Search results for: regulatory T cells
Commenced in January 2007
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Edition: International
Paper Count: 3868

Search results for: regulatory T cells

808 Cannabinoids and Terpenes as Potential Modulators of Efflux Transporters for Overcoming Drug Resistance in Epilepsy

Authors: Tomáš Nejedlý, Dominika Mrázková, Jitka Viktorová

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The blood-brain barrier (BBB) serves as a protective shield, preventing the entry of harmful substances into the central nervous system. On the other hand, it also restricts the transport of neuroactive drugs, such as antiepileptics, which mitigate epileptic seizures. Drug-resistant epilepsy is often associated with the overexpression of efflux transporters, including P-glycoprotein (P-gp) or multidrug resistance protein 1 (MRP1), on the BBB. The aim of this work is to find P-gp and MRP1 inhibitors derived from phytocannabinoids and terpenes. The work evaluates whether these compounds interact directly with P-gp or MRP1 by rhodamine 123 or fluorescein efflux assay. The effect of phytocannabinoids on the gene expression of these transporters is also studied using qPCR and Western blot. These transporters are found in BBB cells; however, we decided to use the human ovarian cancer cell line (A2780ADR) due to its overproduction of P-gp and malignant glioma cell line (U87) due to its overproduction of MRP1. The results showed that while terpenes suppressed the activity of efflux transporters, phytocannabinoids tended to decrease their expression. Terpenes demonstrated an average inhibition of 65%, surpassing phytocannabinoids, which exhibited an average inhibition of approximately 30%. Particularly noteworthy was the modulating effect of (-)-α-bisabolol with the highest activity among the compounds tested. Based on these findings, phytocannabinoids and terpenes emerge as promising natural candidates for addressing drug resistance linked to efflux transporters. Acknowledgment: The project was funded by the Grant No 22-20860S of The Czech Science Foundation.

Keywords: drug-resistant epilepsy, efflux transporters, multidrug resistance protein 1, P-glycoprotein, phytocannabinoids, terpens

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807 Low-Surface Roughness and High Optical Quality CdS Thin Film Grown by Modified Chemical Surface Deposition Method

Authors: A. Elsayed, M. H. Dewaidar, M. Ghali

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We report on deposition of smooth, pinhole-free, low-surface roughness ( < 4nm) and high optical quality cadmium sulfide (CdS) thin films on glass substrates using our new method based on chemical surface deposition principle. In this method, cadmium acetate and thiourea are used as reactants under special growth conditions for deposition of CdS films. X-ray diffraction (XRD) measurements were used to examine the crystal structure properties of the deposited CdS films. In addition, UV-vis transmittance and low-temperature (4K) photoluminescence (PL) measurements were performed for quantifying optical properties of the deposited films. Interestingly, we found that XRD pattern of the deposited films has dramatically changed when the growth temperature was raised during the reaction. Namely, the XRD measurements reveal a structural change of CdS film from Cubic to Hexagonal phase upon increase in the growth temperature from 75 °C to 200 °C. Furthermore, the deposited films show high optical quality as confirmed from observation of both sharp edge in the transmittance spectra and strong PL intensity at room temperature. Also, we found a strong effect of the growth conditions on the optical band gap of the deposited films; where remarkable red-shift in the absorption edge with temperature is clearly seen in both transmission and PL spectra. Such tuning of both optical band gap and crystal structure of the deposited CdS films; can be utilized for tuning the electronic bands alignments between CdS and other light harvesting materials, like CuInGaSe or CdTe, for potential improvement in the efficiency of all-solution processed solar cells devices based on these heterostructures.

Keywords: thin film, CdS, new method, optical properties

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806 Toxicological Validation during the Development of New Catalytic Systems Using Air/Liquid Interface Cell Exposure

Authors: M. Al Zallouha, Y. Landkocz, J. Brunet, R. Cousin, J. M. Halket, E. Genty, P. J. Martin, A. Verdin, D. Courcot, S. Siffert, P. Shirali, S. Billet

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Toluene is one of the most used Volatile Organic Compounds (VOCs) in the industry. Amongst VOCs, Benzene, Toluene, Ethylbenzene and Xylenes (BTEX) emitted into the atmosphere have a major and direct impact on human health. It is, therefore, necessary to minimize emissions directly at source. Catalytic oxidation is an industrial technique which provides remediation efficiency in the treatment of these organic compounds. However, during operation, the catalysts can release some compounds, called byproducts, more toxic than the original VOCs. The catalytic oxidation of a gas stream containing 1000ppm of toluene on Pd/α-Al2O3 can release a few ppm of benzene, according to the operating temperature of the catalyst. The development of new catalysts must, therefore, include chemical and toxicological validation phases. In this project, A549 human lung cells were exposed in air/liquid interface (Vitrocell®) to gas mixtures derived from the oxidation of toluene with a catalyst of Pd/α-Al2O3. Both exposure concentrations (i.e. 10 and 100% of catalytic emission) resulted in increased gene expression of Xenobiotics Metabolising Enzymes (XME) (CYP2E1 CYP2S1, CYP1A1, CYP1B1, EPHX1, and NQO1). Some of these XMEs are known to be induced by polycyclic organic compounds conventionally not searched during the development of catalysts for VOCs degradation. The increase in gene expression suggests the presence of undetected compounds whose toxicity must be assessed before the adoption of new catalyst. This enhances the relevance of toxicological validation of such systems before scaling-up and marketing.

Keywords: BTEX toxicity, air/liquid interface cell exposure, Vitrocell®, catalytic oxidation

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805 Inferring the Ecological Quality of Seagrass Beds from Using Composition and Configuration Indices

Authors: Fabrice Houngnandan, Celia Fery, Thomas Bockel, Julie Deter

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Getting water cleaner and stopping global biodiversity loss requires indices to measure changes and evaluate the achievement of objectives. The endemic and protected seagrass species Posidonia oceanica is a biological indicator used to monitor the ecological quality of marine Mediterranean waters. One ecosystem index (EBQI), two biotic indices (PREI, Bipo), and several landscape indices, which measure the composition and configuration of the P. oceanica seagrass at the population scale have been developed. While the formers are measured at monitoring sites, the landscape indices can be calculated for the entire seabed covered by this ecosystem. This present work aims to search on the link between these indices and the best scale to be used in order to maximize this link. We used data collected between 2014 to 2019 along the French Mediterranean coastline to calculate EBQI, PREI, and Bipo at 100 sites. From the P. oceanica seagrass distribution map, configuration and composition indices around these different sites in 6 different grid sizes (100 m x 100 to 1000 m x 1000 m) were determined. Correlation analyses were first used to find out the grid size presenting the strongest and most significant link between the different types of indices. Finally, several models were compared basis on various metrics to identify the one that best explains the nature of the link between these indices. Our results showed a strong and significant link between biotic indices and the best correlations between biotic and landscape indices within the 600 m x 600 m grid cells. These results showed that the use of landscape indices is possible to monitor the health of seagrass beds at a large scale.

Keywords: ecological indicators, decline, conservation, submerged aquatic vegetation

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804 Case Study Analysis of 2017 European Railway Traffic Management Incident: The Application of System for Investigation of Railway Interfaces Methodology

Authors: Sanjeev Kumar Appicharla

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This paper presents the results of the modelling and analysis of the European Railway Traffic Management (ERTMS) safety-critical incident to raise awareness of biases in the systems engineering process on the Cambrian Railway in the UK using the RAIB 17/2019 as a primary input. The RAIB, the UK independent accident investigator, published the Report- RAIB 17/2019 giving the details of their investigation of the focal event in the form of immediate cause, causal factors, and underlying factors and recommendations to prevent a repeat of the safety-critical incident on the Cambrian Line. The Systems for Investigation of Railway Interfaces (SIRI) is the methodology used to model and analyze the safety-critical incident. The SIRI methodology uses the Swiss Cheese Model to model the incident and identify latent failure conditions (potentially less than adequate conditions) by means of the management oversight and risk tree technique. The benefits of the systems for investigation of railway interfaces methodology (SIRI) are threefold: first is that it incorporates the “Heuristics and Biases” approach advanced by 2002 Nobel laureate in Economic Sciences, Prof Daniel Kahneman, in the management oversight and risk tree technique to identify systematic errors. Civil engineering and programme management railway professionals are aware of the role “optimism bias” plays in programme cost overruns and are aware of bow tie (fault and event tree) model-based safety risk modelling techniques. However, the role of systematic errors due to “Heuristics and Biases” is not appreciated as yet. This overcomes the problems of omission of human and organizational factors from accident analysis. Second, the scope of the investigation includes all levels of the socio-technical system, including government, regulatory, railway safety bodies, duty holders, signaling firms and transport planners, and front-line staff such that lessons are learned at the decision making and implementation level as well. Third, the author’s past accident case studies are supplemented with research pieces of evidence drawn from the practitioner's and academic researchers’ publications as well. This is to discuss the role of system thinking to improve the decision-making and risk management processes and practices in the IEC 15288 systems engineering standard and in the industrial context such as the GB railways and artificial intelligence (AI) contexts as well.

Keywords: accident analysis, AI algorithm internal audit, bounded rationality, Byzantine failures, heuristics and biases approach

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803 Financial Analysis of the Foreign Direct in Mexico

Authors: Juan Peña Aguilar, Lilia Villasana, Rodrigo Valencia, Alberto Pastrana, Martin Vivanco, Juan Peña C

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Each year a growing number of companies entering Mexico in search of the domestic market share. These activities, including stores, telephone long distance and local raw materials and energy, and particularly the financial sector, have managed to significantly increase its weight in the flows of FDI in Mexico , however, you should consider whether these trends FDI are positive for the Mexican economy and these activities increase Mexican exports in the medium term , and its share in GDP , gross fixed capital formation and employment. In general stresses that these activities, by far, have been unable to significantly generate linkages with the rest of the economy, a process that has not favored with competitiveness policies and activities aimed at these neutral or horizontal. Since the nineties foreign direct investment (FDI) has shown a remarkable dynamism, both internationally and in Latin America and in Mexico. Only in Mexico the first recipient of FDI in importance in Latin America during 1990-1995 and was displaced by Brazil since FDI increased from levels below 1 % of GDP during the eighties to around 3 % of GDP during the nineties. Its impact has been significant not only from a macroeconomic perspective , it has also allowed the generation of a new industrial production structure and organization, parallel to a significant modernization of a segment of the economy. The case of Mexico also is particularly interesting and relevant because the destination of FDI until 1993 had focused on the purchase of state assets during privatization process. This paper aims to present FDI flows in Mexico and analyze the different business strategies that have been touched and encouraged by the FDI. On the one hand, looking briefly discuss regulatory issues and source and recipient of FDI sectors. Furthermore, the paper presents in more detail the impacts and changes that generated the FDI contribution of FDI in the Mexican economy , besides the macroeconomic context and later legislative changes that resulted in the current regulations is examined around FDI in Mexico, including aspects of the Free Trade Agreement (NAFTA). It is worth noting that foreign investment can not only be considered from the perspective of the receiving economic units. Instead, these flows also reflect the strategic interests of transnational corporations (TNCs) and other companies seeking access to markets and increased competitiveness of their production networks and global distribution, among other reasons. Similarly it is important to note that foreign investment in its various forms is critically dependent on historical and temporal aspects. Thus, the same functionality can vary significantly depending on the specific characteristics of both receptor units as sources of FDI, including macroeconomic, institutional, industrial organization, and social aspects, among others.

Keywords: foreign direct investment (FDI), competitiveness, neoliberal regime, globalization, gross domestic product (GDP), NAFTA, macroeconomic

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802 Developing Offshore Energy Grids in Norway as Capability Platforms

Authors: Vidar Hepsø

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The energy and oil companies on the Norwegian Continental shelf come from a situation where each asset control and manage their energy supply (island mode) and move towards a situation where the assets need to collaborate and coordinate energy use with others due to increased cost and scarcity of electric energy sharing the energy that is provided. Currently, several areas are electrified either with an onshore grid cable or are receiving intermittent energy from offshore wind-parks. While the onshore grid in Norway is well regulated, the offshore grid is still in the making, with several oil and gas electrification projects and offshore wind development just started. The paper will describe the shift in the mindset that comes with operating this new offshore grid. This transition process heralds an increase in collaboration across boundaries and integration of energy management across companies, businesses, technical disciplines, and engagement with stakeholders in the larger society. This transition will be described as a function of the new challenges with increased complexity of the energy mix (wind, oil/gas, hydrogen and others) coupled with increased technical and organization complexity in energy management. Organizational complexity denotes an increasing integration across boundaries, whether these boundaries are company, vendors, professional disciplines, regulatory regimes/bodies, businesses, and across numerous societal stakeholders. New practices must be developed, made legitimate and institutionalized across these boundaries. Only parts of this complexity can be mitigated technically, e.g.: by use of batteries, mixing energy systems and simulation/ forecasting tools. Many challenges must be mitigated with legitimated societal and institutionalized governance practices on many levels. Offshore electrification supports Norway’s 2030 climate targets but is also controversial since it is exploiting the larger society’s energy resources. This means that new systems and practices must also be transparent, not only for the industry and the authorities, but must also be acceptable and just for the larger society. The paper report from ongoing work in Norway, participant observation and interviews in projects and people working with offshore grid development in Norway. One case presented is the development of an offshore floating windfarm connected to two offshore installations and the second case is an offshore grid development initiative providing six installations electric energy via an onshore cable. The development of the offshore grid is analyzed using a capability platform framework, that describes the technical, competence, work process and governance capabilities that are under development in Norway. A capability platform is a ‘stack’ with the following layers: intelligent infrastructure, information and collaboration, knowledge sharing & analytics and finally business operations. The need for better collaboration and energy forecasting tools/capabilities in this stack will be given a special attention in the two use cases that are presented.

Keywords: capability platform, electrification, carbon footprint, control rooms, energy forecsting, operational model

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801 Hippocampus Proteomic of Major Depression and Antidepressant Treatment: Involvement of Cell Proliferation, Differentiation, and Connectivity

Authors: Dhruv J. Limaye, Hanga Galfalvy, Cheick A. Sissoko, Yung-yu Huang, Chunanning Tang, Ying Liu, Shu-Chi Hsiung, Andrew J. Dwork, Gorazd B. Rosoklija, Victoria Arango, Lewis Brown, J. John Mann, Maura Boldrini

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Memory and emotion require hippocampal cell viability and connectivity and are disrupted in major depressive disorder (MDD). Applying shotgun proteomics and stereological quantification of neural progenitor cells (NPCs), intermediate neural progenitors (INPs), and mature granule neurons (GNs), to postmortem human hippocampus, identified differentially expressed proteins (DEPs), and fewer NPCs, INPs and GNs, in untreated MDD (uMDD) compared with non-psychiatric controls (CTRL) and antidepressant-treated MDD (MDDT). DEPs lower in uMDD vs. CTRL promote mitosis, differentiation, and prevent apoptosis. DEPs higher in uMDD vs. CTRL inhibit the cell cycle, and regulate cell adhesion, neurite outgrowth, and DNA repair. DEPs lower in MDDT vs. uMDD block cell proliferation. We observe group-specific correlations between numbers of NPCs, INPs, and GNs and an abundance of proteins regulating mitosis, differentiation, and apoptosis. Altered protein expression underlies hippocampus cellular and volume loss in uMDD, supports a trophic effect of antidepressants, and offers new treatment targets.

Keywords: proteomics, hippocampus, depression, mitosis, migration, differentiation, mitochondria, apoptosis, antidepressants, human brain

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800 CD133 and CD44 - Stem Cell Markers for Prediction of Clinically Aggressive Form of Colorectal Cancer

Authors: Ognen Kostovski, Svetozar Antovic, Rubens Jovanovic, Irena Kostovska, Nikola Jankulovski

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Introduction:Colorectal carcinoma (CRC) is one of the most common malignancies in the world. The cancer stem cell (CSC) markers are associated with aggressive cancer types and poor prognosis. The aim of study was to determine whether the expression of colorectal cancer stem cell markers CD133 and CD44 could be significant in prediction of clinically aggressive form of CRC. Materials and methods: Our study included ninety patients (n=90) with CRC. Patients were divided into two subgroups: with metatstatic CRC and non-metastatic CRC. Tumor samples were analyzed with standard histopathological methods, than was performed immunohistochemical analysis with monoclonal antibodies against CD133 and CD44 stem cell markers. Results: High coexpression of CD133 and CD44 was observed in 71.4% of patients with metastatic disease, compared to 37.9% in patients without metastases. Discordant expression of both markers was found in 8% of the subgroup with metastatic CRC, and in 13.4% of the subgroup without metastatic CRC. Statistical analyses showed a significant association of increased expression of CD133 and CD44 with the disease stage, T - category and N - nodal status. With multiple regression analysis the stage of disease was designate as a factor with the greatest statistically significant influence on expression of CD133 (p <0.0001) and CD44 (p <0.0001). Conclusion: Our results suggest that the coexpression of CD133 and CD44 have an important role in prediction of clinically aggressive form of CRC. Both stem cell markers can be routinely implemented in standard pathohistological diagnostics and can be useful markers for pre-therapeutic oncology screening.

Keywords: colorectal carcinoma, stem cells, CD133+, CD44+

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799 Deciphering Electrochemical and Optical Properties of Folic Acid for the Applications of Tissue Engineering and Biofuel Cell

Authors: Sharda Nara, Bansi Dhar Malhotra

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Investigation of the vitamins as an electron transfer mediator could significantly assist in merging the area of tissue engineering and electronics required for the implantable therapeutic devices. The present study report that the molecules of folic acid released by Providencia rettgeri via fermentation route under the anoxic condition of the microbial fuel cell (MFC) exhibit characteristic electrochemical and optical properties, as indicated by absorption spectroscopy, photoluminescence (PL), and cyclic voltammetry studies. The absorption spectroscopy has depicted an absorption peak at 263 nm with a small bulge around 293 nm on day two of bacterial culture, whereas an additional peak was observed at 365 nm on the twentieth day. Furthermore, the PL spectra has indicated that the maximum emission occurred at various wavelengths 420, 425, 440, and 445 nm when excited by 310, 325, 350, and 365 nm. The change of emission spectra with varying excitation wavelength might be indicating the presence of tunable optical bands in the folic acid molecules co-related with the redox activity of the molecules. The results of cyclic voltammetry studies revealed that the oxidation and reduction occurred at 0.25V and 0.12V, respectively, indicating the electrochemical behavior of the folic acid. This could be inferred that the released folic acid molecules in a MFC might undergo inter as well as intra molecular electron transfer forming different intermediate states while transferring electrons to the electrode surface. Synchronization of electrochemical and optical properties of folic acid molecules could be potentially promising for the designing of electroactive scaffold and biocompatible conductive surface for the applications of tissue engineering and biofuel cells, respectively.

Keywords: biofuel cell, electroactivity, folic acid, tissue engineering

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798 CCR5 as an Ideal Candidate for Immune Gene Therapy and Modification for the Induced Resistance to HIV-1 Infection

Authors: Alieh Farshbaf, Tayyeb Bahrami

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Introduction: Cc-chemokine receptor-5 (CCR5) is known as a main co-receptor in human immunodeficiency virus type-1 (HIV-1) infection. Many studies showed 32bp deletion (Δ32) in CCR5 gene, provide natural resistance to HIV-1 infection in homozygous individuals. Inducing the resistance mechanism by CCR5 in HIV-1 infected patients eliminated many problems of highly-active-anti retroviral therapy (HAART) drugs like as low safety, side-effects and virus rebounding from latent reservoirs. New treatments solved some restrictions that are based on gene modification and cell therapy. Literature review: The stories of the “Berlin and Boston patients” showed autologous hematopoietic stem cells transplantation (HSCT) could provide effective cure of HIV-1 infected patients. Furthermore, gene modification by zinc finger nuclease (ZFN) demonstrated another successful result again. Despite the other studies for gene therapy by ∆32 genotype, there is another mutation -CCR5 ∆32/m303- that provides HIV-1 resistant. It is a heterozygote genotype for ∆32 and T→A point mutation at nucleotide 303. These results approved the key role of CCR5 gene. Conclusion: Recent studies showed immune gene therapy and cell therapy could provide effective cure for refractory disease like as HIV. Eradication of HIV-1 from immune system was not observed by HAART, because of reloading virus genome from latent reservoirs after stopping them. It is showed that CCR5 could induce natural resistant to HIV-1 infection by the new approaches based on stem cell transplantation and gene modifying.

Keywords: CCR5, HIV-1, stem cell, immune gene therapy, gene modification

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797 Indenyl and Allyl Palladates: Synthesis, Bonding, and Anticancer Activity

Authors: T. Scattolin, E. Cavarzerani, F. Visentin, F. Rizzolio

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Organopalladium compounds have recently attracted attention for their high stability even under physiological conditions and, above all, for their remarkable in vitro cytotoxicity towards cisplatin-resistant cell lines. Among the organopalladium derivatives, those bearing at least one N-heterocyclic carbene ligand (NHC) and the Pd(II)-η³-allyl fragment have exhibited IC₅₀ values in the micro and sub-micromolar range towards several cancer cell lines in vitro and in some cases selectivity towards cancerous vs. non-tumorigenic cells. Herein, a selection of allyl and indenyl palladates were synthesized using a solvent-free method consisting of grinding the corresponding palladium precursors with different saturated and unsaturated azolium salts. All compounds have been fully characterized by NMR, XRD and elemental analyses. The intramolecular H, Cl interaction has been elucidated and quantified using the Voronoi Deformation Density scheme. Most of the complexes showed excellent cytotoxicity towards ovarian cancer cell lines, with I₅₀ values comparable to or even lower than cisplatin. Interestingly, the potent anticancer activity was also confirmed in a high-serous ovarian cancer (HGSOC) patient-derived tumoroid, with a clear superiority of this class of compounds over classical platinum-based agents. Finally, preliminary enzyme inhibition studies of the synthesized palladate complexes against the model TrxR show that the compounds have high activity comparable to or even higher than auranofin and classical Au(I) NHC complexes. Based on such promising data, further in vitro and in vivo experiments and in-depth mechanistic studies are ongoing in our laboratories.

Keywords: anticancer activity, palladium complexes, organoids, indenyl and allyl ligands

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796 Obesity, Leptin Levels and Leptin Receptor Gene Polymorphisms in Afro-Caribbean Subjects

Authors: Lydia Foucan, Christine Rambhojan, Rachel Billy, Christophe Armand, Carl-Thony Michel, Jean-Marc Lacorte, Laurent Larifla

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Leptin, an adipocyte-derived hormone, modulates insulin secretion and action via the leptin receptor (LEPR) that is expressed in pancreatic beta cells, adipose tissue, and muscle. Several polymorphisms have been described in the human LEPR gene including p.K109R (rs1137100), p.Q223R (rs1137101) and p.K656N (rs1805094) polymorphisms. The role of these polymorphisms is not yet studied in Guadeloupian population. Our aim was to explore the association of LEPR polymorphisms (K109R, Q223R and K656N) with leptin levels and obesity in non-diabetic Afro-Caribbean subjects. Genotypic analysis of the three polymorphisms was performed in 425 subjects using TaqMan and KASPar Assays. Serum leptin was measured with ELISA kits Biovendor® (RD191001100). Logistic regressions were used for assessment of statistical associations. Mean age was 47.6 ± 12.7 years. Among the participants, 238 (56 %) were women, 124 (30%) were obese and 155 (36.5%) had abdominal obesity. Carriers of LEPR K656N rs1805094 rare allele had significant higher frequencies of obesity (P = 0.007), abdominal obesity (P = 0.004) and metabolic syndrome (P = 0.021) but mean leptin level was not significantly different between both groups (P = 0.075). Odds ratios, adjusted for age and sex associated with presence of rs1805094 rare allele were 1.8 (1.1-2.9), P = 0.012 for obesity, 2.0 (1.2-3.3), P = 0.008 for abdominal obesity and 1.8 (1.1-3.0), P = 0.031 for MetS. No significant association was found with K109R, Q223R. These findings suggest that the K656N polymorphism (but not the K109R or Q223R polymorphism) of LEPR is associated with obesity, abdominal obesity and metabolic syndrome in this Afro-Caribbean non-diabetic population.

Keywords: Afro-Caribbean, leptin levels, leptin receptor gene polymorphisms, obesity

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795 The Effect of Micro/Nano Structure of Poly (ε-caprolactone) (PCL) Film Using a Two-Step Process (Casting/Plasma) on Cellular Responses

Authors: JaeYoon Lee, Gi-Hoon Yang, JongHan Ha, MyungGu Yeo, SeungHyun Ahn, Hyeongjin Lee, HoJun Jeon, YongBok Kim, Minseong Kim, GeunHyung Kim

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One of the important factors in tissue engineering is to design optimal biomedical scaffolds, which can be governed by topographical surface characteristics, such as size, shape, and direction. Of these properties, we focused on the effects of nano- to micro-sized hierarchical surface. To fabricate the hierarchical surface structure on poly(ε-caprolactone) (PCL) film, we employed a micro-casting technique by pressing the mold and nano-etching technique using a modified plasma process. The micro-sized topography of PCL film was controlled by sizes of the micro structures on lotus leaf. Also, the nano-sized topography and hydrophilicity of PCL film were controlled by a modified plasma process. After the plasma treatment, the hydrophobic property of the PCL film was significantly changed into hydrophilic property, and the nano-sized structure was well developed. The surface properties of the modified PCL film were investigated in terms of initial cell morphology, attachment, and proliferation using osteoblast-like-cells (MG63). In particular, initial cell attachment, proliferation and osteogenic differentiation in the hierarchical structure were enhanced dramatically compared to those of the smooth surface. We believe that these results are because of a synergistic effect between the hierarchical structure and the reactive functional groups due to the plasma process. Based on the results presented here, we propose a new biomimetic surface model that maybe useful for effectively regenerating hard tissues.

Keywords: hierarchical surface, lotus leaf, nano-etching, plasma treatment

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794 The Effect of the Archeological and Architectural Nature of the Cities on the Design of Public Transportation Vehicles

Authors: Mohamed Moheyeldin Mahmoud

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Various Islamic, Coptic and Jewish archeological places are located in many Egyptian neighborhoods such as Alsayeda zainab, Aldarb Alahmar, Algammaleya and many other in which they are daily exposed to a great traffic intensity causing vibrations. Vibrations could be stated as one of the most important challenges that face the archeological buildings and threaten their survival. The impact of vibrations varies according to the nature of the soil, nature and building conditions, how far the source of vibration is and the period of exposure. Traffic vibrations could be also stated as one of the most common types of vibrations having the greatest impact on buildings and archaeological installations. These vibrations result from the way that the vehicles act with different types of roads which vary according to the shape, nature, and type of obstacles. Other elements concerning the vehicle itself such as speed, weight, and load have a direct impact on the vibrations resulting from the vehicle movement that couldn't be neglected. The research aims to determine some of the requirements that must be observed when designing the public means of transport operating in the archaeological areas, in order to preserve the archaeological nature of the place. The research concludes that light weight slow motion vehicles should be used (25-50 km/h at maximum) having a multi-leaf steel spring suspension system instead of having an air-bag one should be used in order to reduce generated vibrations that could destroy the archeological buildings. Isolation layers could be used in the engine chamber in order to reduce the resulting noise causing vibrations. Electrically operated engines that use solar photovoltaic cells as a source of electricity could be used instead of gas ones in order to reduce the resulting engine noise.

Keywords: archeological, design, isolation layers, suspension, vibrations

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793 Captive Insurance in Hong Kong and Singapore: A Promising Risk Management Solution for Asian Companies

Authors: Jin Sheng

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This paper addresses a promising area of insurance sector to develop in Asia. Captive insurance, which provides risk-mitigation services for its parent company, has great potentials to develop in energy, infrastructure, agriculture, logistics, catastrophe, and alternative risk transfer (ART), and will greatly affect the framework of insurance industry. However, the Asian captive insurance market only takes a small proportion in the global market. The recent supply chain interruption case of Hanjin Shipping indicates the significance of risk management for an Asian company’s sustainability and resilience. China has substantial needs and great potentials to develop captive insurance, on account of the currency volatility, enterprises’ credit risks, and legal and operational risks of the Belt and Road initiative. Up to date, Mainland Chinese enterprises only have four offshore captives incorporated by CNOOC, Sinopec, Lenovo and CGN Power), three onshore captive insurance companies incorporated by CNPC, China Railway, and COSCO, as well as one industrial captive insurance organization - China Ship-owners Mutual Assurance Association. Its captive market grows slowly with one or two captive insurers licensed yearly after September 2011. As an international financial center, Hong Kong has comparative advantages in taxation, professionals, market access and well-established financial infrastructure to develop a functional captive insurance market. For example, Hong Kong’s income tax for an insurance company is 16.5%; while China's income tax for an insurance company is 25% plus business tax of 5%. Furthermore, restrictions on market entry and operations of China’s onshore captives make establishing offshore captives in international or regional captive insurance centers such as Singapore, Hong Kong, and other overseas jurisdictions to become attractive options. Thus, there are abundant business opportunities in this area. Using methodology of comparative studies and case analysis, this paper discusses the incorporation, regulatory issues, taxation and prospect of captive insurance market in Hong Kong, China and Singapore. Hong Kong and Singapore are both international financial centers with prominent advantages in tax concessions, technology, implementation, professional services, and well-functioning legal system. Singapore, as the domicile of 71 active captives, has been the largest captive insurance hub in Asia, as well as an established reinsurance hub. Hong Kong is an emerging captive insurance hub with 5 to 10 newly licensed captives each year, according to the Hong Kong Financial Services Development Council. It is predicted that Hong Kong will become a domicile for 50 captive insurers by 2025. This paper also compares the formation of a captive in Singapore with other jurisdictions such as Bermuda and Vermont.

Keywords: Alternative Risk Transfer (ART), captive insurance company, offshore captives, risk management, reinsurance, self-insurance fund

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792 Urban Neighborhood Center Location Evaluating Method Based On UNA the GIS Spatial Analysis Tools: Kerman's Neighborhood in Tehran Case

Authors: Sepideh Jabbari Behnam, Shadabeh Gashtasbi Iraei, Elnaz Mohsenin, MohammadAli Aghajani

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Urban neighborhoods, as important urban forming cells, play a key role in creating urban texture and integrated form. Nowadays, most of neighborhood divisions are based on urban management systems but without considering social issues and the other aspects of urban life. This can cause problems such as providing inappropriate services for city dwellers, the loss of local identity and etc. In this regard for regenerating of such neighborhoods, it is essential to locate neighborhood centers with appropriate access and services for all residents. The main objective of this article is reaching to the location of neighborhood centers in a way that, most of issues relating to the physical features (such as the form of access network and texture permeability and etc.) and other qualities such as land uses, densities and social and economic features can be done simultaneously. This paper attempts to use methods of spatial analysis in order to surveying spatial structure and space syntax of urban textures and Urban Network Analysis Systems. This can be done by one of GIS toolbars which is named UNA (Urban Network Analysis) with the use of its five functions (include: Reach, Betweenness, Gravity, Closeness, Straightness).These functions were written according to space syntax theory and offer its relating output. This paper tries to locate and evaluate the optimal location of neighborhood centers in order to create local centers. This is done through weighing of each of these functions and taking into account of spatial features.

Keywords: evaluate optimal location, Local centers, location of neighborhood centers, Spatial analysis, Urban network

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791 hsa-miR-1204 and hsa-miR-639 Prominent Role in Tamoxifen's Molecular Mechanisms on the EMT Phenomenon in Breast Cancer Patients

Authors: Mahsa Taghavi

Abstract:

In the treatment of breast cancer, tamoxifen is a regularly prescribed medication. The effect of tamoxifen on breast cancer patients' EMT pathways was studied. In this study to see if it had any effect on the cancer cells' resistance to tamoxifen and to look for specific miRNAs associated with EMT. In this work, we used continuous and integrated bioinformatics analysis to choose the optimal GEO datasets. Once we had sorted the gene expression profile, we looked at the mechanism of signaling, the ontology of genes, and the protein interaction of each gene. In the end, we used the GEPIA database to confirm the candidate genes. after that, I investigated critical miRNAs related to candidate genes. There were two gene expression profiles that were categorized into two distinct groups. Using the expression profile of genes that were lowered in the EMT pathway, the first group was examined. The second group represented the polar opposite of the first. A total of 253 genes from the first group and 302 genes from the second group were found to be common. Several genes in the first category were linked to cell death, focal adhesion, and cellular aging. Two genes in the second group were linked to cell death, focal adhesion, and cellular aging. distinct cell cycle stages were observed. Finally, proteins such as MYLK, SOCS3, and STAT5B from the first group and BIRC5, PLK1, and RAPGAP1 from the second group were selected as potential candidates linked to tamoxifen's influence on the EMT pathway. hsa-miR-1204 and hsa-miR-639 have a very close relationship with the candidates genes according to the node degrees and betweenness index. With this, the action of tamoxifen on the EMT pathway was better understood. It's important to learn more about how tamoxifen's target genes and proteins work so that we can better understand the drug.

Keywords: tamoxifen, breast cancer, bioinformatics analysis, EMT, miRNAs

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790 Culture of Primary Cortical Neurons on Hydrophobic Nanofibers Induces the Formation of Organoid-Like Structures

Authors: Nick Weir, Robert Stevens, Alan Hargreaves, Martin McGinnity, Chris Tinsley

Abstract:

Hydrophobic materials have previously demonstrated the ability to elevate cell-cell interactions and promote the formation of neural networks whilst aligned nanofibers demonstrate the ability to induce extensive neurite outgrowth in an aligned manner. Hydrophobic materials typically elicit an immune response upon implantation and thus materials used for implantation are typically hydrophilic. Poly-L-lactic acid (PLLA) is a hydrophobic, non-immunogenic, FDA approved material that can be electrospun to form aligned nanofibers. Primary rat cortical neurons cultured for 10 days on aligned PLLA nanofibers formed 3D cell clusters, approximately 800 microns in diameter. Neurites that extended from these clusters were highly aligned due to the alignment of the nanofibers they were cultured upon and fasciculation was also evident. Plasma treatment of the PLLA nanofibers prior to seeding of cells significantly reduced the hydrophobicity and abolished the cluster formation and neurite fasciculation, whilst reducing the extent and directionality of neurite outgrowth; it is proposed that hydrophobicity induces the changes to cellular behaviors. Aligned PLLA nanofibers induced the formation of a structure that mimics the grey-white matter compartmentalization that is observed in vivo and thus represents a step forward in generating organoids or biomaterial-based implants. Upon implantation into the brain, the biomaterial architectures described here may provide a useful platform for both brain repair and brain remodeling initiatives.

Keywords: hydrophobicity, nanofibers, neurite fasciculation, neurite outgrowth, PLLA

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789 Preparation and Functional Properties of Synbiotic Yogurt Fermented with Lactobacillus brevis PML1 Derived from a Fermented Cereal-Dairy Product

Authors: Farideh Tabatabei-Yazdi, Fereshteh Falah, Alireza Vasiee

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Nowadays, production of functional foods has become very essential. Inulin is one of the most functional hydrocolloid compounds used in such products. In the present study, the production of a synbiotic yogurt containing 1, 2.5, and 5% (w/v) inulin has been investigated. The yogurt was fermented with Lactobacillus brevis PML1 derived from Tarkhineh, an Iranian cereal-dairy fermented food. Furthermore, the physicochemical properties, antioxidant activity, sensory attributes, and microbial viability properties were investigated on the 0th, 7th, and 14th days of storage after fermentation. The viable cells of L. brevis PML1 reached 108 CFU/g, and the product resisted to simulated digestive juices. Moreover, the synbiotic yogurt impressively increased the production of antimicrobial compounds and had the most profound antimicrobial effect on S. typhimurium. The physiochemical properties were in the normal range, and the fat content of the synbiotic yogurt was reduced remarkably. The antioxidant capacity of the fermented yogurt was significantly increased (p<0:05), which was equal to those of DPPH (69:18±1:00%) and BHA (89:16±2:00%). The viability of L. brevis PML1 was increased during storage. Sensory analysis showed that there were significant differences in terms of the impressive parameters between the samples and the control (p<0:05). Addition of 2.5% inulin not only improved the physical properties but also retained the viability of the probiotic after 14 days of storage, in addition to the viability of L. brevis with a viability count above 6 log CFU/g in the yogurt. Therefore, a novel synbiotic product containing L. brevis PML1, which can exert the desired properties, can be used as a suitable carrier for the delivery of the probiotic strain, exerting its beneficial health effects.

Keywords: functional food, lactobacillus brevis, symbiotic yogurt, physiochemical properties

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788 Effects of Probiotics on Specific Immunity in Broiler Chicken in Syria

Authors: Moussa Majed, Omar Yaser

Abstract:

The main objective of this experiment was to study the impact of Probiotic compound on the specific immunity as the case study of infectious bursal disease. Total of 8000 one-day old Ross 108 broiler were randomly divided into two experimental groups; control group (4500 birds) and experimental group (3500 birds). Birds in two groups were reared under similar environmental conditions. Birds in control group received basal diets without probiotic whereas the birds in experimental one were fed basal diets supplemented with a commercial probiotic mixture) probiotic lacting k, which contains bacteria cells beyond to lactobacillus, Streptococcus and bifidobacterium genus that are isolated from gut microflora in healthy chickens(. The commercial probiotic were used according to the manufacturer instruction. 400 blood samples for each group were collected from wing vein every 5-7 days as interval period till 42 days old. Indirect Enzyme-Linked Immunosorbent Assay (ELISA) test was performed to detect the level of infectious bursal disease virus (IBDV) antibodies. The results clearly showed that the mean of immune titers was significantly (p= 0.03) higher in trail group than control one. The coefficient of variance percentages were 55% and 39% for control and trial groups respectively, this illustrates that homogeneity of immunity titers in the trail group was much better comparing with control group. The values of geometric means of titers in the control group and trial group were reported 3820 and 8133, respectively. The crude mortality rate in the experimental group was two times lower comparing with control group (14% and 28% respectively, p = 0.005

Keywords: probiotic, broiler chicken, infectious bursal disease, immunity, ELISA test

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787 Study of the Morpho-Sedimentary Evolution of Tidal Mouths on the Southern Fringe of the Gulf of Gabes, Southeast of Tunisia: Hydrodynamic Circulation and Associated Sedimentary Movements

Authors: Chadlia Ounissi, Maher Gzam, Tahani Hallek, Salah Mahmoudi, Mabrouk Montacer

Abstract:

This work consists of a morphological study of the coastal domain at the central fringe of the Gulf of Gabes, Southeast of Tunisia, belonging to the structural domain of the maritime Jeffara. The diachronic study of tidal mouths in the study area and the observation of morphological markers revealed the existence of hydro-sedimentary processes leading to sedimentary accumulation and filling of the estuarine system. This filling process is materialized by the genesis of a sandy cord and the lateral migration of the tidal mouth. Moreover, we have been able to affirm, by the use of satellite images, that the dominant and responsible current at this particular coastal morphology is directed to the North, having constituted a controversy on the occurrence of what is previously mentioned in the literature. The speed of the lateral displacement of the channel varies as a function of the hydrodynamic forcing. Wave-dominated sites recorded the fastest speed (18 m/year) in the image of the mouth of Wadi el Melah. Tidal dominated sites in the Wadi Zerkine satellite image recorded a very low lateral migration (2 m / year). This variation in speed indicates that the intensity of the coastal current is uneven along the coast. This general pattern of hydrodynamic circulation, to the north, of the central fringe of the Gulf of Gabes, is disturbed by hydro-sedimentary cells.

Keywords: tidal mouth, direction of current, filling, sediment transport, Gulf of Gabes

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786 Single Protoplast of Murraya paniculata L. Jack Regenerated Into Plantlets

Authors: Hasan Basri Jumin, Danil Endriand Basri

Abstract:

Isolated protoplast from embryogenic callus of orange Jessamine (Murraya paniculata L. (Jack) cultured and maintained under growth chamber at the temperature +25oC. The parameter observed are the plating efficiency, the number of spherical embryos, heard-shaped embryos-like structure, shoot formation, and plantlets obtained. Treatment was arranged with 0.0, 0.001, 0.01, 0.1 or 1.0 mg 1-1 Naphthalene acetic acid (NAA), and 0, 300, 500 mg 1/l malt extract (ME) and 0.M sorbitol in the medium with 2.5 % sucrose. Interaction between 0.001 mg/l NAA and 500 mg/l was observed the higher percentage of planting efficiency. For embryo development from callus, the media was added to 0.0 mg/l, 0.001 mg/l, 0.01 ,mg/l, 0.1 mg/l, 1.0 mg/l NAA, and 1.0 %, 2.0 %, 3.0 %, 4.0 % sucrose. Media supplemented with 0.01mg/l NAA, and 1.0% sucrose was found to be a suitable medium for the development of spherical somatic embryos. A combination of 0.1 mg/ indole acetic acid (IAA) and 0.1 mg/l zeatin constituted the spherical somatic embryo became heart-shaped embryos-like structure. A combination between GA3 0.1 mg 1/l GA3 and 0.1 mg 1-1 zeatin is looking high, growing the heart-shaped embryos-like structure to form a shoot. Cells were developed into spherical embryos and grew into heart-shaped embryos, and then spherical somatic embryos developed into shoot formation. Sequence from single protoplast to plantlets was obtained by using a low concentration of plant growth regulator and sucrose; This recovery of single protoplast to be completed plantlets is a new technology in plant cell culture, and this could be used in genetic engineering in citrus.

Keywords: heart-shaped-embryos-like-structure, Muraya-paniculata, plant-growth-regulator, spherical- somatic-embryo, single protoplast, glucose

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785 The Hepatoprotective Effects of Aquatic Extract of Levesticum Officinale against Paraquat Toxicity of Hepatocytes

Authors: Hasan Afarnegan, Ali Shahraki, Jafar Shahraki

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Paraquat is widely used as a strong nitrogen-based herbicide for controlling of weeds in agriculture. This poison is extremely toxic for humans which induces several – organ failure by accumulation in cells and many instances of death occurred due to its poisoning. Paraquat metabolized primarily in the liver. The purpose of this study was to assess the effects of aquatic extract of levisticum officinale on oxidative status and biochemical factors in hepatocytes exposed to paraquat. Our results determined that hepatocytes destruction induced by paraquat is mediated by reactive oxygen species (ROS) production, lipid peroxidation and decrease of mitochondrial membrane potential were significantly (P<0.05) prevented by aquatic extract of Levisicum officinale (100, 200 and 300 µg/ml). These effects of paraquat also prevented via antioxidants and ROS scavengers (α-tocopherol, DMSO, manitol), mitochondrial permeability transition (MPT) pore sealing compound (carnitine).MPT pore sealing compound inhibited the hepatotoxicity, indicating that paraquat induced cell death via mithochondrial pathway. Pretreatment of hepatocytes with aquatic extracts of Levisticum officinale, antioxidants and ROS scavengers also blocked hepatic cell death caused by paraquat, suggesting that oxidative stress may be directly induced decline of mithochondrial membrane potential. In conclusion, paraquat hepatotoxicity can be attributed to oxidative stress and continued by mithochondrial membrane potential disruption. Levisticum officinale aquatic extract, presumably due to its strong antoxidant properties, could protect the destructive effects of paraquat on rat hepatocytes.

Keywords: hepatocyte protection, levisticum officinale, oxidative stress, paraquat

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784 Design and Synthesis of Some Oxadiazole Bearing Benzimidazole Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

Authors: Ismail Celik, Gulgun Ayhan Kilcigil, Berna Guven, Zumra Kara, Arzu Onay-Besikci

Abstract:

Epidermal Growth Factor Receptor is the cell-surface receptor of the ErbB (erythroblastic leukemia viral oncogene homologue receptors) family of tyrosine kinases. It plays a vital role in regulating the proliferation and differentiation of cells. However, a variety of mechanisms, such as EGFR expression, mutation, and ligand-dependent receptor dimerization, are associated with the development of various activated EGFR tumors. EGFR is highly expressed in most solid tumors, including breast, head and neck cancer, non-small cell lung cancer (NSCLC), renal, ovarian, and colon cancers. Thus, specific EGFR inhibition plays one of the key roles in cancer treatment. The compounds used in the treatment as tyrosine kinase inhibitors are known to contain the benzimidazole isosterium indole, pazopanib, and axitinibin indazole rings. In addition, benzimidazoles have been shown to exhibit protein kinase inhibitory activity in addition to their different biological activities.Based on these data, it was planned and synthesized of some oxadiazole bearing benzimidazole derivatives [N-cyclohexyl-5-((2-phenyl/substitutedphenyl-1H-benzo[d]imidazole-1-yl) methyl)-1,3,4-oxadiazole-2-amine]. EGFR kinase inhibitory efficiency of the synthesized compounds was determined by comparing them with a known kinase inhibitor erlotinib in vitro, and two of the compounds bearing phenyl (19a) and 3,4-dibenzyloxyphenyl (21a) ring exhibited significant activities.

Keywords: benzimidazole, EGFR kinase inhibitory, oxadiazole, synthesis

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783 Neutron Irradiated Austenitic Stainless Steels: An Applied Methodology for Nanoindentation and Transmission Electron Microscopy Studies

Authors: P. Bublíkova, P. Halodova, H. K. Namburi, J. Stodolna, J. Duchon, O. Libera

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Neutron radiation-induced microstructural changes cause degradation of mechanical properties and the lifetime reduction of reactor internals during nuclear power plant operation. Investigating the effects of neutron irradiation on mechanical properties of the irradiated material (hardening, embrittlement) is challenging and time-consuming. Although the fast neutron spectrum has the major influence on microstructural properties, the thermal neutron effect is widely investigated owing to Irradiation-Assisted Stress Corrosion Cracking firstly observed in BWR stainless steels. In this study, 300-series austenitic stainless steels used as material for NPP's internals were examined after neutron irradiation at ~ 15 dpa. Although several nanoindentation experimental publications are available to determine the mechanical properties of ion irradiated materials, less is available on neutron irradiated materials at high dpa tested in hot-cells. In this work, we present particular methodology developed to determine the mechanical properties of neutron irradiated steels by nanoindentation technique. Furthermore, radiation-induced damage in the specimens was investigated by High Resolution - Transmission Electron Microscopy (HR-TEM) that showed the defect features, particularly Frank loops, cavity microstructure, radiation-induced precipitates and radiation-induced segregation. The results of nanoindentation measurements and associated nanoscale defect features showed the effect of irradiation-induced hardening. We also propose methodologies to optimized sample preparation for nanoindentation and microscotructural studies.

Keywords: nanoindentation, thermal neutrons, radiation hardening, transmission electron microscopy

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782 Development of Electrospun Membranes with Defined Polyethylene Collagen and Oxide Architectures Reinforced with Medium and High Intensity Statins

Authors: S. Jaramillo, Y. Montoya, W. Agudelo, J. Bustamante

Abstract:

Cardiovascular diseases (CVD) are related to affectations of the heart and blood vessels, within these are pathologies such as coronary or peripheral heart disease, caused by the narrowing of the vessel wall (atherosclerosis), which is related to the accumulation of Low-Density Lipoproteins (LDL) in the arterial walls that leads to a progressive reduction of the lumen of the vessel and alterations in blood perfusion. Currently, the main therapeutic strategy for this type of alteration is drug treatment with statins, which inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), responsible for modulating the rate of cholesterol production and other isoprenoids in the mevalonate pathway. This enzyme induces the expression of LDL receptors in the liver, increasing their number on the surface of liver cells, reducing the plasma concentration of cholesterol. On the other hand, when the blood vessel presents stenosis, a surgical procedure with vascular implants is indicated, which are used to restore circulation in the arterial or venous bed. Among the materials used for the development of vascular implants are Dacron® and Teflon®, which perform the function of re-waterproofing the circulatory circuit, but due to their low biocompatibility, they do not have the ability to promote remodeling and tissue regeneration processes. Based on this, the present research proposes the development of a hydrolyzed collagen and polyethylene oxide electrospun membrane reinforced with medium and high-intensity statins, so that in future research it can favor tissue remodeling processes from its microarchitecture.

Keywords: atherosclerosis, medium and high-intensity statins, microarchitecture, electrospun membrane

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781 Assessment of Isatin as Surface Recognition Group: Design, Synthesis and Anticancer Evaluation of Hydroxamates as Novel Histone Deacetylase Inhibitors

Authors: Harish Rajak, Kamlesh Raghuwanshi

Abstract:

Histone deacetylase (HDAC) are promising target for cancer treatment. The panobinostat (Farydak; Novartis; approved by USFDA in 2015) and chidamide (Epidaza; Chipscreen Biosciences; approved by China FDA in 2014) are the novel HDAC inhibitors ratified for the treatment of patients with multiple myeloma and peripheral T cell lymphoma, respectively. On the other hand, two other HDAC inhibitors, Vorinostat (SAHA; approved by USFDA in 2006) and Romidepsin (FK228; approved by USFDA in 2009) are already in market for the treatment of cutaneous T-cell lymphoma. Several hydroxamic acid based HDAC inhibitors i.e., belinostat, givinostat, PCI24781 and JNJ26481585 are in clinical trials. HDAC inhibitors consist of three pharmacophoric features - an aromatic cap group, zinc binding group (ZBG) and a linker chain connecting cap group to ZBG. Herein, we report synthesis, characterization and biological evaluation of HDAC inhibitors possessing substituted isatin moiety as cap group which recognize the surface of active enzyme pocket and thiosemicarbazide moiety incorporated as linker group responsible for connecting cap group to ZBG (hydroxamic acid). Several analogues were found to inhibit HDAC and cellular proliferation of Hela cervical cancer cells with GI50 values in the micro molar range. Some of the compounds exhibited promising results in vitro antiproliferative studies. Attempts were also made to establish the structure activity relationship among synthesized HDAC inhibitors.

Keywords: HDAC inhibitors, hydroxamic acid derivatives, isatin derivatives, antiproliferative activity, docking

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780 Ibrutinib and the Potential Risk of Cardiac Failure: A Review of Pharmacovigilance Data

Authors: Abdulaziz Alakeel, Roaa Alamri, Abdulrahman Alomair, Mohammed Fouda

Abstract:

Introduction: Ibrutinib is a selective, potent, and irreversible small-molecule inhibitor of Bruton's tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue (CYS-481) at the active site of Btk, leading to inhibition of Btk enzymatic activity. The drug is indicated to treat certain type of cancers such as mantle cell lymphoma (MCL), chronic lymphocytic leukaemia and Waldenström's macroglobulinaemia (WM). Cardiac failure is a condition referred to inability of heart muscle to pump adequate blood to human body organs. There are multiple types of cardiac failure including left and right-sided heart failure, systolic and diastolic heart failures. The aim of this review is to evaluate the risk of cardiac failure associated with the use of ibrutinib and to suggest regulatory recommendations if required. Methodology: Signal Detection team at the National Pharmacovigilance Center (NPC) of Saudi Food and Drug Authority (SFDA) performed a comprehensive signal review using its national database as well as the World Health Organization (WHO) database (VigiBase), to retrieve related information for assessing the causality between cardiac failure and ibrutinib. We used the WHO- Uppsala Monitoring Centre (UMC) criteria as standard for assessing the causality of the reported cases. Results: Case Review: The number of resulted cases for the combined drug/adverse drug reaction are 212 global ICSRs as of July 2020. The reviewers have selected and assessed the causality for the well-documented ICSRs with completeness scores of 0.9 and above (35 ICSRs); the value 1.0 presents the highest score for best-written ICSRs. Among the reviewed cases, more than half of them provides supportive association (four probable and 15 possible cases). Data Mining: The disproportionality of the observed and the expected reporting rate for drug/adverse drug reaction pair is estimated using information component (IC), a tool developed by WHO-UMC to measure the reporting ratio. Positive IC reflects higher statistical association while negative values indicates less statistical association, considering the null value equal to zero. The results of (IC=1.5) revealed a positive statistical association for the drug/ADR combination, which means “Ibrutinib” with “Cardiac Failure” have been observed more than expected when compared to other medications available in WHO database. Conclusion: Health regulators and health care professionals must be aware for the potential risk of cardiac failure associated with ibrutinib and the monitoring of any signs or symptoms in treated patients is essential. The weighted cumulative evidences identified from causality assessment of the reported cases and data mining are sufficient to support a causal association between ibrutinib and cardiac failure.

Keywords: cardiac failure, drug safety, ibrutinib, pharmacovigilance, signal detection

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779 Numerical Simulation of Phase Transfer during Cryosurgery for an Irregular Tumor Using Hybrid Approach

Authors: Rama Bhargava, Surabhi Nishad

Abstract:

The infusion of nanofluids has dramatically enhanced the heat-carrying capacity of the fluids, applicable to many engineering and medical process where the temperature below freezing is required. Cryosurgery is an efficient therapy for the treatment of cancer, but sometimes the excessive cooling may harm the nearby healthy cells. Efforts are therefore done to develop a model which can cause to generate the low temperature as required. In the present study, a mathematical model is developed based on the bioheat transfer equation to simulate the heat transfer from the probe on a tumor (with irregular domain) using the hybrid technique consisting of element free Galerkin method with αα-family of approximation. The probe is loaded will nano-particles. The effects of different nanoparticles, namely Al₂O₃, Fe₃O₄, Au on the heat-producing rate, is obtained. It is observed that the temperature can be brought to (60°C)-(-30°C) at a faster freezing rate on the infusion of different nanoparticles. Besides increasing the freezing rate, the volume of the nanoparticle can also control the size and growth of ice crystals formed during the freezing process. The study is also made to find the time required to achieve the desired temperature. The problem is further extended for multi tumors of different shapes and sizes. The irregular shape of the frozen domain and the direction of ice growth are very sensitive issues, posing a challenge for simulation. The Meshfree method has been one of the accurate methods in such problems as a domain is naturally irregular. The discretization is done using the nodes only. MLS approximation is taken in order to generate the shape functions. Sufficiently accurate results are obtained.

Keywords: cryosurgery, EFGM, hybrid, nanoparticles

Procedia PDF Downloads 105