Search results for: traditional models

Authors: Priyanka Mokashi, Aparna Khanna, Nancy Pandita

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Diabetes mellitus is a chronic metabolic disorder which will be the 7th leading cause of death by 2030. The current line of treatment for the diabetes mellitus is oral antidiabetic drugs (biguanides, sulfonylureas, meglitinides, thiazolidinediones and alpha-glycosidase inhibitors) and insulin therapy depending upon the type 1 or type 2 diabetes mellitus. But, these treatments have their disadvantages, ranging from the developing of resistance to the drugs and adverse effects caused by them. Alternative to these synthetic agents, natural products provides a new insight for the development of more efficient and safe drugs due to their therapeutic values. Enicostema littorale blume (A. Raynal) is a traditional Indian plant belongs to the Gentianaceae family. It is widely distributed in Asia, Africa, and South America. There are few reports on Swrtiamarin, major component of this plant for its antidiabetic activity. However, the antidiabetic activity of flavonoids from E. littorale and their mechanism of action have not yet been elucidated. Flavonoids have a positive relationship with disease prevention and can act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, adipocytes, hepatocytes and skeletal myofibers. They may exert beneficial effects in diabetes by (i) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (ii) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells; (iii) increasing glucose uptake in hepatocytes, skeletal muscle and white adipose tissue (iv) reducing insulin resistance, inflammation and oxidative stress. Therefore, we have isolated four flavonoid rich fractions, Fraction A (FA), Fraction B (FB), Fraction C (FC), Fraction D (FD) from crude alcoholic hot (AH) extract from E. littorale, identified by LC/MS. Total eight flavonoids were identified on the basis of fragmentation pattern. Flavonoid FA showed the presence of swertisin, isovitexin, and saponarin; FB showed genkwanin, quercetin, isovitexin, FC showed apigenin, swertisin, quercetin, 5-O-glucosylswertisin and 5-O-glucosylisoswertisin whereas FD showed the presence of swertisin. Further, these fractions were assessed for their antidiabetic activity on stimulating glucose uptake in insulin-resistant HepG2 cell line model (IR/HepG2). The results showed that FD containing C-glycoside Swertisin has significantly increased the glucose uptake rate of IR/HepG2 cells at the concentration of 10 µg/ml as compared to positive control Metformin (0.5mM) which was determined by glucose oxidase- peroxidase method. It has been reported that enhancement of glucose uptake of cells occurs due the translocation of Glut4 vesicles to cell membrane through IR/IRS1/AKT pathway. Therefore, we have studied expressions of three genes IRS1, AKT and Glut4 by real-time PCR to evaluate whether they follow the same pathway or not. It was seen that the glucose uptake rate has increased in FD treated IR/HepG2 cells due to the activation of insulin receptor substrate-1 (IRS1) followed by protein kinase B (AKT) through phosphoinositide 3-kinase (PI3K) leading to translocation of Glut 4 vesicles to cell membrane, thereby enhancing glucose uptake and insulin sensitivity of insulin resistant HepG2 cells. Hence, the up-regulation indicated the mechanism of action through which FD (Swertisin) acts as antidiabetic candidate in the treatment of type 2 diabetes mellitus.

Keywords: E. littorale, glucose transporter, glucose uptake rate, insulin resistance

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Authors: Alessandro Balbo, Gianvito Colucci, Matteo Nicoli, Laura Savoldi

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Hydrogen is expected to become an undisputed player in the ecological transition throughout the next decades. The decarbonization potential offered by this energy vector provides various opportunities for the so-called “hard-to-abate” sectors, including industrial production of iron and steel, glass, refineries and the heavy-duty transport. In this regard, Italy, in the framework of decarbonization plans for the whole European Union, has been considering a wider use of hydrogen to provide an alternative to fossil fuels in hard-to-abate sectors. This work aims to assess and compare different options concerning the pathway to be followed in the development of the future Italian energy system in order to meet decarbonization targets as established by the Paris Agreement and by the European Green Deal, and to infer a techno-economic analysis of the required asset alternatives to be used in that perspective. To accomplish this objective, the Energy System Optimization Model TEMOA-Italy is used, based on the open-source platform TEMOA and developed at PoliTo as a tool to be used for technology assessment and energy scenario analysis. The adopted assessment strategy includes two different scenarios to be compared with a business-as-usual one, which considers the application of current policies in a time horizon up to 2050. The studied scenarios are based on the up-to-date hydrogen-related targets and planned investments included in the National Hydrogen Strategy and in the Italian National Recovery and Resilience Plan, with the purpose of providing a critical assessment of what they propose. One scenario imposes decarbonization objectives for the years 2030, 2040 and 2050, without any other specific target. The second one (inspired to the national objectives on the development of the sector) promotes the deployment of the hydrogen value-chain. These scenarios provide feedback about the applications hydrogen could have in the Italian energy system, including transport, industry and synfuels production. Furthermore, the decarbonization scenario where hydrogen production is not imposed, will make use of this energy vector as well, showing the necessity of its exploitation in order to meet pledged targets by 2050. The distance of the planned policies from the optimal conditions for the achievement of Italian objectives is be clarified, revealing possible improvements of various steps of the decarbonization pathway, which seems to have as a fundamental element Carbon Capture and Utilization technologies for its accomplishment. In line with the European Commission open science guidelines, the transparency and the robustness of the presented results is ensured by the adoption of the open-source open-data model such as the TEMOA-Italy.

Keywords: decarbonization, energy system optimization models, hydrogen, open-source modeling, TEMOA

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Authors: Gideon J. Bonthuys, Marco van Dijk, Jay N. Bhagwan

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Small scale hydropower used to play a very important role in the provision of energy to urban and rural areas of South Africa. The national electricity grid, however, expanded and offered cheap, coal generated electricity and a large number of hydropower systems were decommissioned. Unfortunately, large numbers of households and communities will not be connected to the national electricity grid for the foreseeable future due to high cost of transmission and distribution systems to remote communities due to the relatively low electricity demand within rural communities and the allocation of current expenditure on upgrading and constructing of new coal fired power stations. This necessitates the development of feasible alternative power generation technologies. A feasibility and implementation model was developed to assist in designing and financially evaluating small-scale hydropower (SSHP) plants. Several sites were identified using the model. The SSHP plants were designed for the selected sites and the designs for the different selected sites were priced using pricing models (civil, mechanical and electrical aspects). Following feasibility studies done on the designed and priced SSHP plants, a feasibility analysis was done and a design chart developed for future similar potential SSHP plant projects. The methodology followed in conducting the feasibility analysis for other potential sites consisted of developing cost and income/saving formulae, developing net present value (NPV) formulae, Capital Cost Comparison Ratio (CCCR) and levelised cost formulae for SSHP projects for the different types of plant installations. It included setting up a model for the development of a design chart for a SSHP, calculating the NPV, CCCR and levelised cost for the different scenarios within the model by varying different parameters within the developed formulae, setting up the design chart for the different scenarios within the model and analyzing and interpreting results. From the interpretation of the develop design charts for feasible SSHP in can be seen that turbine and distribution line cost are the major influences on the cost and feasibility of SSHP. High head, short transmission line and islanded mini-grid SSHP installations are the most feasible and that the levelised cost of SSHP is high for low power generation sites. The main conclusion from the study is that the levelised cost of SSHP projects indicate that the cost of SSHP for low energy generation is high compared to the levelised cost of grid connected electricity supply; however, the remoteness of SSHP for rural electrification and the cost of infrastructure to connect remote rural communities to the local or national electricity grid provides a low CCCR and renders SSHP for rural electrification feasible on this basis.

Keywords: cost, feasibility, rural electrification, small-scale hydropower

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Authors: Divya Palaniappan

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Early Childhood assessment tools must measure the quality and the appropriateness of a curriculum with respect to culture and age of the children. Preschool assessment tools lack psychometric properties and were developed to measure only few areas of development such as specific skills in music, art and adaptive behavior. Existing preschool assessment tools in India are predominantly informal and are fraught with judgmental bias of observers. The World of Discovery TM curriculum focuses on accelerating the physical, cognitive, language, social and emotional development of pre-schoolers in India through various activities. The curriculum caters to every child irrespective of their dominant intelligence as per Gardner’s Theory of Multiple Intelligence which concluded "even students as young as four years old present quite distinctive sets and configurations of intelligences". The curriculum introduces a new theme every week where, concepts are explained through various activities so that children with different dominant intelligences could understand it. For example: The ‘Insects’ theme is explained through rhymes, craft and counting corner, and hence children with one of these dominant intelligences: Musical, bodily-kinesthetic and logical-mathematical could grasp the concept. The child’s progress is evaluated using an assessment tool that measures a cluster of inter-dependent developmental areas: physical, cognitive, language, social and emotional development, which for the first time renders a multi-domain approach. The assessment tool is a 5-point rating scale that measures these Developmental aspects: Cognitive, Language, Physical, Social and Emotional. Each activity strengthens one or more of the developmental aspects. During cognitive corner, the child’s perceptual reasoning, pre-math abilities, hand-eye co-ordination and fine motor skills could be observed and evaluated. The tool differs from traditional assessment methodologies by providing a framework that allows teachers to assess a child’s continuous development with respect to specific activities in real time objectively. A pilot study of the tool was done with a sample data of 100 children in the age group 2.5 to 3.5 years. The data was collected over a period of 3 months across 10 centers in Chennai, India, scored by the class teacher once a week. The teachers were trained by psychologists on age-appropriate developmental milestones to minimize observer’s bias. The norms were calculated from the mean and standard deviation of the observed data. The results indicated high internal consistency among parameters and that cognitive development improved with physical development. A significant positive relationship between physical and cognitive development has been observed among children in a study conducted by Sibley and Etnier. In Children, the ‘Comprehension’ ability was found to be greater than ‘Reasoning’ and pre-math abilities as indicated by the preoperational stage of Piaget’s theory of cognitive development. The average scores of various parameters obtained through the tool corroborates the psychological theories on child development, offering strong face validity. The study provides a comprehensive mechanism to assess a child’s development and differentiate high performers from the rest. Based on the average scores, the difficulty level of activities could be increased or decreased to nurture the development of pre-schoolers and also appropriate teaching methodologies could be devised.

Keywords: child development, early childhood assessment, early childhood curriculum, quantitative assessment of preschool curriculum

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Authors: A. M. Ferrari, L. Volpi, M. Pini, C. Siligardi, F. E. Garcia Muina, D. Settembre Blundo

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A long tradition in the ceramic manufacturing since the 18th century, primarily due to the availability of raw materials and an efficient transport system, let to the birth and development of the Italian ceramic tiles district that nowadays represents a reference point for this sector even at global level. This economic growth has been coupled to attention towards environmental sustainability issues throughout various initiatives undertaken over the years at the level of the production sector, such as certification activities and sustainability policies. In this way, starting from an evaluation of the sustainability in all its aspects, the present work aims to develop a benchmarking helping both producers and consumers. In the present study, throughout the Life Cycle Sustainability Assessment (LCSA) framework, the sustainability has been assessed in all its dimensions: environmental with the Life Cycle Assessment (LCA), economic with the Life Cycle Costing (LCC) and social with the Social Life Cycle Assessment (S-LCA). The annual district production of stoneware tiles during the 2016 reference year has been taken as reference flow for all the three assessments, and the system boundaries cover the entire life cycle of the tiles, except for the LCC for which only the production costs have been considered at the moment. In addition, a preliminary method for the evaluation of local and indoor emissions has been introduced in order to assess the impact due to atmospheric emissions on both people living in the area surrounding the factories and workers. The Life Cycle Assessment results, obtained from IMPACT 2002+ modified assessment method, highlight that the manufacturing process is responsible for the main impact, especially because of atmospheric emissions at a local scale, followed by the distribution to end users, the installation and the ordinary maintenance of the tiles. With regard to the economic evaluation, both the internal and external costs have been considered. For the LCC, primary data from the analysis of the financial statements of Italian ceramic companies show that the higher cost items refer to expenses for goods and services and costs of human resources. The analysis of externalities with the EPS 2015dx method attributes the main damages to the distribution and installation of the tiles. The social dimension has been investigated with a preliminary approach by using the Social Hotspots Database, and the results indicate that the most affected damage categories are health and safety and labor rights and decent work. This study shows the potential of the LCSA framework applied to an industrial sector; in particular, it can be a useful tool for building a comprehensive benchmark for the sustainability of the ceramic industry, and it can help companies to actively integrate sustainability principles into their business models.

Keywords: benchmarking, Italian ceramic industry, life cycle sustainability assessment, porcelain stoneware tiles

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Authors: Bill D. Geis

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Suicide wrongful death forensic cases are the fastest rising tort in mental health law. It is estimated that suicide-related cases have accounted for 15% of U.S. malpractice claims since 2006. Most suicide-related personal injury claims fall into the legal category of “wrongful death.” Though mental health experts may be called on to address a range of forensic questions in wrongful death cases, the central consultation that most experts provide is about the negligence element—specifically, the issue of whether the clinician met the clinical standard of care in assessing, treating, and managing the deceased person’s mental health care. Standards of care, varying from U.S. state to state, are broad and address what a reasonable clinician might do in a similar circumstance. This fact leaves the issue of the suicide standard of care, in each case, up to forensic experts to put forth a reasoned estimate of what the standard of care should have been in the specific case under litigation. Because the general state guidelines for standard of care are broad, forensic experts are readily retained to provide scientific and clinical opinions about whether or not a clinician met the standard of care in their suicide assessment, treatment, and management of the case. In the past and in much of current practice, the assessment of suicide has centered on the elicitation of verbalized suicide ideation. Research in recent years, however, has indicated that the majority of persons who end their lives do not say they are suicidal at their last medical or psychiatric contact. Near-term risk assessment—that goes beyond verbalized suicide ideation—is needed. Our previous research employed structural equation modeling to predict lethal suicide risk--eight negative thought patterns (feeling like a burden on others, hopelessness, self-hatred, etc.) mediated by nine transdiagnostic clinical factors (mental torment, insomnia, substance abuse, PTSD intrusions, etc.) were combined to predict acute lethal suicide risk. This structural equation model, the Lethal Suicide Risk Pattern (LSRP), Acute model, had excellent goodness-of-fit [χ2(df) = 94.25(47)***, CFI = .98, RMSEA = .05, .90CI = .03-.06, p(RMSEA = .05) = .63. AIC = 340.25, ***p < .001.]. A further SEQ analysis was completed for this paper, adding a measure of Acute Suicide Ideation to the previous SEQ. Acceptable prediction model fit was no longer achieved [χ2(df) = 3.571, CFI > .953, RMSEA = .075, .90% CI = .065-.085, AIC = 529.550].This finding suggests that, in this additional study, immediate verbalized suicide ideation information was unhelpful in the assessment of lethal risk. The LSRP and other dynamic, near-term risk models (such as the Acute Suicide Affective Disorder Model and the Suicide Crisis Syndrome Model)—going beyond elicited suicide ideation—need to be incorporated into current clinical suicide assessment training. Without this training, the standard of care for suicide assessment is out of sync with current research—an emerging dilemma for the forensic evaluation of suicide wrongful death cases.

Keywords: forensic evaluation, standard of care, suicide, suicide assessment, wrongful death

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Authors: Fabrizio Ascione, Martina Borrelli, Rosa Francesca De Masi, Silvia Ruggiero, Giuseppe Peter Vanoli

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The refurbishment of public buildings is one of the key factors of energy efficiency policy of European States. Educational buildings account for the largest share of the oldest edifice with interesting potentialities for demonstrating best practice with regards to high performance and low and zero-carbon design and for becoming exemplar cases within the community. In this context, this paper discusses the critical issue of dealing the energy refurbishment of a university building in heating dominated climate of South Italy. More in detail, the importance of using validated models will be examined exhaustively by proposing an analysis on uncertainties due to modelling assumptions mainly referring to the adoption of stochastic schedules for occupant behavior and equipment or lighting usage. Indeed, today, the great part of commercial tools provides to designers a library of possible schedules with which thermal zones can be described. Very often, the users do not pay close attention to diversify thermal zones and to modify or to adapt predefined profiles, and results of designing are affected positively or negatively without any alarm about it. Data such as occupancy schedules, internal loads and the interaction between people and windows or plant systems, represent some of the largest variables during the energy modelling and to understand calibration results. This is mainly due to the adoption of discrete standardized and conventional schedules with important consequences on the prevision of the energy consumptions. The problem is surely difficult to examine and to solve. In this paper, a sensitivity analysis is presented, to understand what is the order of magnitude of error that is committed by varying the deterministic schedules used for occupation, internal load, and lighting system. This could be a typical uncertainty for a case study as the presented one where there is not a regulation system for the HVAC system thus the occupant cannot interact with it. More in detail, starting from adopted schedules, created according to questioner’ s responses and that has allowed a good calibration of energy simulation model, several different scenarios are tested. Two type of analysis are presented: the reference building is compared with these scenarios in term of percentage difference on the projected total electric energy need and natural gas request. Then the different entries of consumption are analyzed and for more interesting cases also the comparison between calibration indexes. Moreover, for the optimal refurbishment solution, the same simulations are done. The variation on the provision of energy saving and global cost reduction is evidenced. This parametric study wants to underline the effect on performance indexes evaluation of the modelling assumptions during the description of thermal zones.

Keywords: energy simulation, modelling calibration, occupant behavior, university building

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Authors: Mai Sirhan, Arieh Sidess

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Asphaltic mixture is a heterogeneous material composed of three main components: aggregates; bitumen and air voids. The professional experience and scientific literature categorize asphaltic mixture as a viscoelastic material, whose behavior is determined by temperature and loading rate. Properties characterization of the asphaltic mixture used under the service conditions is done by compacting and testing cylindric asphalt samples in the laboratory. These samples must resemble in a high degree internal structure of the mixture achieved in service, and the mechanical characteristics of the compacted asphalt layer in the pavement. The laboratory samples are usually compacted in temperatures between 140 and 160 degrees Celsius. In this temperature range, the asphalt has a low degree of strength. The laboratory samples are compacted using the dynamic or vibrational compaction methods. In the compaction process, the aggregates tend to align themselves in certain directions that lead to anisotropic behavior of the asphaltic mixture. This issue has been studied in the Strategic Highway Research Program (SHRP) research, that recommended using the gyratory compactor based on the assumption that this method is the best in mimicking the compaction in the service. In Israel, the Netivei Israel company is considering adopting the Gyratory Method as a replacement for the Marshall method used today. Therefore, the compatibility of the Gyratory Method for the use with Israeli asphaltic mixtures should be investigated. In this research, we aimed to examine the impact of the compaction method used on the mechanical characteristics of the asphaltic mixtures and to evaluate the degree of anisotropy in relation to the compaction method. In order to carry out this research, samples have been compacted in the vibratory and gyratory compactors. These samples were cylindrically cored both vertically (compaction wise) and horizontally (perpendicular to compaction direction). These models were tested under dynamic modulus and permanent deformation tests. The comparable results of the tests proved that: (1) specimens compacted by the vibratory compactor had higher dynamic modulus values than the specimens compacted by the gyratory compactor (2) both vibratory and gyratory compacted specimens had anisotropic behavior, especially in high temperatures. Also, the degree of anisotropy is higher in specimens compacted by the gyratory method. (3) Specimens compacted by the vibratory method that were cored vertically had the highest resistance to rutting. On the other hand, specimens compacted by the vibratory method that were cored horizontally had the lowest resistance to rutting. Additionally (4) these differences between the different types of specimens rise mainly due to the different internal arrangement of aggregates resulting from the compaction method. (5) Based on the initial prediction of the performance of the flexible pavement containing an asphalt layer having characteristics based on the results achieved in this research. It can be concluded that there is a significant impact of the compaction method and the degree of anisotropy on the strains that develop in the pavement, and the resistance of the pavement to fatigue and rutting defects.

Keywords: anisotropy, asphalt compaction, dynamic modulus, gyratory compactor, mechanical properties, permanent deformation, vibratory compactor

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Authors: Ed de Jong

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Avantium is a leading technology development company and a frontrunner in renewable chemistry. Avantium develops disruptive technologies that enable the production of sustainable high value products from renewable materials and actively seek out collaborations and partnerships with like-minded companies and academic institutions globally, to speed up introductions of chemical innovations in the marketplace. In addition, Avantium helps companies to accelerate their catalysis R&D to improve efficiencies and deliver increased sustainability, growth, and profits, by providing proprietary systems and services to this regard. Many chemical building blocks and materials can be produced from biomass, nowadays mainly from 1st generation based carbohydrates, but potential for competition with the human food chain leads brand-owners to look for strategies to transition from 1st to 2nd generation feedstock. The use of non-edible lignocellulosic feedstock is an equally attractive source to produce chemical intermediates and an important part of the solution addressing these global issues (Paris targets). Avantium’s Dawn Technology™ separates the glucose, mixed sugars, and lignin available in non-food agricultural and forestry residues such as wood chips, wheat straw, bagasse, empty fruit bunches or corn stover. The resulting very pure lignin is dense in energy and can be used for energy generation. However, such a material might preferably be deployed in higher added value applications. Bitumen, which is fossil based, are mostly used for paving applications. Traditional hot mix asphalt emits large quantities of the GHG’s CO₂, CH₄, and N₂O, which is unfavorable for obvious environmental reasons. Another challenge for the bitumen industry is that the petrochemical industry is becoming more and more efficient in breaking down higher chain hydrocarbons to lower chain hydrocarbons with higher added value than bitumen. This has a negative effect on the availability of bitumen. The asphalt market, as well as governments, are looking for alternatives with higher sustainability in terms of GHG emission. The usage of alternative sustainable binders, which can (partly) replace the bitumen, contributes to reduce GHG emissions and at the same time broadens the availability of binders. As lignin is a major component (around 25-30%) of lignocellulosic material, which includes terrestrial plants (e.g., trees, bushes, and grass) and agricultural residues (e.g., empty fruit bunches, corn stover, sugarcane bagasse, straw, etc.), it is globally highly available. The chemical structure shows resemblance with the structure of bitumen and could, therefore, be used as an alternative for bitumen in applications like roofing or asphalt. Applications such as the use of lignin in asphalt need both fundamental research as well as practical proof under relevant use conditions. From a fundamental point of view, rheological aspects, as well as mixing, are key criteria. From a practical point of view, behavior in real road conditions is key (how easy can the asphalt be prepared, how easy can it be applied on the road, what is the durability, etc.). The paper will discuss the fundamentals of the use of lignin as bitumen replacement as well as the status of the different demonstration projects in Europe using lignin as a partial bitumen replacement in asphalts and will especially present the results of using Dawn Technology™ lignin as partial replacement of bitumen.

Keywords: biorefinery, wood fractionation, lignin, asphalt, bitumen, sustainability

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Authors: Magdalena Suárez-Ortega, M. Fe. Sánchez-García

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This paper focuses on the analysis of the motivations that lead people to undertake and consolidate their business. It is addressed from the framework of planned behavior theory, which recognizes the importance of the social environment and cultural values, both in the decision to undertake business and in business consolidation. Similarly, it is also based on theories of career development, which emphasize the importance of career management competencies and their connections to other vital aspects of people, including their roles within their families and other personal activities. This connects directly with the impact of entrepreneurship on the career and the professional-personal project of each individual. This study is part of the project titled Career Design and Talent Management (Ministry of Economy and Competitiveness of Spain, State Plan 2013-2016 Excellence Ref. EDU2013-45704-P). The aim of the study is to identify and describe entrepreneurial competencies and motivational profiles in a sample of 248 Spanish entrepreneurs, considering the consolidated profile and the profile in transition (n = 248).In order to obtain the information, the Questionnaire of Motivation and conditioners of the entrepreneurial career (MCEC) has been applied. This consists of 67 items and includes four scales (E1-Conflicts in conciliation, E2-Satisfaction in the career path, E3-Motivations to undertake, E4-Guidance Needs). Cluster analysis (mixed method, combining k-means clustering with a hierarchical method) was carried out, characterizing the groups profiles according to the categorical variables (chi square, p = 0.05), and the quantitative variables (ANOVA). The results have allowed us to characterize three motivational profiles relevant to the motivation, the degree of conciliation between personal and professional life, and the degree of conflict in conciliation, levels of career satisfaction and orientation needs (in the entrepreneurial project and life-career). The first profile is formed by extrinsically motivated entrepreneurs, professionally satisfied and without conflict of vital roles. The second profile acts with intrinsic motivation and also associated with family models, and although it shows satisfaction with their professional career, it finds a high conflict in their family and professional life. The third is composed of entrepreneurs with high extrinsic motivation, professional dissatisfaction and at the same time, feel the conflict in their professional life by the effect of personal roles. Ultimately, the analysis has allowed us to line the kinds of entrepreneurs to different levels of motivation, satisfaction, needs and articulation in professional and personal life, showing characterizations associated with the use of time for leisure, and the care of the family. Associations related to gender, age, activity sector, environment (rural, urban, virtual), and the use of time for domestic tasks are not identified. The model obtained and its implications for the design of training actions and orientation to entrepreneurs is also discussed.

Keywords: motivation, entrepreneurial career, guidance needs, life-work balance, job satisfaction, assessment

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Authors: George R. Puno, Eric N. Bruno

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The natural landscape of the Philippine archipelago plus the current realities of climate change make the country vulnerable to flood hazards. Flooding becomes the recurring natural disaster in the country resulting to lose of lives and properties. Musimusi is among the rivers which exhibited inundation particularly at the inhabited floodplain portion of its watershed. During the event, rescue operations and distribution of relief goods become a problem due to lack of high resolution flood maps to aid local government unit identify the most affected areas. In the attempt of minimizing impact of flooding, hydrologic modelling with high resolution mapping is becoming more challenging and important. This study focused on the analysis of flood extent as a function of different geomorphologic characteristics of Musimusi watershed. The methods include the delineation of morphometric parameters in the Musimusi watershed using Geographic Information System (GIS) and geometric calculations tools. Digital Terrain Model (DTM) as one of the derivatives of Light Detection and Ranging (LiDAR) technology was used to determine the extent of river inundation involving the application of Hydrologic Engineering Center-River Analysis System (HEC-RAS) and Hydrology Modelling System (HEC-HMS) models. The digital elevation model (DEM) from synthetic Aperture Radar (SAR) was used to delineate watershed boundary and river network. Datasets like mean sea level, river cross section, river stage, discharge and rainfall were also used as input parameters. Curve number (CN), vegetation, and soil properties were calibrated based on the existing condition of the site. Results showed that the drainage density value of the watershed is low which indicates that the basin is highly permeable subsoil and thick vegetative cover. The watershed’s elongation ratio value of 0.9 implies that the floodplain portion of the watershed is susceptible to flooding. The bifurcation ratio value of 2.1 indicates higher risk of flooding in localized areas of the watershed. The circularity ratio value (1.20) indicates that the basin is circular in shape, high discharge of runoff and low permeability of the subsoil condition. The heavy rainfall of 167 mm brought by Typhoon Seniang last December 29, 2014 was characterized as high intensity and long duration, with a return period of 100 years produced 316 m3s-1 outflows. Portion of the floodplain zone (1.52%) suffered inundation with 2.76 m depth at the maximum. The information generated in this study is helpful to the local disaster risk reduction management council in monitoring the affected sites for more appropriate decisions so that cost of rescue operations and relief goods distribution is minimized.

Keywords: flooding, geomorphology, mapping, watershed

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Authors: Faith Abdul Rasak Asharaf

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Every city has a threshold known as urban carrying capacity based on which it can withstand a particular density of people, above which the city might need to resort to measures like expanding its boundaries or growing vertically. As a result of this circumstance, the number of squatter communities is growing, as is the claustrophobic feeling of being confined inside a "concrete jungle." The expansion of suburbs, commercial areas, and industrial real estate in the areas surrounding medium-sized cities has resulted in changes to their landscapes and urban forms, as well as a systematic shift in their role in the urban hierarchy when functional endowment and connections to other territories are considered. The urban carrying capacity idea provides crucial guidance for city administrators and planners in better managing, designing, planning, constructing, and distributing urban resources to satisfy the huge demands of an evergrowing urban population. An ecological footprint is a criterion of urban carrying capacity, which is the amount of land required to provide humanity with renewable resources and absorb its trash. However, as each piece of land has its unique carrying capacity, including ecological, social, and economic considerations, these metropolitan areas begin to reach a saturation point over time. Various city models have been tried throughout the years to meet the increasing urban population density by moving the zones of work, life, and leisure to achieve maximum sustainable growth. The current scenario is that of a vertical city and compact city concept, in which the maximum density of people is attempted to fit into a definite area using efficient land use and a variety of other strategies, but this has proven to be a very unsustainable method of growth, as evidenced by the COVID-19 period. Due to a shortage of housing and basic infrastructure, densely populated cities gave rise to massive squatter communities, unable to accommodate the overflowing migrants. To achieve optimum carrying capacity, planning measures such as polycentric city and diffuse city concepts can be implemented, which will help to relieve the congested city core by relocating certain sectors of the town to the city periphery, which will help to create newer spaces for design in terms of public space, transportation, and housing, which is a major concern in the current scenario. The study's goal is focused on suggesting design options and solutions in terms of placemaking for better urban quality and urban life for the citizens once city centres have been de-densified based on urban carrying capacity and ecological footprint, taking the case of Kochi as an apt example of a highly densified city core, focusing on Edappally, which is an agglomeration of many urban factors.

Keywords: urban carrying capacity, urbanization, urban sprawl, ecological footprint

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Authors: Yusuf Berkay Metinal, Gulden Gumusburun Ayalp

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Architectural education is characterized by its distinctive amalgamation of studio-based pedagogy and theoretical instruction. It offers students a comprehensive learning experience that blends practical skill development with critical inquiry and conceptual exploration. Design studios are central to this educational paradigm, which serve as dynamic hubs of creativity and innovation, providing students with immersive environments for experimentation and collaborative engagement. The physical presence and interactive dynamics inherent in studio-based learning underscore the indispensability of face-to-face instruction and interpersonal interaction in nurturing the next generation of architects. However, architectural education underwent a seismic transformation in response to the global COVID-19 pandemic, precipitating an abrupt transition from traditional, in-person instruction to online education modalities. While this shift introduced newfound flexibility in terms of temporal and spatial constraints, it also brought many challenges to the fore. Chief among these challenges was maintaining effective communication and fostering meaningful collaboration among students in virtual learning environments. Besides these challenges, lack of peer learning emerged as a vital issue of the educational experience, particularly crucial for novice students navigating the intricacies of architectural practice. Nevertheless, the pivot to online education also laid bare a discernible decline in educational efficacy, prompting inquiries regarding the enduring viability of online education in architectural pedagogy. Moreover, as educational institutions grappled with the exigencies of remote instruction, discernible disparities between different institutional contexts emerged. While state universities often contended with fiscal constraints that shaped their operational capacities, private institutions encountered challenges from a lack of institutional fortification and entrenched educational traditions. Acknowledging the multifaceted nature of these challenges, this study endeavored to undertake a comprehensive inquiry into the dynamics of online education within architectural pedagogy by interrogating variables such as class level and type of university; the research aimed to elucidate demographic critical success factors that underpin the effectiveness of online education initiatives. To this end, a meticulously constructed questionnaire was administered to architecture students from diverse academic institutions across Turkey, informed by an exhaustive review of extant literature and scholarly discourse. The resulting dataset, comprising responses from 232 participants, underwent rigorous statistical analysis, including independent samples t-test and one-way ANOVA, to discern patterns and correlations indicative of overarching trends and salient insights. In sum, the findings of this study serve as a scholarly compass for educators, policymakers, and stakeholders navigating the evolving landscapes of architectural education. By elucidating the intricate interplay of demographical factors that shape the efficacy of online education in architectural pedagogy, this research offers a scholarly foundation upon which to anchor informed decisions and strategic interventions to elevate the educational experience for future cohorts of aspiring architects.

Keywords: architectural education, COVID-19, distance education, online education

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Authors: Neeti Nayak, Khalid Duri

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Despite the many advances made in transportation planning, the number of injuries and fatalities in the United States which involve motorized vehicles near intersections remain largely unchanged year over year. Data from the National Highway Traffic Safety Administration for 2018 indicates accidents involving motorized vehicles at traffic intersections accounted for 8,245 deaths and 914,811 injuries. Furthermore, collisions involving pedal cyclists killed 861 people (38% at intersections) and injured 46,295 (68% at intersections), while accidents involving pedestrians claimed 6,247 lives (25% at intersections) and injured 71,887 (56% at intersections)- the highest tallies registered in nearly 20 years. Some of the causes attributed to the rising number of accidents relate to increasing populations and the associated changes in land and traffic usage patterns, insufficient visibility conditions, and inadequate applications of traffic controls. Intersections that were initially designed with a particular land use pattern in mind may be rendered obsolete by subsequent developments. Many accidents involving pedestrians are accounted for by locations which should have been designed for safe crosswalks. Conventional solutions for evaluating intersection safety often require costly deployment of engineering surveys and analysis, which limit the capacity of resource-constrained administrations to satisfy their community’s needs for safe roadways adequately, effectively relegating mitigation efforts for high-risk areas to post-incident responses. This paper demonstrates how geospatial technology can identify high-risk locations and evaluate the viability of specific intersection management techniques. GIS is used to simulate relevant real-world conditions- the presence of traffic controls, zoning records, locations of interest for human activity, design speed of roadways, topographic details and immovable structures. The proposed methodology provides a low-cost mechanism for empowering urban planners to reduce the risks of accidents using 2-dimensional data representing multi-modal street networks, parcels, crosswalks and demographic information alongside 3-dimensional models of buildings, elevation, slope and aspect surfaces to evaluate visibility and lighting conditions and estimate probabilities for jaywalking and risks posed by blind or uncontrolled intersections. The proposed tools were developed using sample areas of Southern California, but the model will scale to other cities which conform to similar transportation standards given the availability of relevant GIS data.

Keywords: crosswalks, cyclist safety, geotechnology, GIS, intersection safety, pedestrian safety, roadway safety, transportation planning, urban design

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Authors: Pulkeria Pascoe, Hawa P. Tundui, Marcia Dutra de Barcellos, Hans de Steur, Xavier Gellynck

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A majority of Micro and Small Enterprises (MSEs) experience low or no growth. Understanding their performance remains unfinished and disjointed as there is no consensus on the factors influencing it, especially in developing countries. Using a Resource-Based View (RBV) as the theoretical background, this cross-sectional study employed four regression models to examine the influence of firm-level factors (firm-specific characteristics, firm resources, manager socio-demographic characteristics, and selected management practices) on the overall performance variations among 442 Tanzanian micro and small agri-food processing firms. Study results confirmed the RBV argument that intangible resources make a larger contribution to overall performance variations among firms than that tangible resources. Firms' tangible and intangible resources explained 34.5% of overall performance variations (intangible resources explained the overall performance variability by 19.4% compared to tangible resources, which accounted for 15.1%), ranking first in explaining the overall performance variance. Firm-specific characteristics ranked second by influencing variations in overall performance by 29.0%. Selected management practices ranked third (6.3%), while the manager's socio-demographic factors were last on the list, as they influenced the overall performance variability among firms by only 5.1%. The study also found that firms that focus on proper utilization of tangible resources (financial and physical), set targets, and undertake better working capital management practices performed higher than their counterparts (low and average performers). Furthermore, accumulation and proper utilization of intangible resources (relational, organizational, and reputational), undertaking performance monitoring practices, age of the manager, and the choice of the firm location and activity were the dominant significant factors influencing the variations among average and high performers, relative to low performers. The entrepreneurial background was a significant factor influencing variations in average and low-performing firms, indicating that entrepreneurial skills are crucial to achieving average levels of performance. Firm age, size, legal status, source of start-up capital, gender, education level, and total business experience of the manager were not statistically significant variables influencing the overall performance variations among the agri-food processors under the study. The study has identified both significant and non-significant factors influencing performance variations among low, average, and high-performing micro and small agri-food processing firms in Tanzania. Therefore, results from this study will help managers, policymakers and researchers to identify areas where more attention should be placed in order to improve overall performance of MSEs in agri-food industry.

Keywords: firm-level factors, micro and small enterprises, performance, regression analysis, resource-based-view

Procedia PDF Downloads 78

Authors: Elisa Santana-Monagas, Juan L. Núñez, Jaime León, Samuel Falcón, Celia Fernández, Rocío P. Solís

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Students’ emotional experiences have been a widely discussed theme among researchers, proving a central role on students’ outcomes. Yet, up to now, far too little attention has been paid to teaching practices that negatively relate with students’ negative emotions in the higher education. The present work aims to examine the relationship between teachers’ teaching practices (i.e., students’ evaluations of teaching and autonomy support), the students’ feelings of boredom and agentic engagement and motivation in the higher education context. To do so, the present study incorporates one of the most popular tools in natural processing language to address students’ evaluations of teaching: sentiment analysis. Whereas most research has focused on the creation of SA models and assessing students’ satisfaction regarding teachers and courses to the author’s best knowledge, no research before has included results from SA into an explanatory model. A total of 225 university students (Mean age = 26.16, SD = 7.4, 78.7 % women) participated in the study. Students were enrolled in degree and masters’ studies at the faculty of Education of a public university of Spain. Data was collected using an online questionnaire students could access through a QR code they completed during a teaching period where the assessed teacher was not present. To assess students’ sentiments towards their teachers’ teaching, we asked them the following open-ended question: “If you had to explain a peer who doesn't know your teacher how he or she communicates in class, what would you tell them?”. Sentiment analysis was performed with Microsoft's pre-trained model. For this study, we relied on the probability of the students answer belonging to the negative category. To assess the reliability of the measure, inter-rater agreement between this NLP tool and one of the researchers, who independently coded all answers, was examined. The average pairwise percent agreement and the Cohen’s kappa were calculated with ReCal2. The agreement reached was of 90.8% and Cohen’s kappa .68, both considered satisfactory. To test the hypothesis relations a structural equation model (SEM) was estimated. Results showed that the model fit indices displayed a good fit to the data; χ² (134) = 351.129, p < .001, RMSEA = .07, SRMR = .09, TLI = .91, CFI = .92. Specifically, results show that boredom was negatively predicted by autonomy support practices (β = -.47[-.61, -.33]), whereas for the negative sentiment extracted from SET, this relation was positive (β = .23[.16, .30]). In other words, when students’ opinion towards their instructors’ teaching practices was negative, it was more likely for them to feel bored. Regarding the relations among boredom and student outcomes, results showed a negative predictive value of boredom on students’ motivation to study (β = -.46[-.63, -.29]) and agentic engagement (β = -.24[-.33, -.15]). Altogether, results show a promising future for sentiment analysis techniques in the field of education as they proved the usefulness of this tool when evaluating relations among teaching practices and student outcomes.

Keywords: sentiment analysis, boredom, motivation, agentic engagement

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Authors: Ayodele James Akinola

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This study investigated the use of English in doctor-patient interaction in a university teaching hospital from a southwestern state in Nigeria with the aim of identifying the role of communication in an L2, patterns of communication, discourse strategies, pragmatic acts, and contexts that shape the interaction. Jacob Mey’s Pragmatic Acts notion complemented with Emanuel and Emanuel’s model of doctor-patient relationship provided the theoretical standpoint. Data comprising 7 audio-recorded doctors-patient interactions were collected from a University Hospital in Oyo state, Nigeria. Interactions involving the use of English language were purposefully selected. These were supplemented with patients’ case notes and interviews conducted with doctors. Transcription was patterned alongside modified Arminen’s notations of conversation analysis. In the study, interaction in English between doctor and patients has the preponderance of direct-translation, code-mixing and switching, Nigerianism and use of cultural worldviews to express medical experience. Irrespective of these, three patterns communication, namely the paternalistic, interpretive, and deliberative were identified. These were exhibited through varying discourse strategies. The paternalistic model reflected slightly casual conversational conventions and registers. These were achieved through the pragmemic activities of situated speech acts, psychological and physical acts, via patients’ quarrel-induced acts, controlled and managed through doctors’ shared situation knowledge. All these produced empathising, pacifying, promising and instructing practs. The patients’ practs were explaining, provoking, associating and greeting in the paternalistic model. The informative model reveals the use of adjacency pairs, formal turn-taking, precise detailing, institutional talks and dialogic strategies. Through the activities of the speech, prosody and physical acts, the practs of declaring, alerting and informing were utilised by doctors, while the patients exploited adapting, requesting and selecting practs. The negotiating conversational strategy of the deliberative model featured in the speech, prosody and physical acts. In this model, practs of suggesting, teaching, persuading and convincing were utilised by the doctors. The patients deployed the practs of questioning, demanding, considering and deciding. The contextual variables revealed that other patterns (such as phatic and informative) are also used and they coalesced in the hospital within the situational and psychological contexts. However, the paternalistic model was predominantly employed by doctors with over six years in practice, while the interpretive, informative and deliberative models were found among registrar and others below six years of medical practice. Doctors’ experience, patients’ peculiarities and shared cultural knowledge influenced doctor-patient communication in the study.

Keywords: pragmatics, communication pattern, doctor-patient interaction, Nigerian hospital situation

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Authors: Seyedeh Nasim Mirbahari, Taha Azad, Mehdi Totonchi

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Oncolytic viruses, which only replicate in tumor cells, are being extensively studied for their use in cancer therapy. A particular virus known as the vaccinia virus, a member of the poxvirus family, has demonstrated oncolytic abilities glioma. Treating Glioma with traditional methods such as chemotherapy and radiotherapy is quite challenging. Even though oncolytic viruses have shown immense potential in cancer treatment, their effectiveness in glioblastoma treatment is still low. Therefore, there is a need to improve and optimize immunotherapies for better results. In this study, we have designed oncoVV-TT, which can more effectively target tumor cells while minimizing replication in normal cells by replacing the thymidine kinase gene with a luc-p2a-GFP gene expression cassette. Human glioblastoma cell line U251 MG, rat glioblastoma cell line C6, and non-tumor cell line HFF were plated at 105 cells in a 12-well plates in 2 mL of DMEM-F2 medium with 10% FBS added to each well. Then incubated at 37°C. After 16 hours, the cells were treated with oncoVV-TT at an MOI of 0.01, 0.1 and left in the incubator for a further 24, 48, 72 and 96 hours. Viral replication assay, fluorescence imaging and viability tests, including trypan blue and crystal violet, were conducted to evaluate the cytotoxic effect of oncoVV-TT. The finding shows that oncoVV-TT had significantly higher cytotoxic activity and proliferation rates in tumor cells in a dose and time-dependent manner, with the strongest effect observed in U251 MG. To conclude, oncoVV-TT has the potential to be a promising oncolytic virus for cancer treatment, with a more cytotoxic effect in human glioblastoma cells versus rat glioma cells. To assess the effectiveness of vaccinia virus-mediated viral therapy, we have tested U251mg and C6 tumor cell lines taken from human and rat gliomas, respectively. The study evaluated oncoVV-TT's ability to replicate and lyse cells and analyzed the survival rates of the tested cell lines when treated with different doses of oncoVV-TT. Additionally, we compared the sensitivity of human and mouse glioma cell lines to the oncolytic vaccinia virus. All experiments regarding viruses were conducted under biosafety level 2. We engineered a Vaccinia-based oncolytic virus called oncoVV-TT to replicate specifically in tumor cells. To propagate the oncoVV-TT virus, HeLa cells (5 × 104/well) were plated in 24-well plates and incubated overnight to attach to the bottom of the wells. Subsequently, 10 MOI virus was added. After 48 h, cells were harvested by scraping, and viruses were collected by 3 sequential freezing and thawing cycles followed by removal of cell debris by centrifugation (1500 rpm, 5 min). The supernatant was stored at −80 ◦C for the following experiments. To measure the replication of the virus in Hela, cells (5 × 104/well) were plated in 24-well plates and incubated overnight to attach to the bottom of the wells. Subsequently, 5 MOI virus or equal dilution of PBS was added. At the treatment time of 0 h, 24 h, 48 h, 72 h and 96 h, the viral titers were determined under the fluorescence microscope (BZ-X700; Keyence, Osaka, Japan). Fluorescence intensity was quantified using the imagej software according to the manufacturer’s protocol. For the isolation of single-virus clones, HeLa cells seeded in six-well plates (5×105 cells/well). After 24 h (100% confluent), the cells were infected with a 10-fold dilution series of TianTan green fluorescent protein (GFP)virus and incubated for 4 h. To examine the cytotoxic effect of oncoVV-TT virus ofn U251mg and C6 cell, trypan blue and crystal violet assay was used.

Keywords: oncolytic virus, immune therapy, glioma, vaccinia virus

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Authors: Nikola Toshikj, Michel Ramonda, Sylvain Catrouillet, Jean-Jacques Robin, Sebastien Blanquer

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Biodegradable and biocompatible block copolymers have risen as the golden materials in both medical and environmental applications. Moreover, if their architecture is of controlled manner, higher applications can be foreseen. In the meantime, organocatalytic ROP has been promoted as more rapid and immaculate route, compared to the traditional organometallic catalysis, towards efficient synthesis of block copolymer architectures. Therefore, herein we report novel organocatalytic pathway with guanidine molecules (TBD) for supported synthesis of trimethylene carbonate initiated by poly(caprolactone) as pre-polymer. Pristine PTMC-b-PCL-b-PTMC block copolymer structure, without any residual products and clear desired block proportions, was achieved under 1.5 hours at room temperature and verified by NMR spectroscopies and size-exclusion chromatography. Besides, when elaborating block copolymer films, further stability and amelioration of mechanical properties can be achieved via additional reticulation step of precedently methacrylated block copolymers. Subsequently, stimulated by the insufficient studies on the phase-separation/crystallinity relationship in these semi-crystalline block copolymer systems, their intrinsic thermal and morphology properties were investigated by differential scanning calorimetry and atomic force microscopy. Firstly, by DSC measurements, the block copolymers with χABN values superior to 20 presented two distinct glass transition temperatures, close to the ones of the respecting homopolymers, demonstrating an initial indication of a phase-separated system. In the interim, the existence of the crystalline phase was supported by the presence of melting temperature. As expected, the crystallinity driven phase-separated morphology predominated in the AFM analysis of the block copolymers. Neither crosslinking at melted state, hence creation of a dense polymer network, disturbed the crystallinity phenomena. However, the later revealed as sensible to rapid liquid nitrogen quenching directly from the melted state. Therefore, AFM analysis of liquid nitrogen quenched and crosslinked block copolymer films demonstrated a thermodynamically driven phase-separation clearly predominating over the originally crystalline one. These AFM films remained stable with their morphology unchanged even after 4 months at room temperature. However, as demonstrated by DSC analysis once rising the temperature above the melting temperature of the PCL block, neither the crosslinking nor the liquid nitrogen quenching shattered the semi-crystalline network, while the access to thermodynamical phase-separated structures was possible for temperatures under the poly (caprolactone) melting point. Precisely this coexistence of dual crosslinked/crystalline networks in the same copolymer structure allowed us to establish, for the first time, the shape-memory properties in such materials, as verified by thermomechanical analysis. Moreover, the response temperature to the material original shape depended on the block copolymer emplacement, hence PTMC or PCL as end-block. Therefore, it has been possible to reach a block copolymer with transition temperature around 40°C thus opening potential real-life medical applications. In conclusion, the initial study of phase-separation/crystallinity relationship in PTMC-b-PCL-b-PTMC block copolymers lead to the discovery of novel shape memory materials with superior properties, widely demanded in modern-life applications.

Keywords: biodegradable block copolymers, organocatalytic ROP, self-assembly, shape-memory

Procedia PDF Downloads 123

Authors: Yen Yen Tan, Lynn Lam, Cynthia Lam, Angela Koh, Edwin Seng

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Entrepreneurial education plays a crucial role in nurturing future innovators and change-makers. Over time, significant progress has been made in refining instructional approaches to develop the necessary skills among learners effectively. Two highly valuable frameworks, Kearney's "4 Principles of Entrepreneurial Pedagogy" and Bloom's "Three Domains of Learning," serve as guiding principles in entrepreneurial education. Kearney's principles align with experiential and student-centric learning, which are crucial for cultivating an entrepreneurial mindset. The potential synergies between these frameworks hold great promise for enhancing entrepreneurial acumen among students. However, despite this potential, their integration remains largely unexplored. This study aims to bridge this gap by building upon the Business Essentials through Action (BETA) module and investigating its contributions to nurturing the entrepreneurial mindset. This study employs a quasi-experimental mixed-methods approach, combining quantitative and qualitative elements to ensure comprehensive and insightful data. A cohort of 235 students participated, with 118 enrolled in the BETA module and 117 in a traditional curriculum. Their Personal Entrepreneurial Competencies (PECs) were assessed before admission (pre-Y1) and one year into the course (post-Y1) using a comprehensive 55-item PEC questionnaire, enabling measurement of critical traits such as opportunity-seeking, persistence, and risk-taking. Rigorous computations of individual entrepreneurial competencies and overall PEC scores were performed, including a correction factor to mitigate potential self-assessment bias. The orchestration of Kearney's principles and Bloom's domains within the BETA module necessitates a granular examination. Here, qualitative revelations surface, courtesy of structured interviews aligned with contemporary research methodologies. These interviews act as a portal, ushering us into the transformative journey undertaken by students. Meanwhile, the study pivots to explore the BETA module's influence on students' entrepreneurial competencies from the vantage point of faculty members. A symphony of insights emanates from intimate focus group discussions featuring six dedicated lecturers, who share their perceptions, experiences, and reflective narratives, illuminating the profound impact of pedagogical practices embedded within the BETA module. Preliminary findings from ongoing data analysis indicate promising results, showcasing a substantial improvement in entrepreneurial skills among students participating in the BETA module. This study promises not only to elevate students' entrepreneurial competencies but also to illuminate the broader canvas of applicability for Kearney's principles and Bloom's domains. The dynamic interplay of quantitative analyses, proffering precise competency metrics, and qualitative revelations, delving into the nuanced narratives of transformative journeys, engenders a holistic understanding of this educational endeavour. Through a rigorous quasi-experimental mixed-methods approach, this research aims to establish the BETA module's effectiveness in fostering entrepreneurial acumen among students at Singapore Polytechnic, thereby contributing valuable insights to the broader discourse on educational methodologies.

Keywords: entrepreneurial education, experiential learning, pedagogical frameworks, innovative competencies

Procedia PDF Downloads 54

Authors: Calorine Twebaze, Jesca Balinga

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Field X is located on the Eastern shores of L. Albert, Uganda, on the rift flank where the gross sedimentary fill is typically less than 2,000m. The field was discovered in 2006 and encountered about 20.4m of net pay across three (3) stratigraphic intervals within the discovery well. The field covers an area of 3 km2, with the structural configuration comprising a 3-way dip-closed hanging wall anticline that seals against the basement to the southeast along the bounding fault. Field X had been mapped on reprocessed 3D seismic data, which was originally acquired in 2007 and reprocessed in 2013. The seismic data quality is good across the field, and reprocessing work reduced the uncertainty in the location of the bounding fault and enhanced the lateral continuity of reservoir reflectors. The current study was a re-evaluation of Field X to refine fault interpretation and understand the structural uncertainties associated with the field. The seismic data, and three (3) wells datasets were used during the study. The evaluation followed standard workflows using Petrel software and structural attribute analysis. The process spanned from seismic- -well tie, structural interpretation, and structural uncertainty analysis. Analysis of three (3) well ties generated for the 3 wells provided a geophysical interpretation that was consistent with geological picks. The generated time-depth curves showed a general increase in velocity with burial depth. However, separation in curve trends observed below 1100m was mainly attributed to minimal lateral variation in velocity between the wells. In addition to Attribute analysis, three velocity modeling approaches were evaluated, including the Time-Depth Curve, Vo+ kZ, and Average Velocity Method. The generated models were calibrated at well locations using well tops to obtain the best velocity model for Field X. The Time-depth method resulted in more reliable depth surfaces with good structural coherence between the TWT and depth maps with minimal error at well locations of 2 to 5m. Both the NNE-SSW rift border fault and minor faults in the existing interpretation were reevaluated. However, the new interpretation delineated an E-W trending fault in the northern part of the field that had not been interpreted before. The fault was interpreted at all stratigraphic levels and thus propagates from the basement to the surface and is an active fault today. It was also noted that the entire field is less faulted with more faults in the deeper part of the field. The major structural uncertainties defined included 1) The time horizons due to reduced data quality, especially in the deeper parts of the structure, an error equal to one-third of the reflection time thickness was assumed, 2) Check shot analysis showed varying velocities within the wells thus varying depth values for each well, and 3) Very few average velocity points due to limited wells produced a pessimistic average Velocity model.

Keywords: 3D seismic data interpretation, structural uncertainties, attribute analysis, velocity modelling approaches

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Authors: Vadim Allheily, Rudiger Schmitt, Lionel Merlat, Gildas L'Hostis

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Inflight devices are nowadays major actors in both military and civilian landscapes. Among others, missiles, mortars, rockets or even drones this last decade are increasingly sophisticated, and it is today of prior manner to develop always more efficient defensive systems from all these potential threats. In this frame, recent High Energy Laser weapon prototypes (HEL) have demonstrated some extremely good operational abilities to shot down within seconds flying targets several kilometers off. Whereas test outcomes are promising from both experimental and cost-related perspectives, the deterioration process still needs to be explored to be able to closely predict the effects of a high-energy laser irradiation on typical structures, heading finally to an effective design of laser sources and protective countermeasures. Laser matter interaction researches have a long history of more than 40 years at the French-German Research Institute (ISL). Those studies were tied with laser sources development in the mid-60s, mainly for specific metrology of fast phenomena. Nowadays, laser matter interaction can be viewed as the terminal ballistics of conventional weapons, with the unique capability of laser beams to carry energy at light velocity over large ranges. In the last years, a strong focus was made at ISL on the interaction process of laser radiation with metal targets such as artillery shells. Due to the absorbed laser radiation and the resulting heating process, an encased explosive charge can be initiated resulting in deflagration or even detonation of the projectile in flight. Drones and Unmanned Air Vehicles (UAVs) are of outmost interests in modern warfare. Those aerial systems are usually made up of polymer-based composite materials, whose complexity involves new scientific challenges. Aside this main laser-matter interaction activity, a lot of experimental and numerical knowledge has been gathered at ISL within domains like spectrometry, thermodynamics or mechanics. Techniques and devices were developed to study separately each aspect concerned by this topic; optical characterization, thermal investigations, chemical reactions analysis or mechanical examinations are beyond carried out to neatly estimate essential key values. Results from these diverse tasks are then incorporated into analytic or FE numerical models that were elaborated, for example, to predict thermal repercussion on explosive charges or mechanical failures of structures. These simulations highlight the influence of each phenomenon during the laser irradiation and forecast experimental observations with good accuracy.

Keywords: composite materials, countermeasure, experimental work, high-energy laser, laser-matter interaction, modeling

Procedia PDF Downloads 251

Authors: Silvia Di Giacomo, Marcello Locatelli, Simone Carradori, Francesco Cacciagrano, Chiara Toniolo, Gabriela Mazzanti, Luisa Mannina, Stefania Cesa, Antonella Di Sotto

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Hyperglycemia represents the main pathogenic factor in the development of diabetes complications and has been found associated with mitochondrial dysfunction and oxidative stress, which in turn increase cell dysfunction. Therefore, counteract oxidative species appears to be a suitable strategy for preventing the hyperglycemia-induce cell damage and support the pharmacotherapy of diabetes and metabolic diseases. Antidiabetic potential of many food sources has been linked to the presence of polyphenolic metabolites, particularly flavonoids such as quercetin and its glycosylated form rutin. In line with this evidence, in the present study, we assayed the potential anti-hyperglycemic activity of an ethyl acetate extract from the peel of Punica granatum L. var. Dente di Cavallo (PGE), a fruit well known to traditional medicine for the beneficial properties of its edible juice. The effect of the extract on the glucidic metabolism has been evaluated by assessing its ability to inhibit α-amylase and α-glucosidase, two digestive enzymes responsible for the hydrolysis of dietary carbohydrates: their inhibition can delay the carbohydrate digestion and reduce glucose absorption, thus representing an important strategy for the management of hyperglycemia. Also, the PGE ability to block the release of advanced glycated end-products (AGEs), whose accumulation is known to be responsible for diabetic vascular complications, was studied. The iron-reducing and chelating activities, which are the primary mechanisms by which AGE inhibitors stop their metal-catalyzed formation, were evaluated as possible antioxidant mechanisms. At last, the phenolic content of PGE was characterized by chromatographic and spectrophotometric methods. Our results displayed the ability of PGE to inhibit α-amylase enzyme with a similar potency to the positive control: the IC₅₀ values were 52.2 (CL 27.7 - 101.2) µg/ml and 35.6 (CL 22.8 - 55.5) µg/ml for acarbose and PGE, respectively. PGE also inhibited the α-glucosidase enzyme with about a 25 higher potency than the positive controls of acarbose and quercetin. Furthermore, the extract exhibited ferrous and ferric ion chelating ability, with a maximum effect of 82.1% and 80.6% at a concentration of 250 µg/ml respectively, and reducing properties, reaching the maximum effect of 80.5% at a concentration of 10 µg/ml. At last, PGE was found able to inhibit the AGE production (maximum inhibition of 82.2% at the concentration of 1000 µg/ml), although with lower potency with respect to the positive control rutin. The phytochemical analysis of PGE displayed the presence of high levels of total polyphenols, tannins, and flavonoids, among which ellagic acid, gallic acid and catechin were identified. Altogether these data highlight the ability of PGE to control the carbohydrate metabolism at different levels, both by inhibiting the metabolic enzymes and by affecting the AGE formation likely by chelating mechanisms. It is also noteworthy that peel from pomegranate, although being a waste of juice production, can be reviewed as a nutraceutical source. In conclusion, present results suggest the possible role of PGE as a remedy for preventing hyperglycemia complications and encourage further in vivo studies.

Keywords: anti-hyperglycemic activity, antioxidant properties, nutraceuticals, polyphenols, pomegranate

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Authors: K. Verma, v. S. Moholkar

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In developed countries, water pollution caused by industrial discharge has emerged as a significant environmental concern over the past decades. However, despite ongoing efforts, a fully effective and sustainable remediation strategy has yet to be identified. This paper describes how enzymatic and sonochemical treatments have demonstrated great promise in degrading bio-refractory pollutants. Mainly, a compelling area of interest lies in the combined technique of sono-enzymatic treatment, which has exhibited a synergistic enhancement effect surpassing that of the individual techniques. This study employed the covalent attachment method to immobilize Laccase from Trametes versicolor onto amino-functionalized magnetic Fe₃O₄ nanoparticles. To comprehensively characterize the synthesized free nanoparticles and the laccase-immobilized nanoparticles, various techniques such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), vibrating sample magnetometer (VSM), and surface area through Brunauer-Emmett-Teller (BET) were employed. The size of immobilized Fe₃O₄@Laccase was found to be 60 nm, and the maximum loading of laccase was found to be 24 mg/g of nanoparticle. An investigation was conducted to study the effect of various process parameters, such as immobilized Fe₃O₄ Laccase dose, temperature, and pH, on the % Chemical oxygen demand (COD) removal as a response. The statistical design pinpointed the optimum conditions (immobilized Fe₃O₄ Laccase dose = 1.46 g/L, pH = 4.5, and temperature = 66 oC), resulting in a remarkable 65.58% COD removal within 60 minutes. An even more significant improvement (90.31% COD removal) was achieved with ultrasound-assisted enzymatic reaction utilizing a 10% duty cycle. The investigation of various kinetic models for free and immobilized laccase, such as the Haldane, Yano, and Koga, and Michaelis-Menten, showed that ultrasound application impacted the kinetic parameters Vmax and Km. Specifically, Vmax values for free and immobilized laccase were found to be 0.021 mg/L min and 0.045 mg/L min, respectively, while Km values were 147.2 mg/L for free laccase and 136.46 mg/L for immobilized laccase. The lower Km and higher Vmax for immobilized laccase indicate its enhanced affinity towards the substrate, likely due to ultrasound-induced alterations in the enzyme's confirmation and increased exposure of active sites, leading to more efficient degradation. Furthermore, the toxicity and Liquid chromatography-mass spectrometry (LC-MS) analysis revealed that after the treatment process, the wastewater exhibited 70% less toxicity than before treatment, with over 25 compounds degrading by more than 75%. At last, the prepared immobilized laccase had excellent recyclability retaining 70% activity up to 6 consecutive cycles. A straightforward manufacturing strategy and outstanding performance make the recyclable magnetic immobilized Laccase (Fe₃O₄ Laccase) an up-and-coming option for various environmental applications, particularly in water pollution control and treatment.

Keywords: kinetic, laccase enzyme, sonoenzymatic, ultrasound irradiation

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Authors: Swati Srivastava, Mattia Lauriola, Yuval Gilad, Adi Kimchi, Yosef Yarden

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The glucocorticoid receptor (GR) has been proposed to play important, but incompletely understood roles in cancer. Glucocorticoids (GCs) are widely used as co-medication of various carcinomas, due to their ability to reduce the toxicity of chemotherapy. Furthermore, GR antagonism has proven to be a strategy to treat triple negative breast cancer and castration-resistant prostate cancer. These observations suggest differential GR involvement in cancer subtypes. The goal of our study has been to elaborate the current understanding of GR signaling in tumor progression and metastasis. Our study involves two cellular models, non-tumorigenic breast epithelial cells (MCF10A) and Ewing sarcoma cells (CHLA9). In our breast cell model, the results indicated that the GR agonist dexamethasone inhibits EGF-induced mammary cell migration, and this effect was blocked when cells were stimulated with a GR antagonist, namely RU486. Microarray analysis for gene expression revealed that the mechanism underlying inhibition involves dexamenthasone-mediated repression of well-known activators of EGFR signaling, alongside with enhancement of several EGFR’s negative feedback loops. Because GR mainly acts primarily through composite response elements (GREs), or via a tethering mechanism, our next aim has been to find the transcription factors (TFs) which can interact with GR in MCF10A cells.The TF-binding motif overrepresented at the promoter of dexamethasone-regulated genes was predicted by using bioinformatics. To validate the prediction, we performed high-throughput Protein Complementation Assays (PCA). For this, we utilized the Gaussia Luciferase PCA strategy, which enabled analysis of protein-protein interactions between GR and predicted TFs of mammary cells. A library comprising both nuclear receptors (estrogen receptor, mineralocorticoid receptor, GR) and TFs was fused to fragments of GLuc, namely GLuc(1)-X, X-GLuc(1), and X-GLuc(2), where GLuc(1) and GLuc(2) correspond to the N-terminal and C-terminal fragments of the luciferase gene.The resulting library was screened, in human embryonic kidney 293T (HEK293T) cells, for all possible interactions between nuclear receptors and TFs. By screening all of the combinations between TFs and nuclear receptors, we identified several positive interactions, which were strengthened in response to dexamethasone and abolished in response to RU486. Furthermore, the interactions between GR and the candidate TFs were validated by co-immunoprecipitation in MCF10A and in CHLA9 cells. Currently, the roles played by the uncovered interactions are being evaluated in various cellular processes, such as cellular proliferation, migration, and invasion. In conclusion, our assay provides an unbiased network analysis between nuclear receptors and other TFs, which can lead to important insights into transcriptional regulation by nuclear receptors in various diseases, in this case of cancer.

Keywords: epidermal growth factor, glucocorticoid receptor, protein complementation assay, transcription factor

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Authors: Lily Ranjbar, Haori Yang

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Online education has been around for several decades, but the importance of online education became evident after the COVID-19 pandemic. Eventhough the online delivery approach works well for knowledge building through delivering content and oversight processes, it has limitations in developing hands-on laboratory skills, especially in the STEM field. During the pandemic, many education institutions faced numerous challenges in delivering lab-based courses, especially in the STEM field. Also, many students worldwide were unable to practice working with lab equipment due to social distancing or the significant cost of highly specialized equipment. The laboratory plays a crucial role in nuclear science and engineering education. It can engage students and improve their learning outcomes. In addition, online education and virtual labs have gained substantial popularity in engineering and science education. Therefore, developing virtual labs is vital for institutions to deliver high-class education to their students, including their online students. The School of Nuclear Science and Engineering (NSE) at Oregon State University, in partnership with SpectralLabs company, has developed an Advanced Virtual Radiation Detection and Measurement Lab (AVR-DML) to offer a fully online Master of Health Physics program. It was essential for us to use a system that could simulate nuclear modules that accurately replicate the underlying physics, the nature of radiation and radiation transport, and the mechanics of the instrumentations used in the real radiation detection lab. It was all accomplished using a Realistic, Adaptive, Interactive Learning System (RAILS). RAILS is a comprehensive software simulation-based learning system for use in training. It is comprised of a web-based learning management system that is located on a central server, as well as a 3D-simulation package that is downloaded locally to user machines. Users will find that the graphics, animations, and sounds in RAILS create a realistic, immersive environment to practice detecting different radiation sources. These features allow students to coexist, interact and engage with a real STEM lab in all its dimensions. It enables them to feel like they are in a real lab environment and to see the same system they would in a lab. Unique interactive interfaces were designed and developed by integrating all the tools and equipment needed to run each lab. These interfaces provide students full functionality for data collection, changing the experimental setup, and live data collection with real-time updates for each experiment. Students can manually do all experimental setups and parameter changes in this lab. Experimental results can then be tracked and analyzed in an oscilloscope, a multi-channel analyzer, or a single-channel analyzer (SCA). The advanced virtual radiation detection and measurement laboratory developed in this study enabled the NSE school to offer a fully online MHP program. This flexibility of course modality helped us to attract more non-traditional students, including international students. It is a valuable educational tool as students can walk around the virtual lab, make mistakes, and learn from them. They have an unlimited amount of time to repeat and engage in experiments. This lab will also help us speed up training in nuclear science and engineering.

Keywords: advanced radiation detection and measurement, virtual laboratory, realistic adaptive interactive learning system (rails), online education in stem fields, student engagement, stem online education, stem laboratory, online engineering education

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Authors: Weiam Daear, Patrick Lai, Elmar Prenner

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The human body offers many avenues that could be used for drug delivery. The pulmonary route, which is delivered through the lungs, presents many advantages that have sparked interested in the field. These advantages include; 1) direct access to the lungs and the large surface area it provides, and 2) close proximity to the blood circulation. The air-blood barrier of the alveoli is about 500 nm thick. The air-blood barrier consist of a monolayer of lipids and few proteins called the lung surfactant and cells. This monolayer consists of ~90% lipids and ~10% proteins that are produced by the alveolar epithelial cells. The two major lipid classes constitutes of various saturation and chain length of phosphatidylcholine (PC) and phosphatidylglycerol (PG) representing 80% of total lipid component. The major role of the lung surfactant monolayer is to reduce surface tension experienced during breathing cycles in order to prevent lung collapse. In terms of the pulmonary drug delivery route, drugs pass through various parts of the respiratory system before reaching the alveoli. It is at this location that the lung surfactant functions as the air-blood barrier for drugs. As the field of nanomedicine advances, the use of nanoparticles (NPs) as drug delivery vehicles is becoming very important. This is due to the advantages NPs provide with their large surface area and potential specific targeting. Therefore, studying the interaction of NPs with lung surfactant and whether they affect its stability becomes very essential. The aim of this research is to develop a biomimetic model of the human lung surfactant followed by a biophysical analysis of the interaction of polymeric NPs. This biomimetic model will function as a fast initial mode of testing for whether NPs affect the stability of the human lung surfactant. The model developed thus far is an 8-component lipid system that contains major PC and PG lipids. Recently, a custom made 16:0/16:1 PC and PG lipids were added to the model system. In the human lung surfactant, these lipids constitute 16% of the total lipid component. According to the author’s knowledge, there is not much monolayer data on the biophysical analysis of the 16:0/16:1 lipids, therefore more analysis will be discussed here. Biophysical techniques such as the Langmuir Trough is used for stability measurements which monitors changes to a monolayer's surface pressure upon NP interaction. Furthermore, Brewster Angle Microscopy (BAM) employed to visualize changes to the lateral domain organization. Results show preferential interactions of NPs with different lipid groups that is also dependent on the monolayer fluidity. Furthermore, results show that the film stability upon compression is unaffected, but there are significant changes in the lateral domain organization of the lung surfactant upon NP addition. This research is significant in the field of pulmonary drug delivery. It is shown that NPs within a certain size range are safe for the pulmonary route, but little is known about the mode of interaction of those polymeric NPs. Moreover, this work will provide additional information about the nanotoxicology of NPs tested.

Keywords: Brewster angle microscopy, lipids, lung surfactant, nanoparticles

Procedia PDF Downloads 173

Authors: John G. Skelly, Peter K. Dearden, Thomas W. R. Harrop, Sarah N. Inwood, Joseph Guhlin

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The Argentine stem weevil (ASW; L. bonariensis) is an economically important pasture pest in New Zealand, which causes about $200 million of damage per annum. Microctonus hyperodae (Mh), a parasite of the ASW in its natural range in South America, was introduced into New Zealand to curb the pasture damage caused by the ASW. Mh is an endoparasitic wasp that lays its eggs in the ASW halting its reproduction. Mh was initially successful at preventing ASW proliferation and reducing pasture damage. The effectiveness of Mh has since declined due to decreased parasitism rates and has resulted in increased pasture damage. Although the mechanism through which ASW has developed resistance to Mh has not been discovered, it has been proposed to be due to the different reproductive modes used by Mh and the ASW in New Zealand. The ASW reproduces sexually, whereas Mh reproduces asexually, which has been hypothesised to have allowed the ASW to ‘out evolve’ Mh. Other species within the Microctonus genus reproduce both sexually and asexually. Strains of Microctonus aethiopoides (Ma), a species closely related to Mh, reproduce either by sexual or asexual reproduction. Comparing the genomes of sexual and asexual Microctonus may allow for the identification of the mechanism of asexual reproduction and other characteristics that may improve Mh as a biocontrol agent. The genomes of Mh and three strains of Ma, two of which reproduce sexually and one reproduces asexually, have been sequenced and annotated. The French (MaFR) and Moroccan (MaMO) reproduce sexually, whereas the Irish strain (MaIR) reproduces asexually. Like Mh, The Ma strains are also used as biocontrol agents, but for different weevil species. The genomes of Mh and MaIR were subsequently upgraded using Hi-C, resulting in a set of high quality, highly contiguous genomes. A subset of the genes involved in mitosis and meiosis, which have been identified though the use of Hidden Markov Models generated from genes involved in these processes in other Hymenoptera, have been catalogued in Mh and the strains of Ma. Meiosis and mitosis genes were broadly conserved in both sexual and asexual Microctonus species. This implies that either the asexual species have retained a subset of the molecular components required for sexual reproduction or that the molecular mechanisms of mitosis and meiosis are different or differently regulated in Microctonus to other insect species in which these mechanisms are more broadly characterised. Bioinformatic analysis of the chemoreceptor compliment in Microctonus has revealed some variation in the number of olfactory receptors, which may be related to host preference. Phylogenetic analysis of olfactory receptors highlights variation, which may be able to explain different host range preferences in the Microctonus. Hi-C clustering implies that Mh has 12 chromosomes, and MaIR has 8. Hence there may be variation in gene regulation between species. Genome alignment of Mh and MaIR implies that there may be large scale genome structural variation. Greater insight into the genetics of these agriculturally important group of parasitic wasps may be beneficial in restoring or maintaining their biocontrol efficacy.

Keywords: argentine stem weevil, asexual, genomics, Microctonus hyperodae

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Authors: Nigar Kantarci Carsibasi

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Coarse-grained elastic network models, namely Gaussian network model (GNM) and Anisotropic network model (ANM), are utilized in order to investigate the fluctuation dynamics of Murine Double Minute 2 (MDM2), which is the native inhibitor of p53. Conformational dynamics of MDM2 are elucidated in unbound, p53 bound, and non-peptide small molecule inhibitor bound forms. With this, it is aimed to gain insights about the alterations brought to global dynamics of MDM2 by native peptide inhibitor p53, and two small molecule inhibitors (HDM201 and NVP-CGM097) that are undergoing clinical stages in cancer studies. MDM2 undergoes significant conformational changes upon inhibitor binding, carrying pieces of evidence of induced-fit mechanism. Small molecule inhibitors examined in this work exhibit similar fluctuation dynamics and characteristic mode shapes with p53 when complexed with MDM2, which would shed light on the design of novel small molecule inhibitors for cancer therapy. The results showed that residues Phe 19, Trp 23, Leu 26 reside in the minima of slowest modes of p53, pointing to the accepted three-finger binding model. Pro 27 displays the most significant hinge present in p53 and comes out to be another functionally important residue. Three distinct regions are identified in MDM2, for which significant conformational changes are observed upon binding. Regions I (residues 50-77) and III (residues 90-105) correspond to the binding interface of MDM2, including (α2, L2, and α4), which are stabilized during complex formation. Region II (residues 77-90) exhibits a large amplitude motion, being highly flexible, both in the absence and presence of p53 or other inhibitors. MDM2 exhibits a scattered profile in the fastest modes of motion, while binding of p53 and inhibitors puts restraints on MDM2 domains, clearly distinguishing the kinetically hot regions. Mode shape analysis revealed that the α4 domain controls the size of the cleft by keeping the cleft narrow in unbound MDM2; and open in the bound states for proper penetration and binding of p53 and inhibitors, which points to the induced-fit mechanism of p53 binding. P53 interacts with α2 and α4 in a synchronized manner. Collective modes are shifted upon inhibitor binding, i.e., second mode characteristic motion in MDM2-p53 complex is observed in the first mode of apo MDM2; however, apo and bound MDM2 exhibits similar features in the softest modes pointing to pre-existing modes facilitating the ligand binding. Although much higher amplitude motions are attained in the presence of non-peptide small molecule inhibitor molecules as compared to p53, they demonstrate close similarity. Hence, NVP-CGM097 and HDM201 succeed in mimicking the p53 behavior well. Elucidating how drug candidates alter the MDM2 global and conformational dynamics would shed light on the rational design of novel anticancer drugs.

Keywords: cancer, drug design, elastic network model, MDM2

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Authors: Sundaram Arulmozhiraja, Kanade Shimizu, Yuta Yamamoto, Satoshi Ichikawa, Maenaka Katsumi, Hiroaki Tokiwa

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Drug discovery is shifting from small molecule based drugs targeting local active site to middle molecules (MM) targeting large, flat, and groove-shaped binding sites, for example, protein-protein interface because at least half of all targets assumed to be involved in human disease have been classified as “difficult to drug” with traditional small molecules. Hence, MMs such as peptides, natural products, glycans, nucleic acids with various high potent bioactivities become important targets for drug discovery programs in the recent years as they could be used for ‘undruggable” intracellular targets. Cell membrane permeability is one of the key properties of pharmacodynamically active MM drug compounds and so evaluating this property for the potential MMs is crucial. Computational prediction for cell membrane permeability of molecules is very challenging; however, recent advancement in the molecular dynamics simulations help to solve this issue partially. It is expected that MMs with high membrane permeability will enable drug discovery research to expand its borders towards intracellular targets. Further to understand the chemistry behind the permeability of MMs, it is necessary to investigate their conformational changes during the permeation through membrane and for that their interactions with the membrane field should be studied reliably because these interactions involve various non-bonding interactions such as hydrogen bonding, -stacking, charge-transfer, polarization dispersion, and non-classical weak hydrogen bonding. Therefore, parameters-based classical mechanics calculations are hardly sufficient to investigate these interactions rather, quantum mechanical (QM) calculations are essential. Fragment molecular orbital (FMO) method could be used for such purpose as it performs ab initio QM calculations by dividing the system into fragments. The present work is aimed to study the cell permeability of middle molecules using molecular dynamics simulations and FMO-QM calculations. For this purpose, a natural compound syringolin and its analogues were considered in this study. Molecular simulations were performed using NAMD and Gromacs programs with CHARMM force field. FMO calculations were performed using the PAICS program at the correlated Resolution-of-Identity second-order Moller Plesset (RI-MP2) level with the cc-pVDZ basis set. The simulations clearly show that while syringolin could not permeate the membrane, its selected analogues go through the medium in nano second scale. These correlates well with the existing experimental evidences that these syringolin analogues are membrane-permeable compounds. Further analyses indicate that intramolecular -stacking interactions in the syringolin analogues influenced their permeability positively. These intramolecular interactions reduce the polarity of these analogues so that they could permeate the lipophilic cell membrane. Conclusively, the cell membrane permeability of various middle molecules with potent bioactivities is efficiently studied using molecular dynamics simulations. Insight of this behavior is thoroughly investigated using FMO-QM calculations. Results obtained in the present study indicate that non-bonding intramolecular interactions such as hydrogen-bonding and -stacking along with the conformational flexibility of MMs are essential for amicable membrane permeation. These results are interesting and are nice example for this theoretical calculation approach that could be used to study the permeability of other middle molecules. This work was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number 18ae0101047.

Keywords: fragment molecular orbital theory, membrane permeability, middle molecules, molecular dynamics simulation

Procedia PDF Downloads 179