Search results for: enzyme linked immunosorbent assay (ELISA)

Authors: Lachin Mikjtarnejad, Mohsen Farzaneh

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Various microbes, such as fungi and bacteria species, are naturally found in the fruit microbiota, and some of them act as a pathogen and result in fruit rot. Among non-pathogenic microbes, yeasts (single-celled microorganisms belonging to the fungi kingdom) can colonize fruit tissues and interact with them without causing any damage to them. Although yeasts are part of the plant microbiota, there is little information about their interactions with plants in comparison with bacteria and filamentous fungi. According to several existing studies, some yeasts can colonize different plant species and have the biological control ability to suppress some of the plant pathogens. It means those specific yeast-colonized plants are more resistant to some plant pathogens. The major objective of the present investigation is to isolate yeast strains from apple fruit and screen their ability to control Penicillium expansum, the causal agent of blue mold of fruits. In the present study, psychrotrophic and epiphytic yeasts were isolated from apple fruits that were stored at low temperatures (0–1°C). Totally, 42 yeast isolates were obtained and identified by molecular analysis based on genomic sequences of the D1/D2 and ITS1/ITS4 regions of their rDNA. All isolated yeasts were primarily screened by' in vitro dual culture assay against P. expansum by measuring the fungus' relative growth inhibition after 10 days of incubation. The results showed that the mycelial growth of P. expansum was reduced between 41–53% when challenged by promising yeast strains. The isolates with the strongest antagonistic activity belonged to Metschnikowia pulcherrima A13, Rhodotorula mucilaginosa A41, Leucosporidium Scottii A26, Aureobasidium pullulans A19, Pichia guilliermondii A32, Cryptococcus flavescents A25, and Pichia kluyveri A40. The results of seven superior isolates to inhibit blue mold decay on fruit showed that isolates A. pullulans A19, L. scottii A26, and Pi. guilliermondii A32 could significantly reduce the fruit rot and decay with 26 mm, 22 mm and 20 mm zone diameter, respectively, compared to the control sample with 43 mm. Our results show Pi. guilliermondii strain A13 was the most effective yeast isolates in inhibiting P. expansum on apple fruits. In addition, various biological control mechanisms of promising biological isolates against blue mold have been evaluated to date, including competition for nutrients and space, production of volatile metabolites, reduction of spore germination, production of siderophores and production of extracellular lytic enzymes such as chitinase and β-1,3-glucanase. However, the competition for nutrients and the ability to inhibit P. expansum spore growth have been introduced as the prevailing mechanisms among them. Accordingly, in our study, isolates A13, A41, A40, A25, A32, A19 and A26 inhibited the germination of P. expansum, whereas isolates A13 and A19 were the strongest inhibitors of P. expansum mycelia growth, causing 89.13% and 81.75 % reduction in the mycelial surface, respectively. All the promising isolates produced chitinase and β-1,3-glucanase after 3, 5 and 7 days of cultivation. Finally, based on our findings, we are proposing that, Pi. guilliermondiias as an effective biocontrol agent and alternative to chemical fungicides to control the blue mold of apple fruit.

Keywords: yeast, yeast enzymes, biocontrol, post harvest diseases

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Authors: Hilal T. Sasmazel, Seda Surucu

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Skin tissue engineering is a promising field for the treatment of skin defects using scaffolds. This approach involves the use of living cells and biomaterials to restore, maintain, or regenerate tissues and organs in the body by providing; (i) larger surface area for cell attachment, (ii) proper porosity for cell colonization and cell to cell interaction, and (iii) 3-dimensionality at macroscopic scale. Recent studies on this area mainly focus on fabrication of scaffolds that can closely mimic the natural extracellular matrix (ECM) for creation of tissue specific niche-like environment at the subcellular scale. Scaffolds designed as ECM-like architectures incorporating into the host with minimal scarring/pain and facilitate angiogenesis. This study is related to combining of synthetic PCL and natural chitosan polymers to form 3D PCL/Chitosan core-shell structures for skin tissue engineering applications. Amongst the polymers used in tissue engineering, natural polymer chitosan and synthetic polymer poly(ε-caprolactone) (PCL) are widely preferred in the literature. Chitosan has been among researchers for a very long time because of its superior biocompatibility and structural resemblance to the glycosaminoglycan of bone tissue. However, the low mechanical flexibility and limited biodegradability properties reveals the necessity of using this polymer in a composite structure. On the other hand, PCL is a versatile polymer due to its low melting point (60°C), ease of processability, degradability with non-enzymatic processes (hydrolysis) and good mechanical properties. Nevertheless, there are also several disadvantages of PCL such as its hydrophobic structure, limited bio-interaction and susceptibility to bacterial biodegradation. Therefore, it became crucial to use both of these polymers together as a hybrid material in order to overcome the disadvantages of both polymers and combine advantages of those. The scaffolds here were fabricated by using electrospinning technique and the characterizations of the samples were done by contact angle (CA) measurements, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-Ray Photoelectron spectroscopy (XPS). Additionally, gas permeability test, mechanical test, thickness measurement and PBS absorption and shrinkage tests were performed for all type of scaffolds (PCL, chitosan and PCL/chitosan core-shell). By using ImageJ launcher software program (USA) from SEM photographs the average inter-fiber diameter values were calculated as 0.717±0.198 µm for PCL, 0.660±0.070 µm for chitosan and 0.412±0.339 µm for PCL/chitosan core-shell structures. Additionally, the average inter-fiber pore size values exhibited decrease of 66.91% and 61.90% for the PCL and chitosan structures respectively, compare to PCL/chitosan core-shell structures. TEM images proved that homogenous and continuous bead free core-shell fibers were obtained. XPS analysis of the PCL/chitosan core-shell structures exhibited the characteristic peaks of PCL and chitosan polymers. Measured average gas permeability value of produced PCL/chitosan core-shell structure was determined 2315±3.4 g.m-2.day-1. In the future, cell-material interactions of those developed PCL/chitosan core-shell structures will be carried out with L929 ATCC CCL-1 mouse fibroblast cell line. Standard MTT assay and microscopic imaging methods will be used for the investigation of the cell attachment, proliferation and growth capacities of the developed materials.

Keywords: chitosan, coaxial electrospinning, core-shell, PCL, tissue scaffold

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Authors: Tracie Catlett

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Students enrolled in high-achieving schools are under tremendous pressure to perform at high levels inside and outside the classroom. Achievement pressure is a prevalent source of stress for students enrolled in high-achieving schools, and female students, in particular, experience a higher frequency and higher levels of stress compared to their male peers. The practice of mindfulness in a school setting is one tool that has been linked to improved self-regulation of emotions, increased positive emotions, and stress reduction. A mixed methods randomized pretest-posttest no-treatment control trial evaluated the effects of a six-session mindfulness intervention taught during a regularly scheduled life skills period in an independent day school, one type of high-achieving school. Twenty-nine students in Grades 10 and 11 were randomized by class, where Grade 11 students were in the intervention group (n = 14) and Grade 10 students were in the control group (n = 15). Findings from the study produced mixed results. There was no evidence that the mindfulness program reduced participants’ stress levels and negative emotions. In fact, contrary to what was expected, students enrolled in the intervention group experienced higher levels of stress and increased negative emotions at posttreatment when compared to pretreatment. Neither the within-group nor the between-groups changes in stress level were statistically significant, p > .05, and the between-groups effect size was small, d = .2. The study found evidence that the mindfulness program may have had a positive impact on students’ ability to regulate their emotions. The within-group comparison and the between-groups comparison at posttreatment found that students in the mindfulness course experienced statistically significant improvement in the in their ability to regulate their emotions at posttreatment, p = .009 < .05 and p =. 034 < .05, respectively. The between-groups effect size was medium, d =.7, suggesting that the positive differences in emotion regulation difficulties were substantial and have practical implications. The analysis of gender differences, as they relate to stress and emotions, revealed that female students perceive higher levels of stress and report experiencing stress more often than males. There were no gender differences when analyzing sources of stress experienced by the student participants. Both females and males experience regular achievement pressures related to their school performance and worry about their future, college acceptance, grades, and parental expectations. Females reported an increased awareness of their stress and actively engaged in practicing mindfulness to manage their stress. Students in the treatment group expressed that the practice of mindfulness resulted in feelings of relaxation and calmness.

Keywords: achievement pressure, adolescents, emotion regulation, emotions, high-achieving schools, independent schools, mindfulness, negative affect, positive affect, stress

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Authors: Alireza Shams, Ali Zamanian, Atefehe Shamosi, Farnaz Ghorbani

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Introduction: Although the application of a new strategy remains a remarkable challenge for treatment of disabilities due to neuronal defects, progress in Nanomedicine and tissue engineering, suggesting the new medical methods. One of the promising strategies for reconstruction and regeneration of nervous tissue is replacing of lost or damaged cells by specific scaffolds after Compressive, ischemic and traumatic injuries of central nervous system. Furthermore, ultrastructure, composition, and arrangement of tissue scaffolds are effective on cell grafts. We followed implantation and differentiation of mesenchyme stem cells to neural cells on Gelatin Polylactic-co-glycolic acid (PLGA) scaffolds coated with iron nanoparticles. The aim of this study was to evaluate the capability of stem cells to differentiate into motor neuron-like cells under topographical cues and morphogenic factors. Methods and Materials: Bone marrow mesenchymal stem cells (BMMSCs) was obtained by primary cell culturing of adult rat bone marrow got from femur bone by flushing method. BMMSCs were incubated with DMEM/F12 (Gibco), 15% FBS and 100 U/ml pen/strep as media. Then, BMMSCs seeded on Gel/PLGA scaffolds and tissue culture (TCP) polystyrene embedded and incorporated by Fe Nano particles (FeNPs) (Fe3o4 oxide (M w= 270.30 gr/mol.). For neuronal differentiation, 2×10 5 BMMSCs were seeded on Gel/PLGA/FeNPs scaffolds was cultured for 7 days and 0.5 µ mol. Retinoic acid, 100 µ mol. Ascorbic acid,10 ng/ml. Basic fibroblast growth factor (Sigma, USA), 250 μM Iso butyl methyl xanthine, 100 μM 2-mercaptoethanol, and 0.2 % B27 (Invitrogen, USA) added to media. Proliferation of BMMSCs was assessed by using MTT assay for cell survival. The morphology of BMMSCs and scaffolds was investigated by scanning electron microscopy analysis. Expression of neuron-specific markers was studied by immunohistochemistry method. Data were analyzed by analysis of variance, and statistical significance was determined by Turkey’s test. Results: Our results revealed that differentiation and survival of BMMSCs into motor neuron-like cells on Gel/PLGA/FeNPs as a biocompatible and biodegradable scaffolds were better than those cultured in Gel/PLGA in absence of FeNPs and TCP scaffolds. FeNPs had raised physical power but decreased capacity absorption of scaffolds. Well defined oriented pores in scaffolds due to FeNPs may activate differentiation and synchronized cells as a mechanoreceptor. Induction effects of magnetic FeNPs by One way flow of channels in scaffolds help to lead the cells and can facilitate direction of their growth processes. Discussion: Progression of biological properties of BMMSCs and the effects of FeNPs spreading under magnetic field was evaluated in this investigation. In vitro study showed that the Gel/PLGA/FeNPs scaffold provided a suitable structure for motor neuron-like cells differentiation. This could be a promising candidate for enhancing repair and regeneration in neural defects. Dynamic and static magnetic field for inducing and construction of cells can provide better results for further experimental studies.

Keywords: differentiation, mesenchymal stem cells, nano particles, neuronal defects, Scaffolds

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Authors: Ashir Ahmed

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Generally, radicalization happens when a person's thinking and behaviour become significantly different from how most of the members of their society and community view social issues and participate politically. Radicalization often leads to violent extremism that refers to the beliefs and actions of people who support or use violence to achieve ideological, religious or political goals. Studies on radicalization negate the common myths that someone must be in a group to be radicalised or anyone who experiences radical thoughts is a violent extremist. Moreover, it is erroneous to suggest that radicalisation is always linked to religion. Generally, the common motives of radicalization include ideological, issue-based, ethno-nationalist or separatist underpinning. Moreover, there are number of factors that further augments the chances of someone being radicalised and may choose the path of violent extremism and possibly terrorism. Since there are numbers of factors (and sometimes quite different) contributing in radicalization and violent extremism, it is highly unlikely to devise a single solution that could produce effective outcomes to deal with radicalization, violent extremism and terrorism. The pathway to deradicalization, like the pathway to radicalisation, is different for everyone. Considering the need of having customized deradicalization resolution, this study proposes a multi-tier framework, called ‘pyramid of deradicalization’ that first help identifying the stage at which an individual could be on the radicalization pathway and then propose a customize strategy to deal with the respective stage. The first tier (tier 1) addresses broader community and proposes a ‘universal approach’ aiming to offer community-based design and delivery of educational programs to raise awareness and provide general information on possible factors leading to radicalization and their remedies. The second tier focuses on the members of community who are more vulnerable and are disengaged from the rest of the community. This tier proposes a ‘targeted approach’ targeting the vulnerable members of the community through early intervention such as providing anonymous help lines where people feel confident and comfortable in seeking help without fearing the disclosure of their identity. The third tier aims to focus on people having clear evidence of moving toward extremism or getting radicalized. The people falls in this tier are believed to be supported through ‘interventionist approach’. The interventionist approach advocates the community engagement and community-policing, introducing deradicalization programmes to the targeted individuals and looking after their physical and mental health issues. The fourth and the last tier suggests the strategies to deal with people who are actively breaking the law. ‘Enforcement approach’ suggests various approaches such as strong law enforcement, fairness and accuracy in reporting radicalization events, unbiased treatment by law based on gender, race, nationality or religion and strengthen the family connections.It is anticipated that the operationalization of the proposed framework (‘pyramid of deradicalization’) would help in categorising people considering their tendency to become radicalized and then offer an appropriate strategy to make them valuable and peaceful members of the community.

Keywords: deradicalization, framework, terrorism, violent extremism

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Authors: Juan Sebastian Huertas Piedrahita, Jaime Arturo Lopez Duque, Eduardo Luis Perez Londoño, Julián S. Rodríguez

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The process of generating computer vision is called artificial vision. The artificial vision is a branch of artificial intelligence that allows the obtaining, processing, and analysis of any type of information especially the ones obtained through digital images. Actually the artificial vision is used in manufacturing areas for quality control and production, as these processes can be realized through counting algorithms, positioning, and recognition of objects that can be measured by a single camera (or more). On the other hand, the companies use assembly lines formed by conveyor systems with actuators on them for moving pieces from one location to another in their production. These devices must be previously programmed for their good performance and must have a programmed logic routine. Nowadays the production is the main target of every industry, quality, and the fast elaboration of the different stages and processes in the chain of production of any product or service being offered. The principal base of this project is to program a computer that recognizes geometric figures (circle, square, and triangle) through a camera, each one with a different color and link it with a group of conveyor systems to organize the mentioned figures in cubicles, which differ from one another also by having different colors. This project bases on artificial vision, therefore the methodology needed to develop this project must be strict, this one is detailed below: 1. Methodology: 1.1 The software used in this project is QT Creator which is linked with Open CV libraries. Together, these tools perform to realize the respective program to identify colors and forms directly from the camera to the computer. 1.2 Imagery acquisition: To start using the libraries of Open CV is necessary to acquire images, which can be captured by a computer’s web camera or a different specialized camera. 1.3 The recognition of RGB colors is realized by code, crossing the matrices of the captured images and comparing pixels, identifying the primary colors which are red, green, and blue. 1.4 To detect forms it is necessary to realize the segmentation of the images, so the first step is converting the image from RGB to grayscale, to work with the dark tones of the image, then the image is binarized which means having the figure of the image in a white tone with a black background. Finally, we find the contours of the figure in the image to detect the quantity of edges to identify which figure it is. 1.5 After the color and figure have been identified, the program links with the conveyor systems, which through the actuators will classify the figures in their respective cubicles. Conclusions: The Open CV library is a useful tool for projects in which an interface between a computer and the environment is required since the camera obtains external characteristics and realizes any process. With the program for this project any type of assembly line can be optimized because images from the environment can be obtained and the process would be more accurate.

Keywords: artificial intelligence, artificial vision, binarized, grayscale, images, RGB

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Authors: Malkit Singh

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This paper presents an in-depth analysis of the problem of migration from Punjab to the West while analyzing the history and patterns of generations of migration of Punjabis to the West. A special emphasis is given to link the present socio-economic and political crisis with the historical pattern of Punjabis’ migration to the West from colonial India to Independent Bharat, along with the stories of the success and failures of Western aspirants’ youth from Punjab. The roots of the migration from Punjab to the West have been traced from the invasion of the British in Punjab, resulting in the socio-economic and political dismantling of the Punjabi society, which resulted in the migration of the Punjabis to the other colonies of the British Empire. The grim position at home despite of all the efforts and hard work by the majority of the Punjabis, particularly from the farmer community and the shining lifestyle of some families of the village or vicinity who have some relatives in the West have encouraged the large number of Punjabis to change their fortune by working in West. However, the Visa and Work Permit regime has closed the doors of the West for those who are unskilled, semi-skilled and not qualified for the visa and work permit norms, but their inspiration to change their fortune by working abroad at any cost has resulted into the development of big business fraud of immigration agent and firms in Punjab that resulted into the loss of the thousands lives, imprisonment in the foreign and selling of the properties of the Punjabis. The greed for the greener pastures in the West and, the plight of the deserted wives of NRIs and the illegal routes adopted by the Punjabi youth due to the non-availability of visas and work permits are dealt in a comprehensive method. The rise and fall of Punjab as a land of the breadbasket of Bharat and the marginalization of the farmers with middle and small holdings due to the capital-intensive techniques are linked with the forced migration of the Punjabis. The failure of the government to address and respond to the rampant corruption, agriculture failure and the resulting problems of law and order before and after the troubled period of militancy in Punjab and the resulting migration to the West are comprehensively covered. The new trend of the Student Visa and Study abroad, particularly in Canada, Australia, and New Zealand, despite of the availability of quality education at very low cost in India. The early success of some students in getting study visas from Australia, Canada, New Zealand etc. and getting permanent immigration to these countries have encouraged the majority of Punjabi youth to leave their motherland for better opportunities in the prosperous lands, that is, again, failed as these countries are flooded with the Punjabi students. Moreover, the total failure of the political leadership of Punjab to address the basic needs of society, like law and order and stop the drug menace issues in the post-militancy Punjab is also done to understand the problem.

Keywords: Punjab, migration, West, agriculture

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Authors: Ram Sharma, Esha Chatterjee, Santosh Kumar Guru, Kunal Nepali

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A tractable anti-lung cancer agent was identified via the installation of a Ring C expanded synthetic analogue of the alkaloid vasicinone [7,8,9,10-tetrahydroazepino[2,1-b] quinazolin-12(6H)-one (TAZQ)] as a surface recognition part in the HDAC inhibitory three-component model. Noteworthy to mention that the candidature of TAZQ was deemed suitable for accommodation in HDAC inhibitory pharmacophore as per the results of the fragment recruitment process conducted by our laboratory. TAZQ was pinpointed through the fragment screening program as a synthetically flexible fragment endowed with some moderate cell growth inhibitory activity against the lung cancer cell lines, and it was anticipated that the use of the aforementioned fragment to generate hydroxamic acid functionality (zinc-binding motif) bearing HDAC inhibitors would boost the antitumor efficacy of TAZQ. Consistent with our aim of applying epigenetic targets to the treatment of lung cancer, a strikingly potent anti-lung cancer scaffold (compound 6) was pinpointed through a series of in-vitro experiments. Notably, the compounds manifested a magnificent activity profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80 - 0.96 µM), and the effects were found to be mediated through preferential HDAC6 inhibition (IC50 = 12.9 nM). In addition to HDAC6 inhibition, the compounds also elicited HDAC1 and HDAC3 inhibitory activity with an IC50 value of 49.9 nM and 68.5 nM, respectively. The HDAC inhibitory ability of compound 6 was also confirmed from the results of the western blot experiment that revealed its potential to decrease the expression levels of HDAC isoforms (HDAC1, HDAC3, and HDAC6). Noteworthy to mention that complete downregulation of the HDAC6 isoform was exerted by compound 6 at 0.5 and 1 µM. Moreover, in another western blot experiment, treatment with hydroxamic acid 6 led to upregulation of H3 acK9 and α-Tubulin acK40 levels, ascertaining its inhibitory activity toward both the class I HDACs and Class II B HDACs. The results of other assays were also encouraging as treatment with compound 6 led to the suppression of the colony formation ability of A549 cells, induction of apoptosis, and increase in autophagic flux. In silico studies led us to rationalize the results of the experimental assay, and some key interactions of compound 6 with the amino acid residues of HDAC isoforms were identified. In light of the impressive activity spectrum of compound 6, a pH-responsive nanocarrier (hyaluronic acid-compound 6 nanoparticles) was prepared. The dialysis bag approach was used for the assessment of the nanoparticles under both normal and acidic circumstances, and the pH-sensitive nature of hyaluronic acid-compound 6 nanoparticles was confirmed. Delightfully, the nanoformulation was devoid of cytotoxicity against the L929 mouse fibroblast cells (normal settings) and exhibited selective cytotoxicity towards the A549 lung cancer cell lines. In a nutshell, compound 6 appears to be a promising adduct, and a detailed investigation of this compound might yield a therapeutic for the treatment of lung cancer.

Keywords: HDAC inhibitors, lung cancer, scaffold, hyaluronic acid, nanoparticles

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Authors: Gianluca Castelnuovo, Giada Pietrabissa, Gian Mauro Manzoni, Margherita Novelli, Emanuele Maria Giusti, Roberto Cattivelli, Enrico Molinari

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Diabesity could be defined as a new global epidemic of obesity and being overweight with many complications and chronic conditions. Such conditions include not only type 2 diabetes, but also cardiovascular diseases, hypertension, dyslipidemia, hypercholesterolemia, cancer, and various psychosocial and psychopathological disorders. The financial direct and indirect burden (considering also the clinical resources involved and the loss of productivity) is a real challenge in many Western health-care systems. Recently the Lancet journal defined diabetes as a 21st-century challenge. In order to promote patient compliance in diabesity treatment reducing costs, evidence-based interventions to improve weight-loss, maintain a healthy weight, and reduce related comorbidities combine different treatment approaches: dietetic, nutritional, physical, behavioral, psychological, and, in some situations, pharmacological and surgical. Moreover, new technologies can provide useful solutions in this multidisciplinary approach, above all in maintaining long-term compliance and adherence in order to ensure clinical efficacy. Psychological therapies with diet and exercise plans could better help patients in achieving weight loss outcomes, both inside hospitals and clinical centers and during out-patient follow-up sessions. In the management of chronic diseases clinical psychology play a key role due to the need of working on psychological conditions of patients, their families and their caregivers. mHealth approach could overcome limitations linked with the traditional, restricted and highly expensive in-patient treatment of many chronic pathologies: one of the best up-to-date application is the management of obesity with type 2 diabetes, where mHealth solutions can provide remote opportunities for enhancing weight reduction and reducing complications from clinical, organizational and economic perspectives. A stepped care mHealth-based approach is an interesting perspective in chronic care management of obesity with type 2 diabetes. One promising future direction could be treating obesity, considered as a chronic multifactorial disease, using a stepped-care approach: -mhealth or traditional based lifestyle psychoeducational and nutritional approach. -health professionals-driven multidisciplinary protocols tailored for each patient. -inpatient approach with the inclusion of drug therapies and other multidisciplinary treatments. -bariatric surgery with psychological and medical follow-up In the chronic care management of globesity mhealth solutions cannot substitute traditional approaches, but they can supplement some steps in clinical psychology and medicine both for obesity prevention and for weight loss management.

Keywords: clinical health psychology, mhealth, obesity, type 2 diabetes, stepped care, chronic care management

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Authors: C. A. Barros, Ana P. Barroso

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Any industrial company needs to determine the amount of variation that exists within its measurement process and guarantee the reliability of their data, studying the performance of their measurement system, in terms of linearity, bias, repeatability and reproducibility and stability. This issue is critical for automotive industry suppliers, who are required to be certified by the 16949:2016 standard (replaces the ISO/TS 16949) of International Automotive Task Force, defining the requirements of a quality management system for companies in the automotive industry. Measurement System Analysis (MSA) is one of the mandatory tools. Frequently, the measurement system in companies is not connected to the equipment and do not incorporate the methods proposed by the Automotive Industry Action Group (AIAG). To address these constraints, an R&D project is in progress, whose objective is to develop a web and cloud-based MSA tool. This MSA tool incorporates Industry 4.0 concepts, such as, Internet of Things (IoT) protocols to assure the connection with the measuring equipment, cloud computing, artificial intelligence, statistical tools, and advanced mathematical algorithms. This paper presents the preliminary findings of the project. The web and cloud-based MSA tool is innovative because it implements all statistical tests proposed in the MSA-4 reference manual from AIAG as well as other emerging methods and techniques. As it is integrated with the measuring devices, it reduces the manual input of data and therefore the errors. The tool ensures traceability of all performed tests and can be used in quality laboratories and in the production lines. Besides, it monitors MSAs over time, allowing both the analysis of deviations from the variation of the measurements performed and the management of measurement equipment and calibrations. To develop the MSA tool a ten-step approach was implemented. Firstly, it was performed a benchmarking analysis of the current competitors and commercial solutions linked to MSA, concerning Industry 4.0 paradigm. Next, an analysis of the size of the target market for the MSA tool was done. Afterwards, data flow and traceability requirements were analysed in order to implement an IoT data network that interconnects with the equipment, preferably via wireless. The MSA web solution was designed under UI/UX principles and an API in python language was developed to perform the algorithms and the statistical analysis. Continuous validation of the tool by companies is being performed to assure real time management of the ‘big data’. The main results of this R&D project are: MSA Tool, web and cloud-based; Python API; New Algorithms to the market; and Style Guide of UI/UX of the tool. The MSA tool proposed adds value to the state of the art as it ensures an effective response to the new challenges of measurement systems, which are increasingly critical in production processes. Although the automotive industry has triggered the development of this innovative MSA tool, other industries would also benefit from it. Currently, companies from molds and plastics, chemical and food industry are already validating it.

Keywords: automotive Industry, industry 4.0, Internet of Things, IATF 16949:2016, measurement system analysis

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Authors: Konstantinos Kottikas, Vlasis Stathakopoulos, Ioannis G. Theodorakis, Efthymia Kottika

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Theorists have argued that Market Orientation is comprised of two facets, namely the Market Driven and the Market Driving components. The present theoretical paper centers on the latter, which to date has been notably under-investigated. The term Market Driving (MD) pertains to influencing the structure of the market, or the behavior of market players in a direction that enhances the competitive edge of the firm. Presently, the main objectives of the paper are the specification of key antecedents and outcomes of Market Driving behavior. Market Driving firms behave proactively, by leading their customers and changing the rules of the game rather than by responding passively to them. Leading scholars were the first to conceptually conceive the notion, followed by some qualitative studies and a limited number of quantitative publications. However, recently, academicians noted that research on the topic remains limited, expressing a strong necessity for further insights. Concerning the key antecedents, top management’s Transformational Leadership (i.e. the form of leadership which influences organizational members by aligning their values, goals and aspirations to facilitate value-consistent behaviors) is one of the key drivers of MD behavior. Moreover, scholars have linked the MD concept with Entrepreneurship. Finally, the role that Employee’s Creativity plays in the development of MD behavior has been theoretically exemplified by a stream of literature. With respect to the key outcomes, it has been demonstrated that MD Behavior positively triggers firm Performance, while theorists argue that it empowers the Competitive Advantage of the firm. Likewise, researchers explicate that MD Behavior produces Radical Innovation. In order to test the robustness of the proposed theoretical framework, a combination of qualitative and quantitative methods is proposed. In particular, the conduction of in-depth interviews with distinguished executives and academicians, accompanied with a large scale quantitative survey will be employed, in order to triangulate the empirical findings. Given that it triggers overall firm’s success, the MD concept is of high importance to managers. Managers can become aware that passively reacting to market conditions is no longer sufficient. On the contrary, behaving proactively, leading the market, and shaping its status quo are new innovative approaches that lead to a paramount competitive posture and Innovation outcomes. This study also exemplifies that managers can foster MD Behavior through Transformational Leadership, Entrepreneurship and recruitment of Creative Employees. To date, the majority of the publications on Market Orientation is unilaterally directed towards the responsive (i.e. the Market Driven) component. The present paper further builds on scholars’ exhortations, and investigates the Market Driving facet, ultimately aspiring to conceptually integrate the somehow fragmented scientific findings, in a holistic framework.

Keywords: entrepreneurial orientation, market driving behavior, market orientation

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Authors: Erika Mattio

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The aim of this project is to study the Chinese presence in Ethiopia, in the area between the Saba River and the Coptic areas of the Tigray, with detailed documentation of the Danakil region, from which the salt pickers caravans departed; the study was created to understand the relationships and consequences of the Chinese advance in these areas, inhabited by tribes linked to ancient, still practiced religious rituals, and home to unique landscapes and archaeological sites. Official estimates of the number of Chinese in Africa vary widely; on the continent, there are increasingly diverse groups of Chinese migrants in terms of language, dialect, class, education, and employment. Based on this and on a very general state of the art, it was decided to increase the studies on this phenomenon, focusing the attention on one of the most interesting countries for its diversity, cultural wealth, and for strong Chinese presence: Ethiopia. The study will be integrated with interdisciplinary investigation methods, such as landscape archeology, historiographic research, participatory anthropology, geopolitics, and cultural anthropology and ethnology. There are two main objectives of the research. The first is to predict what will happen to these populations and how the territory will be modified, trying to monitor the growth of infrastructure in the country and the effects it will have on the population. Risk analyzes will be carried out to understand what the foreign presence may entail, such as the absence of sustenance for local populations, the ghettoization of foreigners, unemployment of natives and the exodus of the population to the capital; the relationships between families and the local population will be analyzed, trying to understand the dynamics of socialization and interaction. Thanks to the use of GIS, the areas affected by the Chinese presence will be geo-referenced and mapped, delimiting the areas most affected and creating a risk analysis, both in desert areas and in archaeologically and historically relevant areas. The second point is to document the life and rituals of Ethiopian populations in order not to lose the aspects of uniqueness that risk being lost. Local interviews will collect impressions and criticisms from the local population to understand if the Chinese presence is perceived as a threat or as a solution. Furthermore, Afar leaders in the Logya area will be interviewed, in truly exclusive research, to understand their links with the foreign presence. From the north, along the Saba river, we will move to the northwest, in the Tigray region, to know the impressions in the Coptic area, currently less threatened by the Chinese presence but still affected by urbanization proposals. There will also be documented the Coptic rituals of Gennà and Timkat, unique expressions of a millennial tradition. This will allow the understanding of whether the Maoist presence could influence the religious rites and forms of belief present in the country, or the country will maintain its cultural independence.

Keywords: Ethiopia, GIS, risk perceptions, salt caravans

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Authors: Benjamin Osei Tutu, Sharon Annison

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On 21^st November, 2016, an outbreak of foodborne illness occurred after a buffet lunch served during a stakeholders’ consultation meeting held in Accra. An investigation was conducted to characterise the affected people, determine the etiologic food, the source of contamination and the etiologic agent and to implement appropriate public health measures to prevent future occurrences. A retrospective cohort study was conducted via telephone interviews, using a structured questionnaire developed from the buffet menu. A case was defined as any person suffering from symptoms of foodborne illness e.g. diarrhoea and/or abdominal cramps after eating food served during the stakeholder consultation meeting in Accra on 21^st November, 2016. The exposure status of all the members of the cohort was assessed by taking the food history of each respondent during the telephone interview. The data obtained was analysed using Epi Info 7. An environmental risk assessment was conducted to ascertain the source of the food contamination. Risks of foodborne infection from the foods eaten were determined using attack rates and odds ratios. Data was obtained from 54 people who consumed food served during the stakeholders’ meeting. Out of this population, 44 people reported with symptoms of food poisoning representing 81.45% (overall attack rate). The peak incubation period was seven hours with a minimum and maximum incubation periods of four and 17 hours, respectively. The commonly reported symptoms were diarrhoea (97.73%, 43/44), vomiting (84.09%, 37/44) and abdominal cramps (75.00%, 33/44). From the incubation period, duration of illness and the symptoms, toxin-mediated food poisoning was suspected. The environmental risk assessment of the implicated catering facility indicated a lack of time/temperature control, inadequate knowledge on food safety among workers and sanitation issues. Limited number of food samples was received for microbiological analysis. Multivariate analysis indicated that illness was significantly associated with the consumption of the snacks served (OR 14.78, P < 0.001). No stool and blood or samples of etiologic food were available for organism isolation; however, the suspected etiologic agent was Staphylococcus aureus or Clostridium perfringens. The outbreak could probably be due to the consumption of unwholesome snack (tuna sandwich or chicken. The contamination and/or growth of the etiologic agent in the snack may be due to the breakdown in cleanliness, time/temperature control and good food handling practices. Training of food handlers in basic food hygiene and safety is recommended.

Keywords: Accra, buffet, conference, C. perfringens, cohort study, food poisoning, gastroenteritis, office workers, Staphylococcus aureus

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Authors: Pietro P. Falciglia, Erica Gagliano, Vincenza Brancato, Alfio Catalfo, Guglielmo Finocchiaro, Guido De Guidi, Stefano Romano, Paolo Roccaro, Federico G. A. Vagliasindi

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Cesium-137 (¹³⁷Cs) is a major radionuclide in spent nuclear fuel processing, and it represents the most important cause of contamination related to nuclear accidents. Cesium-137 has long-term radiological effects representing a major concern for the human health. Several physico-chemical methods have been proposed for ¹³⁷Cs removal from impacted water: ion-exchange, adsorption, chemical precipitation, membrane process, coagulation, and electrochemical. However, these methods can be limited by ionic selectivity and efficiency, or they present very restricted full-scale application due to equipment and chemical high costs. On the other hand, adsorption is considered a more cost-effective solution, and activated carbons (ACs) are known as a low-cost and effective adsorbent for a wide range of pollutants among which radionuclides. However, adsorption of Cs onto ACs has been investigated in very few and not exhaustive studies. In addition, exhausted activated carbons are generally discarded in landfill, that is not an eco-friendly and economic solution. Consequently, the regeneration of exhausted ACs must be considered a preferable choice. Several alternatives, including conventional thermal-, solvent-, biological- and electrochemical-regeneration, are available but are affected by several economic or environmental concerns. Microwave (MW) irradiation has been widely used in industrial and environmental applications and it has attracted many attentions to regenerating activated carbons. The growing interest in MW irradiation is based on the passive ability of the irradiated medium to convert a low power irradiation energy into a rapid and large temperature increase if the media presents good dielectric features. ACs are excellent MW-absorbers, with a high mechanical strength and a good resistance towards heating process. This work investigates the feasibility of MW irradiation for the regeneration of Cs-exhausted ACs. Adsorption batch experiments were carried out using commercially available granular activated carbon (GAC), then Cs-saturated AC samples were treated using a controllable bench-scale 2.45-GHz MW oven and investigating different adsorption-regeneration cycles. The regeneration efficiency (RE), weight loss percentage, and textural properties of the AC samples during the adsorption-regeneration cycles were also assessed. Main results demonstrated a relatively low adsorption capacity for Cs, although the feasibility of ACs was strictly linked to their dielectric nature, which allows a very efficient thermal regeneration by MW irradiation. The weight loss percentage was found less than 2%, and an increase in RE after three cycles was also observed. Furthermore, MW regeneration preserved the pore structure of the regenerated ACs. For a deeper exploration of the full-scale applicability of MW regeneration, further investigations on more adsorption-regeneration cycles or using fixed-bed columns are required.

Keywords: adsorption mechanisms, cesium, granular activated carbons, microwave regeneration

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Authors: Jesus Rodriguez Viejo

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The aim of this paper is to study cross-cultural interactions between the West and Byzantium, in the fields of art and religion, by analyzing the decoration of one luxury manuscript. The Spanish National Library is home to one of the most extraordinary examples of illuminated manuscript production of Norman Sicily – the Messina Missal. Dating from the late twelfth century, this liturgical book was the result of the intense activity of artistic patronage of an Englishman, Richard Palmer. Appointed bishop of the Sicilian city in the second half of the century, Palmer set a painting workshop attached to his cathedral. The illuminated manuscripts produced there combine a clear Byzantine iconographic language with a myriad of elements imported from France, such as a large number of decorated initials. The most remarkable depiction contained in the Missal is that of the Theotokos (fol. 80r). Its appearance immediately recalls portative Byzantine icons of the Mother of God in South Italy and Byzantium and implies the intervention of an artist familiar with icon painting. The richness of this image is a clear proof of the prestige that Byzantine art enjoyed in the island after the Norman takeover. The production of the school of Messina under Richard Palmer could be considered a counterpart in the field of manuscript illumination of the court art of the Sicilian kings in Palermo and the impressive commissions for the cathedrals of Monreale and Cefalù. However, the ethnic composition of Palmer’s workshop has never been analyzed and therefore, we intend to shed light on the permanent presence of Greek-speaking artists in Norman Messina. The east of the island was the last stronghold of the Greeks and soon after the Norman conquest, the previous exchanges between the cities of this territory and Byzantium restarted again, mainly by way of trade. Palmer was not a Norman statesman, but a churchman and his love for religion and culture prevailed over the wars and struggles for power of the Sicilian kingdom in the central Mediterranean. On the other hand, the representation of the Theotokos can prove that Eastern devotional approaches to images were still common in the east of the island more than a century after the collapse of Byzantine rule. Local Norman lords repeatedly founded churches devoted to Greek saints and medieval Greek-speaking authors were widely copied in Sicilian scriptoria. The Madrid Missal and its Theotokos are doubtless the product of Western initiative but in a land culturally dominated by Byzantium. Westerners, such as Palmer and his circle, could have been immersed in this Hellenophile culture and therefore, naturally predisposed to perform prayers and rituals, in both public and private contexts, linked to ideas and practices of Greek origin, such as the concept of icon.

Keywords: history of art, byzantine art, manuscripts, norman sicily, messina, patronage, devotion, iconography

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Authors: Camila Lee Park, Mauro Fracarolli Nunes

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Understood as the preference for products and services that do not involve moral dilemmas, ethical consumption has been increasingly discussed by scholars, practitioners, and consumers. Among its diverse trends, the defense of animal rights and welfare seems to have gained particular momentum in past decades. Not surprisingly, companies, governments, ideologues, and virtually any institution or group interested in (re)shaping society invest in the building of narratives oriented to influence consumption behavior. The animal rights movement, for example, is devoted to the elimination of the use of animals in science, as well as of commercial animal agriculture and hunting activities. Although advances in ethical consumption may be observed in practice, it still seems more popular as rhetoric. Diverse scholars have addressed the disparities between self-professed ethical consumers and their actual purchase patterns, with differences being attributed to factors such as price sensitivity, lack of information, quality, cynicism, and limited availability. The gap is also linked to the 'consumer sovereignty myth', according to which consumers are only able to choose from a pre-determined range of choices made before products reach them. On the other hand, academics also debate ethical consumption behavior as more likely to occur when it assumes compliance with social norms. As sustainability becomes a permanent issue, customers may tend to adhere to ethical consumption, either because of an individual value or due to a social one. Regardless of these efforts, the actual value attributed to ethical businesses remains unclear. Likewise, the power of stakeholders’ initiatives to influence corporate strategies is dubious. In search to offer new perspectives on these matters, the present study concentrates on the following research questions: Do customers value products/companies that respect animal rights? If so, does such enhanced value convert into actions from the part of the companies? Broadly, we aim to understand if customers’ perception holds performative traits (i.e., are capable of either trigger or contribute to changes in organizational behaviour around the respect for animal rights). In addressing these issues, two preliminary behavioral vignette-based experiments were conducted, with the perspectives of 307 participants being assessed. Building on a case of the cosmetics industry, social, emotional, and functional values were hypothesized as directly impacting positive word-of-mouth, which, in turn, would carry direct effects on purchase intention. A first structural equation model was analyzed with the combined samples of studies I and II. Results suggest that emotional value strongly impacts both positive word-of-mouth and purchase intention. Data confirms initial expectations on customers valuing products and companies that comply with ethical postures concerning animals, especially if social-oriented practices are also present.

Keywords: animal rights, business ethics, emotional value, ethical consumption

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Authors: Chen Shuwen, Nunthapin Chantachaimongkol

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Since the world has moved into a transitional period, known as globalization; the business environment is now more complicated than ever before. Corporate information has become a matter of great importance for stakeholders, in order to understand the current situation. As a result of this, the concept of corporate governance has been broadly introduced to manage and control the affairs of corporations while businesses are required to disclose both financial and non-financial information to public via various communication channels such as the annual report, the financial report, the company’s website, etc. However, currently there are several other issues related to asymmetric information such as moral hazard or adverse selection that still occur intensively in workplaces. To prevent such problems in the business, it is required to have an understanding of what factors strengthen their transparency, accountability, fairness, and responsibility. Under aforementioned arguments, this paper aims to propose a conceptual framework that enables an investigation on how corporate governance mechanism influences disclosure efficiency of listed companies in the Association of Southeast Asia Nations (ASEAN) and the factors that should be considered for further development of good behaviors, particularly in regards to voluntary disclosure practices. To achieve its purpose, extensive reviews of literature are applied as a research methodology. It is divided into three main steps. Firstly, the theories involved with both corporate governance and disclosure practices such as agency theory, contract theory, signaling theory, moral hazard theory, and information asymmetry theory are examined to provide theoretical backgrounds. Secondly, the relevant literatures based on multi- perspectives of corporate governance, its attributions and their roles on business processes, the influences of corporate governance mechanisms on business performance, and the factors determining corporate governance characteristics as well as capability are reviewed to outline the parameters that should be included in the proposed model. Thirdly, the well-known regulatory document OECD principles and previous empirical studies on the corporate disclosure procedures are evaluated to identify the similarities and differentiations with the disclosure patterns in the ASEAN. Following the processes and consequences of the literature review, abundant factors and variables are found. Further to the methodology, additional critical factors that also have an impact on the disclosure behaviors are addressed in two groups. In the first group, the factors which are linked to the national characteristics - the quality of national code, legal origin, culture, the level of economic development, and so forth. Whereas in the second group, the discoveries which refer to the firm’s characteristics - ownership concentration, ownership’s rights, controlling group, and so on. However, because of research limitations, only some literature are chosen and summarized to form part of the conceptual framework that explores the relationship between corporate governance and the disclosure practices of listed companies in ASEAN.

Keywords: corporate governance, disclosure practice, ASEAN, listed company

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Authors: Rayanne Branco Dos Santos Lima, Lorena Pinheiro Barbosa, Kamila Ferreira Lima, Victor Manuel Tegoma Ruiz, Monyka Brito Lima Dos Santos, Maria Wendiane Gueiros Gaspar, Luzia Camila Coelho Ferreira, Leandro Cardozo Dos Santos Brito, Deyse Maria Alves Rocha

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Introduction: The lack of regulation of the baby's sleep-wake pattern in the first years of life affects the health of thousands of women. Maternal sleep deprivation can trigger or aggravate psychosomatic problems such as depression, anxiety and stress that can directly influence maternal safety, with consequences for the baby's and mother's sleep. Such conditions can affect the family's quality of life and child development. Objective: To correlate maternal security with maternal state anxiety scores and the mother's and baby's total sleep time. Method: Cross-sectional study carried out with 96 mothers of babies aged 10 to 24 months, accompanied by nursing professionals linked to a Federal University in Northeast Brazil. Study variables were maternal security, maternal state anxiety scores, infant latency and sleep time, and total nocturnal sleep time of mother and infant. Maternal safety was calculated using a four-point Likert scale (1=not at all safe, 2=somewhat safe, 3=very safe, 4=completely safe). Maternal anxiety was measured by State-Trait Anxiety Inventory, state-anxiety subscale whose scores vary from 20 to 80 points, and the higher the score, the higher the anxiety levels. Scores below 33 are considered mild; from 33 to 49, moderate and above 49, high. As for the total nocturnal sleep time, values between 7-9 hours of sleep were considered adequate for mothers, and values between 9-12 hours for the baby, according to the guidelines of the National Sleep Foundation. For the sleep latency time, a time equal to or less than 20 min was considered adequate. It is noteworthy that the latency time and the time of night sleep of the mother and the baby were obtained by the mother's subjective report. To correlate the data, Spearman's correlation was used in the statistical package R version 3.6.3. Results: 96 women and babies participated, aged 22 to 38 years (mean 30.8) and 10 to 24 months (mean 14.7), respectively. The average of maternal security was 2.89 (unsafe); Mean maternal state anxiety scores were 43.75 (moderate anxiety). The babies' average sleep latency time was 39.6 min (>20 min). The mean sleep times of the mother and baby were, respectively, 6h and 42min and 8h and 19min, both less than the recommended nocturnal sleep time. Maternal security was positively correlated with maternal state anxiety scores (rh=266, p=0.009) and negatively correlated with infant sleep latency (rh= -0.30. P=0.003). Baby sleep time was positively correlated with maternal sleep time. (rh 0.46, p<0.001). Conclusion: The more secure the mothers considered themselves, the higher the anxiety scores and the shorter the baby's sleep latency. Also, the longer the baby sleeps, the longer the mother sleeps. Thus, interventions are needed to promote the quality and efficiency of sleep for both mother and baby.

Keywords: sleep, anxiety, infant, mother-child relations

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Authors: Roberta Martino, Viviana Ventre

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Intertemporal choices are choices under conditions of uncertainty in which the consequences are distributed over time. The Discounted Utility Model is the essential reference for describing the individual in the context of intertemporal choice. The model is based on the idea that the individual selects the alternative with the highest utility, which is calculated by multiplying the cardinal utility of the outcome, as if the reception were instantaneous, by the discount function that determines a decrease in the utility value according to how the actual reception of the outcome is far away from the moment the choice is made. Initially, the discount function was assumed to have an exponential trend, whose decrease over time is constant, in line with a profile of a rational investor described by classical economics. Instead, empirical evidence called for the formulation of alternative, hyperbolic models that better represented the actual actions of the investor. Attitudes that do not comply with the principles of classical rationality are termed anomalous, i.e., difficult to rationalize and describe through normative models. The development of behavioral finance, which describes investor behavior through cognitive psychology, has shown that deviations from rationality are due to the limited rationality condition of human beings. What this means is that when a choice is made in a very difficult and information-rich environment, the brain does a compromise job between the cognitive effort required and the selection of an alternative. Moreover, the evaluation and selection phase of the alternative, the collection and processing of information, are dynamics conditioned by systematic distortions of the decision-making process that are the behavioral biases involving the individual's emotional and cognitive system. In this paper we present an original decomposition of the discount function to investigate the psychological principles of hyperbolic discounting. It is possible to decompose the curve into two components: the first component is responsible for the smaller decrease in the outcome as time increases and is related to the individual's impatience; the second component relates to the change in the direction of the tangent vector to the curve and indicates how much the individual perceives the indeterminacy of the future indicating his or her aversion to uncertainty. This decomposition allows interesting conclusions to be drawn with respect to the concept of impatience and the emotional drives involved in decision-making. The contribution that neuroscience can make to decision theory and inter-temporal choice theory is vast as it would allow the description of the decision-making process as the relationship between the individual's emotional and cognitive factors. Neurofinance is a discipline that uses a multidisciplinary approach to investigate how the brain influences decision-making. Indeed, considering that the decision-making process is linked to the activity of the prefrontal cortex and amygdala, neurofinance can help determine the extent to which abnormal attitudes respect the principles of rationality.

Keywords: impatience, intertemporal choice, neurofinance, rationality, uncertainty

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Authors: Yi H. Wong, Li L. Chan, Chee O. Leong, Stephen Ambu, Joon W. Mak, Priyadashi S. Sahu

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Background: Acanthamoeba is a free-living opportunistic protist which is ubiquitously distributed in the environment. Virulent Acanthamoeba can cause fatal encephalitis in immunocompromised patients and potential blinding keratitis in immunocompetent contact lens wearers. Approximately 24 species have been identified but only the A. castellanii, A. polyphaga and A. culbertsoni are commonly associated with human infections. Until to date, the precise molecular basis for Acanthamoeba pathogenesis remains unclear. Previous studies reported that Acanthamoeba virulence can be diminished through prolonged axenic culture but revived through serial mouse passages. As no clear explanation on this reversible pathogenesis is established, hereby, we postulate that the epigenetic regulators, DNA-methyltransferases (DNMT) and histone-deacetylases (HDAC), could possibly be involved in granting the virulence plasticity of Acanthamoeba spp. Methods: Four rounds of mouse passages were conducted to revive the virulence potential of the virulence-attenuated Acanthamoeba castellanii strain (ATCC 50492). Briefly, each mouse (n=6/group) was inoculated intraperitoneally with Acanthamoebae cells (2x 105 trophozoites/mouse) and incubated for 2 months. Acanthamoebae cells were isolated from infected mouse organs by culture method and subjected to subsequent mouse passage. In vitro cytopathic, encystment and gelatinolytic assays were conducted to evaluate the virulence characteristics of Acanthamoebae isolates for each passage. PCR primers which targeted on the 2 members (DNMT1 and DNMT2) and 5 members (HDAC1 to 5) of the DNMT and HDAC gene families respectively were custom designed. Quantitative real-time PCR (qPCR) was performed to detect and quantify the relative expression of the two gene families in each Acanthamoeba isolates. Beta-tubulin of A. castellanii (Genbank accession no: XP_004353728) was included as housekeeping gene for data normalisation. PCR mixtures were also analyzed by electrophoresis for amplicons detection. All statistical analyses were performed using the paired one-tailed Student’s t test. Results: Our pathogenicity tests showed that the virulence-reactivated Acanthamoeba had a higher degree of cytopathic effect on vero cells, a better resistance to encystment challenge and a higher gelatinolytic activity which was catalysed by serine protease. qPCR assay showed that DNMT1 expression was significantly higher in the virulence-reactivated compared to the virulence-attenuated Acanthamoeba strain (p ≤ 0.01). The specificity of primers which targeted on DNMT1 was confirmed by sequence analysis of PCR amplicons, which showed a 97% similarity to the published DNA-methyltransferase gene of A. castellanii (GenBank accession no: XM_004332804.1). Out of the five primer pairs which targeted on the HDAC family genes, only HDAC4 expression was significantly difference between the two variant strains. In contrast to DNMT1, HDAC4 expression was much higher in the virulence-attenuated Acanthamoeba strain. Conclusion: Our mouse passages had successfully restored the virulence of the attenuated strain. Our findings suggested that DNA-methyltransferase (DNMT1) and histone deacetylase (HDAC4) expressions are associated with virulence potential of Acanthamoeba spp.

Keywords: acanthamoeba, DNA-methyltransferase, histone deacetylase, virulence-associated proteins

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Authors: Hugo Lefeuvre, Jerôme Donnard, Michael Descostes, Sophie Billon, Samuel Duval, Tugdual Oger, Herve Toubon, Paul Sardini

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Spectroscopic autoradiography is a method of interest for geological sample analysis. Indeed, researchers may face different issues such as radioelement identification and quantification in the field of environmental studies. Imaging gaseous ionization detectors find their place in geosciences for conducting specific measurements of radioactivity to improve the monitoring of natural processes using naturally-occurring radioactive tracers, but also for the nuclear industry linked to the mining sector. In geological samples, the location and identification of the radioactive-bearing minerals at the thin-section scale remains a major challenge as the detection limit of the usual elementary microprobe techniques is far higher than the concentration of most of the natural radioactive decay products. The spatial distribution of each decay product in the case of uranium in a geomaterial is interesting for relating radionuclides concentration to the mineralogy. The present study aims to provide spectroscopic autoradiography analysis method for measuring the initial energy of alpha particles with a parallel ionization multiplier gaseous detector. The analysis method has been developed thanks to Geant4 modelling of the detector. The track of alpha particles recorded in the gas detector allow the simultaneous measurement of the initial point of emission and the reconstruction of the initial particle energy by a selection based on the linear energy distribution. This spectroscopic autoradiography method was successfully used to reproduce the alpha spectra from a 238U decay chain on a geological sample at the thin-section scale. The characteristics of this measurement are an energy spectrum resolution of 17.2% (FWHM) at 4647 keV and a spatial resolution of at least 50 µm. Even if the efficiency of energy spectrum reconstruction is low (4.4%) compared to the efficiency of a simple autoradiograph (50%), this novel measurement approach offers the opportunity to select areas on an autoradiograph to perform an energy spectrum analysis within that area. This opens up possibilities for the detailed analysis of heterogeneous geological samples containing natural alpha emitters such as uranium-238 and radium-226. This measurement will allow the study of the spatial distribution of uranium and its descendants in geo-materials by coupling scanning electron microscope characterizations. The direct application of this dual modality (energy-position) of analysis will be the subject of future developments. The measurement of the radioactive equilibrium state of heterogeneous geological structures, and the quantitative mapping of 226Ra radioactivity are now being actively studied.

Keywords: alpha spectroscopy, digital autoradiography, mining activities, natural decay products

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Authors: Natalia Alvarado, Myldred Hernandez-Gonzalez, Mary Laird, Madeline Phillips, Elizabeth Miller, Luis Mendez, Teresa Satterfield Linares

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Objectives: Focusing on the reported levels of depressive symptoms from Hispanic individuals in the U.S. during the ongoing COVID-19 pandemic, we analyze the psychological effects of being labeled an ‘essential worker/trabajador(a) esencial.’ We situate this attribute within the complex context of how an individual’s mental health is linked to work status and his/her community’s attitude toward such a status. Method: 336 Spanish-speaking adults (Mage = 34.90; SD = 11.00; 46% female) living in the U.S. participated in a mixed-method study. Participants completed a self-report Spanish-language survey consisting of COVID-19 prompts (e.g., Soy un trabajador esencial durante la pandemia. I am an ‘essential worker’ during the pandemic), civic engagement scale (CES) attitudes (e.g., Me siento responsable de mi comunidad. I feel responsible for my community) and behaviors (e.g., Ayudo a los miembros de mi comunidad. I help members of my community), and the Center for Epidemiological Studies Depression Scale (e.g., Me sentía deprimido/a. I felt depressed). The survey was conducted several months into the pandemic and before the vaccine distribution. Results: Regression analyses show that being labeled an essential worker was correlated to CES attitudes (b= .28, p < .001) and higher CES behaviors (b= .32, p < .001). Essential worker status also reported higher levels of depressive symptoms (b= .17, p < .05). In addition, we found that CES attitudes and CES behaviors were related to higher levels of depressive symptoms (b= .11, p <.05, b = .22, p < .001, respectively). These findings suggest that those who are on the frontlines during the COVID-19 pandemic suffer higher levels of depressive symptoms, despite their affirming community attitudes and behaviors. Discussion: Hispanics/Latinxs make up 53% of the high-proximity employees who must work in person and in close contact with others; this is the highest rate of any racial or ethnic category. Moreover, 31% of Hispanics are classified as essential workers. Our outcomes show that those labeled as trabajadores esenciales convey attitudes of remaining strong and resilient for COVID-19 victims. They also express community attitudes and behaviors reflecting a sense of responsibility to continue working to help others during these unprecedented times. However, we also find that the pressure of maintaining basic needs for others exacerbates mental health challenges and stressors, as many essential workers are anxious and stressed about their physical and economic security. As a result, community attitudes do not protect from depressive symptoms as Hispanic essential workers are failing to balance everyone’s needs, including their own (e.g., physical exhaustion and psychological distress). We conclude with a discussion on alternatives to the phrase ‘essential worker’ and of incremental steps that can be taken to address pandemic-related mental health issues targeting US Hispanic workers.

Keywords: COVID-19, essential worker, mental health, race and ethnicity

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Authors: S. Wiak, L. Szymanski, Z. Kolacinski, G. Raniszewski, L. Pietrzak, Z. Staniszewska

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The term ‘cancer’ is given to a collection of related diseases that may affect any part of the human body. It is a pathological behaviour of cells with the potential to undergo abnormal breakdown in the processes that control cell proliferation, differentiation, and death of particular cells. Although cancer is commonly considered as modern disease, there are beliefs that drastically growing number of new cases can be linked to the extensively prolonged life expectancy and enhanced techniques for cancer diagnosis. Magnetic hyperthermia therapy is a novel approach to cancer treatment, which may greatly contribute to higher efficiency of the therapy. Employing carbon nanotubes as nanocarriers for magnetic particles, it is possible to decrease toxicity and invasiveness of the treatment by surface functionalisation. Despite appearing in recent years, magnetic particle hyperthermia has already become of the highest interest in the scientific and medical environment. The reason why hyperthermia therapy brings so much hope for future treatment of cancer lays in the effect that it produces in malignant cells. Subjecting them to thermal shock results in activation of numerous degradation processes inside and outside the cell. The heating process initiates mechanisms of DNA destruction, protein denaturation and induction of cell apoptosis, which may lead to tumour shrinkage, and in some cases, it may even cause complete disappearance of cancer. The factors which have the major impact on the final efficiency of the treatment include temperatures generated inside the tissues, time of exposure to the heating process, and the character of an individual cancer cell type. The vast majority of cancer cells is characterised by lower pH, persistent hypoxia and lack of nutrients, which can be associated to abnormal microvasculature. Since in healthy tissues we cannot observe presence of these conditions, they should not be seriously affected by elevation of the temperature. The aim of this work is to investigate the influence of iron content in iron filled Carbon Nanotubes on the desired nanoparticles for cancer therapy. In the article, the development and demonstration of the method and the model device for hyperthermic selective destruction of cancer cells are presented. This method was based on the synthesis and functionalization of carbon nanotubes serving as ferromagnetic material nanocontainers. The methodology of the production carbon- ferromagnetic nanocontainers (FNCs) includes the synthesis of carbon nanotubes, chemical, and physical characterization, increasing the content of a ferromagnetic material and biochemical functionalization involving the attachment of the key addresses. The ferromagnetic nanocontainers were synthesised in CVD and microwave plasma system. The research work has been financed from the budget of science as a research project No. PBS2/A5/31/2013.

Keywords: hyperthermia, carbon nanotubes, cancer colon cells, radio frequency field

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Authors: Stefano Pelaggi

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The research is focused on youth labor and mobility in Berlin. Mobility has become a common denominator in our daily lives but it does not primarily move according to monetary incentives. Labor, knowledge and leisure overlap on this point as cities are trying to attract people who could participate in production of the innovations while the new migrants are experiencing the lifestyle of the host cities. The research will present the project of empirical study focused on Italian workers in the digital industry in Berlin, trying to underline the connection between pleasure, leisure with the choice of life abroad. Berlin has become the epicenter of the European Internet start-up scene, but people suitable to work for digital industries are not moving in Berlin to make a career, most of them are attracted to the city for different reasons. This point makes a clear exception to traditional migration flows, which are always originated from a specific search of employment opportunities or strong ties, usually families, in a place that could guarantee success in finding a job. Even the skilled migration has always been originated from a specific need, finding the right path for a successful professional life. In a society where the lack of free time in our calendar seems to be something to be ashamed, the actors of youth mobility incorporate some categories of experiential tourism within their own life path. Professional aspirations, lifestyle choices of the protagonists of youth mobility are geared towards meeting the desires and aspirations that define leisure. While most of creative work places, in particular digital industries, uses the category of fun as a primary element of corporate policy, virtually extending the time to work for the whole day; more and more people around the world are deciding their path in life, career choices on the basis of indicators linked to the realization of the self, which may include factors like a warm climate, cultural environment. All indicators that are usually eradicated from the hegemonic approach to labor. The interpretative framework commonly used seems to be mostly focused on a dualism between Florida's theories and those who highlight the absence of conflict in his studies. While the flexibility of the new creative industries is minimizing leisure, incorporating elements of leisure itself in work activities, more people choose their own path of life by placing great importance to basic needs, through a gaze on pleasure that is only partially driven by consumption. The multi localism is the co-existence of different identities and cultures that do not conflict because they reject the bind on territory. Local loses its strength of opposition to global, with an attenuation of the whole concept of citizenship, territory and even integration. A similar perspective could be useful to search a new approach to all the studies dedicated to the gentrification process, while studying the new migrations flow.

Keywords: brain drain, digital industry, leisure and gentrification, multi localism

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Authors: Marina Passero, Tianhua Zhai, Zuyi (Jacky) Huang

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Alzheimer’s disease has become a major public health issue, as indicated by the increasing populations of Americans living with Alzheimer’s disease. After decades of extensive research in Alzheimer’s disease, only seven drugs have been approved by Food and Drug Administration (FDA) to treat Alzheimer’s disease. Five of these drugs were designed to treat the dementia symptoms, and only two drugs (i.e., Aducanumab and Lecanemab) target the progression of Alzheimer’s disease, especially the accumulation of amyloid-b plaques. However, controversial comments were raised for the accelerated approvals of either Aducanumab or Lecanemab, especially with concerns on safety and side effects of these two drugs. There is still an urgent need for further drug discovery to target the biological processes involved in the progression of Alzheimer’s disease. Excessive cholesterol has been found to accumulate in the brain of those with Alzheimer’s disease. Cholesterol can be synthesized in both the blood and the brain, but the majority of biosynthesis in the adult brain takes place in astrocytes and is then transported to the neurons via ApoE. The blood brain barrier separates cholesterol metabolism in the brain from the rest of the body. Various proteins contribute to the metabolism of cholesterol in the brain, which offer potential targets for Alzheimer’s treatment. In the astrocytes, SREBP cleavage-activating protein (SCAP) binds to Sterol Regulatory Element-binding Protein 2 (SREBP2) in order to transport the complex from the endoplasmic reticulum to the Golgi apparatus. Cholesterol is secreted out of the astrocytes by ATP-Binding Cassette A1 (ABCA1) transporter. Lipoprotein receptors such as triggering receptor expressed on myeloid cells 2 (TREM2) internalize cholesterol into the microglia, while lipoprotein receptors such as Low-density lipoprotein receptor-related protein 1 (LRP1) internalize cholesterol into the neuron. Cytochrome P450 Family 46 Subfamily A Member 1 (CYP46A1) converts excess cholesterol to 24S-hydroxycholesterol (24S-OHC). Cholesterol has been approved for its direct effect on the production of amyloid-beta and tau proteins. The addition of cholesterol to the brain promotes the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), secretase, and amyloid precursor protein (APP), which all aid in amyloid-beta production. The reduction of cholesterol esters in the brain have been found to reduce phosphorylated tau levels in mice. In this work, a computational pipeline was developed to identify the protein targets involved in cholesterol regulation in brain and further to identify chemical compounds as the inhibitors of a selected protein target. Since extensive evidence shows the strong correlation between brain cholesterol regulation and Alzheimer’s disease, a detailed literature review on genes or pathways related to the brain cholesterol synthesis and regulation was first conducted in this work. An interaction network was then built for those genes so that the top gene targets were identified. The involvement of these genes in Alzheimer’s disease progression was discussed, which was followed by the investigation of existing clinical trials for those targets. A ligand-protein docking program was finally developed to screen 1.5 million chemical compounds for the selected protein target. A machine learning program was developed to evaluate and predict the binding interaction between chemical compounds and the protein target. The results from this work pave the way for further drug discovery to regulate brain cholesterol to combat Alzheimer’s disease.

Keywords: Alzheimer’s disease, drug discovery, ligand-protein docking, gene-network analysis, cholesterol regulation

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Authors: Xabier Barandiaran, Igone Guerra

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The economic and financial crisis that hit European countries in 2008 revealed the inability of governments to respond unilaterally to the so-called “wicked” problems that affect our societies. Closely linked to this, the increasing disaffection of citizens towards politics has resulted in growing distrust of the citizenry not only in the institutions in general but also in the political system, in particular. Precisely, these two factors provoked the action of the local government of Gipuzkoa (Basque Country) to move from old ways of “doing politics” to a new way of “thinking politics” based on a collaborative approach, in which innovative modes of public decision making are prominent. In this context, in 2015, the initiative Etorkizuna Eraikiz (Building the Future), a contemporary form of networked governance, was launched by the Provincial Government. The paper focuses on the Etorkizuna Eraikiz initiative, a sound commitment from a local government to build jointly with the citizens the future of the territory. This paper will present preliminary results obtained from three different experiences of co-creation developed within Etorkizuna Eraikiz in which the formulation of networked governance is a mandatory pre-requisite. These experiences show how the network building approach among the different agents of the territory as well as the co-creation of public policies is the cornerstone of this challenging mission. Through the analysis of the information and documentation gathered during the four years of Etorkizuna-Eraikiz, and, specifically by delving into the strategy promoted by the initiative, some emerging analytical conclusions resulting from the promotion of this collaborative culture will be presented. For example, some preliminary results have shown a significant positive relationship between shared leadership and the formulation of the public good. In the period 2016-2018, a total of 73 projects were launched and funding by the Provincial Government of Gipuzkoa within the Etorkizuna Eraikiz initiative, that indicates greater engagement of the citizenry in the process of policy-making and therefore improving, somehow, the quality of the public policies. These statements have been supported by the last survey about the perspectives of the citizens toward politics and policies. Some of the more prominent results show us that there is still a high level of distrust in Politics (78,9% of respondents) but a greater trust in institutions such the Political Government of Gipuzkoa (40,8% of respondents declared as “good” the performance of this provincial institution). Regarding the Etorkizuna Eraikiz Initiative, it is being more readily recognized by citizens over this period of time (25,4% of the respondents in June 2018 agreed to know about the initiative giving it a mark of 5,89 ) and thus build trust and a sense of ownership. Although, there is a clear requirement for further research on the linkages between collaborative governance and level of trust, the paper, based on these findings, will provide some managerial and theoretical implications for collaborative governance in the territory.

Keywords: network governance, collaborative governance, public sector innovation, citizen participation, trust

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Authors: Soma Ghosh, Balaram Mohapatra, Pinaki Sar, Abhijeet Mukherjee

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Microbial role in arsenic (As) mobilization in the groundwater aquifers of Brahmaputra river basin (BRB) in India, severely threatened by high concentrations of As, remains largely unknown. The present study, therefore, is a molecular and ecophysiological characterization of an indigenous bacterium strain IIIJ3-1 isolated from As contaminated groundwater of BRB and application of this strain in several microcosm set ups differing in their organic carbon (OC) source and terminal electron acceptors (TEA), to understand its role in As dissolution under aerobic and anaerobic conditions. Strain IIIJ3-1 was found to be a new facultative anaerobic, gram-positive, endospore-forming strain capable of arsenite (As3+) oxidation and dissimilatory arsenate (As5+) reduction. The bacterium exhibited low genomic (G+C)% content (45 mol%). Although, its 16S rRNA gene sequence revealed a maximum similarity of 99% with Bacillus cereus ATCC 14579(T) but the DNA-DNA relatedness of their genomic DNAs was only 49.9%, which remains well below the value recommended to delimit different species. Abundance of fatty acids iC17:0, iC15:0 and menaquinone (MK) 7 though corroborates its taxonomic affiliation with B. cereus sensu-lato group, presence of hydroxy fatty acids (HFAs), C18:2, MK5 and MK6 marked its uniqueness. Besides being highly As resistant (MTC=10mM As3+, 350mM As5+), metabolically diverse, efficient aerobic As3+ oxidizer; it exhibited near complete dissimilatory reduction of As5+ (1 mM). Utilization of various carbon sources with As5+ as TEA revealed lactate to serve as the best electron donor. Aerobic biotransformation assay yielded a lower Km for As3+ oxidation than As5+ reduction. Arsenic homeostasis was found to be conferred by the presence of arr, arsB, aioB, and acr3(1) genes. Scanning electron microscopy (SEM) coupled with energy dispersive X-ray (EDX) analysis of this bacterium revealed reduction in cell size upon exposure to As and formation of As-rich electron opaque dots following growth with As3+. Incubation of this strain with sediment (sterilised) collected from BRB aquifers under varying OC, TEA and redox conditions revealed that the strain caused highest As mobilization from solid to aqueous phase under anaerobic condition with lactate and nitrate as electron donor and acceptor, respectively. Co-release of highest concentrations of oxalic acid, a well known bioweathering agent, considerable fold increase in viable cell counts and SEM-EDX and X-ray diffraction analysis of the sediment after incubation under this condition indicated that As release is consequent to microbial bioweathering of the minerals. Co-release of other elements statistically proves decoupled release of As with Fe and Zn. Principle component analysis also revealed prominent role of nitrate under aerobic and/or anaerobic condition in As release by strain IIIJ3-1. This study, therefore, is the first to isolate, characterize and reveal As mobilization property of a strain belonging to the Bacillus cereus sensu lato group isolated from highly As contaminated aquifers of Brahmaputra River Basin.

Keywords: anaerobic microcosm, arsenic rich electron opaque dots, Arsenic release, Bacillus strain IIIJ3-1

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Authors: Luiza Toschi

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This work presents part of an empirical and theoretical master's degree meta-research that is interested in the relationship between the disciplinary area of Social Communication, to be investigated with the characteristics of the Bourdieusian scientific field, and the emergence of public interest in Nonviolent Communication (NVC) in Brazil and the world. To this end, the state of the art of this conceptual and practical relationship is investigated based on scientific productions available in spaces of academic credibility, such as conferences and scientific journals renowned in the field. From there, agents and the sociological aspects that make them contribute or not to scientific production in Brazil and the world are mapped. In this work, a brief dive into the international context is presented to understand if and how nonviolent communication permeates scientific production in communication in a systematic way. Using three accessible articles published between 2013 and 2022 in the 117 magazines classified as Quartiles Q1 in the Journal Ranking of Communication, the international production on the subject is compared with the Brazilian one from its context. The social conditions of the international circulation of ideas are thus discussed. Science is a product of its social environment, arising from relations of interest and power that compete in the political dimension at the same time as in the epistemological dimension. In this way, scientific choices are linked to the resources mobilized from or through the prestige and recognition of peers. In this sense, an object of interest stands out to a scientist for its academic value, but also and inseparably that which has a social interest within the collective, their social stratification, and the context of legitimacy created in their surroundings, influenced by cultural universalism. In Brazil, three published articles were found in congresses and journals that mention NVC in their abstract or keywords. All were written by Public Relations undergraduate students. Between the most experienced researchers who guided or validated the publications, it is possible to find two professionals who are interested in the Culture of Peace and Dialogy. Likewise, internationally, only three of the articles found mention the term in their abstract or title. Two analyze journalistic coverage based on the principles of NVC and Journalism for Peace. The third is from one of the Brazilian researchers identified as interested in dialogic practices, who analyses audiovisual material and promotes epistemological reflections. If, on the one hand, some characteristics inside and outside Brazil are similar: small samples, relationship with peace studies, and female researchers, two of whom are Brazilian, on the other hand, differences are obvious. If within the country, the subject is mostly Organizational Communication, outside this intersection, it is not presented explicitly. Furthermore, internationally, there is an interest in analyzing from the perspective of NVC, which has not been found so far in publications in Brazil. Up to the present moment, it is possible to presume that, universally, the legitimacy of the topic is sought by its association with conflict conciliation research and communication for peace.

Keywords: academic field sociology, international circulation of ideas, meta research in communication, nonviolent communication

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Authors: M. Louise Humbert, Karen E. Chad, Natalie E. Houser, Marta E. Erlandson

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Physical literacy is the motivation, confidence, physical competence, knowledge, and understanding to value and takes responsibility for engagement in physical activities for life. In recent years, physical literacy has emerged as a determinant of health, promoting a positive lifelong physical activity trajectory. Physical literacy’s holistic approach and emphasis on the intrinsic valuation of movement provide an encouraging avenue for intervention among children to develop competent and confident movers. Although there is research on physical literacy interventions, no evidence exists on the outcomes of multi-sectoral interventions involving a combination of home, school, and community contexts. Since children interact with and in a wide range of contexts (home, school, community) daily, interventions designed to address a combination of these contexts are critical to the development of physical literacy. Working with school administrators and teachers, sports and recreation leaders, and community members, our team of university and community researchers conducted and evaluated one of the first multi-contextual and multi-sectoral physical literacy interventions in Canada. Schools played a critical role in this multi-sector intervention, and in this project, teachers and administrators focused their actions on developing physical literacy in students 10 to 14 years of age through the instruction of physical literacy-focused physical education lessons. Little is known about the experiences of educators when they work alongside an array of community representatives to develop physical literacy in school-aged children. Given the uniqueness of this intervention, we sought to answer the question, ‘What were the experiences of school-based educators involved in a multi-sectoral partnership focused on creating a physical literacy enriched community intervention?’ A thematic analysis approach was used to analyze data collected from interviews with educators and administrators, informal conversations, documents, and observations at workshops and meetings. Results indicated that schools and educators played the largest role in this multi-sector intervention. Educators initially reported a limited understanding of physical literacy and expressed a need for resources linked to the physical education curriculum. Some anxiety was expressed by the teachers as their students were measured, and educators noted they wanted to increase their understanding and become more involved in the assessment of physical literacy. Teachers reported that the intervention’s focus on physical literacy positively impacted the scheduling and their instruction of physical education. Administrators shared their desire for school and division-level actions targeting physical literacy development like the current focus on numeracy and literacy, treaty education, and safe schools. As this was one of the first multi-contextual and multi-sectoral physical literacy interventions, it was important to document creation and delivery experiences to encourage future growth in the area and develop suggested best practices.

Keywords: physical literacy, multi sector intervention, physical education, teachers

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Authors: Mei Chen, Yingping Hou, Michelle Hao, Soheil Aghamohammadzadeh, Esteban Terzo, Roger Clark, Vijay Modur

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Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genetic skin condition characterized by skin tearing and unremitting blistering upon minimal trauma. Repeated blistering, fibrosis, and scarring lead to aggressive squamous cell carcinoma later in life. RDEB is caused by mutations in the COL7A1 gene encoding collagen type VII (C7), the major component of anchoring fibrils mediating epidermis-dermis adherence. Nonsense mutations in the COL7A1 gene of a subset of RDEB patients leads to premature termination codons (PTC). Similarly, most Junctional Epidermolysis Bullosa (JEB) cases are caused by nonsense mutations in the LAMB3 gene encoding the β3 subunit of laminin 332. Currently, there is an unmet need for the treatment of RDEB and JEB. Zikani Therapeutics has discovered an array of macrocyclic compounds with ring structures similar to macrolide antibiotics that can facilitate readthrough activity of nonsense mutations in the COL7A1 and LAMB3 genes by acting as Ribosome Modulating Agents (RMAs). The medicinal chemistry synthetic advancements of these macrocyclic compounds have allowed targeting the human ribosome while preserving the structural elements responsible for the safety and pharmacokinetic profile of clinically used macrolide antibiotics. Methods: C7 expression was used as a measure of readthrough activity by immunoblot assays in two primary human fibroblasts from RDEB patients (R578X/R578X and R163X/R1683X-COL7A1). Similarly, immunoblot assays in C325X/c.629-12T > A-LAMB3 keratinocytes were used to measure readthrough activity for JEB. The relative readthrough activity of each compound was measured relative to Gentamicin. An imaging-based fibroblast migration assay was used as an assessment of C7 functionality in RDEB-fibroblasts over 16-20 hrs. The incubation period for the above experiments was 48 hrs for RDEB fibroblasts and 72 hours for JEB keratinocytes. Results: 9 RMAs demonstrated increased protein expression in both patient RDEB fibroblasts. The highest readthrough activity at tested concentrations without cytotoxicities increased protein expression up to 179% of Gentamicin (400 µg/ml), with favored readthrough activity in R163X/R1683X-COL7A1 fibroblasts. Concurrent with protein expression, fibroblast hypermotility phenotype observed in RDEB was rescued by reducing motility by ~35% to WT levels (the same level as 690 µM Gentamicin treated cells). Laminin β3 expression was also shown to be increased by 6 RMAs in keratinocytes to 33-83% of (400 µg/ml) Gentamicin. Conclusions: To date, 9 RMAs have been identified that enhance the expression of functional C7 in a mutation-dependent manner in two different RDEB patient fibroblast backgrounds (R578X/R578X and R163X/R1683X-COL7A1). A further 6 RMAs have been identified that enhance the readthrough of C325X-LAMB3 in JEB patient keratinocytes. Based on the clinical trial conducted by us with topical gentamycin in 2017, Zikani’s RMAs achieve clinically significant levels of read-through for the treatment of recessive dystrophic and Junctional Epidermolysis Bullosa.

Keywords: epidermolysis bullosa, nonsense mutation, readthrough, ribosome modulation

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