Search results for: product life cycle assessment
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 16409

Search results for: product life cycle assessment

13649 Enhancing the Structural and Electrochemical Performance of Li-Rich Layered Metal Oxides Cathodes for Li-Ion Battery by Coating with the Active Material

Authors: Cyril O. Ehi-Eromosele, Ajayi Kayode

Abstract:

The Li-rich layered metal oxides (LLO) are the most promising candidates for promising electrodes of high energy Li-ion battery (LIB). In literature, these electrode system has either been designed as a hetero-structure of the primary components (composite) or as a core-shell structure with improved electrochemistry reported for both configurations when compared with its primary components. With the on-going efforts to improve on the electrochemical performance of the LIB, it is important to investigate comparatively the structural and electrochemical characteristics of the core-shell like and ‘composite’ forms of these materials with the same compositions and synthesis conditions which could influence future engineering of these materials. Therefore, this study concerns the structural and electrochemical properties of the ‘composite’ and core-shell like LLO cathode materials with the same nominal composition of 0.5Li₂MnO₃-0.5LiNi₀.₅Mn₀.₃Co₀.₂O₂ (LiNi₀.₅Mn₀.₃Co₀.₂O₂ as core and Li₂MnO₃ as the shell). The results show that the core-shell sample (–CS) gave better electrochemical performance than the ‘composite’ sample (–C). Both samples gave the same initial charge capacity of ~300 mAh/g when cycled at 10 mA/g and comparable charge capacity (246 mAh/g for the –CS sample and 240 mAh/g for the –C sample) when cycled at 200 mA/g. However, the –CS sample gave a higher initial discharge capacity at both current densities. The discharge capacity of the –CS sample was 232 mAh/g and 164 mAh/g while the –C sample is 208 mAh/g and 143 mAh/g at the current densities of 10 mA/g and 200 mA/g, respectively. Electrochemical impedance spectroscopy (EIS) results show that the –CS sample generally exhibited a smaller resistance than the –C sample both for the uncycled and after 50th cycle. Detailed structural analysis is on-going, but preliminary results show that the –CS sample had bigger unit cell volume and a higher degree of cation mixing. The thermal stability of the –CS sample was higher than the –C sample. XPS investigation also showed that the pristine –C sample gave a more reactive surface (showing formation of carbonate species to a greater degree) which could result in the greater resistance seen in the EIS result. To reinforce the results obtained for the 0.5Li₂MnO₃-0.5LiNi₀.₅Mn₀.₃Co₀.₃O₂ composition, the same investigations were extended to another ‘composite’ and core-shell like LLO cathode materials also with the same nominal composition of 0.5Li₂MnO₃-0.5LiNi₀.₃Mn₀.₃Co₀.₃O₂. In this case, the aim was to determine the electrochemical performance of the material using a low Ni content (LiNi₀.₃Mn₀.₃Co₀.₃O₂) as the core to clarify the contributions of the core-shell configuration to the electrochemical performance of these materials. Ni-rich layered oxides show active catalytic surface leading to electrolyte oxidation resulting in poor thermal stability and cycle life. Here, the core-shell sample also gave better electrochemical performance than the ‘composite’ sample with 0.5Li₂MnO₃-0.5LiNi₀.₃Mn₀.₃Co₀.₃O₂ composition. Furthermore, superior electrochemical performance was also recorded for the core-shell like spinel modified LLO (0.5Li₂MnO₃-0.45LiNi₀.₅Mn₀.₃Co₀.₂O₂-0.05LiNi₀.₅Mn₁.₅O₄) when compared to the composite system. These results show that the core-shell configuration can generally be used to improve the structural and electrochemical properties of the LLO and spinel modified LLO materials.

Keywords: lithium-ion battery, lithium rich oxide cathode, core-shell structure, composite structure

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13648 Framework for Performance Measure of Super Resolution Imaging

Authors: Varsha Hemant Patil, Swati A. Bhavsar, Abolee H. Patil

Abstract:

Image quality assessment plays an important role in image evaluation. This paper aims to present an investigation of classic techniques in use for image quality assessment, especially for super-resolution imaging. Researchers have contributed a lot towards the development of super-resolution imaging techniques. However, not much attention is paid to the development of metrics for testing the performance of developed techniques. In this paper, the study report of existing image quality measures is given. The paper classifies reviewed approaches according to functionality and suitability for super-resolution imaging. Probable modifications and improvements of these to suit super-resolution imaging are presented. The prime goal of the paper is to provide a comprehensive reference source for researchers working towards super-resolution imaging and suggest a better framework for measuring the performance of super-resolution imaging techniques.

Keywords: interpolation, MSE, PSNR, SSIM, super resolution

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13647 Stability Indicating RP – HPLC Method Development, Validation and Kinetic Study for Amiloride Hydrochloride and Furosemide in Pharmaceutical Dosage Form

Authors: Jignasha Derasari, Patel Krishna M, Modi Jignasa G.

Abstract:

Chemical stability of pharmaceutical molecules is a matter of great concern as it affects the safety and efficacy of the drug product.Stability testing data provides the basis to understand how the quality of a drug substance and drug product changes with time under the influence of various environmental factors. Besides this, it also helps in selecting proper formulation and package as well as providing proper storage conditions and shelf life, which is essential for regulatory documentation. The ICH guideline states that stress testing is intended to identify the likely degradation products which further help in determination of the intrinsic stability of the molecule and establishing degradation pathways, and to validate the stability indicating procedures. A simple, accurate and precise stability indicating RP- HPLC method was developed and validated for simultaneous estimation of Amiloride Hydrochloride and Furosemide in tablet dosage form. Separation was achieved on an Phenomenexluna ODS C18 (250 mm × 4.6 mm i.d., 5 µm particle size) by using a mobile phase consisting of Ortho phosphoric acid: Acetonitrile (50:50 %v/v) at a flow rate of 1.0 ml/min (pH 3.5 adjusted with 0.1 % TEA in Water) isocratic pump mode, Injection volume 20 µl and wavelength of detection was kept at 283 nm. Retention time for Amiloride Hydrochloride and Furosemide was 1.810 min and 4.269 min respectively. Linearity of the proposed method was obtained in the range of 40-60 µg/ml and 320-480 µg/ml and Correlation coefficient was 0.999 and 0.998 for Amiloride hydrochloride and Furosemide, respectively. Forced degradation study was carried out on combined dosage form with various stress conditions like hydrolysis (acid and base hydrolysis), oxidative and thermal conditions as per ICH guideline Q2 (R1). The RP- HPLC method has shown an adequate separation for Amiloride hydrochloride and Furosemide from its degradation products. Proposed method was validated as per ICH guidelines for specificity, linearity, accuracy; precision and robustness for estimation of Amiloride hydrochloride and Furosemide in commercially available tablet dosage form and results were found to be satisfactory and significant. The developed and validated stability indicating RP-HPLC method can be used successfully for marketed formulations. Forced degradation studies help in generating degradants in much shorter span of time, mostly a few weeks can be used to develop the stability indicating method which can be applied later for the analysis of samples generated from accelerated and long term stability studies. Further, kinetic study was also performed for different forced degradation parameters of the same combination, which help in determining order of reaction.

Keywords: amiloride hydrochloride, furosemide, kinetic study, stability indicating RP-HPLC method validation

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13646 A Finite Elements Model for the Study of Buried Pipelines Affected by Strike-Slip Fault

Authors: Reza Akbari, Jalal MontazeriFashtali, PeymanMomeni Taromsari

Abstract:

Pipeline systems, play an important role as a vital element in reducing or increasing the risk of earthquake damage and vulnerability. Pipelines are suitable, cheap, fast, and safe routes for transporting oil, gas, water, sewage, etc. The sepipelines must pass from a wide geographical area; hence they will structurally face different environmental and underground factors of earthquake forces’ effect. Therefore, structural engineering analysis and design for this type of lines requires the understanding of relevant parameters behavior and lack of familiarity with them can cause irreparable damages and risks to design and execution, especially in the face of earthquakes. Today, buried pipelines play an important role in human life cycle, thus, studying the vulnerability of pipeline systems is of particular importance. This study examines the behavior of buried pipelines affected by strike-slip fault. Studied fault is perpendicular to the tube axis and causes stress and deformation in the tube by sliding horizontally. In this study, the pipe-soil interaction is accurately simulated, so that one can examine the large displacements and strains, nonlinear material behavior and contact and friction conditions of soil and pipe. The results can be used for designing buried pipes and determining the amount of fault displacement that causes the failure of the buried pipes.

Keywords: pipe lines , earthquake , fault , soil-fault interaction

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13645 Design and Implementation of Control System in Underwater Glider of Ganeshblue

Authors: Imam Taufiqurrahman, Anugrah Adiwilaga, Egi Hidayat, Bambang Riyanto Trilaksono

Abstract:

Autonomous Underwater Vehicle glider is one of the renewal of underwater vehicles. This vehicle is one of the autonomous underwater vehicles that are being developed in Indonesia. Glide ability is obtained by controlling the buoyancy and attitude of the vehicle using the movers within the vehicle. The glider motion mechanism is expected to provide energy resistance from autonomous underwater vehicles so as to increase the cruising range of rides while performing missions. The control system on the vehicle consists of three parts: controlling the attitude of the pitch, the buoyancy engine controller and the yaw controller. The buoyancy and pitch controls on the vehicle are sequentially referring to the finite state machine with pitch angle and depth of diving inputs to obtain a gliding cycle. While the yaw control is done through the rudder for the needs of the guide system. This research is focused on design and implementation of control system of Autonomous Underwater Vehicle glider based on PID anti-windup. The control system is implemented on an ARM TS-7250-V2 device along with a mathematical model of the vehicle in MATLAB using the hardware-in-the-loop simulation (HILS) method. The TS-7250-V2 is chosen because it complies industry standards, has high computing capability, minimal power consumption. The results show that the control system in HILS process can form glide cycle with depth and angle of operation as desired. In the implementation using half control and full control mode, from the experiment can be concluded in full control mode more precision when tracking the reference. While half control mode is considered more efficient in carrying out the mission.

Keywords: control system, PID, underwater glider, marine robotics

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13644 Admission Control Policy for Remanufacturing Activities with Quality Variation of Returns

Authors: Sajjad Farahani, Wilkistar Otieno, Xiaohang Yue

Abstract:

This paper develops a model for the optimal disposition decision for product returns in a remanufacturing system with limited recoverable inventory capacity. In this model, a constant demand is satisfied by remanufacturing returned products which are up to the minimum required quality grade. The quality grade of returned products is uncertain and remanufacturing cost increases as the quality level decreases, and remanufacturer wishes to determine which returned product to accept to be remanufactured for reselling, and any unaccepted returns may be salvaged at a value that increases with their quality level. Accepted returns can be stocked for remanufacturing upon demand requests, but incur a holding cost. A Markov decision problem is formulated in order to evaluate various performance measures for this system and obtain the optimal remanufacturing policy. A detailed numerical study reveals that our approach to the disposition problem outperforms the current industrial practice ignoring quality grade of returned products. In addition, we identify conditions under which this improvement is the highest.

Keywords: green supply chain management, matrix geometric method, production recovery, reverse supply chains

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13643 Aftershock Collapse Capacity Assessment of Mid-Rise Steel Moment Frames Subjected to As-Recorded Mainshock-Aftershock

Authors: Mohammadmehdi Torfehnejada, Serhan Senso

Abstract:

Aftershock collapse capacity of Special Steel Moment Frames (SSMFs) is evaluated under aftershock earthquakes by considering building heights 8 and 12 stories. The assessment evaluates the residual collapse capacity under aftershock excitation when various levels of damage have been induced by the mainshock. For this purpose, incremental dynamic analysis (IDA) under aftershock follows the mainshock imposing the intended damage level. The study results indicate that aftershock collapse capacity of this structure may decrease remarkably when the structure is subjected to large mainshock damage. The capacity reduction under aftershock is finally related to the mainshock damage level through regression equations.

Keywords: aftershock collapse capacity, special steel moment frames, mainshock-aftershock sequences, incremental dynamic analysis, mainshock damage

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13642 Neighborhood Sustainability Assessment Tools: A Conceptual Framework for Their Use in Building Adaptive Capacity to Climate Change

Authors: Sally Naji, Julie Gwilliam

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Climate change remains a challenging matter for the human and the built environment in the 21st century, where the need to consider adaptation to climate change in the development process is paramount. However, there remains a lack of information regarding how we should prepare responses to this issue, such as through developing organized and sophisticated tools enabling the adaptation process. This study aims to build a systematic framework approach to investigate the potentials that Neighborhood Sustainability Assessment tools (NSA) might offer in enabling both the analysis of the emerging adaptive capacity to climate change. The analysis of the framework presented in this paper aims to discuss this issue in three main phases. The first part attempts to link sustainability and climate change, in the context of adaptive capacity. It is argued that in deciding to promote sustainability in the context of climate change, both the resilience and vulnerability processes become central. However, there is still a gap in the current literature regarding how the sustainable development process can respond to climate change. As well as how the resilience of practical strategies might be evaluated. It is suggested that the integration of the sustainability assessment processes with both the resilience thinking process, and vulnerability might provide important components for addressing the adaptive capacity to climate change. A critical review of existing literature is presented illustrating the current lack of work in this field, integrating these three concepts in the context of addressing the adaptive capacity to climate change. The second part aims to identify the most appropriate scale at which to address the built environment for the climate change adaptation. It is suggested that the neighborhood scale can be considered as more suitable than either the building or urban scales. It then presents the example of NSAs, and discusses the need to explore their potential role in promoting the adaptive capacity to climate change. The third part of the framework presents a comparison among three example NSAs, BREEAM Communities, LEED-ND, and CASBEE-UD. These three tools have been selected as the most developed and comprehensive assessment tools that are currently available for the neighborhood scale. This study concludes that NSAs are likely to present the basis for an organized framework to address the practical process for analyzing and yet promoting Adaptive Capacity to Climate Change. It is further argued that vulnerability (exposure & sensitivity) and resilience (Interdependence & Recovery) form essential aspects to be addressed in the future assessment of NSA’s capability to adapt to both short and long term climate change impacts. Finally, it is acknowledged that further work is now required to understand impact assessment in terms of the range of physical sectors (Water, Energy, Transportation, Building, Land Use and Ecosystems), Actor and stakeholder engagement as well as a detailed evaluation of the NSA indicators, together with a barriers diagnosis process.

Keywords: adaptive capacity, climate change, NSA tools, resilience, sustainability

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13641 Evaluation of the Power Generation Effect Obtained by Inserting a Piezoelectric Sheet in the Backlash Clearance of a Circular Arc Helical Gear

Authors: Barenten Suciu, Yuya Nakamoto

Abstract:

Power generation effect, obtained by inserting a piezo- electric sheet in the backlash clearance of a circular arc helical gear, is evaluated. Such type of screw gear is preferred since, in comparison with the involute tooth profile, the circular arc profile leads to reduced stress-concentration effects, and improved life of the piezoelectric film. Firstly, geometry of the circular arc helical gear, and properties of the piezoelectric sheet are presented. Then, description of the test-rig, consisted of a right-hand thread gear meshing with a left-hand thread gear, and the voltage measurement procedure are given. After creating the tridimensional (3D) model of the meshing gears in SolidWorks, they are 3D-printed in acrylonitrile butadiene styrene (ABS) resin. Variation of the generated voltage versus time, during a meshing cycle of the circular arc helical gear, is measured for various values of the center distance. Then, the change of the maximal, minimal, and peak-to-peak voltage versus the center distance is illustrated. Optimal center distance of the gear, to achieve voltage maximization, is found and its significance is discussed. Such results prove that the contact pressure of the meshing gears can be measured, and also, the electrical power can be generated by employing the proposed technique.

Keywords: circular arc helical gear, contact problem, optimal center distance, piezoelectric sheet, power generation

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13640 Comparison of Catalyst Support for High Pressure Reductive Amination

Authors: Tz-Bang Du, Cheng-Han Hsieh, Li-Ping Ju, Hung-Jie Liou

Abstract:

Polyether amines synthesize by secondary hydroxyl polyether diol play an important role in epoxy hardener. The low molecular weight product is used in low viscosity and high transparent polyamine product for the logo, ground cover, especially for wind turbine blade, while the high molecular weight products are used in advanced agricultures such as a high-speed railway. High-pressure reductive amination process is required for producing these amines. In the condition of higher than 150 atm pressure and 200 degrees Celsius temperature, supercritical ammonia is used as a reactant and also a solvent. It would be a great challenge to select a catalyst support for such high-temperature alkaline circumstance. In this study, we have established a six-autoclave-type (SAT) high-pressure reactor for amination catalyst screening, which six experiment conditions with different temperature and pressure could be examined at the same time. We synthesized copper-nickel catalyst on different shaped alumina catalyst support and evaluated the catalyst activity for high-pressure reductive amination of polypropylene glycol (PPG) by SAT reactor. Ball type gamma alumina, ball type activated alumina and pellet type gamma alumina catalyst supports are evaluated in this study. Gamma alumina supports have shown better activity on PPG reductive amination than activated alumina support. In addition, the catalysts are evaluated in fixed bed reactor. The diamine product was successfully synthesized via this catalyst and the strength of the catalysts is measured. The crush strength of blank supports is about 13.5 lb for both gamma alumina and activated alumina. The strength increases to 20.3 lb after synthesized to be copper-nickel catalyst. After test in the fixed bed high-pressure reductive amination process for 100 hours, the crush strength of the used catalyst is 3.7 lb for activated alumina support, 12.0 lb for gamma alumina support. The gamma alumina is better than activated alumina to use as catalyst support in high-pressure reductive amination process.

Keywords: high pressure reductive amination, copper nickel catalyst, polyether amine, alumina

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13639 Research Facility Assessment for Biomass Combustion in Moving Grate Furnaces

Authors: Francesco Gallucci, Mariangela Salerno, Ettore Guerriero, Manfredi Amalfi, Giancarlo Chiatti, Fulvio Palmieri

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The paper deals with the experimental activities on a biomass combustion test-bed. More in detail, experimental campaigns have been devoted to investigate the operation of a biomass moving grate furnace. A research-oriented facility based on a moving grate furnace (350kW) has been set up in order to perform experimental activities in a wide range of test configurations. The paper reports the description of the complete biomass-plant and the assessment of the system operation. As the first step, the chemical and physical properties of the used wooden biomass have been preliminarily investigated. Once the biomass fuel has been characterized, investigations have been devoted to point out the operation of the furnace. It has been operated at full load, highlighting the influence of biomass combustion parameters on particulate matter and gaseous emission.

Keywords: biomass, combustion, experimental, pollutants

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13638 Study of Regulation and Registration Law of Veterinary Biological Drugs in Iran and Comparison between FDA, EMA and WHO

Authors: Hoda Dehghani, Zahra Dehghani

Abstract:

Considering the obvious growth and variety of veterinary biological product and increase consumption and also the price, it is necessary to establish the rules and serious monitoring of this products which are less expensive than the original products. The scope of this research is the study of comparing the registration criteria and procedures of veterinary biological drugs in the world's leading agencies such as EMA, FDA, and WHO. For this, purpose the rules and regulations for registration of these drugs in prestigious organizations such as the FDA, EMA and WHO were examined and compared with the existing legislation in Iran. Studies show that EMA is the forefront of the compilation and registration of drugs in the world. China is a one of the greatest country in the development of drugs and establishes very closely guidelines with creditable global guidelines, and Now, is the first country to implement the rules codified in the Far East and followed by china, India and, South Korea and Taiwan have taken incorporate the industry's top ranking in Asia. At now, Asia by creating appropriate indicators not only as a powerful center in the field of drug delivery but also as a competitor to the United States is a major source of drug discovery and creation of innovation. the activities such as clinical trials and pharmaceutical investment is the speed of technology on the continent.

Keywords: veterinary biological product, regulation of registration, biological products, regularity authorities

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13637 A Dynamic Model for Assessing the Advanced Glycation End Product Formation in Diabetes

Authors: Victor Arokia Doss, Kuberapandian Dharaniyambigai, K. Julia Rose Mary

Abstract:

Advanced Glycation End (AGE) products are the end products due to the reaction between excess reducing sugar present in diabetes and free amino group in protein lipids and nucleic acids. Thus, non-enzymic glycation of molecules such as hemoglobin, collagen, and other structurally and functionally important proteins add to the pathogenic complications such as diabetic retinopathy, neuropathy, nephropathy, vascular changes, atherosclerosis, Alzheimer's disease, rheumatoid arthritis, and chronic heart failure. The most common non-cross linking AGE, carboxymethyl lysine (CML) is formed by the oxidative breakdown of fructosyllysine, which is a product of glucose and lysine. CML is formed in a wide variety of tissues and is an index to assess the extent of glycoxidative damage. Thus we have constructed a mathematical and computational model that predicts the effect of temperature differences in vivo, on the formation of CML, which is now being considered as an important intracellular milieu. This hybrid model that had been tested for its parameter fitting and its sensitivity with available experimental data paves the way for designing novel laboratory experiments that would throw more light on the pathological formation of AGE adducts and in the pathophysiology of diabetic complications.

Keywords: advanced glycation end-products, CML, mathematical model, computational model

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13636 Factors Relating to Travel Behavior at the Floating Market of Thai Tourists

Authors: Siri-orn Champatong

Abstract:

The purpose of this research was to study factors that were related with travel behaviors of Thai tourists at the Ayothaya Floating Market, Phra Nakhon Sri Ayutthaya. The quantitative research was conducted with 400 samples of Thai tourists traveling to the Ayothaya Floating Market. The Questionnaire was a tool used to collect data, and the statistics used for data analysis were mean and Pearson product moment correlation coefficient. The results found that Thai tourists focused on attraction, easy access and facilities of the tourist spot at a high level. In addition, they gave priority to the marketing mix in the dimension of products, price, and distribution channels at a high level as well. For marketing promotion, it was at the moderate level. The results of hypothesis testing revealed that factors related to the attractions of the tourist destination, easy access to the tourist destination, the facilities of the tourist spot, and product and price of the marketing mix were associated with travel behaviors in the aspect of the number of visits used and the budget on tourism.

Keywords: floating market, marketing mix, tourism attractions, travelling behavior

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13635 Bioaccessible Phenolics, Phenolic Bioaccessibility and Antioxidant Activity of Pumpkin Flour

Authors: Emine Aydin, Duygu Gocmen

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Pumpkin flour (PF) has a long shelf life and can be used as a nutritive, functional (antioxidant properties, phenolic contents, etc.) and coloring agent in many food items, especially in bakery products, sausages, instant noodles, pasta and flour mixes. Pre-treatment before drying is one of the most important factors affecting the quality of a final powdered product. Pretreatment, such as soaking in a bisulfite solution, provides that total carotenoids in raw materials rich in carotenoids, especially pumpkins, are retained in the dried product. This is due to the beneficial effect of antioxidant additives in the protection of carotenoids in the dehydrated plant foods. The oxygen present in the medium is removed by the radical SO₂, and thus the carotene degradation caused by the molecular oxygen is inhibited by the presence of SO₂. In this study, pumpkin flours (PFs) produced by two different applications (with or without metabisulfite pre-treatment) and then dried in a freeze dryer. The phenolic contents and antioxidant activities of pumpkin flour were determined. In addition to this, the compound of bioavailable phenolic substances which is obtained by PF has also been investigated using in vitro methods. As a result of researches made in recent years, it has been determined that all nutrients taken with foodstuffs are not bioavailable. Bioavailability changes depending on physical properties, chemical compounds, and capacities of individual digestion of foods. Therefore in this study; bioaccessible phenolics and phenolic bioaccessibility were also determined. The phenolics of the samples with metabisulfite application were higher than those of the samples without metabisulfite pre-treatment. Soaking in metabisulfite solution might have a protective effect for phenolic compounds. Phenolics bioaccessibility of pumpkin flours was investigated in order to assess pumpkin flour as sources of accessible phenolics. The higher bioaccessible phenolics (384.19 mg of GAE 100g⁻¹ DW) and phenolic bioaccessibility values (33.65 mL 100 mL⁻¹) were observed in the pumpkin flour with metabisulfite pre-treatment. Metabisulfite application caused an increase in bioaccessible phenolics of pumpkin flour. According to all assay (ABTS, CUPRAC, DPPH, and FRAP) results, both free and bound phenolics of pumpkin flour with metabisulfite pre-treatment had higher antioxidant activity than those of the sample without metabisulfite pre-treatment. The samples subjected to MS pre-treatment exhibited higher antioxidant activities than those of the samples without MS pre-treatment, this possibly due to higher phenolic contents of the samples with metabisulfite applications. As a result, metabisulfite application caused an increase in phenolic contents, bioaccessible phenolics, phenolic bioaccessibility and antioxidant activities of pumpkin flour. It can be said that pumpkin flour can be used as an alternative functional and nutritional ingredient in bakery products, dairy products (yoghurt, ice-cream), soups, sauces, infant formulae, confectionery, etc.

Keywords: pumpkin flour, bioaccessible phenolics, phenolic bioaccessibility, antioxidant activity

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13634 Death Anxiety, Quality of Life, and Self-Esteem of the Elderly in Surat Thani Province, Thailand

Authors: W. Phokhwang-Just, A. Saraketrin, P. Thongpet, J. Udomkitpipat, J. Kaewsakulthong

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The more people get older and live longer, the more health problems they may have. This cross-sectional study aims to study a correlation between death anxiety, quality of life, and self-esteem as well as factors affecting these variables in the elderly living in Surat Thani Province, Thailand. Of 382 elderly people, who were proportionally sampled from 19 districts in Surat Thani Province, 256 (67%) already returned the questionnaires. The Thai version of Templer’s Death Anxiety, Quality of Life (WHO-BREF), and of Rosenberg’s Self-Esteem Questionnaires were employed. The result showed that the samples had a mean age of 72 years old, 53% were female, 62% were married, 61% graduated with primary-school, and 61% had at least one chronic disease Approximately, 19% of them had 3 diseases. The quality of life (QOL), self-esteem (SE), and death anxiety (DA) of samples were in moderate (n= 91, mean = 86.89, SD = 15.47), high (n = 138, mean = 29.33, SD=4.77), and low level (n= 85, mean = 6.23, SD= 3.65), respectively. The QOL was not significantly different between male and female as well as among different marital status. The female elderly had more DA and less SE than male (t= 2.095, df = 83; t =-3.258, df =135, respectively, p < 0.05). The female elderly, who were separated or widow, had a higher level of DA than did the married elderly (LSD: p < 0.05). The married elderly had a higher level of SE than did the separated, widowed (Tukey HSD, LSD: p < 0.05), or single elderly (LSD: p < 0.05). The more diseases the elderly got, the lower level of QOL they had (r = -0.335, p < 0.05). The QOL was significantly correlated with SE (r =0.434, p < 0.05), but not significantly related to DA (r = -0.200, p = 0.069). The lower level of SE the elderly had, the higher level of DA they become (r = -2.71, p < 0.05). In order to promote the QOL, the SE of the elderly should be enhanced. Consequently, the DA can be minimized. Healthcare providers should provide care that promotes QOL, SE, and reduces DA of the elderly, especially those, who are female, single, and separated or widowed as well as those, who have more diseases than the others

Keywords: death anxiety, quality of life, self-esteem, elderly

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13633 Managing Uncertainty in Unmanned Aircraft System Safety Performance Requirements Compliance Process

Authors: Achim Washington, Reece Clothier, Jose Silva

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System Safety Regulations (SSR) are a central component to the airworthiness certification of Unmanned Aircraft Systems (UAS). There is significant debate on the setting of appropriate SSR for UAS. Putting this debate aside, the challenge lies in how to apply the system safety process to UAS, which lacks the data and operational heritage of conventionally piloted aircraft. The limited knowledge and lack of operational data result in uncertainty in the system safety assessment of UAS. This uncertainty can lead to incorrect compliance findings and the potential certification and operation of UAS that do not meet minimum safety performance requirements. The existing system safety assessment and compliance processes, as used for conventional piloted aviation, do not adequately account for the uncertainty, limiting the suitability of its application to UAS. This paper discusses the challenges of undertaking system safety assessments for UAS and presents current and envisaged research towards addressing these challenges. It aims to highlight the main advantages associated with adopting a risk based framework to the System Safety Performance Requirement (SSPR) compliance process that is capable of taking the uncertainty associated with each of the outputs of the system safety assessment process into consideration. Based on this study, it is made clear that developing a framework tailored to UAS, would allow for a more rational, transparent and systematic approach to decision making. This would reduce the need for conservative assumptions and take the risk posed by each UAS into consideration while determining its state of compliance to the SSR.

Keywords: Part 1309 regulations, risk models, uncertainty, unmanned aircraft systems

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13632 Amniotic Fluid Mesenchymal Stem Cells Selected for Neural Specificity Ameliorates Chemotherapy Induced Hearing Loss and Pain Perception

Authors: Jan F. Talts, Amit Saxena, Kåre Engkilde

Abstract:

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by anti-neoplastic agents, with a prevalence from 19 % to 85 %. Clinically, CIPN is a mostly sensory neuropathy leading to pain and to motor and autonomic changes. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors, especially because currently, there is no single effective method of preventing CIPN. Hearing loss is the most common form of sensory impairment in humans and can be caused by ototoxic chemical compounds such as chemotherapy (platinum-based antineoplastic agents).In rodents, single or repeated cisplatin injections induce peripheral neuropathy and hearing impairment mimicking human disorder, allowing studying the efficacy of new pharmacological candidates in chemotherapy-induced hearing loss and peripheral neuropathy. RNA sequencing data from full term amniotic fluid (TAF) mesenchymal stemcell (MSC) clones was used to identify neural-specific markers present on TAF-MSC. Several prospective neural markers were tested by flow cytometry on cultured TAF-MSC. One of these markers was used for cell-sorting using Tyto MACSQuant cell sorter, and the neural marker positive cell population was expanded for several passages to the final therapeutic product stage. Peripheral neuropathy and hearing loss was induced in mice by administration of cisplatin in three week-long cycles. The efficacy of neural-specific TAF-MSC in treating hearing loss and pain perception was evaluated by administration of three injections of 3 million cells/kg by intravenous route or three injections of 3 million cells/kg by intra-arterial route after each cisplatin cycle treatment. Auditory brainstem responses (ABR) are electric potentials recorded from scalp electrodes, and the first ABR wave represents the summed activity of the auditory nerve fibers contacting the inner hair cells. For ABR studies, mice were anesthetized, then earphones were placed in the left ear of each mouse, an active electrode was placed in the vertex of the skull, a reference electrode under the skin of the mastoid bone, and a ground electrode in the neck skin. The stimuli consisted of tone pips of five frequencies (2, 4, 6, 12, 16, and 24 kHz) at various sound levels (from 0 to 90 dB) ranging to cover the mouse auditory frequency range. The von Frey test was used to assess the onset and maintenance of mechanical allodynia over time. Mice were placed in clear plexiglass cages on an elevated mesh floor and tested after 30 min of habituation. Mechanical paw withdrawal threshold was examined using an electronic von Frey anesthesiometer. Cisplatin groups treated with three injections of 3 million cells/kg by intravenous route and three injections of 3 million cells/kg by intra-arterial route after each cisplatin cycle treatment presented, a significant increase of hearing acuity characterized by a decrease of ABR threshold and a decrease of neuropathic pain characterized by an increase of von Frey paw withdrawal threshold compared to controls only receiving cisplatin. This study shows that treatment with MSCselected for neural specificity presents significant positive efficacy on the chemotherapy-induced neuropathic pain and the chemotherapy-induced hearing loss.

Keywords: mesenchymal stem cell, peripheral neuropathy, amniotic fluid, regenerative medicine

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13631 Allylation of Active Methylene Compounds with Cyclic Baylis-Hillman Alcohols: Why Is It Direct and Not Conjugate?

Authors: Karim Hrratha, Khaled Essalahb, Christophe Morellc, Henry Chermettec, Salima Boughdiria

Abstract:

Among the carbon-carbon bond formation types, allylation of active methylene compounds with cyclic Baylis-Hillman (BH) alcohols is a reliable and widely used method. This reaction is a very attractive tool in organic synthesis of biological and biodiesel compounds. Thus, in view of an insistent and peremptory request for an efficient and straightly method for synthesizing the desired product, a thorough analysis of various aspects of the reaction processes is an important task. The product afforded by the reaction of active methylene with BH alcohols depends largely on the experimental conditions, notably on the catalyst properties. All experiments reported that catalysis is needed for this reaction type because of the poor ability of alcohol hydroxyl group to be as a suitable leaving group. Within the catalysts, several transition- metal based have been used such as palladium in the presence of acid or base and have been considered as reliable methods. Furthemore, acid catalysts such as BF3.OEt2, BiX3 (X= Cl, Br, I, (OTf)3), InCl3, Yb(OTf)3, FeCl3, p-TsOH and H-montmorillonite have been employed to activate the C-C bond formation through the alkylation of active methylene compounds. Interestingly a report of a smoothly process for the ability of 4-imethyaminopyridine(DMAP) to catalyze the allylation reaction of active methylene compounds with cyclic Baylis-Hillman (BH) alcohol appeared recently. However, the reaction mechanism remains ambiguous, since the C- allylation process leads to an unexpected product (noted P1), corresponding to a direct allylation instead of conjugate allylation, which involves the most electrophilic center according to the electron withdrawing group CO effect. The main objective of the present theoretical study is to better understand the role of the DMAP catalytic activity as well as the process leading to the end- product (P1) for the catalytic reaction of a cyclic BH alcohol with active methylene compounds. For that purpose, we have carried out computations of a set of active methylene compounds varying by R1 and R2 toward the same alcohol, and we have attempted to rationalize the mechanisms thanks to the acid–base approach, and conceptual DFT tools such as chemical potential, hardness, Fukui functions, electrophilicity index and dual descriptor, as these approaches have shown a good prediction of reactions products.The present work is then organized as follows: In a first part some computational details will be given, introducing the reactivity indexes used in the present work, then Section 3 is dedicated to the discussion of the prediction of the selectivity and regioselectivity. The paper ends with some concluding remarks. In this work, we have shown, through DFT method at the B3LYP/6-311++G(d,p) level of theory that: The allylation of active methylene compounds with cyclic BH alcohol is governed by orbital control character. Hence the end- product denoted P1 is generated by direct allylation.

Keywords: DFT calculation, gas phase pKa, theoretical mechanism, orbital control, charge control, Fukui function, transition state

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13630 Housing First, Not Housing Only: The Life Skills Project

Authors: Sara Cumming, Julianne DiSanto, Leah Burton

Abstract:

Homelessness in Canada is a persistent problem. It has been widely argued that the best tactic for eradicating homelessness is to approach social issues from a Housing First perspective—an approach that centers on quickly moving people into permanent and independent housing and then providing them additional support and services as needed. It is recognized that life skills training is both necessary and an effective way to reduce cyclical homelessness; however, there is a scarcity of research on effective ways to teach life skills; this problem was exacerbated in a pandemic context, where in-person delivery was severely restricted or no longer possible. Very little attention has been paid to the diverse cultural needs of clients in a multicultural context and the need to foster cultural knowledge/awareness in individuals to successfully contribute to the cultural safety of communities. This research attempts to fill these gaps in the literature and in practice by employing a community-engaged research (CER) approach. Academic, government, funders, front-line staff, and clients at 15 not-for-profits from across the Greater Toronto Area in Ontario, Canada, collaborated to co-create a virtual, client-centric, equity, diversity, and inclusion (EDI) informed life skill learning management system. We employed a triangulation methodology for this research. An environmental scan was conducted for best practices. Two separate Creative Problem Solving Sessions were held with over 100 front-line workers, managers, and executive directors who work with homeless populations. Quantitative and open-ended surveys were completed by over 200 individuals with experience with homelessness. All sections of this research aimed to discover the areas of skills that individuals need to maintain housing and to ascertain what a more client-driven EDI approach to life skills training should include. This research will showcase which life skills are deemed essential for homeless and precariously housed individuals.

Keywords: homelessness, Housing First, life skills, community engaged research

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13629 Optimized Renewable Energy Mix for Energy Saving in Waste Water Treatment Plants

Authors: J. D. García Espinel, Paula Pérez Sánchez, Carlos Egea Ruiz, Carlos Lardín Mifsut, Andrés López-Aranguren Oliver

Abstract:

This paper shortly describes three main actuations over a Waste Water Treatment Plant (WWTP) for reducing its energy consumption: Optimization of the biological reactor in the aeration stage by including new control algorithms and introducing new efficient equipment, the installation of an innovative hybrid system with zero Grid injection (formed by 100kW of PV energy and 5 kW of mini-wind energy generation) and an intelligent management system for load consumption and energy generation control in the most optimum way. This project called RENEWAT, involved in the European Commission call LIFE 2013, has the main objective of reducing the energy consumptions through different actions on the processes which take place in a WWTP and introducing renewable energies on these treatment plants, with the purpose of promoting the usage of treated waste water for irrigation and decreasing the C02 gas emissions. WWTP is always required before waste water can be reused for irrigation or discharged in water bodies. However, the energetic demand of the treatment process is high enough for making the price of treated water to exceed the one for drinkable water. This makes any policy very difficult to encourage the re-use of treated water, with a great impact on the water cycle, particularly in those areas suffering hydric stress or deficiency. The cost of treating waste water involves another climate-change related burden: the energy necessary for the process is obtained mainly from the electric network, which is, in most of the cases in Europe, energy obtained from the burning of fossil fuels. The innovative part of this project is based on the implementation, adaptation and integration of solutions for this problem, together with a new concept of the integration of energy input and operative energy demand. Moreover, there is an important qualitative jump between the technologies used and the alleged technologies to use in the project which give it an innovative character, due to the fact that there are no similar previous experiences of a WWTP including an intelligent discrimination of energy sources, integrating renewable ones (PV and Wind) and the grid.

Keywords: aeration system, biological reactor, CO2 emissions, energy efficiency, hybrid systems, LIFE 2013 call, process optimization, renewable energy sources, wasted water treatment plants

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13628 Oxidation of Amitriptyline by Bromamine-T in Acidic Buffer Medium: A Kinetic and Mechanistic Approach

Authors: Chandrashekar, R. T. Radhika, B. M. Venkatesha, S. Ananda, Shivalingegowda, T. S. Shashikumar, H. Ramachandra

Abstract:

The kinetics of the oxidation of amitriptyline (AT) by sodium N-bromotoluene sulphonamide (C6H5SO2NBrNa) has been studied in an acidic buffer medium of pH 1.2 at 303 K. The oxidation reaction of AT was followed spectrophotometrically at maximum wavelength, 410 nm. The reaction rate shows a first order dependence each on concentration of AT and concentration of sodium N-bromotoluene sulphonamide. The reaction also shows an inverse fractional order dependence at low or high concentration of HCl. The dielectric constant of the solvent shows negative effect on the rate of reaction. The addition of halide ions and the reduction product of BAT have no significant effect on the rate. The rate is unchanged with the variation in the ionic strength (NaClO4) of the medium. Addition of reaction mixtures to be aqueous acrylamide solution did not initiate polymerization, indicating the absence of free radical species. The stoichiometry of the reaction was found to be 1:1 and oxidation product of AT is identified. The Michaelis-Menton type of kinetics has been proposed. The CH3C6H5SO2NHBr has been assumed to be the reactive oxidizing species. Thermodynamical parameters were computed by studying the reactions at different temperatures. A mechanism consistent with observed kinetics is presented.

Keywords: amitriptyline, bromamine-T, kinetics, oxidation

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13627 Estimation of Population Mean Using Characteristics of Poisson Distribution: An Application to Earthquake Data

Authors: Prayas Sharma

Abstract:

This paper proposed a generalized class of estimators, an exponential class of estimators based on the adaption of Sharma and Singh (2015) and Solanki and Singh (2013), and a simple difference estimator for estimating unknown population mean in the case of Poisson distributed population in simple random sampling without replacement. The expressions for mean square errors of the proposed classes of estimators are derived from the first order of approximation. It is shown that the adapted version of Solanki and Singh (2013), the exponential class of estimator, is always more efficient than the usual estimator, ratio, product, exponential ratio, and exponential product type estimators and equally efficient to simple difference estimator. Moreover, the adapted version of Sharma and Singh's (2015) estimator is always more efficient than all the estimators available in the literature. In addition, theoretical findings are supported by an empirical study to show the superiority of the constructed estimators over others with an application to earthquake data of Turkey.

Keywords: auxiliary attribute, point bi-serial, mean square error, simple random sampling, Poisson distribution

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13626 Risk Assessment of Building Information Modelling Adoption in Construction Projects

Authors: Amirhossein Karamoozian, Desheng Wu, Behzad Abbasnejad

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Building information modelling (BIM) is a new technology to enhance the efficiency of project management in the construction industry. In addition to the potential benefits of this useful technology, there are various risks and obstacles to applying it in construction projects. In this study, a decision making approach is presented for risk assessment in BIM adoption in construction projects. Various risk factors of exerting BIM during different phases of the project lifecycle are identified with the help of Delphi method, experts’ opinions and related literature. Afterward, Shannon’s entropy and Fuzzy TOPSIS (Technique for Order Preference by Similarity to Ideal Situation) are applied to derive priorities of the identified risk factors. Results indicated that lack of knowledge between professional engineers about workflows in BIM and conflict of opinions between different stakeholders are the risk factors with the highest priority.

Keywords: risk, BIM, fuzzy TOPSIS, construction projects

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13625 Study of Effect of Gear Tooth Accuracy on Transmission Mount Vibration

Authors: Kalyan Deepak Kolla, Ketan Paua, Rajkumar Bhagate

Abstract:

Transmission dynamics occupy major role in customer perception of the product in both senses of touch and quality of sound. The quantity and quality of sound perceived is more concerned with the whine noise of the gears engaged. Whine noise is tonal in nature and tonal noises cause fatigue and irritation to customers, which in turn affect the quality of the product. Transmission error is the usual suspect for whine noise, which can be caused due to misalignments, tolerances, manufacturing variabilities. In-cabin noise is also more sensitive to the gear design. As the details of the gear tooth design and manufacturing are in microns, anything out of the tolerance zone, either in design or manufacturing, will cause a whine noise. This will also cause high variation in stress and deformation due to change in the load and leads to the fatigue failure of the gears. Hence gear design and development take priority in the transmission development process. This paper aims to study such variability by considering five pairs of helical spur gears and their effect on the transmission error, contact pattern and vibration level on the transmission.

Keywords: gears, whine noise, manufacturing variability, mount vibration variability

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13624 Utilization of Bio-Glycerol to Synthesize Fuel Additive in Presence of Modified Mesoporous Heterogeneous Catalysts

Authors: Ala’a H. Al-Muhtaseb, Farrukh Jamil, Sandeep K. Saxena

Abstract:

The fast growth rate of energy consumption along with world population expected to demand 50% more energy by 2030 than nowadays. At present, the energy demand is mostly provided by limited fossil fuel sources such as oil, natural gas, and coal that are resulting in dramatic increase in CO2 emissions from combustion of fossil fuels. The growth of the biodiesel industry over the last decade has resulted in a price drop because glycerol is obtained as a by-product during transesterification of vegetable oil or animal fats, which accounts for one tenth of every gallon of biodiesel produced. The production of oxygenates from glycerol gains much importance due to the excellent diesel-blending property of the oxygenates that not only improve the quality of the fuel but also increases the overall yield of the biodiesel in helping to meet the target for energy production from renewable sources for transport in the energy utilization directives. The reaction of bio-glycerol with bio-acetone was carried out in a magnetically stirred two necked round bottom flaskS. Condensation of bio-glycerol with acetone in the presence of various modified forms of beta zeolite has been done for synthesizing solketal (AB-2 modified with nitric acid, AB-3 modified with oxalic acid). Among all modified forms of beta zeolite, AB-2 showed the best performance for maximum glycerol conversion 94.26 % with 94.21 % solketal selectivity and minimum acetal formation 0.05 %. The physiochemical properties of parent beta zeolite and all its modified forms were analyzed by XRD, SEM, TEM, BET, FTIR and TPD. It has been revealed that AB-2 catalysts with high pore volume and surface area gave high glycerol conversion with maximum solketal selectivity. Despite this, the crystallinity of AB-3 was lower than AB-2 which helps to provide the shorter path length for reactants and product but due high pore volume AB-2 was preferred which gave maximum bio-glycerol conversion. Temperature does matter the glycerol conversion and selectivity of solketal, as it increases from 40 ºC to 60 ºC the conversion of glycerol rises from 80.04 % to 94.26 % and selectivity of solketal from 80.0 % to 94.21 % but further increase in temperature to 100 ºC glycerol conversion reduced to 93.06 % and solketal selectivity to 92.08 %. AB-2 was found to be highly stable as up to 4 repeated experimental runs there was less than 10% decrease in its activity. This process offers an attractive route for converting bio-glycerol, the main by-product of biodiesel to solketal with bio-acetone; a value-added green product with potential industrial applications as a valuable green fuel additive or combustion promoter for gasoline/diesel engines.

Keywords: beta-zeolite, bio-glycerol, catalyst, solketal

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13623 Synthesis and Characterization of Anti-Psychotic Drugs Based DNA Aptamers

Authors: Shringika Soni, Utkarsh Jain, Nidhi Chauhan

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Aptamers are recently discovered ~80-100 bp long artificial oligonucleotides that not only demonstrated their applications in therapeutics; it is tremendously used in diagnostic and sensing application to detect different biomarkers and drugs. Synthesizing aptamers for proteins or genomic template is comparatively feasible in laboratory, but drugs or other chemical target based aptamers require major specification and proper optimization and validation. One has to optimize all selection, amplification, and characterization steps of the end product, which is extremely time-consuming. Therefore, we performed asymmetric PCR (polymerase chain reaction) for random oligonucleotides pool synthesis, and further use them in Systematic evolution of ligands by exponential enrichment (SELEX) for anti-psychotic drugs based aptamers synthesis. Anti-psychotic drugs are major tranquilizers to control psychosis for proper cognitive functions. Though their low medical use, their misuse may lead to severe medical condition as addiction and can promote crime in social and economical impact. In this work, we have approached the in-vitro SELEX method for ssDNA synthesis for anti-psychotic drugs (in this case ‘target’) based aptamer synthesis. The study was performed in three stages, where first stage included synthesis of random oligonucleotides pool via asymmetric PCR where end product was analyzed with electrophoresis and purified for further stages. The purified oligonucleotide pool was incubated in SELEX buffer, and further partition was performed in the next stage to obtain target specific aptamers. The isolated oligonucleotides are characterized and quantified after each round of partition, and significant results were obtained. After the repetitive partition and amplification steps of target-specific oligonucleotides, final stage included sequencing of end product. We can confirm the specific sequence for anti-psychoactive drugs, which will be further used in diagnostic application in clinical and forensic set-up.

Keywords: anti-psychotic drugs, aptamer, biosensor, ssDNA, SELEX

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13622 Ratio of Omega-6/Omega-3 Fatty Acids in Spelt and Flaxseed Pasta

Authors: Jelena Filipovic, Milenko Kosutic

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The dynamic way of life has the tendency to simplify and decrease preparing healthy, quick, cheap and safe meals. Spelt pasta is meeting most of these goals. Contrary to bread, pasta can be stored a long time without deterioration in flavour, odour and usability without losing quality. This paper deals with the chemical composition and content of fatty acids in flaxseed and spelt flour. Ratio of essential fatty acids ω-6/ω-3 is also analysed in spelt pasta and pasta with 0%, 10% and 20% flaxseed flour. Gas chromatography with mass spectrometry is used for carrying out a quantitative analysis of flaxseed flour, spelt flour and pasta liposoluble extracts. Flaxseed flour has a better fatty acid profile than spelt flour, with low levels of saturated fat (approximately 9g/100g), high concentration of linolenic acid (57g/100g) and lower content of linoleic acid (16g/100g), as well as superior ω-6/ω-3 ratio that is 1:4. Flaxseed flour in the share of 10% and 20% in spelt pasta positively contributes to the essential fatty acids daily intake recommended by nutritionists and the improvement of ω-6/ω-3 ratio (6,7:1 and 1:1.2). This paper points out that investigated pasta with flaxseed is a new product with improved functional properties due to high level of ω-3 fatty acids and it is acceptable for consumers in regard to sensory properties.

Keywords: flaxseed, spelt, fatty acids, ω-3/ω-6 ratio, pasta

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13621 Modeling Usage Patterns of Mobile App Service in App Market Using Hidden Markov Model

Authors: Yangrae Cho, Jinseok Kim, Yongtae Park

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Mobile app service ecosystem has been abruptly emerged, explosively grown, and dynamically transformed. In contrast with product markets in which product sales directly cause increment in firm’s income, customer’s usage is less visible but more valuable in service market. Especially, the market situation with cutthroat competition in mobile app store makes securing and keeping of users as vital. Although a few service firms try to manage their apps’ usage patterns by fitting on S-curve or applying other forecasting techniques, the time series approaches based on past sequential data are subject to fundamental limitation in the market where customer’s attention is being moved unpredictably and dynamically. We therefore propose a new conceptual approach for detecting usage pattern of mobile app service with Hidden Markov Model (HMM) which is based on the dual stochastic structure and mainly used to clarify unpredictable and dynamic sequential patterns in voice recognition or stock forecasting. Our approach could be practically utilized for app service firms to manage their services’ lifecycles and academically expanded to other markets.

Keywords: mobile app service, usage pattern, Hidden Markov Model, pattern detection

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13620 TNF Modulation of Cancer Stem Cells in Renal Clear Cell Carcinoma

Authors: Rafia S. Al-lamki, Jun Wang, Simon Pacey, Jordan Pober, John R. Bradley

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Tumor necrosis factor alpha (TNF), signaling through TNFR2, may act an autocrine growth factor for renal tubular epithelial cells. Clear cell renal carcinomas (ccRCC) contain cancer stem cells (CSCs) that give rise to progeny which form the bulk of the tumor. CSCs are rarely in cell cycle and, as non-proliferating cells, resist most chemotherapeutic agents. Thus, recurrence after chemotherapy may result from the survival of CSCs. Therapeutic targeting of both CSCs and the more differentiated bulk tumor populations may provide a more effective strategy for treatment of RCC. In this study, we hypothesized that TNFR2 signaling will induce CSCs in ccRCC to enter cell cycle so that treatment with ligands that engage TNFR2 will render CSCs susceptible to chemotherapy. To test this hypothesis, we have utilized wild-type TNF (wtTNF) or specific muteins selective for TNFR1 (R1TNF) or TNFR2 (R2TNF) to treat either short-term organ cultures of ccRCC and adjacent normal kidney (NK) tissue or cultures of CD133+ cells isolated from ccRCC and adjacent NK, hereafter referred to as stem cell-like cells (SCLCs). The effect of cyclophosphamide (CP), currently an effective anticancer agent, was tested on CD133+SCLCs from ccRCC and NK before and after R2TNF treatment. Responses to TNF were assessed by flow cytometry (FACS), immunofluorescence, and quantitative real-time PCR, TUNEL, and cell viability assays. Cytotoxic effect of CP was analyzed by Annexin V and propidium iodide staining with FACS. In addition, we assessed the effect of TNF on isolated SCLCs differentiation using a three-dimensional (3D) culture system. Clinical samples of ccRCC contain a greater number SCLCs compared to NK and the number of SCSC increases with higher tumor grade. Isolated SCLCs show expression of stemness markers (oct4, Nanog, Sox2, Lin28) but not differentiation markers (cytokeratin, CD31, CD45, and EpCAM). In ccRCC organ cultures, wtTNF and R2TNF increase CD133 and TNFR2 expression and promote cell cycle entry whereas wtTNF and R1TNF increase TNFR1 expression and promote cell death of SCLCs. Similar findings are observed in SCLCs isolated from NK but the effect was greater in SCLCs isolated from ccRCC. Application of CP distinctly triggered apoptotic and necrotic cell death in SLCSs pre-treatment with R2TNF as compared to CP treatment alone, with SCLCs from ccRCC more sensitive to CP compared to SLCS from NK. Furthermore, TNF promotes differentiation of SCLCs to an epithelial phenotype in 3D cultures, confirmed by cytokeratin expression and loss of stemness markers Nanog and Sox2. The differentiated cells show positive expression of TNF and TNFR2. These findings provide evidence that selective engagement of TNFR2 drive CSCs to cell proliferation/differentiation, and targeting of cycling cells with TNFR2 agonist in combination with anti-cancer agents may be a potential therapy for RCC.

Keywords: cancer stem cells, ccRCC, cell cycle, cell death, TNF, TNFR1, TNFR2, CD133

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