Search results for: computational fluid dynamic (CFD)

Authors: Milu T. Cherian, Sergio C. Chai, Morgan A. Casal, Taosheng Chen

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This study aims to use CINPA1, a recently discovered small-molecule inhibitor of the xenobiotic receptor CAR (constitutive androstane receptor) for understanding the binding modes of CAR and to guide CAR-mediated gene expression profiling studies in human primary hepatocytes. CAR and PXR are xenobiotic sensors that respond to drugs and endobiotics by modulating the expression of metabolic genes that enhance detoxification and elimination. Elevated levels of drug metabolizing enzymes and efflux transporters resulting from CAR activation promote the elimination of chemotherapeutic agents leading to reduced therapeutic effectiveness. Multidrug resistance in tumors after chemotherapy could be associated with errant CAR activity, as shown in the case of neuroblastoma. CAR inhibitors used in combination with existing chemotherapeutics could be utilized to attenuate multidrug resistance and resensitize chemo-resistant cancer cells. CAR and PXR have many overlapping modulating ligands as well as many overlapping target genes which confounded attempts to understand and regulate receptor-specific activity. Through a directed screening approach we previously identified a new CAR inhibitor, CINPA1, which is novel in its ability to inhibit CAR function without activating PXR. The cellular mechanisms by which CINPA1 inhibits CAR function were also extensively examined along with its pharmacokinetic properties. CINPA1 binding was shown to change CAR-coregulator interactions as well as modify CAR recruitment at DNA response elements of regulated genes. CINPA1 was shown to be broken down in the liver to form two, mostly inactive, metabolites. The structure-activity differences of CINPA1 and its metabolites were used to guide computational modeling using the CAR-LBD structure. To rationalize how ligand binding may lead to different CAR pharmacology, an analysis of the docked poses of human CAR bound to CITCO (a CAR activator) vs. CINPA1 or the metabolites was conducted. From our modeling, strong hydrogen bonding of CINPA1 with N165 and H203 in the CAR-LBD was predicted. These residues were validated to be important for CINPA1 binding using single amino-acid CAR mutants in a CAR-mediated functional reporter assay. Also predicted were residues making key hydrophobic interactions with CINPA1 but not the inactive metabolites. Some of these hydrophobic amino acids were also identified and additionally, the differential coregulator interactions of these mutants were determined in mammalian two-hybrid systems. CINPA1 represents an excellent starting point for future optimization into highly relevant probe molecules to study the function of the CAR receptor in normal- and pathophysiology, and possible development of therapeutics (for e.g. use for resensitizing chemoresistant neuroblastoma cells).

Keywords: antagonist, chemoresistance, constitutive androstane receptor (CAR), multi-drug resistance, structure activity relationship (SAR), xenobiotic resistance

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Authors: Pawel Magryta, Mateusz Paszko

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In today's world, a big problem of individual mobility, especially in large urban areas, occurs. Commonly used grand way of transport such as buses, trains or cars do not fulfill their tasks, i.e. they are not able to meet the increasing mobility needs of the growing urban population. Additional to that, the limitations of civil infrastructure construction in the cities exist. Nowadays the most common idea is to transfer the part of urban transport on the level of air transport. However to do this, there is a need to develop an individual flying transport vehicle. The biggest problem occurring in this concept is the type of the propulsion system from which the vehicle will obtain a lifting force. Standard propeller drives appear to be too noisy. One of the ideas is to provide the required take-off and flight power by the machine using the innovative ejector system. This kind of the system will be designed through a suitable choice of the three-dimensional geometric structure with special shape of nozzle in order to generate overpressure. The authors idea is to make a device that would allow to cumulate the overpressure using the a five-sided geometrical structure that will be limited on the one side by the blowing flow of air jet. In order to test this hypothesis a computer simulation study of aerodynamic drag of such 3D structures have been made. Based on the results of these studies, the tests on real model were also performed. The final stage of work was a comparative analysis of the results of simulation and real tests. The CFD simulation studies of air flow was conducted using the Star CD - Star Pro 3.2 software. The design of virtual model was made using the Catia v5 software. Apart from the objective to obtain advanced aviation propulsion system, all of the tests and modifications of 3D structures were also aimed at achieving high efficiency of this device while maintaining the ability to generate high value of overpressures. This was possible only in case of a large mass flow rate of air. All these aspects have been possible to verify using CFD methods for observing the flow of the working medium in the tested model. During the simulation tests, the distribution and size of pressure and velocity vectors were analyzed. Simulations were made with different boundary conditions (supply air pressure), but with a fixed external conditions (ambient temp., ambient pressure, etc.). The maximum value of obtained overpressure is 2 kPa. This value is too low to exploit the power of this device for the individual transport vehicle. Both the simulation model and real object shows a linear dependence of the overpressure values obtained from the different geometrical parameters of three-dimensional structures. Application of computational software greatly simplifies and streamlines the design and simulation capabilities. This work has been financed by the Polish Ministry of Science and Higher Education.

Keywords: aviation propulsion, CFD, 3d structure, aerodynamic drag

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Authors: Brenda Ravenscroft, Ulemu Luhanga, Bev King

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A comprehensive evaluation of online learning needs to include a blend of educational design, technology use, and online instructional practices that integrate technology appropriately for developing and delivering quality online courses. Research shows that classroom-based evaluation tools do not adequately capture the dynamic relationships between content, pedagogy, and technology in online courses. Furthermore, studies suggest that using classroom evaluations for online courses yields lower than normal scores for instructors, and may affect faculty negatively in terms of administrative decisions. In 2014, the Faculty of Arts and Science at Queen’s University responded to this evidence by seeking an alternative to the university-mandated evaluation tool, which is designed for classroom learning. The Faculty is deeply engaged in e-learning, offering large variety of online courses and programs in the sciences, social sciences, humanities and arts. This paper describes the process by which a new student survey instrument for online courses was developed and piloted, the methods used to analyze the data, and the ways in which the instrument was subsequently adapted based on the results. It concludes with a critical reflection on the challenges of evaluating e-learning. The Student Evaluation of Online Teaching Effectiveness (SEOTE), developed by Arthur W. Bangert in 2004 to assess constructivist-compatible online teaching practices, provided the starting point. Modifications were made in order to allow the instrument to serve the two functions required by the university: student survey results provide the instructor with feedback to enhance their teaching, and also provide the institution with evidence of teaching quality in personnel processes. Changes were therefore made to the SEOTE to distinguish more clearly between evaluation of the instructor’s teaching and evaluation of the course design, since, in the online environment, the instructor is not necessarily the course designer. After the first pilot phase, involving 35 courses, the results were analyzed using Stobart's validity framework as a guide. This process included statistical analyses of the data to test for reliability and validity, student and instructor focus groups to ascertain the tool’s usefulness in terms of the feedback it provided, and an assessment of the utility of the results by the Faculty’s e-learning unit responsible for supporting online course design. A set of recommendations led to further modifications to the survey instrument prior to a second pilot phase involving 19 courses. Following the second pilot, statistical analyses were repeated, and more focus groups were used, this time involving deans and other decision makers to determine the usefulness of the survey results in personnel processes. As a result of this inclusive process and robust analysis, the modified SEOTE instrument is currently being considered for adoption as the standard evaluation tool for all online courses at the university. Audience members at this presentation will be stimulated to consider factors that differentiate effective evaluation of online courses from classroom-based teaching. They will gain insight into strategies for introducing a new evaluation tool in a unionized institutional environment, and methodologies for evaluating the tool itself.

Keywords: evaluation, online courses, student survey, teaching effectiveness

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Authors: Francesca Fermi, Paola Astegiano, Angelo Martino, Stephanie Heitel, Michael Krail

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In order to achieve the targeted emission reductions for the decarbonisation of the European economy by 2050, fundamental contributions are required from both energy and transport sectors. The objective of this paper is to analyse the impacts of a largescale diffusion of e-vehicles, either battery-based or fuel cells, together with the implementation of transport policies aiming at decreasing the use of motorised private modes in order to achieve greenhouse gas emission reduction goals, in the context of a future high share of renewable energy. The analysis of the impacts and challenges of future scenarios on transport sector is performed with the ASTRA (ASsessment of TRAnsport Strategies) model. ASTRA is a strategic system-dynamic model at European scale (EU28 countries, Switzerland and Norway), consisting of different sub-modules related to specific aspects: the transport system (e.g. passenger trips, tonnes moved), the vehicle fleet (composition and evolution of technologies), the demographic system, the economic system, the environmental system (energy consumption, emissions). A key feature of ASTRA is that the modules are linked together: changes in one system are transmitted to other systems and can feed-back to the original source of variation. Thanks to its multidimensional structure, ASTRA is capable to simulate a wide range of impacts stemming from the application of transport policy measures: the model addresses direct impacts as well as second-level and third-level impacts. The simulation of the different scenarios is performed within the REFLEX project, where the ASTRA model is employed in combination with several energy models in a comprehensive Modelling System. From the transport sector perspective, some of the impacts are driven by the trend of electricity price estimated from the energy modelling system. Nevertheless, the major drivers to a low carbon transport sector are policies related to increased fuel efficiency of conventional drivetrain technologies, improvement of demand management (e.g. increase of public transport and car sharing services/usage) and diffusion of environmentally friendly vehicles (e.g. electric vehicles). The final modelling results of the REFLEX project will be available from October 2018. The analysis of the impacts and challenges of future scenarios is performed in terms of transport, environmental and social indicators. The diffusion of e-vehicles produces a consistent reduction of future greenhouse gas emissions, although the decarbonisation target can be achieved only with the contribution of complementary transport policies on demand management and supporting the deployment of low-emission alternative energy for non-road transport modes. The paper explores the implications through time of transport policy measures on mobility and environment, underlying to what extent they can contribute to a decarbonisation of the transport sector. Acknowledgements: The results refer to the REFLEX project which has received grants from the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 691685.

Keywords: decarbonisation, greenhouse gas emissions, e-mobility, transport policies, energy

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Authors: Shiv Kumar

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In the shifting scenario of postmodern age that foregrounds the multiplicity of meanings and discourses, the present research article seeks to investigate various paradigm shift of contemporary performances concerning Haryanvi Saangs, so-called folk plays, which are being performed widely in the regional territory of Haryana, a northern state of India. Folk arts cannot be studied efficiently by using the tools of literary criticism because it differs from the literature in many aspects. One of the most essential differences is that literary works invariably have an author. Folk works, on the contrary, never have an author. The situation is quite clear: either we acknowledge the presence of folk art as a phenomenon in the social and cultural history of people, or we do not acknowledge it and argue it is a poetical or art of fiction. This paper is an effort to understand the performative tradition of Saang which is traditionally known as Saang, Swang or Svang became a popular source for instruction and entertainment in the region and neighbouring states. Scholars and critics have long been debating about the origin of the word swang/svang/saang and their relationship to the Sanskrit word –Sangit, which means singing and music. But in the cultural context of Haryana, the word Saang means ‘to impersonate’ or ‘to imitate’ or ‘to copy someone or something’. The stories they portray are derived for the most part from the same myths, tales, epics and from the lives of Indian religious and folk heroes. Literally, the use of poetic sense, the implication of prose style and elaborate figurative technique are worthwhile to compile the productivity of a performance. All use music and song as an integral part of the performance so that it is also appropriate to call them folk opera. These folk plays are performed strictly by aboriginal people in the state. These people, sometimes denominated as Saangi, possess a culture distinct from the rest of Indian folk performances. The concerned form is also known with various other names like Manch, Khayal, Opera, Nautanki. The group of such folk plays can be seen as a dynamic activity and performed in the open space of the theatre. Nowadays, producers contributed greatly in order to create a rapidly growing musical outlet for budding new style of folk presentation and give rise to the electronic focus genre utilizing many musicians and performers who had to become precursors of the folk tradition in the region. Moreover, the paper proposes to examine available sources relative to this article, and it is believed to draw some different conclusions. For instance, to be a spectator of ongoing performances will contribute to providing enough guidance to move forward on this root. In this connection, the paper focuses critically upon the major performative aspects of Haryanvi Saang in relation to several inquiries such as the study of these plays in the context of Indian literary scenario, gender visualization and their dramatic representation, a song-music tradition in folk creativity and development of Haryanvi dramatic art in the contemporary socio-political background.

Keywords: folk play, indigenous, performance, Saang, tradition

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Authors: Arti Singh, Carolyn Jenkins, Oyedunni S. Arulogun, Mayowa O. Owolabi, Fred S. Sarfo, Bruce Ovbiagele, Enzinne Sylvia

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Background: Stroke, the leading cause of adult-onset disability and the second leading cause of death, is a major public health concern particularly pertinent in Sub-Saharan Africa (SSA), where nearly 80% of all global stroke mortalities occur. The Stroke Investigative Research and Education Network (SIREN) seeks to comprehensively characterize the genomic, sociocultural, economic, and behavioral risk factors for stroke and to build effective teams for research to address and decrease the burden of stroke and other non communicable diseases in SSA. One of the first steps to address this goal was to effectively engage the communities that suffer the high burden of disease in SSA. This study describes how the SIREN project engaged six sites in Ghana and Nigeria over the past three years, describing the community engagement activities that have arisen since inception. Aim: The aim of community engagement (CE) within SIREN is to elucidate information about knowledge, attitudes, beliefs, and practices (KABP) about stroke and its risk factors from individuals of African ancestry in SSA, and to educate the community about stroke and ways to decrease disabilities and deaths from stroke using socioculturally appropriate messaging and messengers. Methods: Community Advisory Board (CABs), Focus Group Discussions (FGDs) and community outreach programs. Results: 27 FGDs with 168 participants including community heads, religious leaders, health professionals and individuals with stroke among others, were conducted, and over 60 CE outreaches have been conducted within the SIREN performance sites. Over 5,900 individuals have received education on cardiovascular risk factors and about 5,000 have been screened for cardiovascular risk factors during the outreaches. FGDs and outreach programs indicate that knowledge of stroke, as well as risk factors and follow-up evidence-based care is limited and often late. Other findings include: 1) Most recognize hypertension as a major risk factor for stroke. 2) About 50% report that stroke is hereditary and about 20% do not know organs affected by stroke. 3) More than 95% willing to participate in genetic testing research and about 85% willing to pay for testing and recommend the test to others. 4) Almost all indicated that genetic testing could help health providers better treat stroke and help scientists better understand the causes of stroke. The CABs provided stakeholder input into SIREN activities and facilitated collaborations among investigators, community members and stakeholders. Conclusion: The CE core within SIREN is a first-of-its kind public outreach engagement initiative to evaluate and address perceptions about stroke and genomics by patients, caregivers, and local leaders in SSA and has implications as a model for assessment in other high-stroke risk populations. SIREN’s CE program uses best practices to build capacity for community-engaged research, accelerate integration of research findings into practice and strengthen dynamic community-academic partnerships within our communities. CE has had several major successes over the past three years including our multi-site collaboration examining the KABP about stroke (symptoms, risk factors, burden) and genetic testing across SSA.

Keywords: community advisory board, community engagement, focus groups, outreach, SSA, stroke

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Authors: S. B. R. Slagmulder

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Monitoring inspiratory effort and dynamic lung stress in patients on pressure support ventilation in the ICU is important for protecting against self inflicted lung injury (P-SILI) and diaphragm dysfunction. Strategies to address the detrimental effects of respiratory drive and effort can lead to improved patient outcomes. Two non-invasive estimation methods, occlusion pressure (Pocc) and P0.1, have been proposed for achieving lung and diaphragm protective ventilation. However, their relationship and interpretation in neuro ICU patients is not well understood. P0.1 is the airway pressure measured during a 100-millisecond occlusion of the inspiratory port. It reflects the neural drive from the respiratory centers to the diaphragm and respiratory muscles, indicating the patient's respiratory drive during the initiation of each breath. Occlusion pressure, measured during a brief inspiratory pause against a closed airway, provides information about the inspiratory muscles' strength and the system's total resistance and compliance. Research Objective: Understanding the relationship between Pocc and P0.1 in brain-injured patients can provide insights into the interpretation of these values in pressure support ventilation. This knowledge can contribute to determining extubation readiness and optimizing ventilation strategies to improve patient outcomes. The central goal is to asses a study protocol for determining the relationship between Pocc and P0.1 in brain-injured patients on pressure support ventilation and their ability to predict successful extubation. Additionally, comparing these values between brain-damaged and non-brain-damaged patients may provide valuable insights. Key Areas of Inquiry: 1. How do Pocc and P0.1 values correlate within brain injury patients undergoing pressure support ventilation? 2. To what extent can Pocc and P0.1 values serve as predictive indicators for successful extubation in patients with brain injuries? 3. What differentiates the Pocc and P0.1 values between patients with brain injuries and those without? Methodology: P0.1 and occlusion pressures are standard measurements for pressure support ventilation patients, taken by attending doctors as per protocol. We utilize electronic patient records for existing data. Unpaired T-test will be conducted to compare P0.1 and Pocc values between both study groups. Associations between P0.1 and Pocc and other study variables, such as extubation, will be explored with simple regression and correlation analysis. Depending on how the data evolve, subgroup analysis will be performed for patients with and without extubation failure. Results: While it is anticipated that neuro patients may exhibit high respiratory drive, the linkage between such elevation, quantified by P0.1, and successful extubation remains unknown The analysis will focus on determining the ability of these values to predict successful extubation and their potential impact on ventilation strategies. Conclusion: Further research is pending to fully understand the potential of these indices and their impact on mechanical ventilation in different patient populations and clinical scenarios. Understanding these relationships can aid in determining extubation readiness and tailoring ventilation strategies to improve patient outcomes in this specific patient population. Additionally, it is vital to account for the influence of sedatives, neurological scores, and BMI on respiratory drive and occlusion pressures to ensure a comprehensive analysis.

Keywords: brain damage, diaphragm dysfunction, occlusion pressure, p0.1, respiratory drive

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Authors: Mette Dalgaard Nielsen

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The paper serves the purpose of providing an eco-systemic typology of fashion resale business models in Denmark while pointing to possibilities to learn from its wisdom during a time when a fundamental break with the dominant linear fashion paradigm has become inevitable. As we transgress planetary boundaries and can no longer continue the unsustainable path of over-exploiting the Earth’s resources, the global fashion industry faces a tremendous need for change. One of the preferred answers to the fashion industry’s sustainability crises lies in the circular economy, which aims to maximize the utilization of resources by keeping garments in use for longer. Thus, in the context of fashion, resale business models that allow pre-owned garments to change hands with the purpose of being reused in continuous cycles are considered to be among the most efficient forms of circularity. Methodologies: The paper is based on empirical data from an ongoing project and a series of qualitative pilot studies that have been conducted on the Danish resale market over a 2-year time period from Fall 2021 to Fall 2023. The methodological framework is comprised of (n) ethnography and fieldwork in selected resale environments, as well as semi-structured interviews and a workshop with eight business partners from the Danish fashion and textiles industry. By focusing on the real-world circulation of pre-owned garments, which is enabled by the identified resale business models, the research lets go of simplistic hypotheses to the benefit of dynamic, vibrant and non-linear processes. As such, the paper contributes to the emerging research field of circular economy and fashion, which finds itself in a critical need to move from non-verified concepts and theories to empirical evidence. Findings: Based on the empirical data and anchored in the business partners, the paper analyses and presents five distinct resale business models with different product, service and design characteristics. These are 1) branded resale, 2) trade-in resale, 3) peer-2-peer resale, 4) resale boutiques and consignment shops and 5) resale shelf/square meter stores and flea markets. Together, the five business models represent a plurality of resale-promoting business model design elements that have been found to contribute to the circulation of pre-owned garments in various ways for different garments, users and businesses in Denmark. Hence, the provided typology points to the necessity of prioritizing several rather than single resale business model designs, services and initiatives for the resale market to help reconfigure the linear fashion model and create a circular-ish future. Conclusions: The article represents a twofold research ambition by 1) presenting an original, up-to-date eco-systemic typology of resale business models in Denmark and 2) using the typology and its eco-systemic traits as a tool to understand different business model design elements and possibilities to help fashion grow out of its linear growth model. By basing the typology on eco-systemic mechanisms and actual exemplars of resale business models, it becomes possible to envision the contours of a genuine alternative to business as usual that ultimately helps bend the linear fashion model towards circularity.

Keywords: circular business models, circular economy, fashion, resale, strategic design, sustainability

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Authors: Navid Kaboudi, Ali Shayanfar

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Introduction: Feeding infants with safe milk from the beginning of their life is an important issue. Drugs which are used by mothers can affect the composition of milk in a way that is not only unsuitable, but also toxic for infants. Consuming permeable drugs during that sensitive period by mother could lead to serious side effects to the infant. Due to the ethical restrictions of drug testing on humans, especially women, during their lactation period, computational approaches based on structural parameters could be useful. The aim of this study is to develop mechanistic models to predict the M/P ratio of drugs during breastfeeding period based on their structural descriptors. Methods: Two hundred and nine different chemicals with their M/P ratio were used in this study. All drugs were categorized into two groups based on their M/P value as Malone classification: 1: Drugs with M/P>1, which are considered as high risk 2: Drugs with M/P>1, which are considered as low risk Thirty eight chemical descriptors were calculated by ACD/labs 6.00 and Data warrior software in order to assess the penetration during breastfeeding period. Later on, four specific models based on the number of hydrogen bond acceptors, polar surface area, total surface area, and number of acidic oxygen were established for the prediction. The mentioned descriptors can predict the penetration with an acceptable accuracy. For the remaining compounds (N= 147, 158, 160, and 174 for models 1 to 4, respectively) of each model binary regression with SPSS 21 was done in order to give us a model to predict the penetration ratio of compounds. Only structural descriptors with p-value<0.1 remained in the final model. Results and discussion: Four different models based on the number of hydrogen bond acceptors, polar surface area, and total surface area were obtained in order to predict the penetration of drugs into human milk during breastfeeding period About 3-4% of milk consists of lipids, and the amount of lipid after parturition increases. Lipid soluble drugs diffuse alongside with fats from plasma to mammary glands. lipophilicity plays a vital role in predicting the penetration class of drugs during lactation period. It was shown in the logistic regression models that compounds with number of hydrogen bond acceptors, PSA and TSA above 5, 90 and 25 respectively, are less permeable to milk because they are less soluble in the amount of fats in milk. The pH of milk is acidic and due to that, basic compounds tend to be concentrated in milk than plasma while acidic compounds may consist lower concentrations in milk than plasma. Conclusion: In this study, we developed four regression-based models to predict the penetration class of drugs during the lactation period. The obtained models can lead to a higher speed in drug development process, saving energy, and costs. Milk/plasma ratio assessment of drugs requires multiple steps of animal testing, which has its own ethical issues. QSAR modeling could help scientist to reduce the amount of animal testing, and our models are also eligible to do that.

Keywords: logistic regression, breastfeeding, descriptors, penetration

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Authors: Julia Ive, Lucia Specia

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Understanding and detecting toxicity is an important problem to support safer human interactions online. Our work focuses on the important problem of contextual toxicity detection, where automated classifiers are tasked with determining whether a short textual segment (usually a sentence) is toxic within its conversational context. We use “toxicity” as an umbrella term to denote a number of variants commonly named in the literature, including hate, abuse, offence, among others. Detecting toxicity in context is a non-trivial problem and has been addressed by very few previous studies. These previous studies have analysed the influence of conversational context in human perception of toxicity in controlled experiments and concluded that humans rarely change their judgements in the presence of context. They have also evaluated contextual detection models based on state-of-the-art Deep Learning and Natural Language Processing (NLP) techniques. Counterintuitively, they reached the general conclusion that computational models tend to suffer performance degradation in the presence of context. We challenge these empirical observations by devising better contextual predictive models that also rely on NLP data augmentation techniques to create larger and better data. In our study, we start by further analysing the human perception of toxicity in conversational data (i.e., tweets), in the absence versus presence of context, in this case, previous tweets in the same conversational thread. We observed that the conclusions of previous work on human perception are mainly due to data issues: The contextual data available does not provide sufficient evidence that context is indeed important (even for humans). The data problem is common in current toxicity datasets: cases labelled as toxic are either obviously toxic (i.e., overt toxicity with swear, racist, etc. words), and thus context does is not needed for a decision, or are ambiguous, vague or unclear even in the presence of context; in addition, the data contains labeling inconsistencies. To address this problem, we propose to automatically generate contextual samples where toxicity is not obvious (i.e., covert cases) without context or where different contexts can lead to different toxicity judgements for the same tweet. We generate toxic and non-toxic utterances conditioned on the context or on target tweets using a range of techniques for controlled text generation(e.g., Generative Adversarial Networks and steering techniques). On the contextual detection models, we posit that their poor performance is due to limitations on both of the data they are trained on (same problems stated above) and the architectures they use, which are not able to leverage context in effective ways. To improve on that, we propose text classification architectures that take the hierarchy of conversational utterances into account. In experiments benchmarking ours against previous models on existing and automatically generated data, we show that both data and architectural choices are very important. Our model achieves substantial performance improvements as compared to the baselines that are non-contextual or contextual but agnostic of the conversation structure.

Keywords: contextual toxicity detection, data augmentation, hierarchical text classification models, natural language processing

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Authors: Keping Zuo, Jia Yin Chia, Gideon Praveen Kumar Vijayakumar, Foad Kabinejadian, Fangsen Cui, Pei Ho, Hwa Liang Leo

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Carotid artery is the major vessel supplying blood to the brain. Carotid artery stenosis is one of the three major causes of stroke and the stroke is the fourth leading cause of death and the first leading cause of disability in most developed countries. Although there is an increasing interest in carotid artery stenting for treatment of cervical carotid artery bifurcation therosclerotic disease, currently available bare metal stents cannot provide an adequate protection against the detachment of the plaque fragments over diseased carotid artery, which could result in the formation of micro-emboli and subsequent stroke. Our research group has recently developed a novel preferential covered-stent for carotid artery aims to prevent friable fragments of atherosclerotic plaques from flowing into the cerebral circulation, and yet retaining the ability to preserve the flow of the external carotid artery. The preliminary animal studies have demonstrated the potential of this novel covered-stent design for the treatment of carotid therosclerotic stenosis. The purpose of this study is to evaluate the biomechanical property of PU membrane of different concentration configurations in order to refine the stent coating technique and enhance the clinical performance of our novel carotid covered stent. Results from this study also provide necessary material property information crucial for accurate simulation analysis for our stents. Method: Medical grade Polyurethane (ChronoFlex AR) was used to prepare PU membrane specimens. Different PU membrane configurations were subjected to uniaxial test: 22%, 16%, and 11% PU solution were made by mixing the original solution with proper amount of the Dimethylacetamide (DMAC). The specimens were then immersed in physiological saline solution for 24 hours before test. All specimens were moistened with saline solution before mounting and subsequent uniaxial testing. The specimens were preconditioned by loading the PU membrane sample to a peak stress of 5.5 Mpa for 10 consecutive cycles at a rate of 50 mm/min. The specimens were then stretched to failure at the same loading rate. Result: The results showed that the stress-strain response curves of all PU membrane samples exhibited nonlinear characteristic. For the ultimate failure stress, 22% PU membrane was significantly higher than 16% (p<0.05). In general, our preliminary results showed that lower concentration PU membrane is stiffer than the higher concentration one. From the perspective of mechanical properties, 22% PU membrane is a better choice for the covered stent. Interestingly, the hyperelastic Ogden model is able to accurately capture the nonlinear, isotropic stress-strain behavior of PU membrane with R2 of 0.9977 ± 0.00172. This result will be useful for future biomechanical analysis of our stent designs and will play an important role for computational modeling of our covered stent fatigue study.

Keywords: carotid artery, covered stent, nonlinear, hyperelastic, stress, strain

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Authors: Michael A. Unbehauen, Gregory D. Sloan, Alberto J. Squatrito

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Missile proliferation and global stability are intrinsically linked. Missile threats continually appear at the forefront of global security issues. North Korea’s recently demonstrated nuclear and intercontinental ballistic missile (ICBM) capabilities, for the first time since the Cold War, renewed public interest in strategic missile defense capabilities. To protect from limited ICBM attacks from so-called rogue actors, the United States developed the Ground-based Midcourse Defense (GMD) system. This study examines if the GMD missile defense shield has contributed to a safer world or triggered a new arms race. Based upon increased missile-related developments and the lack of adherence to international missile treaties, it is generally perceived that the GMD system is a destabilizing factor for global security. By examining the current state of arms control treaties as well as existing missile arsenals and ongoing efforts in technologies to overcome U.S. missile defenses, this study seeks to analyze the contribution of GMD to global stability. A thorough investigation cannot ignore that, through the establishment of this limited capability, the U.S. violated longstanding, successful weapons treaties and caused concern among states that possess ICBMs. GMD capability contributes to the perception that ICBM arsenals could become ineffective, creating an imbalance in favor of the United States, leading to increased global instability and tension. While blame for the deterioration of global stability and non-adherence to arms control treaties is often placed on U.S. missile defense, the facts do not necessarily support this view. The notion of a renewed arms race due to GMD is supported neither by current missile arsenals nor by the inevitable development of new and enhanced missile technology, to include multiple independently targeted reentry vehicles (MIRVs), maneuverable reentry vehicles (MaRVs), and hypersonic glide vehicles (HGVs). The methodology in this study encapsulates a period of time, pre- and post-GMD introduction, while analyzing international treaty adherence, missile counts and types, and research in new missile technologies. The decline in international treaty adherence, coupled with a measurable increase in the number and types of missiles or research in new missile technologies during the period after the introduction of GMD, could be perceived as a clear indicator of GMD contributing to global instability. However, research into improved technology (MIRV, MaRV and HGV) prior to GMD, as well as a decline of various global missile inventories and testing of systems during this same period, would seem to invalidate this theory. U.S. adversaries have exploited the perception of the U.S. missile defense shield as a destabilizing factor as a pretext to strengthen and modernize their militaries and justify their policies. As a result, it can be concluded that global stability has not significantly decreased due to GMD; but rather, the natural progression of technological and missile development would inherently include innovative and dynamic approaches to target engagement, deterrence, and national defense.

Keywords: arms control, arms race, global security, GMD, ICBM, missile defense, proliferation

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Authors: Brenagh E. Schlingermann, Clare Lodge, Paula Rankin

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Background: Gaelic football, hurling and camogie are highly popular field games in Ireland. Research into the epidemiology of injury in Gaelic games revealed that approximately three quarters of the injuries in the games occur in the lower extremity. These injuries can have player, team and institutional impacts due to multiple factors including financial burden and time loss from competition. Research has shown it is possible to record injury data consistently with the GAA through a closed online recording system known as the GAA injury surveillance database. It has been established that determining the incidence of injury is the first step of injury prevention. The goals of this study were to create a dynamic GAA15 injury prevention programme which addressed five key components/goals; avoid positions associated with a high risk of injury, enhance flexibility, enhance strength, optimize plyometrics and address sports specific agilities. These key components are internationally recognized through the Prevent Injury, Enhance performance (PEP) programme which has proven reductions in ACL injuries by 74%. In national Gaelic games the programme is known as the GAA15 which has been devised from the principles of the PEP. No such injury prevention strategies have been published on this cohort in Gaelic games to date. This study will investigate the effects of the GAA15 on injury incidence and neuromuscular function in Gaelic games. Methods: A total of 154 players (mean age 20.32 ± 2.84) were recruited from the GAA teams within the Institute of Technology Carlow (ITC). Preseason and post season testing involved two objective screening tests; Y balance test and Three Hop Test. Practical workshops, with ongoing liaison, were provided to the coaches on the implementation of the GAA15. The programme was performed before every training session and game and the existing GAA injury surveillance database was accessed to monitor player’s injuries by the college sports rehabilitation athletic therapist. Retrospective analysis of the ITC clinic records were performed in conjunction with the database analysis as a means of tracking injuries that may have been missed. The effects of the programme were analysed by comparing the intervention groups Y balance and three hop test scores to an age/gender matched control group. Results: Year 1 results revealed significant increases in neuromuscular function as a result of the GAA15. Y Balance test scores for the intervention group increased in both the posterolateral (p=.005 and p=.001) and posteromedial reach directions (p= .001 and p=.001). A decrease in performance was determined for the three hop test (p=.039). Overall twenty-five injuries were reported during the season resulting in an injury rate of 3.00 injuries/1000hrs of participation; 1.25 injuries/1000hrs training and 4.25 injuries/1000hrs match play. Non-contact injuries accounted for 40% of the injuries sustained. Year 2 results are pending and expected April 2016. Conclusion: It is envisaged that implementation of the GAA15 will continue to reduce the risk of injury and improve neuromuscular function in collegiate Gaelic games athletes.

Keywords: GAA15, Gaelic games, injury prevention, neuromuscular training

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Authors: Ani Kojoyan

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The Syrian refugee crisis has been a matter of worldwide concern during the recent years. And though refugees’ problems are contextualized in terms of time and space, the refugee crisis still remains a global issue to discuss. Since the start of the conflict, Armenia has welcomed thousands of Syrian refugees too. Taking into consideration Armenia’s current socio-economic and geopolitical situation, the flow of refugees is a challenge both for the country and for refugees themselves. However, these people are not simply refugees from Syria, they are Syrian-Armenian refugees; people whose ancestors were survivals of the Armenian Genocide, perpetrated by the Ottoman Turks in 1915, people whose ancestors became refugees a century ago in Syria and now, ironically, a century later they follow their ancestors’ paths, turning into refugees themselves in their historical homeland, facing various difficulties, among them socio-economic, socio-ideological, and identity and gender issues, the latter being the main topic of discussion in the present paper. The situation presented above makes us discuss certain questions within this study: how do Syrian-Armenian refugees define themselves and their status? Which are their gender roles in the socio-economic context? How do social and economic challenges re-shape Syrian-Armenian women refugees’ identities? The study applies qualitative research methods of analysis, which includes semi-structured and in-depth interviews with 15 participants (18-25, 26-40 age groups), and two focus group works, involving 8 participants (18-35 age group) for each focus group activity. The activities were carried out in October 2016, Yerevan, Armenia. The study also includes Secondary Data Analysis. In addition, in order to centralize refugee women’s experiences and identity issues, the study adopts a qualitative lens from a feminist standpoint position. It is based on the assumption that human activity structures and limits understanding, and that the distorted comprehension of events or activities has emerged from the male-oriented dominant judgement which can be discovered through uncovering the understanding of the situation from women’s activity perspectives. The findings suggest that identity is dynamic, complex, over-changing and sensitive to time and space, gender and class. The process of re-shaping identity is even more complicated and multi-layered and is based on internal and external factors, conditioned by individual and collective needs and interests. Refugees are mostly considered as people who lost their identity in the past since they have no longer connection anywhere and try to find it in the present. In turn, female refugees, being a more vulnerable class, go through more complicated identity re-formulating discourse negotiations. They stand between the borders of the old and new, borders of lost and re-found selves, borders of creating and self-fashioning, between illusions and the challenging reality. Particularly, refugee women become more sensitive within the discourses of the private and the public domains: some of them try to create a ‘new-self’, creating their space in a new society, whereas others try to negotiate their affective/emotional labour within their own family domains.

Keywords: feminist standpoint position, gender, identity, refugee studies, Syrian-Armenian women refugees

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Authors: Simran Baweja, Bhavika Kalal, Surajit Maity

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Photoinduced tautomerization reactions have been the centre of attention among scientific community over past several decades because of their significance in various biological systems. 7-azaindole (7AI) is considered as a model system for DNA base pairing and to understand the role of such tautomerization reactions in mutations. To the best of our knowledge, extensive studies have been carried on 7-azaindole and its solvent clusters exhibiting proton/ hydrogen transfer in both solution as well as gas phase. Derivatives of above molecule, like 2,7- and 2,6-diazaindoles are proposed to have even better photophysical properties due to the presence of -aza group on the 2nd position. However, there are a few studies in the solution phase which suggest the relevance of these molecules, but there are no experimental studies reported in the gas phase yet. In our current investigation, we present the first gas phase spectroscopic data of 2,7-diazaindole (2,7-DAI) and its solvent cluster (2,7-DAI-H2O). In this, we have employed state-of-the-art laser spectroscopic methods such as fluorescence excitation (LIF), dispersed fluorescence (DF), resonant two-photon ionization time of flight mass spectrometry (2C-R2PI), photoionization efficiency spectroscopy (PIE), IR-UV double resonance spectroscopy i.e. fluorescence-dip infrared spectroscopy (FDIR) and resonant ion-dip infrared spectroscopy (IDIR) to understand the electronic structure of the molecule. The origin band corresponding to S1 ← S0 transition of the bare 2,7-DAI is found to be positioned at 33910 cm-1 whereas the origin band corresponding to S1 ← S0 transition of the 2,7-DAI-H2O is positioned at 33074 cm-1. The red shifted transition in case of solvent cluster suggests the enhanced feasibility of excited state hydrogen/ proton transfer. The ionization potential for the 2,7-DAI molecule is found to be 8.92 eV, which is significantly higher that the previously reported 7AI (8.11 eV) molecule, making it a comparatively complex molecule to study. The ionization potential is reduced by 0.14 eV in case of 2,7-DAI-H2O (8.78 eV) cluster compared to that of 2,7-DAI. Moreover, on comparison with the available literature values of 7AI, we found the origin band of 2,7-DAI and 2,7-DAI-H2O to be red shifted by -729 and -280 cm-1 respectively. The ground and excited state N-H stretching frequencies of the 27DAI molecule were determined using fluorescence-dip infrared spectra (FDIR) and resonant ion dip infrared spectroscopy (IDIR), obtained at 3523 and 3467 cm-1, respectively. The lower value of vNH in the electronic excited state of 27DAI implies the higher acidity of the group compared to the ground state. Moreover, we have done extensive computational analysis, which suggests that the energy barrier in excited state reduces significantly as we increase the number of catalytic solvent molecules (S= H2O, NH3) as well as the polarity of solvent molecules. We found that the ammonia molecule is a better candidate for hydrogen transfer compared to water because of its higher gas-phase basicity. Further studies are underway to understand the excited state dynamics and photochemistry of such N-rich chromophores.

Keywords: photoinduced tautomerization reactions, gas phse spectroscopy, ), IR-UV double resonance spectroscopy, resonant two-photon ionization time of flight mass spectrometry (2C-R2PI)

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Authors: Babatunde Kolawole

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This paper embarks on an exploration of the compelling interplay between documentary filmmaking and activism, delving into their symbiotic relationship and profound impact on advocacy and social justice causes. Through an in-depth analysis of diverse case studies, it seeks to illuminate the instances where documentary films have emerged as potent tools for effecting social change and advancing the principles of justice. This research underscores the vital role played by documentary filmmakers in harnessing the medium's unique capacity to engage, educate, and mobilize audiences while advocating for societal transformation. The primary focus of this study is on a selection of compelling case studies spanning various topics and causes, each exemplifying the marriage between documentary filmmaking and activism. These case studies encompass a broad spectrum of subjects, from environmental conservation and climate change to civil rights movements and human rights struggles. By examining these real-world instances, this paper endeavors to provide a comprehensive understanding of the strategies, challenges, and ethical considerations that underpin the practice of documentary filmmaking as a form of activism. Throughout the paper, it becomes evident that the potency of documentary filmmaking lies in its ability to blend artistry with social impact. The selected case studies vividly demonstrate how documentary filmmakers, armed with cameras and a passion for change, have emerged as critical agents of societal transformation. Whether it be exposing environmental atrocities, shedding light on systemic inequalities, or giving voice to marginalized communities, these documentaries have played a pivotal role in pushing the boundaries of advocacy and social justice. One of the key themes explored in this paper is the evolving nature of documentary filmmaking as a tool for activism. It delves into the shift from traditional observational documentaries to more participatory and immersive approaches, highlighting the dynamic ways in which filmmakers engage with their subjects and audiences. This evolution is exemplified in case studies where filmmakers have collaborated with the communities they document, fostering a sense of agency and empowerment among those whose stories are being told. Furthermore, this research underscores the ethical considerations inherent in the intersection of documentary filmmaking and activism. It scrutinizes questions surrounding representation, objectivity, and the responsibility of filmmakers in portraying complex social issues. By dissecting ethical dilemmas faced by documentary filmmakers in these case studies, this paper encourages a critical examination of the ethical boundaries and obligations in the realm of advocacy-driven filmmaking. In conclusion, this paper aims to shed light on the remarkable potential of documentary filmmaking as a catalyst for activism and social justice. Through the lens of compelling case studies, it illustrates the transformative power of the medium in effecting change, amplifying underrepresented voices, and mobilizing global audiences. It is hoped that this research will not only inform the discourse on documentary activism but also inspire filmmakers, scholars, and advocates to continue leveraging the cinematic art form as a formidable force for a more just and equitable world.

Keywords: film, filmmaker, documentary, human right

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Authors: Roni Ramon-Gonen, Amir Dori, Shahar Shelly

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Background and objectives: Healthcare professionals produce abundant textual information in their daily clinical practice. The extraction of insights from all the gathered information, mainly unstructured and lacking in normalization, is one of the major challenges in computational medicine. In this respect, text mining assembles different techniques to derive valuable insights from unstructured textual data, so it has led to being especially relevant in Medicine. Neurological patient’s history allows the clinician to define the patient’s symptoms and along with the result of the nerve conduction study (NCS) and electromyography (EMG) test, assists in formulating a differential diagnosis. Past medical history (PMH) helps to direct the latter. In this study, we aimed to identify relevant PMH, understand which PMHs are common among patients in the referral cohort and documented by the medical staff, and examine the differences by sex and age in a large cohort based on textual format notes. Methods: We retrospectively identified all patients with abnormal NCS between May 2016 to February 2022. Age, gender, and all NCS attributes reports were recorded, including the summary text. All patients’ histories were extracted from the text report by a query. Basic text cleansing and data preparation were performed, as well as lemmatization. Very popular words (like ‘left’ and ‘right’) were deleted. Several words were replaced with their abbreviations. A bag of words approach was used to perform the analyses. Different visualizations which are common in text analysis, were created to easily grasp the results. Results: We identified 5282 unique patients. Three thousand and five (57%) patients had documented PMH. Of which 60.4% (n=1817) were males. The total median age was 62 years (range 0.12 – 97.2 years), and the majority of patients (83%) presented after the age of forty years. The top two documented medical histories were diabetes mellitus (DM) and surgery. DM was observed in 16.3% of the patients, and surgery at 15.4%. Other frequent patient histories (among the top 20) were fracture, cancer (ca), motor vehicle accident (MVA), leg, lumbar, discopathy, back and carpal tunnel release (CTR). When separating the data by sex, we can see that DM and MVA are more frequent among males, while cancer and CTR are less frequent. On the other hand, the top medical history in females was surgery and, after that, DM. Other frequent histories among females are breast cancer, fractures, and CTR. In the younger population (ages 18 to 26), the frequent PMH were surgery, fractures, trauma, and MVA. Discussion: By applying text mining approaches to unstructured data, we were able to better understand which medical histories are more relevant in these circumstances and, in addition, gain additional insights regarding sex and age differences. These insights might help to collect epidemiological demographical data as well as raise new hypotheses. One limitation of this work is that each clinician might use different words or abbreviations to describe the same condition, and therefore using a coding system can be beneficial.

Keywords: abnormal studies, healthcare analytics, medical history, nerve conduction studies, text mining, textual analysis

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Authors: Vera G. Dianova, Lori P. Montross, Charles M. Burke

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In the digital age, the widespread and frequently excessive use of mobile phones amongst university students is recognized as a significant distractor which interferes with their ability to enter a deep state of concentration during studies and diminishes their prospects of experiencing the enjoyable and instrumental state of flow, as defined and described by psychologist M. Csikszentmihalyi. This study has targeted 50 university students with the aim of teaching them to cultivate their ability to engage in deep work and to attain the state of flow, fostering more effective and enjoyable learning experiences. Prior to the start of the intervention, all participating students completed a comprehensive survey based on a variety of validated scales assessing their inclination toward lifelong learning, frequency of flow experiences during study, frustration tolerance, sense of agency, as well as their love of learning and daily time devoted to non-academic mobile phone activities. Several days after this initial assessment, students received a 90-minute lecture on the principles of flow and deep work, accompanied by a critical discourse on the detrimental effects of excessive mobile phone usage. They were encouraged to practice deep work and strive for frequent flow states throughout the semester. Subsequently, students submitted weekly surveys, including the 10-item CORE Dispositional Flow Scale, a 3-item agency scale and furthermore disclosed their average daily hours spent on non-academic mobile phone usage. As a final step, at the end of the semester students engaged in reflective report writing, sharing their experiences and evaluating the intervention's effectiveness. They considered alterations in their love of learning, reflected on the implications of their mobile phone usage, contemplated improvements in their tolerance for boredom and perseverance in complex tasks, and pondered the concept of lifelong learning. Additionally, students assessed whether they actively took steps towards managing their recreational phone usage and towards improving their commitment to becoming lifelong learners. Employing a mixed-methods approach our study offers insights into the dynamics of concentration, flow, mobile phone usage and attitudes towards learning among undergraduate and graduate university students. The findings of this study aim to promote profound contemplation, on the part of both students and instructors, on the rapidly evolving digital-age higher education environment. In an era defined by digital and AI advancements, the ability to concentrate, to experience the state of flow, and to love learning has never been more crucial. This study underscores the significance of addressing mobile phone distractions and providing strategies for cultivating deep concentration. The insights gained can guide educators in shaping effective learning strategies for the digital age. By nurturing a love for learning and encouraging lifelong learning, educational institutions can better prepare students for a rapidly changing labor market, where adaptability and continuous learning are paramount for success in a dynamic career landscape.

Keywords: deep work, flow, higher education, lifelong learning, love of learning

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Authors: Jonas De Kerf, Rein De Cooman, Sara De Gieter

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For many decades, scholars have aimed to understand how work can become more meaningful by maximizing both potential and enhancing feelings of satisfaction. One of the largest contributions towards such positive psychology was made with the introduction of the concept of ‘flow,’ which refers to a condition in which people feel intense engagement and effortless action. Since then, valuable research on work-related flow has indicated that this state of mind is related to positive outcomes for both organizations (e.g., social, supportive climates) and workers (e.g., job satisfaction). Yet, scholars still do not fully comprehend how such deep involvement at work is obtained, given the notion that flow is considered a short-term, complex, and dynamic experience. Most research neglects that people who experience flow ought to be optimally challenged so that intense concentration is required. Because attention is at the core of this enjoyable state of mind, this study aims to comprehend how elements that affect workers’ cognitive functioning impact flow at work. Research on cognitive performance suggests that working on mentally demanding tasks (e.g., information processing tasks) requires workers to concentrate deeply, as a result leading to flow experiences. Based on social facilitation theory, working on such tasks in an isolated environment eases concentration. Prior research has indicated that working at home (instead of working at the office) or in a closed office (rather than in an open-plan office) impacts employees’ overall functioning in terms of concentration and productivity. Consequently, we advance such knowledge and propose an interaction by combining cognitive task characteristics and work environments among part-time teleworkers. Hence, we not only aim to shed light on the relation between cognitive tasks and flow but also provide empirical evidence that workers performing such tasks achieve the highest states of flow while working either at home or in closed offices. In July 2022, an experience-sampling study will be conducted that uses a semi-random signal schedule to understand how task and environment predictors together impact part-time teleworkers’ flow. More precisely, about 150 knowledge workers will fill in multiple surveys a day for two consecutive workweeks to report their flow experiences, cognitive tasks, and work environments. Preliminary results from a pilot study indicate that on a between level, tasks high in information processing go along with high self-reported fluent productivity (i.e., making progress). As expected, evidence was found for higher fluency in productivity for workers performing information processing tasks both at home and in a closed office, compared to those performing the same tasks at the office or in open-plan offices. This study expands the current knowledge on work-related flow by looking at a task and environmental predictors that enable workers to obtain such a peak state. While doing so, our findings suggest that practitioners should strive for ideal alignments between tasks and work locations to work with both deep involvement and gratification.

Keywords: cognitive work, office lay-out, work location, work-related flow

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Authors: Fstemeh Rais Esmaili, Ehsan Ranjbar

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Pedestrian streets as one type of urban public spaces have an important role in improving the quality of urban life. In Iran, planning and designing of pedestrian streets is in its primary steps. In spite of starting this approach in Iran, and designing several pedestrian streets, there are still not organized studies about quality assessment of pedestrian streets. As a result, the strength and weakness points of the initial experiences have not been utilized. This inattention to quality assessment have caused designing pedestrian streets to be limited to just vehicles traffic control and preliminary actions like paving; so that, special potentials of pedestrian streets for creating social, livable and dynamic public spaces have not been used. This article, as an organized study about quality assessment of pedestrian streets in Iran, tries to reach two main goals: first, introducing a framework for quality assessment of pedestrian streets in Iran, and second, creating a context for improving the quality of pedestrian streets especially for further experiences. The main research methods are description and context analyzing. With respect to comparative analysis of ideas about quality, considering international and local case studies and analyzing existing condition of Saf Pedestrian Street, a particular model for quality assessment has been introduced. In this model, main components and assessment criteria have been presented. On the basis of this model, questionnaire and checklist for assessment have been prepared. The questionnaire and interview have been used to assess qualities which are in direct contact with people and the checklist has been used for analyzing visual qualities by authors through observation. Some results of questionnaire and checklist show that 7 of 11 primary components, diversity, flexibility, cleanness, legibility and imaginably, identity, livability, form and physical setting are rated low and very low in quality degree. Three components, efficiency, comfort and distinctiveness, have medium and low quality degree and one component, access, linkage and permeability has high quality degree. Therefore, based on implemented analyzing process, Saf Pedestrian Street needs to be improved and these quality improvement priorities are determined based on presented criteria. Adaption of final results with existing condition illustrates the shortage of services for satisfying user’s needs, inflexibility and impossibility of using spaces in various times, lack of facilities for different climatic conditions, lack of facilities such as drinking fountain, inappropriate designing of existing urban furniture like garbage cans, and creating pollution and unsuitable view, lack of visual attractions, neglecting disabled persons in designing entrances, shortage of benches and their undesirable designing, lack of vegetation, absence of special characters making it different from other streets, preventing people taking part in the space causing lack of affiliation, lack of appropriate elements for leisure time and lack of exhilaration in the space. On the other hand, these results present high access and permeability, high safety, less sound pollution and more relief, comfortable movement along the way due to suitable pavement and economic efficiency, as the strength points of Saf pedestrian street.

Keywords: pedestrian streets, quality assessment, quality criteria, Saf Pedestrian Street

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Authors: Dan Kanmegne

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Africa will become the most populated continent by the end of the century, with around 4 billion inhabitants. Food security and climate changes will become continental issues since agricultural practices depend on climate but also contribute to global emissions and land degradation. Agroforestry has been identified as a cost-efficient and reliable strategy to address these two issues. It is defined as the integrated management of trees and crops/animals in the same land unit. Agroforestry provides benefits in terms of goods (fruits, medicine, wood, etc.) and services (windbreaks, fertility, etc.), and is acknowledged to have a great potential for carbon sequestration; therefore it can be integrated into reduction mechanisms of carbon emissions. Particularly in sub-Saharan Africa, the constraint stands in the lack of information about both areas under agroforestry and the characterization (composition, structure, and management) of each agroforestry system at the country level. This study describes and quantifies “what is where?”, earliest to the quantification of carbon stock in different systems. Remote sensing (RS) is the most efficient approach to map such a dynamic technology as agroforestry since it gives relatively adequate and consistent information over a large area at nearly no cost. RS data fulfill the good practice guidelines of the Intergovernmental Panel On Climate Change (IPCC) that is to be used in carbon estimation. Satellite data are getting more and more accessible, and the archives are growing exponentially. To retrieve useful information to support decision-making out of this large amount of data, satellite data needs to be organized so to ensure fast processing, quick accessibility, and ease of use. A new solution is a data cube, which can be understood as a multi-dimensional stack (space, time, data type) of spatially aligned pixels and used for efficient access and analysis. A data cube for Burkina Faso has been set up from the cooperation project between the international service provider WASCAL and Germany, which provides an accessible exploitation architecture of multi-temporal satellite data. The aim of this study is to map and characterize agroforestry systems using the Burkina Faso earth observation data cube. The approach in its initial stage is based on an unsupervised image classification of a normalized difference vegetation index (NDVI) time series from 2010 to 2018, to stratify the country based on the vegetation. Fifteen strata were identified, and four samples per location were randomly assigned to define the sampling units. For safety reasons, the northern part will not be part of the fieldwork. A total of 52 locations will be visited by the end of the dry season in February-March 2020. The field campaigns will consist of identifying and describing different agroforestry systems and qualitative interviews. A multi-temporal supervised image classification will be done with a random forest algorithm, and the field data will be used for both training the algorithm and accuracy assessment. The expected outputs are (i) map(s) of agroforestry dynamics, (ii) characteristics of different systems (main species, management, area, etc.); (iii) assessment report of Burkina Faso data cube.

Keywords: agroforestry systems, Burkina Faso, earth observation data cube, multi-temporal image classification

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Authors: Wenfa Yu, Thuva Gnanasampanthan, John Finlay, Jessica Clarke, Charlotte Anderson, Tony Clare, Axel Rosenhahn

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Marine biofouling is a worldwide problem at vast economic and ecological costs. Historically it was combated with toxic coatings such as tributyltin. As those coatings being banned nowadays, finding environmental friendly antifouling solution has become an urgent topic. In this study antifouling coatings consisted of natural occurring polysaccharides hyaluronic acid (HA), alginic acid (AA), chitosan (Ch) and polyelectrolyte polyethylenimine (PEI) are constructed into polyelectrolyte multilayers (PEMs) in a Layer-by-Layer (LbL) method. LbL PEM construction is a straightforward way to assemble biomacromolecular coatings on surfaces. Advantages about PEM include ease of handling, highly diverse PEM composition, precise control over the thickness and so on. PEMs have been widely employed in medical application and there are numerous studies regarding their protein adsorption, elasticity and cell adhesive properties. With the adjustment of coating composition, termination layer charge, coating morphology and cross-linking method, it is possible to prepare low marine biofouling coatings with PEMs. In this study, using spin coating technology, PEM construction was achieved at smooth multilayers with roughness as low as 2nm rms and highly reproducible thickness around 50nm. To obtain stability in sea water, the multilayers were covalently cross-linked either thermally or chemically. The cross-linking method affected surface energy, which was reflected in water contact angle, thermal cross-linking led to hydrophobic surfaces and chemical cross-linking generated hydrophilic surfaces. The coatings were then evaluated regarding its protein resistance and biological species resistance. While the hydrophobic thermally cross-linked PEM had low resistance towards proteins, the resistance of chemically cross-linked PEM strongly depended on the PEM termination layer and the charge of the protein, opposite charge caused high adsorption and same charge low adsorption, indicating electrostatic interaction plays a crucial role in the protein adsorption processes. Ulva linza was chosen as the biological species for antifouling performance evaluation. Despite of the poor resistance towards protein adsorption, thermally cross-linked PEM showed good resistance against Ulva spores settlement, the chemically cross-linked multilayers showed poor resistance regardless of the termination layer. Marine species adhesion is a complex process, although it involves proteins as bioadhesives, protein resistance its own is not a fully indicator for its antifouling performance. The species will pre select the surface, responding to cues like surface energy, chemistry, or charge and so on. Thus making it difficult for one single factors to determine its antifouling performance. Preparing PEM coating is a comprehensive work involving choosing polyelectrolyte combination, determining termination layer and the method for cross-linking. These decisions will affect PEM properties such as surface energy, charge, which is crucial, since biofouling is a process responding to surface properties in a highly sensitive and dynamic way.

Keywords: hyaluronic acid, polyelectrolyte multilayers, protein resistance, Ulva linza zoospores

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Authors: Hsien-Te Lin

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The purpose of this paper is to introduce the BCFES (building carbon footprint evaluation system), which is a LCA (life cycle assessment) tool developed by the Low Carbon Building Alliance (LCBA) in Taiwan. A qualified BCFES for the building industry should fulfill the function of evaluating carbon footprint throughout all stages in the life cycle of building projects, including the production, transportation and manufacturing of materials, construction, daily energy usage, renovation and demolition. However, many existing BCFESs are too complicated and not very designer-friendly, creating obstacles in the implementation of carbon reduction policies. One of the greatest obstacle is the misapplication of the carbon footprint inventory standards of PAS2050 or ISO14067, which are designed for mass-produced goods rather than building projects. When these product-oriented rules are applied to building projects, one must compute a tremendous amount of data for raw materials and the transportation of construction equipment throughout the construction period based on purchasing lists and construction logs. This verification method is very cumbersome by nature and unhelpful to the promotion of low carbon design. With a view to provide an engineer-oriented BCFE with pre-diagnosis functions, a component input/output (I/O) database system and a scenario simulation method for building energy are proposed herein. Most existing BCFESs base their calculations on a product-oriented carbon database for raw materials like cement, steel, glass, and wood. However, data on raw materials is meaningless for the purpose of encouraging carbon reduction design without a feedback mechanism, because an engineering project is not designed based on raw materials but rather on building components, such as flooring, walls, roofs, ceilings, roads or cabinets. The LCBA Database has been composited from existing carbon footprint databases for raw materials and architectural graphic standards. Project designers can now use the LCBA Database to conduct low carbon design in a much more simple and efficient way. Daily energy usage throughout a building's life cycle, including air conditioning, lighting, and electric equipment, is very difficult for the building designer to predict. A good BCFES should provide a simplified and designer-friendly method to overcome this obstacle in predicting energy consumption. In this paper, the author has developed a simplified tool, the dynamic Energy Use Intensity (EUI) method, to accurately predict energy usage with simple multiplications and additions using EUI data and the designed efficiency levels for the building envelope, AC, lighting and electrical equipment. Remarkably simple to use, it can help designers pre-diagnose hotspots in building carbon footprint and further enhance low carbon designs. The BCFES-LCBA offers the advantages of an engineer-friendly component I/O database, simplified energy prediction methods, pre-diagnosis of carbon hotspots and sensitivity to good low carbon designs, making it an increasingly popular carbon management tool in Taiwan. To date, about thirty projects have been awarded BCFES-LCBA certification and the assessment has become mandatory in some cities.

Keywords: building carbon footprint, life cycle assessment, energy use intensity, building energy

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Authors: Xu Qian

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This abstract examines the concept of resilience in adolescents from both adolescent medicine and child psychology perspectives. It discusses the role of healthcare providers in fostering resilience among adolescents, encompassing physical, psychological, and social aspects. The paper highlights evidence-based interventions and practical strategies for promoting resilience in this population. Introduction: Resilience plays a crucial role in the healthy development of adolescents, enabling them to navigate through the challenges of this transitional period. This abstract explores the concept of resilience from the perspectives of adolescent medicine and child psychology, shedding light on the collective efforts of healthcare providers in fostering resilience. By integrating the principles and practices of these two disciplines, this abstract emphasizes the multidimensional nature of resilience and its significance in the overall well-being of adolescents. Methods: A comprehensive literature review was conducted, encompassing research articles, empirical studies, and expert opinions from both adolescent medicine and child psychology fields. The search included databases such as PubMed, PsycINFO, and Google Scholar, focusing on publications from the past decade. The review aimed to identify evidence-based interventions and practical strategies employed by healthcare providers to promote resilience among adolescents. Results: The review revealed several key findings regarding the promotion of resilience in adolescents. Firstly, resilience is a dynamic process influenced by individual characteristics, environmental factors, and the interaction between the two. Secondly, healthcare providers play a critical role in fostering resilience by addressing the physical, psychological, and social needs of adolescents. This entails comprehensive healthcare services that integrate medical care, mental health support, and social interventions. Thirdly, evidence-based interventions such as cognitive-behavioral therapy, social skills training, and positive youth development programs have shown promising outcomes in enhancing resilience. Discussion: The integration of adolescent medicine and child psychology perspectives provides a comprehensive framework for promoting resilience in adolescents. By acknowledging the interplay between physical health, psychological well-being, and social functioning, healthcare providers can tailor interventions to address the specific needs and challenges faced by adolescents. Collaborative efforts between medical professionals, psychologists, educators, and families are vital in creating a supportive environment that fosters resilience. Additionally, the findings highlight the importance of early identification and intervention, emphasizing the need for routine screening and assessment to identify adolescents at risk and provide timely support. Conclusion: Promoting resilience in adolescents requires a holistic approach that integrates adolescent medicine and child psychology perspectives. By recognizing the multifaceted nature of resilience, healthcare providers can implement evidence-based interventions and practical strategies to enhance the well-being of adolescents. The collaboration between healthcare professionals from different disciplines, alongside the involvement of families and communities, is crucial for creating a resilient support system. By investing in the promotion of resilience during adolescence, we can empower young individuals to overcome adversity and thrive in their journey toward adulthood.

Keywords: psychology, clinical psychology, child psychology, adolescent psychology, adolescent

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Authors: Luis Castiella, Mariano Rueda, Catalina Palacio

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The world’s rapid urbanisation represents an excellent opportunity to implement initiatives that are oriented towards a country’s general development. However, this phenomenon has created considerable pressure on current urban models, pushing them nearer to a crisis. As a result, several factors usually associated with underdevelopment have been steadily rising. Moreover, actions taken by public authorities have not been able to keep up with the speed of urbanisation, which has impeded them from meeting the demands of society, responding with reactionary policies instead of with coordinated, organised efforts. In contrast, the concept of a Smart City which emerged around two decades ago, in principle, represents a city that utilises innovative technologies to remedy the everyday issues of the citizen, empowering them with the newest available technology and information. This concept has come to adopt a wider meaning, including human and social capital, as well as productivity, economic growth, quality of life, environment and participative governance. These developments have also disrupted the management of institutions such as academia, which have become key in generating scientific advancements that can solve pressing problems, and in forming a specialised class that is able to follow up on these breakthroughs. In this light, the Ministry of Modernisation of the Argentinian Nation has created a model that is rooted in the concept of a ‘Smart City’. This effort considered all the dimensions that are at play in an urban environment, with careful monitoring of each sub-dimensions in order to establish the government’s priorities and improving the effectiveness of its operations. In an attempt to ameliorate the overall efficiency of the country’s economic and social development, these focused initiatives have also encouraged citizen participation and the cooperation of the private sector: replacing short-sighted policies with some that are coherent and organised. This process was developed gradually. The first stage consisted in building the model’s structure; the second, at applying the method created on specific case studies and verifying that the mechanisms used respected the desired technical and social aspects. Finally, the third stage consists in the repetition and subsequent comparison of this experiment in order to measure the effects on the ‘treatment group’ over time. The first trial was conducted on 717 municipalities and evaluated the dimension of Governance. Results showed that levels of governmental maturity varied sharply with relation to size: cities with less than 150.000 people had a strikingly lower level of governmental maturity than cities with more than 150.000 people. With the help of this analysis, some important trends and target population were made apparent, which enabled the public administration to focus its efforts and increase its probability of being successful. It also permitted to cut costs, time, and create a dynamic framework in tune with the population’s demands, improving quality of life with sustained efforts to develop social and economic conditions within the territorial structure.

Keywords: composite index, comprehensive model, smart cities, strategic framework

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

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

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

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Authors: Amir Shouri, Fereshteh Tabe

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Master planning and urban infrastructure’s thoughtful and sequential design strategies will play the major role in reducing the damages of natural disasters, war and or social/population related conflicts for cities. Defensive strategies have been revised during the history of mankind after having damages from natural depressions, war experiences and terrorist attacks on cities. Lessons learnt from Earthquakes, from 2 world war casualties in 20th century and terrorist activities of all times. Particularly, after Hurricane Sandy of New York in 2012 and September 11th attack on New York’s World Trade Centre (WTC) in 21st century, there have been series of serious collaborations between law making authorities, urban planners and architects and defence related organizations to firstly, getting prepared and/or prevent such activities and secondly, reduce the human loss and economic damages to minimum. This study will work on developing a model of planning for New York City, where its citizens will get minimum impacts in threat-full time with minimum economic damages to the city after the stress is passed. The main discussion in this proposal will focus on pre-hazard, hazard-time and post-hazard transformative policies and strategies that will reduce the “Life casualties” and will ease “Economic Recovery” in post-hazard conditions. This proposal is going to scrutinize that one of the key solutions in this path might be focusing on all overlaying possibilities on architectural platforms of three fundamental infrastructures, the transportation, the power related sources and defensive abilities on a dynamic-transformative framework that will provide maximum safety, high level of flexibility and fastest action-reaction opportunities in stressful periods of time. “Planning Fore Stress” is going to be done in an analytical, qualitative and quantitative work frame, where it will study cases from all over the world. Technology, Organic Design, Materiality, Urban forms, city politics and sustainability will be discussed in deferent cases in international scale. From the modern strategies of Copenhagen for living friendly with nature to traditional approaches of Indonesian old urban planning patterns, the “Iron Dome” of Israel to “Tunnels” in Gaza, from “Ultra-high-performance quartz-infused concrete” of Iran to peaceful and nature-friendly strategies of Switzerland, from “Urban Geopolitics” in cities, war and terrorism to “Design of Sustainable Cities” in the world, will all be studied with references and detailed look to analysis of each case in order to propose the most resourceful, practical and realistic solutions to questions on “New City Divisions”, “New City Planning and social activities” and “New Strategic Architecture for Safe Cities”. This study is a developed version of a proposal that was announced as winner at MoMA in 2013 in call for ideas for Rockaway after Sandy Hurricane took place.

Keywords: urban scale, city safety, natural disaster, war and terrorism, city divisions, architecture for safe cities

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Authors: B.L. España-Sánchez, E. Luna-Hernández, R.A. Mauricio-Sánchez, M.E. Cruz-Soto, F. Padilla-Vaca, R. Muñoz, L. Granados-López, L.R. Ovalle-Flores, J.L. Menchaca-Arredondo, G. Luna-Bárcenas

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Treatment of burn injured has been considered an important clinical problem due to the fluid control and the presence of microorganisms during the healing process. Conventional treatment includes antiseptic techniques, topical medication and surgical removal of damaged skin, to avoid bacterial growth. In order to accelerate this process, different alternatives for tissue regeneration have been explored, including artificial skin, polymers, hydrogels and hybrid materials. Some requirements consider a nonreactive organic polymer with high biocompatibility and skin adherence, avoiding bacterial infections. Chitin-derivative biopolymer such as chitosan (CS) has been used in skin regeneration following third-degree burns. The biological interest of CS is associated with the improvement of tissue cell stimulation, biocompatibility and antibacterial properties. In particular, antimicrobial properties of CS can be significantly increased when is blended with nanostructured materials. Silver-based nanocomposites have gained attention in medicine due to their high antibacterial properties against pathogens, related to their high surface area/volume ratio at nanomolar concentrations. Silver nanocomposites can be blended or synthesized with chitin-derivative biopolymers in order to obtain a biodegradable/antimicrobial hybrid with improved physic-mechanical properties. In this study, nanocomposites based on chitosan/silver nanoparticles (CS/nAg) were synthesized by the in situ chemical reduction method, improving their antibacterial properties against pathogenic bacteria and enhancing the healing process in thermal burn injuries produced in an animal model. CS/nAg was prepared in solution by the chemical reduction method, using AgNO₃ as precursor. CS was dissolved in acetic acid and mixed with different molar concentrations of AgNO₃: 0.01, 0.025, 0.05 and 0.1 M. Solutions were stirred at 95°C during 20 hours, in order to promote the nAg formation. CS/nAg solutions were placed in Petri dishes and dried, to obtain films. Structural analyses confirm the synthesis of silver nanoparticles (nAg) by means of UV-Vis and TEM, with an average size of 7.5 nm and spherical morphology. FTIR analyses showed the complex formation by the interaction of hydroxyl and amine groups with metallic nanoparticles, and surface chemical analysis (XPS) shows low concentration of Ag⁰/Ag⁺ species. Topography surface analyses by means of AFM shown that hydrated CS form a mesh with an average diameter of 10 µm. Antibacterial activity against S. aureus and P. aeruginosa was improved in all evaluated conditions, such as nAg loading and interaction time. CS/nAg nanocomposites films did not show Ag⁰/Ag⁺ release in saline buffer and rat serum after exposition during 7 days. Healing process was significantly enhanced by the presence of CS/nAg nanocomposites, inducing the production of myofibloblasts, collagen remodelation, blood vessels neoformation and epidermis regeneration after 7 days of injury treatment, by means of histological and immunohistochemistry assays. The present work suggests that hydrated CS/nAg nanocomposites can be formed a mesh, improving the bacterial penetration and the contact with embedded nAg, producing complete growth inhibition after 1.5 hours. Furthermore, CS/nAg nanocomposites improve the cell tissue regeneration in thermal burn injuries induced in rats. Synthesis of antibacterial, non-toxic, and biocompatible nanocomposites can be an important issue in tissue engineering and health care applications.

Keywords: antibacterial, chitosan, healing process, nanocomposites, silver

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Authors: Lauren B. Birney

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This project focuses upon the expansion of the existing "Curriculum and Community Enterprise for the Restoration of New York Harbor in New York City Public Schools" NSF EHR DRL 1440869, NSF EHR DRL 1839656 and NSF EHR DRL 1759006. This project is recognized locally as “Curriculum and Community Enterprise for Restoration Science,” or CCERS. CCERS is a comprehensive model of ecological restoration-based STEM education for urban public-school students. Following an accelerated rollout, CCERS is now being implemented in 120+ Title 1 funded NYC Department of Education middle schools, led by two cohorts of 250 teachers, serving more than 11,000 students in total. Initial results and baseline data suggest that the CCERS model, with the Billion Oyster Project (BOP) as its local restoration ecology-based STEM curriculum, is having profound impacts on students, teachers, school leaders, and the broader community of CCERS participants and stakeholders. Students and teachers report being receptive to the CCERS model and deeply engaged in the initial phase of curriculum development, citizen science data collection, and student-centered, problem-based STEM learning. The BOP CCERS Digital Platform will serve as the central technology hub for all research, data, data analysis, resources, materials and student data to promote global interactions between communities, Research conducted included qualitative and quantitative data analysis. We continue to work internally on making edits and changes to accommodate a dynamic society. The STEM Collaboratory NYC® at Pace University New York City continues to act as the prime institution for the BOP CCERS project since the project’s inception in 2014. The project continues to strive to provide opportunities in STEM for underrepresented and underserved populations in New York City. The replicable model serves as an opportunity for other entities to create this type of collaboration within their own communities and ignite a community to come together and address the notable issue. Providing opportunities for young students to engage in community initiatives allows for a more cohesive set of stakeholders, ability for young people to network and provide additional resources for those students in need of additional support, resources and structure. The project has planted more than 47 million oysters across 12 acres and 15 reef sites, with the help of more than 8,000 students and 10,000 volunteers. Additional enhancements and features on the BOP CCERS Digital Platform will continue over the next three years through funding provided by the National Science Foundation, NSF DRL EHR 1759006/1839656 Principal Investigator Dr. Lauren Birney, Professor Pace University. Early results from the data indicate that the new version of the Platform is creating traction both nationally and internationally among community stakeholders and constituents. This project continues to focus on new collaborative partners that will support underrepresented students in STEM Education. The advanced Digital Platform will allow for us connect with other countries and networks on a larger Global scale.

Keywords: STEM education, environmental restoration science, technology, citizen science

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Authors: Meiling Yu, Nadia Rouatbi, Khuloud T. Al-Jamal

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Background: Treatment of neurological disorders with modern medical and surgical approaches remains difficult. Gene therapy, allowing the delivery of genetic materials that encodes potential therapeutic molecules, represents an attractive option. The treatment of brain diseases with gene therapy requires the gene-editing tool to be delivered efficiently to the central nervous system. In this study, we explored the efficiency of different delivery routes, namely intravenous (i.v.), intra-cranial (i.c.), and intra-nasal (i.n.), to deliver stable nucleic acid-lipid particles (SNALPs) containing gene-editing tools namely Cas9 mRNA and sgRNA encoding for GFP as a reporter protein. We hypothesise that SNALPs can reach the brain and perform gene-editing to different extents depending on the administration route. Intranasal administration (i.n.) offers an attractive and non-invasive way to access the brain circumventing the blood–brain barrier. Successful delivery of gene-editing tools to the brain offers a great opportunity for therapeutic target validation and nucleic acids therapeutics delivery to improve treatment options for a range of neurodegenerative diseases. In this study, we utilised Rosa26-Cas9 knock-in mice, expressing GFP, to study brain distribution and gene-editing efficiency of SNALPs after i.v.; i.c. and i.n. routes of administration. Methods: Single guide RNA (sgRNA) against GFP has been designed and validated by in vitro nuclease assay. SNALPs were formulated and characterised using dynamic light scattering. The encapsulation efficiency of nucleic acids (NA) was measured by RiboGreen™ assay. SNALPs were incubated in serum to assess their ability to protect NA from degradation. Rosa26-Cas9 knock-in mice were i.v., i.n., or i.c. administered with SNALPs to test in vivo gene-editing (GFP knockout) efficiency. SNALPs were given as three doses of 0.64 mg/kg sgGFP following i.v. and i.n. or a single dose of 0.25 mg/kg sgGFP following i.c.. knockout efficiency was assessed after seven days using Sanger Sequencing and Inference of CRISPR Edits (ICE) analysis. In vivo, the biodistribution of DiR labelled SNALPs (SNALPs-DiR) was assessed at 24h post-administration using IVIS Lumina Series III. Results: Serum-stable SNALPs produced were 130-140 nm in diameter with ~90% nucleic acid loading efficiency. SNALPs could reach and stay in the brain for up to 24h following i.v.; i.n. and i.c. administration. Decreasing GFP expression (around 50% after i.v. and i.c. and 20% following i.n.) was confirmed by optical imaging. Despite the small number of mice used, ICE analysis confirmed GFP knockout in mice brains. Additional studies are currently taking place to increase mice numbers. Conclusion: Results confirmed efficient gene knockout achieved by SNALPs in Rosa26-Cas9 knock-in mice expressing GFP following different routes of administrations in the following order i.v.= i.c.> i.n. Each of the administration routes has its pros and cons. The next stages of the project involve assessing gene-editing efficiency in wild-type mice and replacing GFP as a model target with therapeutic target genes implicated in Motor Neuron Disease pathology.

Keywords: CRISPR, nanoparticles, brain diseases, administration routes

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