of twenty 3D-structures of human HDAC8 isoforms were selected using BLAST-P search against PDB. Multiple sequence alignment was carried out using ClustalW and PDB-3F07 having least missing and mutated regions was selected for study. The missing residues of loop region were constructed using MODELLER and energy was minimized. A set of 216 structural analogues (>90% identity) of VPA were obtained from Pubchem and ZINC database and their energy was optimized with Chemsketch software using 3-D CHARMM-type force field. Four major neurotransmitters (GABAt, SSADH, α-KGDH, GAD) involved in anticonvulsant activity were docked with VPA and its analogues. Out of 216 analogues, 75 were selected on the basis of lower binding energy and inhibition constant as compared to VPA, thus predicted to have anti-convulsant activity. Selected hHDAC8 structure was then subjected to MD Simulation using licenced version YASARA with AMBER99SB force field. The structure was solvated in rectangular box of TIP3P. The simulation was carried out with periodic boundary conditions and electrostatic interactions and treated with Particle mesh Ewald algorithm. pH of system was set to 7.4, temperature 323K and pressure 1atm respectively. Simulation snapshots were stored every 25ps. The MD simulation was carried out for 20ns and pdb file of HDAC8 structure was saved every 2ns. The structures were analysed using castP and UCSF Chimera and most stabilized structure (20ns) was used for docking study. Molecular docking of 75 selected VPA-analogues with PDB-3F07 was performed using AUTODOCK4.2.6. Lamarckian Genetic Algorithm was used to generate conformations of docked ligand and structure. The docking study revealed that VPA and its analogues have more affinity towards ‘hydrophobic active site channel’, due to its hydrophobic properties and allows VPA and their analogues to take part in van der Waal interactions with TYR24, HIS42, VAL41, TYR20, SER138, TRP137 while TRP137 and SER138 showed hydrogen bonding interaction with VPA-analogues. 14 analogues showed better binding affinity than VPA. ADMET SAR server was used to predict the ADMET properties of selected VPA analogues for predicting their druggability. On the basis of ADMET screening, 09 molecules were selected and are being used for in-vivo evaluation using Danio rerio model.

Keywords: HDAC8, docking, molecular dynamics simulation, valproic acid

Procedia PDF Downloads 250

Authors: Yosef Ferede Bogale

Abstract:

The purpose of this study was to evaluate the degree of customer satisfaction and the variables influencing it in the instance of the Bank of Abyssinia branches in the districts of Arada and Bole in Addis Ababa. The study was carried out utilizing a mixed research approach and a descriptive and explanatory research design in Addis Ababa, the capital city of Ethiopia. Both primary and secondary data were employed in this investigation. The study's target population consisted of 1000 of the bank's most prestigious clients. With a 93% response rate, 265 respondents from both genders in the active age group had higher levels of education and work experience and were in the active age group. Customers of the case bank under consideration comprised the study's target audience. The respondents, who belonged to both gender groups, were in the active age bracket with superior levels of education and work experience. As a result, this investigation discovered that the degree of client satisfaction was assigned a medium rating. Additionally given a middling rating were the company's image practices, employee competency, technology, and service quality. Further, the results also demonstrate that corporate image, employees’ competency, technology, and service quality all positively and significantly affect customer happiness. This study found that, to varying degrees, company image, technology, competence, and high-quality financial services will all improve consumer happiness. According to this report, banks should monitor customer satisfaction and service quality at least twice a year. This is because there is a growing movement among bank service providers for accountability, and measuring these factors is crucial. This study also recommends that banks make every effort to satisfy consumers' expectations to the highest level.

Keywords: customer satisfaction, corporate image, quality services risk, bank

Procedia PDF Downloads 62

Authors: Jae-Neung Lee, Keun-Chang Kwak

Abstract:

This paper describes an analysis of Yacht Simulator international trends and also explains about Yacht. Examples of yacht Simulator using Yacht Simulator include image processing for totaling the total number of vehicles, edge/target detection, detection and evasion algorithm, image processing using SIFT (scale invariant features transform) matching, and application of median filter and thresholding.

Keywords: yacht simulator, simulator, trends analysis, SIFT

Procedia PDF Downloads 432

Authors: Sophio Kobauri, Temur Kantaria, Nina Kulikova, David Tugushi, Ramaz Katsarava

Abstract:

The elaboration of effective drug delivery vehicles is still topical nowadays since targeted drug delivery is one of the most important challenges of the modern nanomedicine. The last decade has witnessed enormous research focused on synthetic cationic polymers (CPs) due to their flexible properties, in particular as non-viral gene delivery systems, facile synthesis, robustness, not oncogenic and proven gene delivery efficiency. However, the toxicity is still an obstacle to the application in pharmacotherapy. For overcoming the problem, creation of new cationic compounds including the polymeric nano-size particles – nano-containers (NCs) loading with different pharmaceuticals and biologicals is still relevant. In this regard, a variety of NCs-based drug delivery systems have been developed. We have found that amino acid-based biodegradable polymers called as pseudo-proteins (PPs), which can be cleared from the body after the fulfillment of their function are highly suitable for designing pharmaceutical NCs. Among them, one of the most promising are NCs made of biodegradable Cationic PPs (CPPs). For preparing new cationic NCs (CNCs), we used CPPs composed of positively charged amino acid L-arginine (R). The CNCs were fabricated by two approaches using: (1) R-based homo-CPPs; (2) Blends of R-based CPPs with regular (neutral) PPs. According to the first approach NCs we prepared from CPPs 8R3 (composed of R, sebacic acid and 1,3-propanediol) and 8R6 (composed of R, sebacic acid and 1,6-hexanediol). The NCs prepared from these CPPs were 72-101 nm in size with zeta potential within +30 ÷ +35 mV at a concentration 6 mg/mL. According to the second approach, CPPs 8R6 was blended in organic phase with neutral PPs 8L6 (composed of leucine, sebacic acid and 1,6-hexanediol). The NCs prepared from the blends were 130-140 nm in size with zeta potential within +20 ÷ +28 mV depending on 8R6/8L6 ratio. The stability studies of fabricated NCs showed that no substantial change of the particle size and distribution and no big particles’ formation is observed after three months storage. In vitro biocompatibility study of the obtained NPs with four different stable cell lines: A549 (human), U-937 (human), RAW264.7 (murine), Hepa 1-6 (murine) showed both type cathionic NCs are biocompatible. The obtained data allow concluding that the obtained CNCs are promising for the application as biodegradable drug delivery vehicles. This work was supported by the joint grant from the Science and Technology Center in Ukraine and Shota Rustaveli National Science Foundation of Georgia #6298 'New biodegradable cationic polymers composed of arginine and spermine-versatile biomaterials for various biomedical applications'.

Keywords: biodegradable polymers, cationic pseudo-proteins, nano-containers, drug delivery vehicles

Procedia PDF Downloads 155

Authors: Xinxiu Li, Chuqian Zheng, Yanyan Qian, Hong Fan

Abstract:

Objectives: In hepatocellular carcinoma (HCC), oncogenes are continuously and robustly transcribed due to aberrant expression of essential components of the trans-acting super-enhancers (SE) complex. Preclinical and clinical trials are now being conducted on small-molecule inhibitors that target core-transcriptional components, including as transcriptional bromodomain protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7), in a number of malignant tumors. This study aims to explore whether co-overexpression of BRD4 and CDK7 is a potential marker of worse prognosis and a combined therapeutic target in HCC. Methods: The expression pattern of BRD4 and CDK7 and their correlation with prognosis in HCC were analyzed by RNA sequencing data and survival data of HCC patients from TCGA and GEO datasets. The protein levels of BRD4 and CDK7 were determined by immunohistochemistry (IHC), and survival data of patients were analyzed using the Kaplan-Meier method. The mRNA expression levels of genes in HCC cell lines were evaluated by quantitative PCR (q-PCR). CCK-8 and colony formation assays were conducted to assess cell proliferation of HCC upon treatment with BRD4 inhibitor JQ1 or/and CDK7 inhibitor THZ1. Results: It was shown that BRD4 and CDK7 were often overexpressed in HCCs and were associated with poor prognosis of HCC by analyzing the TCGA and GEO datasets. BRD4 or CDK7 overexpression was related to a lower survival rate. It's interesting to note that co-overexpression of CDK7 and BRD4 was a worse prognostic factor in HCC. Treatment with JQ1 or THZ1 alone had an inhibitory effect on cell proliferation; however, when JQ1 and THZ1 were combined, there was a more notable suppression of cell growth. At the same time, the combined use of JQ1 and THZ1 synergistically suppresses the expression of HCC driver genes. Conclusion: Our research revealed that BRD4 and CDK7 coupled can be a useful biomarker in HCC prognosis and the combination of JQ1 and THZ1 can be a promising therapeutic therapy against HCC.

Keywords: BRD4, CDK7, cell proliferation, combined inhibition

Procedia PDF Downloads 54