Search results for: targeting logic

Authors: Dominik Kowitzke

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Housing constructions have direct and indirect environmental impacts especially caused by soil sealing and gray energy consumption related to the use of construction materials. Accordingly, the German government introduced regulations limiting additional annual soil sealing. At the same time, in many regions like metropolitan areas the demand for further housing is high and of current concern in the media and politics. It is argued that meeting this demand by making better use of the existing housing supply is more sustainable than the construction of new housing units. In this context, targeting the phenomenon of so-called over the housing of empty nest households seems worthwhile to investigate for its potential to free living space and thus, reduce the need for new housing constructions and related environmental harm. Over housing occurs if no space adjustment takes place in household lifecycle stages when children move out from home and the space formerly created for the offspring is from then on under-utilized. Although in some cases the housing space consumption might actually meet households’ equilibrium preferences, frequently space-wise adjustments to the living situation doesn’t take place due to transaction or information costs, habit formation, or government intervention leading to increasing costs of relocations like real estate transfer taxes or tenant protection laws keeping tenure rents below the market price. Moreover, many detached houses are not long-term designed in a way that freed up space could be rent out. Findings of this research based on socio-economic survey data, indeed, show a significant difference between the living space of empty nest and a comparison group of households which never had children. The approach used to estimate the average difference in living space is a linear regression model regressing the response variable living space on a two-dimensional categorical variable distinguishing the two groups of household types and further controls. This difference is assumed to be the under-utilized space and is extrapolated to the total amount of empty nests in the population. Supporting this result, it is found that households that move, despite market frictions impairing the relocation, after children left their home tend to decrease the living space. In the next step, only for areas with tight housing markets in Germany and high construction activity, the total under-utilized space in empty nests is estimated. Under the assumption of full substitutability of housing space in empty nests and space in new dwellings in these locations, it is argued that in a perfect market with empty nest households consuming their equilibrium demand quantity of housing space, dwelling constructions in the amount of the excess consumption of living space could be saved. This, on the other hand, would prevent environmental harm quantified in carbon dioxide equivalence units related to average constructions of detached or multi-family houses. This study would thus provide information on the amount of under-utilized space inside dwellings which is missing in public data and further estimates the external effect of over housing in environmental terms.

Keywords: empty nests, environment, Germany, households, over housing

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

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

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

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Authors: Zylfi Shehu, Shpetim Madani, Bashkim Delia

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Context: The study focuses on the interest and engagement of high school students in Tirana, Albania, in physical activity, sports, and foreign languages. It acknowledges the numerous physiological benefits of physical activity, such as cardiovascular health and improved mood. It also recognizes the importance of physical activity in childhood and adolescence for proper skeletal development and long-term health. Research Aim: The main purpose of the study is to investigate and analyze the preferences and interests of male and female high school students in Tirana regarding their functional development, physical activity, sports participation, and choice of foreign languages. The aim is to provide insights for the students and teachers to guide future objectives and improve the quality of physical education. Methodology: The study employed a survey-based approach, targeting both male and female students in public high schools in Tirana. A total of 410 students aged 15 to 19 years old, participated in the study. The data collected from the survey were processed using Excel and presented through tables and graphs. Findings: The results revealed that team sports were more favored by the students, with football being the preferred choice among males, while basketball and volleyball were more popular among females. Additionally, English was found to be the most preferred foreign language, selected by a higher percentage of females (38.57%) compared to males (16.90%). German followed as the second preferred language. Theoretical Importance: This study contributes to the understanding of students' interests in physical activity, sports, and foreign languages in Tirana's high schools. The findings highlight the need to focus on specific sports and languages to cater to students' preferences and guide future educational objectives. It also emphasizes the importance of physical education in promoting students' overall well-being and highlights potential areas for policy and program improvement. Data Collection and Analysis Procedures: The study collected data through surveys administered to high school students in Tirana. The survey responses were processed and analyzed using Excel, and the findings were presented through tables and graphs. The data analysis allowed for the identification of preferences and trends among male and female students, providing valuable insights for future decision-making. Question Addressed: The study aimed to address the question of high school students' interest in physical activity, sports, and foreign languages. It sought to understand the preferences and choices made by students in Tirana and investigate factors such as gender, family income, and accessibility to extracurricular sports activities. Conclusion: The study revealed that high school students in Tirana show a preference for team sports, with football being the most favored among males and basketball and volleyball among females. English was found to be the most preferred foreign language. The findings provide important insights for educators and policymakers to enhance physical education programs and consider students' preferences and interests to foster a more effective learning environment. The study also emphasizes the importance of physical activity and sports in promoting students' physical and mental well-being.

Keywords: female, male, foreign languages, sports, physical education, high school students

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Authors: Denisa Denglerova, Radim Sip

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Academic sources as well as international agreements and national documents define inclusion in terms of several criteria: equal opportunities, fulfilling individual needs, development of human resources, community participation. In order for these criteria to be met, the community must be cohesive. Community cohesion, which is a relatively new concept, is not determined by homogeneity, but by the acceptance of diversity among the community members and utilisation of its positive potential. This brings us to a central category of inclusion - appreciating diversity and using it to a positive effect. However, school diversity is a real phenomenon, which schools need to tackle more and more often. This is also indicated by the number of publications focused on diversity in schools. These sources present recent analyses of using identity as a tool of coping with the demands of a diversified society. The aim of this study is to identify and describe in detail the processes taking place in selected schools, which contribute to their pro-inclusive character. The research is designed around a multiple case study of three pro-inclusive schools. Paradigmatically speaking, the research is rooted in situational epistemology. This is also related to the overall framework of interpretation, for which we are going to use innovative methods of situational analysis. In terms of specific research outcomes this will manifest itself in replacing the idea of “objective theory” by the idea of “detailed cartography of a social world”. The cartographic approach directs both the logic of data collection and the choice of methods of their analysis and interpretation. The research results include detection of the following sensitive concepts: Key persons. All participants can contribute to promoting an inclusion-friendly environment; however, some do so with greater motivation than others. These could include school management, teachers with a strong vision of equality, or school counsellors. They have a significant effect on the transformation of the school, and are themselves deeply convinced that inclusion is necessary. Accordingly, they select suitable co-workers; they also inspire some of the other co-workers to make changes, leading by example. Employees with strongly opposing views gradually leave the school, and new members of staff are introduced to the concept of inclusion and openness from the beginning. Manifestations of school openness in working with diversity on all important levels. By this we mean positive manipulation with diversity both in the relationships between “traditional” school participants (directors, teachers, pupils) and school-parent relationships, or relationships between schools and the broader community, in terms of teaching methods as well as ways how the school culture affects the school environment. Other important detected concepts significantly helping to form a pro-inclusive environment in the school are individual and parallel classes; freedom and responsibility of both pupils and teachers, manifested on the didactic level by tendencies towards an open curriculum; ways of asserting discipline in the school environment.

Keywords: inclusion, diversity, education, sensitive concept, situational analysis

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Authors: Joana Pimenta, Lorena Coelho, José Silva, Vanessa Miranda, Jorge Laranjeira, Rui Soares

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In this paper, the results of R&D on an innovative food package for increased shelf-life are presented. SAP4MA aims at the development of a printed active device that enables smart packaging solutions for food preservation, targeting the extension of the shelf-life of the packed food through the controlled release of active natural antioxidant agents at the onset of the food degradation process. To do so, SAP4MA focuses on the development of active devices such as printed heaters and batteries/supercapacitors in a label format to be integrated on packaging lids during its injection molding process, promoting the passive release of natural antioxidants after the product is packed, during transportation and in the shelves, and actively when the end-user activates the package, just prior to consuming the product at home. When the active device present on the lid is activated, the release of the natural antioxidants embedded in the inner layer of the packaging lid in direct contact with the headspace atmosphere of the food package starts. This approach is based on the use of active functional coatings composed of nano encapsulated active agents (natural antioxidants species) in the prevention of the oxidation of lipid compounds in food by agents such as oxygen. Thus keeping the product quality during the shelf-life, not only when the user opens the packaging, but also during the period from food packaging up until the purchase by the consumer. The active systems that make up the printed smart label, heating circuit, and battery were developed using screen-printing technology. These systems must operate under the working conditions associated with this application. The printed heating circuit was studied using three different substrates and two different conductive inks. Inks were selected, taking into consideration that the printed circuits will be subjected to high pressures and temperatures during the injection molding process. The circuit must reach a homogeneous temperature of 40ºC in the entire area of the lid of the food tub, promoting a gradual and controlled release of the antioxidant agents. In addition, the circuit design involves a high level of study in order to guarantee maximum performance after the injection process and meet the specifications required by the control electronics component. Furthermore, to characterize the different heating circuits, the electrical resistance promoted by the conductive ink and the circuit design, as well as the thermal behavior of printed circuits on different substrates, were evaluated. In the injection molding process, the serpentine-shaped design developed for the heating circuit was able to resolve the issues connected to the injection point; in addition, the materials used in the support and printing had high mechanical resistance against the pressure and temperature inherent to the injection process. Acknowledgment: This research has been carried out within the Project “Smart and Active Packing for Margarine Product” (SAP4MA) running under the EURIPIDES Program being co-financed by COMPETE 2020 – the Operational Programme for Competitiveness and Internationalization and under Portugal 2020 through the European Regional Development Fund (ERDF).

Keywords: smart package, printed heat circuits, printed batteries, flexible and printed electronic

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Authors: Roberta Mugellesi Dow

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As the climate crisis becomes unignorable, it is imperative that new services are developed addressing not only the needs of customers but also taking into account its impact on the environment. The Telecommunication and Integrated Application (TIA) Directorate of ESA is supporting the green transition with particular attention to the sustainable mobility.“Accelerating the shift to sustainable and smart mobility” is at the core of the European Green Deal strategy, which seeks a 90% reduction in related emissions by 2050 . Transforming the way that people and goods move is essential to increasing mobility while decreasing environmental impact, and transport must be considered holistically to produce a shared vision of green intermodal mobility. The use of space technologies, integrated with terrestrial technologies, is an enabler of smarter traffic management and increased transport efficiency for automated and connected multimodal mobility. Satellite connectivity, including future 5G networks, and digital technologies such as Digital Twin, AI, Machine Learning, and cloud-based applications are key enablers of sustainable mobility.SatCom is essential to ensure that connectivity is ubiquitously available, even in remote and rural areas, or in case of a failure, by the convergence of terrestrial and SatCom connectivity networks, This is especially crucial when there are risks of network failures or cyber-attacks targeting terrestrial communication. SatCom ensures communication network robustness and resilience. The combination of terrestrial and satellite communication networks is making possible intelligent and ubiquitous V2X systems and PNT services with significantly enhanced reliability and security, hyper-fast wireless access, as well as much seamless communication coverage. SatNav is essential in providing accurate tracking and tracing capabilities for automated vehicles and in guiding them to target locations. SatNav can also enable location-based services like car sharing applications, parking assistance, and fare payment. In addition to GNSS receivers, wireless connections, radar, lidar, and other installed sensors can enable automated vehicles to monitor surroundings, to ‘talk to each other’ and with infrastructure in real-time, and to respond to changes instantaneously. SatEO can be used to provide the maps required by the traffic management, as well as evaluate the conditions on the ground, assess changes and provide key data for monitoring and forecasting air pollution and other important parameters. Earth Observation derived data are used to provide meteorological information such as wind speed and direction, humidity, and others that must be considered into models contributing to traffic management services. The paper will provide examples of services and applications that have been developed aiming to identify innovative solutions and new business models that are allowed by new digital technologies engaging space and non space ecosystem together to deliver value and providing innovative, greener solutions in the mobility sector. Examples include Connected Autonomous Vehicles, electric vehicles, green logistics, and others. For the technologies relevant are the hybrid satcom and 5G providing ubiquitous coverage, IoT integration with non space technologies, as well as navigation, PNT technology, and other space data.

Keywords: sustainability, connectivity, mobility, satellites

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Authors: Mohammad Lemar Zalmai, Osman Hurol Turkakin, Cemil Akcay, Ekrem Manisali

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In public construction projects, determining the contract period in the award phase is one of the most important factors. The contract period establishes the baseline for creating the cash flow curve and progress payment planning in the post-award phase. If overestimated, project duration causes losses for both the owner and the contractor. Therefore, it is essential to base construction project duration on reliable forecasting. In Turkey, schedules are usually built using the bar chart (Gantt) schedule, especially for governmental construction agencies. The usage of these schedules is limited for bidding purposes. Although the bar-chart schedule is useful in some cases, it lacks logical connections between activities; it would be harder to obtain the activities that have more effects than others on the project's total duration, especially in large complex projects. In this study, a construction schedule is prepared with Critical Path Method (CPM) that addresses the above-mentioned discrepancies. CPM is a simple and effective method that displays project time and critical paths, showing results of forward and backward calculations with considering the logic relationships between activities; it is a powerful tool for planning and managing all kinds of construction projects and is a very convenient method for the construction industry. CPM provides a much more useful and precise approach than traditional bar-chart diagrams that form the basis of construction planning and control. CPM has two main application utilities in the construction field; the first one is obtaining project duration, which is called an as-planned schedule that includes as-planned activity durations with relationships between subsequent activities. Another utility is during the project execution; each activity is tracked, and their durations are recorded in order to obtain as-built schedule, which is named as a black box of the project. The latter is more useful for delay analysis, and conflict resolutions. These features of CPM have been popular around the world. However, it has not been yet extensively used in Turkey. In this study, a real construction project is investigated as a case study; CPM-based scheduling is used for establishing both of as-built and as-planned schedules. Problems that emerged during the construction phase are identified and categorized. Subsequently, solutions are suggested. Two scenarios were considered. In the first scenario, project progress was monitored based as CPM was used to track and manage progress; this was carried out based on real-time data. In the second scenario, project progress was supposedly tracked based on the assumption that the Gantt chart was used. The S-curves of the two scenarios are plotted and interpreted. Comparing the results, possible faults of the latter scenario are highlighted, and solutions are suggested. The importance of CPM implementation has been emphasized and it has been proposed to make it mandatory for preparation of construction schedule based on CPM for public construction projects contracts.

Keywords: as-built, case-study, critical path method, Turkish government sector projects

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Authors: S. Delgado, C. Cerrada, R. S. Gómez

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This research introduces an approach to voxelizing the surfaces of triangular meshes with efficiency and accuracy. Our method leverages parallel equidistant scan-lines and introduces a Gap Detection technique to address the limitations of existing approaches. We present a comprehensive study showcasing the method's effectiveness, scalability, and versatility in different scenarios. Voxelization is a fundamental process in computer graphics and simulations, playing a pivotal role in applications ranging from scientific visualization to virtual reality. Our algorithm focuses on enhancing the voxelization process, especially for complex models and high resolutions. One of the major challenges in voxelization in the Graphics Processing Unit (GPU) is the high cost of discovering the same voxels multiple times. These repeated voxels incur in costly memory operations with no useful information. Our scan-line-based method ensures that each voxel is detected exactly once when processing the triangle, enhancing performance without compromising the quality of the voxelization. The heart of our approach lies in the use of parallel, equidistant scan-lines to traverse the interiors of triangles. This minimizes redundant memory operations and avoids revisiting the same voxels, resulting in a significant performance boost. Moreover, our method's computational efficiency is complemented by its simplicity and portability. Written as a single compute shader in Graphics Library Shader Language (GLSL), it is highly adaptable to various rendering pipelines and hardware configurations. To validate our method, we conducted extensive experiments on a diverse set of models from the Stanford repository. Our results demonstrate not only the algorithm's efficiency, but also its ability to produce 26 tunnel free accurate voxelizations. The Gap Detection technique successfully identifies and addresses gaps, ensuring consistent and visually pleasing voxelized surfaces. Furthermore, we introduce the Slope Consistency Value metric, quantifying the alignment of each triangle with its primary axis. This metric provides insights into the impact of triangle orientation on scan-line based voxelization methods. It also aids in understanding how the Gap Detection technique effectively improves results by targeting specific areas where simple scan-line-based methods might fail. Our research contributes to the field of voxelization by offering a robust and efficient approach that overcomes the limitations of existing methods. The Gap Detection technique fills a critical gap in the voxelization process. By addressing these gaps, our algorithm enhances the visual quality and accuracy of voxelized models, making it valuable for a wide range of applications. In conclusion, "Closing the Gap: Efficient Voxelization with Equidistant Scan-lines and Gap Detection" presents an effective solution to the challenges of voxelization. Our research combines computational efficiency, accuracy, and innovative techniques to elevate the quality of voxelized surfaces. With its adaptable nature and valuable innovations, this technique could have a positive influence on computer graphics and visualization.

Keywords: voxelization, GPU acceleration, computer graphics, compute shaders

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Authors: LouAnne Boyd

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From the perspective of self-advocates, the biggest unaddressed problem is not the symptoms of an autism spectrum diagnosis but the social stigma that accompanies autism. This societal perspective is in contrast to the focus on the majority of interventions. Autism interventions, and consequently, most innovative technologies for autism, aim to improve deficits that occur within the person. For example, the most common Human-Computer Interaction research projects in assistive technology for autism target social skills from a normative perspective. The premise of the autism technologies is that difficulties occur inside the body, hence, the medical model focuses on ways to improve the ailment within the person. However, other technological approaches to support people with autism do exist. In the realm of Human Computer Interaction, there are other modes of research that provide critique of the medical model. For example, critical design, whose intended audience is industry or other HCI researchers, provides products that are the opposite of interventionist work to bring attention to the misalignment between the lived experience and the societal perception of autism. For example, parodies of interventionist work exist to provoke change, such as a recent project called Facesavr, a face covering that helps allistic adults be more independent in their emotional processing. Additionally, from a critical disability studies’ perspective, assistive technologies perpetuate harmful normalizing behaviors. However, these critical approaches can feel far from the frontline in terms of taking direct action to positively impact end users. From a critical yet more pragmatic perspective, projects such as Counterventions lists ways to reduce the likelihood of perpetuating ableism in interventionist’s work by reflectively analyzing a series of evolving assistive technology projects through a societal lens, thus leveraging the momentum of the evolving ecology of technologies for autism. Therefore, all current paradigms fall short of addressing the largest need—the negative impact of social stigma. The current work introduces a new paradigm for technologies for autism, borrowing from a paradigm introduced two decades ago around changing the narrative related to eating disorders. It is the shift from reprimanding poor habits to celebrating positive aspects of eating. This work repurposes Celebratory Technology for Neurodiversity and intended to reduce social stigma by targeting for the public at large. This presentation will review how requirements were derived from current research on autism social stigma as well as design sessions with autistic adults. Congruence between these two sources revealed three key design implications for technology: provide awareness of the autistic experience; generate acceptance of the neurodivergence; cultivate an appreciation for talents and accomplishments of neurodivergent people. The current pilot work in Celebratory Technology offers a new paradigm for supporting autism by shifting the burden of change from the person with autism to address changing society’s biases at large. Shifting the focus of research outside of the autistic body creates a new space for a design that extends beyond the bodies of a few and calls on all to embrace humanity as a whole.

Keywords: neurodiversity, social stigma, accessibility, inclusion, celebratory technology

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Authors: Dipanwita Chakravortty

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Officially, the Israel Defence Forces (IDF) follows a policy of 'gender equality and partnership' which institutionalises norms regarding equal duty towards the nation. It reiterates the equality in unbiased opportunities and resources for Jewish men and women to participate in the military as equal citizens. At the same time, as a military institution, the IDF supports gender biases and crystallises the same through various interactions among women soldiers, male soldiers and the institution. These biases are expressed through various stages and processes in the military institution like biased training, discriminatory postings of women soldiers, lack of combat training and acceptance of sexual harassment. The gender-military debates in Israel is largely devoted to female emancipation and converting the militarised women’s experiences into mainstream debates. This critical scholarship, largely female-based and located in Israel, has been consistently critical of the structural policies of the IDF that have led to continued discriminatory practices against women soldiers. This has compelled the military to increase its intake of women soldiers and make its structural policies more gender-friendly. Nonetheless, the continued thriving of gender discrimination in the IDF resulted in scholars looking deep into the failure of these policies in bringing about a change. This article looks into two research objectives, firstly to analyse existing gender relations in the IDF which impact the practices and prejudices in the institution and secondly to look beyond the structural discrimination as part of the gender debates in the IDF. The proposed research uses the structural-functional model as a framework to study the discourses and norms emerging out of the interaction between gender and military as two distinct social institutions. Changing gender-military debates will be discussed in great detail to understanding the in-depth relation between the Israeli society and the military due to the conscription model. The main arguments of the paper deal with the functional aspect of the military service rather than the structural component of the institution. Traditional stereotypes of military institutions along with cultural notions of a female body restrict the complete integration of women soldiers despite favourable legislations and policies. These result in functional discriminations like uneven promotion, sexual violence, restructuring gender identities and creating militarised bodies. The existing prejudices encourage younger women recruits to choose from within the accepted pink-collared jobs in the military rather than ‘breaking the barriers.’ Some women recruits do try to explore new avenues and make a mark for themselves. Most of them face stiff discrimination but they accept it as part of military life. The cyclical logic behind structural norms leading to functional discrimination which then emphasises traditional stereotypes and hampers change in the institutional norms compels the IDF to continue to strive towards gender equality within the institution without practical realisation.

Keywords: women soldiers, Israel Defence Forces, gender-military debates, security studies

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Authors: Nalika S. Rajapaksha, James Airton, Amina Aboobakar, Nick Chappell, Andy Dyer

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Nutrient pollution and their impact on water quality is a key concern in England. Many water quality issues originate from multiple sources of pollution spread across the catchment. The river water quality in England has improved since 1990s and wastewater effluent discharges into rivers now contain less phosphorus than in the past. However, excess phosphorus is still recognised as the prevailing issue for rivers failing Water Framework Directive (WFD) good ecological status. To achieve WFD Phosphorus objectives, Wastewater Treatment Works (WwTW) permit limits are becoming increasingly stringent. Nevertheless, in some rural catchments, the apportionment of Phosphorus pollution can be greater from agricultural runoff and other sources such as septic tanks. Therefore, the challenge of meeting the requirements of watercourses to deliver WFD objectives often goes beyond water company activities, providing significant opportunities to co-deliver activities in wider catchments to reduce nutrient load at source. The aim of this study was to apply the United Utilities' Catchment Systems Thinking (CaST) strategy and pilot an innovative permitting approach - Catchment Nutrient Balancing (CNB) in a rural catchment in Cumbria (the River Petteril) in collaboration with the regulator and others to achieve WFD objectives and multiple benefits. The study area is mainly agricultural land, predominantly livestock farms. The local ecology is impacted by significant nutrient inputs which require intervention to meet WFD obligations. There are a range of Phosphorus inputs into the river, including discharges from wastewater assets but also significantly from agricultural contributions. Solely focusing on the WwTW discharges would not have resolved the problem hence in order to address this issue effectively, a CNB trial was initiated at a small WwTW, targeting the removal of a total of 150kg of Phosphorus load, of which 13kg were to be reduced through the use of catchment interventions. Various catchment interventions were implemented across selected farms in the upstream of the catchment and also an innovative polonite reactive filter media was implemented at the WwTW as an alternative to traditional Phosphorus treatment methods. During the 3 years of this trial, the impact of the interventions in the catchment and the treatment works were monitored. In 2020 and 2022, it respectively achieved a 69% and 63% reduction in the phosphorus level in the catchment against the initial reduction target of 9%. Phosphorus treatment at the WwTW had a significant impact on overall load reduction. The wider catchment impact, however, was seven times greater than the initial target when wider catchment interventions were also established. While it is unlikely that all the Phosphorus load reduction was delivered exclusively from the interventions implemented though this project, this trial evidenced the enhanced benefits that can be achieved with an integrated approach, that engages all sources of pollution within the catchment - rather than focusing on a one-size-fits-all solution. Primarily, the CNB approach and the act of collaboratively engaging others, particularly the agriculture sector is likely to yield improved farm and land management performance and better compliance, which can lead to improved river quality as well as wider benefits.

Keywords: agriculture, catchment nutrient balancing, phosphorus pollution, water quality, wastewater

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Authors: Ved Vrat Verma, Rani Gupta, Manisha Goel

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γ-glutamyltranspeptidase (GGT: EC 2.3.2.2) is an N-terminal nucleophile hydrolase conserved in all three domains of life. GGT plays a key role in glutathione metabolism where it catalyzes the breakage of the γ-glutamyl bonds and transfer of γ-glutamyl group to water (hydrolytic activity) or amino acids or short peptides (transpeptidase activity). GGTs from bacteria, archaea, and eukaryotes (human, rat and mouse) are homologous proteins sharing >50% sequence similarity and conserved four layered αββα sandwich like three dimensional structural fold. These proteins though similar in their structure to each other, are quite diverse in their enzyme activity: some GGTs are better at hydrolysis reactions but poor in transpeptidase activity, whereas many others may show opposite behaviour. GGT is known to be involved in various diseases like asthma, parkinson, arthritis, and gastric cancer. Its inhibition prior to chemotherapy treatments has been shown to sensitize tumours to the treatment. Microbial GGT is known to be a virulence factor too, important for the colonization of bacteria in host. However, all known inhibitors (mimics of its native substrate, glutamate) are highly toxic because they interfere with other enzyme pathways. However, a few successful efforts have been reported previously in designing species specific inhibitors. We aim to leverage the diversity seen in GGT family (pathogen vs. eukaryotes) for designing specific inhibitors. Thus, in the present study, we have used DIVERGE software to identify sites in GGT proteins, which are crucial for the functional and structural divergence of these proteins. Since, type II divergence sites vary in clade specific manner, so type II divergent sites were our focus of interest throughout the study. Type II divergent sites were identified for pathogen vs. eukaryotes clusters and sites were marked on clade specific representative structures HpGGT (2QM6) and HmGGT (4ZCG) of pathogen and eukaryotes clade respectively. The crucial divergent sites within 15 A radii of the binding cavity were highlighted, and in-silico mutations were performed on these sites to delineate the role of these sites on the mechanism of catalysis and protein folding. Further, the amino acid network (AAN) analysis was also performed by Cytoscape to delineate assortative mixing for cavity divergent sites which could strengthen our hypothesis. Additionally, molecular dynamics simulations were performed for wild complexes and mutant complexes close to physiological conditions (pH 7.0, 0.1 M ionic strength and 1 atm pressure) and the role of putative divergence sites and structural integrities of the homologous proteins have been analysed. The dynamics data were scrutinized in terms of RMSD, RMSF, non-native H-bonds and salt bridges. The RMSD, RMSF fluctuations of proteins complexes are compared, and the changes at protein ligand binding sites were highlighted. The outcomes of our study highlighted some crucial divergent sites which could be used for novel inhibitors designing in a species-specific manner. Since, for drug development, it is challenging to design novel drug by targeting similar protein which exists in eukaryotes, so this study could set up an initial platform to overcome this challenge and help to deduce the more effective targets for novel drug discovery.

Keywords: γ-glutamyltranspeptidase, divergence, species-specific, drug design

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

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

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

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Authors: Diana Reckien

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Vulnerability assessments are increasingly used to support policy-making in complex environments, like urban areas. Usually, vulnerability studies include the construction of aggregate (sub-) indices and the subsequent mapping of indices across an area of interest. Vulnerability studies show a couple of advantages: they are great communication tools, can inform a wider general debate about environmental issues, and can help allocating and efficiently targeting scarce resources for adaptation policy and planning. However, they also have a number of challenges: Vulnerability assessments are constructed on the basis of a wide range of methodologies and there is no single framework or methodology that has proven to serve best in certain environments, indicators vary highly according to the spatial scale used, different variables and metrics produce different results, and aggregate or composite vulnerability indicators that are mapped easily distort or bias the picture of vulnerability as they hide the underlying causes of vulnerability and level out conflicting reasons of vulnerability in space. So, there is urgent need to further develop the methodology of vulnerability studies towards a common framework, which is one reason of the paper. We introduce a social vulnerability approach, which is compared with other approaches of bio-physical or sectoral vulnerability studies relatively developed in terms of a common methodology for index construction, guidelines for mapping, assessment of sensitivity, and verification of variables. Two approaches are commonly pursued in the literature. The first one is an additive approach, in which all potentially influential variables are weighted according to their importance for the vulnerability aspect, and then added to form a composite vulnerability index per unit area. The second approach includes variable reduction, mostly Principal Component Analysis (PCA) that reduces the number of variables that are interrelated into a smaller number of less correlating components, which are also added to form a composite index. We test these two approaches of constructing indices on the area of New York City as well as two different metrics of variables used as input and compare the outcome for the 5 boroughs of NY. Our analysis yields that the mapping exercise yields particularly different results in the outer regions and parts of the boroughs, such as Outer Queens and Staten Island. However, some of these parts, particularly the coastal areas receive the highest attention in the current adaptation policy. We imply from this that the current adaptation policy and practice in NY might need to be discussed, as these outer urban areas show relatively low social vulnerability as compared with the more central parts, i.e. the high dense areas of Manhattan, Central Brooklyn, Central Queens and the Southern Bronx. The inner urban parts receive lesser adaptation attention, but bear a higher risk of damage in case of hazards in those areas. This is conceivable, e.g., during large heatwaves, which would more affect more the inner and poorer parts of the city as compared with the outer urban areas. In light of the recent planning practice of NY one needs to question and discuss who in NY makes adaptation policy for whom, but the presented analyses points towards an under representation of the needs of the socially vulnerable population, such as the poor, the elderly, and ethnic minorities, in the current adaptation practice in New York City.

Keywords: vulnerability mapping, social vulnerability, additive approach, Principal Component Analysis (PCA), New York City, United States, adaptation, social sensitivity

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Authors: Ana Alvarenga De Castro

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Food sovereignty has been brought by the international peasants’ movement, La Via Campesina, as a precondition to food security, speaking about the right of each nation to keep its own supply of foods respecting cultural, sustainable practices and productive diversity. The political conceptualization nowadays goes beyond saying that this term is about achieving the rights of farmers to control the food systems according to local specificities, and about equality in the access to natural resources and quality food. The current feminization of agroecosystems and of food insecurity identified by researchers and recognized by international agencies like the UN and FAO has enhanced the feminist discourse into the food sovereignty movement, considering the historical inequalities that place women farmers in subaltern positions inside the families and rural communities. The current tendency in many rural areas of more women taking responsibility for food production and still facing the lack of access to natural resources meets particular aspects in Latin America due to the global economic logic which places the Global South in the position of raw material supplier for the industrialized North, combined with regional characteristics. In this context, Latin American countries play the role of commodities exporters in the international labor division, including among exported items grains, soybean paste, and ores, to the expense of local food chains which provide domestic quality food supply under more sustainable practices. The connections between gender inequalities and global territorial inequalities related to the access and control of food and natural resources are pointed out by feminist political ecology - FPE - authors, and are linked in this article to the potentialities and limitations of women farmers to reproduce diversified agroecosystems in the tropical environments. The work brings the importance of local practices held by women farmers which are crucial to maintaining sustainable agricultural systems and their results on seeds, soil, biodiversity and water conservation. This work presents an analysis of documents, releases, videos and other publicized experiences launched by some peasants’ organizations in Latin America which evidence the different technical and political answers that meet food sovereignty from peasants’ groups that are attributed to women farmers. They are associated with articles presenting the empirical analysis of women farmers' practices in Latin America. The combination drove to discuss the benefits of peasants' conceptions about food systems and their connections with local realities and the gender issues linked to the food sovereignty conceptualization. Conclusion meets that reality on the field cannot reach food sovereignty's ideal homogeneously and that agricultural sustainable practices are dependent on rights' achievement and social inequalities' eradication.

Keywords: food sovereignty, gender, diversified agricultural systems, access to natural resources

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Authors: Avi Shrivastava

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In 2021, two heart-wrenching scenes, shown live on television screens across countries, painted a grim picture of refugees. One of them was of people clinging onto an airplane's wings in their desperate attempt to flee war-torn Afghanistan. They ultimately fell to their death. The other scene was the U.S. government authorities separating children from their parents or guardians to deter migrants/refugees from coming to the U.S. These events show the desperation refugees feel when they are trying to leave their homes in disaster zones. However, data paints a grave picture of the current refugee situation. It also indicates that a bleak future lies ahead for the refugees across the globe. Data and information are the two threads that intertwine to weave the shimmery fabric of modern society. Data and information are often used interchangeably, but they differ considerably. For example, information analysis reveals rationale, and logic, while data analysis, on the other hand, reveals a pattern. Moreover, patterns revealed by data can enable us to create the necessary tools to combat huge problems on our hands. Data analysis paints a clear picture so that the decision-making process becomes simple. Geopolitical and economic data can be used to predict future refugee hotspots. Accurately predicting the next refugee hotspots will allow governments and relief agencies to prepare better for future refugee crises. The refugee crisis does not have binary answers. Given the emotionally wrenching nature of the ground realities, experts often shy away from realistically stating things as they are. This hesitancy can cost lives. When decisions are based solely on data, emotions can be removed from the decision-making process. Data also presents irrefutable evidence and tells whether there is a solution or not. Moreover, it also responds to a nonbinary crisis with a binary answer. Because of all that, it becomes easier to tackle a problem. Data science and A.I. can predict future refugee crises. With the recent explosion of data due to the rise of social media platforms, data and insight into data has solved many social and political problems. Data science can also help solve many issues refugees face while staying in refugee camps or adopted countries. This paper looks into various ways data science can help solve refugee problems. A.I.-based chatbots can help refugees seek legal help to find asylum in the country they want to settle in. These chatbots can help them find a marketplace where they can find help from the people willing to help. Data science and technology can also help solve refugees' many problems, including food, shelter, employment, security, and assimilation. The refugee problem seems to be one of the most challenging for social and political reasons. Data science and machine learning can help prevent the refugee crisis and solve or alleviate some of the problems that refugees face in their journey to a better life. With the explosion of data in the last decade, data science has made it possible to solve many geopolitical and social issues.

Keywords: refugee crisis, artificial intelligence, data science, refugee camps, Afghanistan, Ukraine

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Authors: Maryam Mohammad Hadi, Heather Nesbitt, Hamzah Masood, Hashim Ahmed, Mark Emberton, John Callan, Alexander MacRobert, Anthony McHale, Nikolitsa Nomikou

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Sonodynamic therapy (SDT) utilises ultrasound in combination with sensitizers, such as porphyrins, for the production of cytotoxic reactive oxygen species (ROS) and the confined ablation of tumours. Ultrasound can be applied locally, and the acoustic waves, at frequencies between 0.5-2 MHz, are transmitted efficiently through tissue. SDT does not require highly toxic agents, and the cytotoxic effect only occurs upon ultrasound exposure at the site of the lesion. Therefore, this approach is not associated with adverse side effects. Further highlighting the benefits of SDT, no cancer cell population has shown resistance to therapy-triggered ROS production or their cytotoxic effects. This is particularly important, given the as yet unresolved issues of radiation and chemo-resistance, to the authors’ best knowledge. Another potential future benefit of this approach – considering its non-thermal mechanism of action – is its possible role as an adjuvant to immunotherapy. Substantial pre-clinical studies have demonstrated the efficacy and targeting capability of this therapeutic approach. However, SDT has yet to be fully characterised and appropriately exploited for the treatment of cancer. In this study, a formulation based on multistimulus-responsive sensitizer-containing nanoparticles that can accumulate in advanced prostate tumours and increase the therapeutic efficacy of SDT has been developed. The formulation is based on a polyglutamate-tyrosine (PGATyr) co-polymer carrying hematoporphyrin. The efficacy of SDT in this study was demonstrated using prostate cancer as the translational exemplar. The formulation was designed to respond to the microenvironment of advanced prostate tumours, such as the overexpression of the proteolytic enzymes, cathepsin-B and prostate-specific membrane antigen (PSMA), that can degrade the nanoparticles, reduce their size, improving both diffusions throughout the tumour mass and cellular uptake. The therapeutic modality was initially tested in vitro using LNCaP and PC3 cells as target cell lines. The SDT efficacy was also examined in vivo, using male SCID mice bearing LNCaP subcutaneous tumours. We have demonstrated that the PGATyr co-polymer is digested by cathepsin B and that digestion of the formulation by cathepsin-B, at tumour-mimicking conditions (acidic pH), leads to decreased nanoparticle size and subsequent increased cellular uptake. Sonodynamic treatment, at both normoxic and hypoxic conditions, demonstrated ultrasound-induced cytotoxic effects only for the nanoparticle-treated prostate cancer cells, while the toxicity of the formulation in the absence of ultrasound was minimal. Our in vivo studies in immunodeficient mice, using the hematoporphyrin-containing PGATyr nanoparticles for SDT, showed a 50% decrease in LNCaP tumour volumes within 24h, following IV administration of a single dose. No adverse effects were recorded, and body weight was stable. The results described in this study clearly demonstrate the promise of SDT to revolutionize cancer treatment. It emphasizes the potential of this therapeutic modality as a fist line treatment or in combination treatment for the elimination or downstaging of difficult to treat cancers, such as prostate, pancreatic, and advanced colorectal cancer.

Keywords: sonodynamic therapy, nanoparticles, tumour ablation, ultrasound

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Authors: Anna Lower, Michal Lower, Robert Masztalski, Agnieszka Szumilas

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Contemporary cities are facing serious congestion and parking problems. In urban transport policy the introduction of the park and ride system (P&R) is an increasingly popular way of limiting vehicular traffic. The determining of P&R facilities location is a key aspect of the system. Criteria for assessing the quality of the selected location are formulated generally and descriptively. The research outsourced to specialists are expensive and time consuming. The most focus is on the examination of a few selected places. The practice has shown that the choice of the location of these sites in a intuitive way without a detailed analysis of all the circumstances, often gives negative results. Then the existing facilities are not used as expected. Methods of location as a research topic are also widely taken in the scientific literature. Built mathematical models often do not bring the problem comprehensively, e.g. assuming that the city is linear, developed along one important communications corridor. The paper presents a new method where the expert knowledge is applied to fuzzy inference model. With such a built system even a less experienced person could benefit from it, e.g. urban planners, officials. The analysis result is obtained in a very short time, so a large number of the proposed location can also be verified in a short time. The proposed method is intended for testing of car parks location in a city. The paper will show selected examples of locations of the P&R facilities in cities planning to introduce the P&R. The analysis of existing objects will also be shown in the paper and they will be confronted with the opinions of the system users, with particular emphasis on unpopular locations. The research are executed using the fuzzy inference model which was built and described in more detail in the earlier paper of the authors. The results of analyzes are compared to documents of P&R facilities location outsourced by the city and opinions of existing facilities users expressed on social networking sites. The research of existing facilities were conducted by means of the fuzzy model. The results are consistent with actual users feedback. The proposed method proves to be good, but does not require the involvement of a large experts team and large financial contributions for complicated research. The method also provides an opportunity to show the alternative location of P&R facilities. The performed studies show that the method has been confirmed. The method can be applied in urban planning of the P&R facilities location in relation to the accompanying functions. Although the results of the method are approximate, they are not worse than results of analysis of employed experts. The advantage of this method is ease of use, which simplifies the professional expert analysis. The ability of analyzing a large number of alternative locations gives a broader view on the problem. It is valuable that the arduous analysis of the team of people can be replaced by the model's calculation. According to the authors, the proposed method is also suitable for implementation on a GIS platform.

Keywords: fuzzy logic inference, park and ride system, P&R facilities, P&R location

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Authors: A. Newman-Tancredi, R. Depoortère, P. Gruca, E. Litwa, M. Lason, M. Papp

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The N-methyl-D-aspartic acid (NMDA) receptor antagonist, ketamine, can elicit rapid-acting antidepressant (RAAD) effects in treatment-resistant patients, but it requires parenteral co-administration with a classical antidepressant under medical supervision. In addition, ketamine can also produce serious side effects that limit its long-term use, and there is much interest in identifying RAADs based on ketamine’s mechanism of action but with safer profiles. Ketamine elicits GABAergic interneuron inhibition, glutamatergic neuron stimulation, and, notably, activation of serotonin 5-HT1A receptors in the prefrontal cortex (PFC). Direct activation of the latter receptor subpopulation with selective ‘biased agonists’ may therefore be a promising strategy to identify novel RAADs and, consistent with this hypothesis, the prototypical cortical biased agonist, NLX-101, exhibited robust RAAD-like activity in the chronic mild stress model of depression (CMS). The present study compared the effects of a novel, selective 5-HT1A receptor-biased agonist, NLX-204, with those of ketamine and NLX-101. Materials and methods: CMS procedure was conducted on Wistar rats; drugs were administered either intraperitoneally (i.p.) or by bilateral intracortical microinjection. Ketamine: 10 mg/kg i.p. or 10 µg/side in PFC; NLX-204 and NLX-101: 0.08 and 0.16 mg/kg i.p. or 16 µg/side in PFC. In addition, interaction studies were carried out with systemic NLX-204 or NLX-101 (each at 0.16 mg/kg i.p.) in combination with intracortical WAY-100635 (selective 5-HT1A receptor antagonist; 2 µg/side) or muscimol (GABA-A receptor agonist, 12.5 ng/side). Anhedonia was assessed by CMS-induced decrease in sucrose solution consumption; anxiety-like behavior was assessed using the Elevated Plus Maze (EPM), and cognitive impairment was assessed by the Novel Object Recognition (NOR) test. Results: A single administration of NLX-204 was sufficient to reverse the CMS-induced deficit in sucrose consumption, similarly to ketamine and NLX-101. NLX-204 also reduced CMS-induced anxiety in the EPM and abolished CMS-induced NOR deficits. These effects were maintained (EPM and NOR) or enhanced (sucrose consumption) over a subsequent 2-week period of treatment. The anti-anhedonic response of the drugs was also maintained for several weeks Following treatment discontinuation, suggesting that they had sustained effects on neuronal networks. A single PFC administration of NLX-204 reversed deficient sucrose consumption, similarly to ketamine and NLX-101. Moreover, the anti-anhedonic activities of systemic NLX-204 and NLX 101 were abolished by coadministration with intracortical WAY-100635 or muscimol. Conclusions: (i) The antidepressant-like activity of NLX-204 in the rat CMS model was as rapid as that of ketamine or NLX-101, supporting targeting cortical 5-HT1A receptors with selective, biased agonists to achieve RAAD effects. (ii)The anti-anhedonic activity of systemic NLX-204 was mimicked by local administration of the compound in the PFC, confirming the involvement of cortical circuits in its RAAD-like effects. (iii) Notably, the effects of systemic NLX-204 and NLX-101 were abolished by PFC administration of muscimol, indicating that they act by (indirectly) eliciting a reduction in cortical GABAergic neurotransmission. This is consistent with ketamine’s mechanism of action and suggests that there are converging NMDA and 5-HT1A receptor signaling cascades in PFC underlying the RAAD-like activities of ketamine and NLX-204. Acknowledgements: The study was financially supported by NCN grant no. 2019/35/B/NZ7/00787.

Keywords: depression, ketamine, serotonin, 5-HT1A receptor, chronic mild stress

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Authors: Moustafa Osman Mohammed

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This paper introduces Luhmann’s autopoietic social systems starting with the original concept of autopoiesis by biologists and scientists, including the modification of general systems based on socialized medicine. A specific type of autopoietic system is explained in the three existing groups of the ecological phenomena: interaction, social and medical sciences. This hypothesis model, nevertheless, has a nonlinear interaction with its natural environment ‘interactional cycle’ for the exchange of photon energy with molecular without any changes in topology. The external forces in the systems environment might be concomitant with the natural fluctuations’ influence (e.g. radioactive radiation, electromagnetic waves). The cantilever sensor deploys insights to the future chip processor for prevention of social metabolic systems. Thus, the circuits with resonant electric and optical properties are prototyped on board as an intra–chip inter–chip transmission for producing electromagnetic energy approximately ranges from 1.7 mA at 3.3 V to service the detection in locomotion with the least significant power losses. Nowadays, therapeutic systems are assimilated materials from embryonic stem cells to aggregate multiple functions of the vessels nature de-cellular structure for replenishment. While, the interior actuators deploy base-pair complementarity of nucleotides for the symmetric arrangement in particular bacterial nanonetworks of the sequence cycle creating double-stranded DNA strings. The DNA strands must be sequenced, assembled, and decoded in order to reconstruct the original source reliably. The design of exterior actuators have the ability in sensing different variations in the corresponding patterns regarding beat-to-beat heart rate variability (HRV) for spatial autocorrelation of molecular communication, which consists of human electromagnetic, piezoelectric, electrostatic and electrothermal energy to monitor and transfer the dynamic changes of all the cantilevers simultaneously in real-time workspace with high precision. A prototype-enabled dynamic energy sensor has been investigated in the laboratory for inclusion of nanoscale devices in the architecture with a fuzzy logic control for detection of thermal and electrostatic changes with optoelectronic devices to interpret uncertainty associated with signal interference. Ultimately, the controversial aspect of molecular frictional properties is adjusted to each other and forms its unique spatial structure modules for providing the environment mutual contribution in the investigation of mass temperature changes due to pathogenic archival architecture of clusters.

Keywords: autopoiesis, nanoparticles, quantum photonics, portable energy, photonic structure, photodynamic therapeutic system

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Authors: Ellana Boada, Eric Santos-Clotas, Alba Cabrera-Codony, Maria Martin, Lluis Baneras, Frederic Gich

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Volatile methylsiloxanes (VMS) are a group of manmade silicone compounds widely used in household and industrial applications that end up on the biogas produced through the anaerobic digestion of organic matter in landfills and wastewater treatment plants. The presence of VMS during the biogas energy conversion can cause damage on the engines, reducing the efficiency of this renewable energy source. Non regenerative adsorption onto activated carbon is the most widely used technology to remove siloxanes from biogas, while new trends point out that biotechnology offers a low-cost and environmentally friendly alternative to conventional technologies. The first objective of this research was to enrich, isolate and identify bacterial species able to grow using siloxane molecules as a sole carbon source: anoxic wastewater sludge was used as initial inoculum in liquid anoxic enrichments, adding D4 (as representative siloxane compound) previously adsorbed on activated carbon. After several months of acclimatization, liquid enrichments were plated onto solid media containing D4 and thirty-four bacterial isolates were obtained. 16S rRNA gene sequencing allowed the identification of strains belonging to the following species: Ciceribacter lividus, Alicycliphilus denitrificans, Pseudomonas aeruginosa and Pseudomonas citronellolis which are described to be capable to degrade toxic volatile organic compounds. Kinetic assays with 8 representative strains revealed higher cell growth in the presence of D4 compared to the control. Our second objective was to characterize the community composition and diversity of the microbial community present in the enrichments and to elucidate whether the isolated strains were representative members of the community or not. DNA samples were extracted, the 16S rRNA gene was amplified (515F & 806R primer pair), and the microbiome analyzed from sequences obtained with a MiSeq PE250 platform. Results showed that the retrieved isolates only represented a minor fraction of the microorganisms present in the enrichment samples, which were represented by Alpha, Beta, and Gamma proteobacteria as dominant groups in the category class thus suggesting that other microbial species and/or consortia may be important for D4 biodegradation. These results highlight the need of additional protocols for the isolation of relevant D4 degraders. Currently, we are developing molecular tools targeting key genes involved in siloxane biodegradation to identify and quantify the capacity of the isolates to metabolize D4 in batch cultures supplied with a synthetic gas stream of air containing 60 mg m⁻³ of D4 together with other volatile organic compounds found in the biogas mixture (i.e. toluene, hexane and limonene). The isolates were used as inoculum in a biotrickling filter containing lava rocks and activated carbon to assess their capacity for siloxane removal. Preliminary results of biotrickling filter performance showed 35% of siloxane biodegradation in a contact time of 14 minutes, denoting that biological siloxane removal is a promising technology for biogas upgrading.

Keywords: bacterial cultivation, biogas upgrading, microbiome, siloxanes

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Authors: Marie Alexandre, Jean Bernatchez

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This paper focuses on the complexity of the face-to-face-to-distance learning transition process. Our research action aims to support the process of transition from classroom to distance learning for teachers in higher education with regard to pedagogical practices that can meet the various needs of students using digital learning environments. In Quebec and elsewhere in the world, the advent of digital education is helping to transform teaching, which is significantly changing the role of teachers. While distance education implies a dissociation of teaching and learning to a variable degree in space and time, distance education (DE) is becoming more and increasingly becoming a preferred option for maintaining the delivery of certain programs and providing access to programs and to provide access to quality activities throughout Quebec. Given the impact of teaching practices on educational success, this paper reports on the results of three research objectives: 1) To document teachers' knowledge of teaching in distance education through the design, experimentation and production of a repertoire of the determinants of pedagogical practices in response to students' needs. 2) Explain, according to a gendered logic, the adequacy between the pedagogical practices implemented in distance learning and the response to the profiles and needs expressed by students using digital learning environments; 3) Produce a model of a support approach during the process of transition from classroom to distance learning at the college level. A mixed methodology, i.e., a quantitative component (questionnaire survey) and a qualitative component (explanatory interviews and living lab) was used in cycles that were part of an ongoing validation process. The intervention includes the establishment of a professional collaboration group, webinars training webinars for the participating teachers on the didactic issue of knowledge-teaching in FAD, the didactic use of technologies, and the differentiated socialization models of educational success in college education. All of the tools developed will be used by partners in the target environment as well as by all teacher educators, students in initial teacher training, practicing teachers, and the general public. The results show that access to training leading to qualifications and commitment to educational success reflects the existing links between the people in the educational community. The relational stakes of being present in distance education take on multiple configurations and different dimensions of learning testify to needs and realities that are sometimes distinct depending on the life cycle. This project will be of interest to partners in the targeted field as well as to all teacher trainers, students in initial teacher training, practicing college teachers, and to university professors. The entire educational community will benefit from digital resources in education. The scientific knowledge resulting from this action research will benefit researchers in the fields of pedagogy, didactics, teacher training and pedagogy in higher education in a digital context.

Keywords: action research, didactics, digital learning environment, distance learning, higher education, pedagogy technological, pedagogical content knowledge

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Authors: Gleyce Assis Da Silva Barbosa

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In recent years, we have witnessed a vertiginous growth of large education companies. Daughters of national and world capital, these companies expand both through consolidated physical networks in the form of branches spread across the territory and through institutional networks such as business networks through mergers, acquisitions, creation of new companies and influence. They do this by incorporating small, medium and large schools and universities, teaching systems and other products and services. They are also able to weave their webs directly or indirectly in philanthropic circles, limited partnerships, family businesses and even in public education through various mechanisms of outsourcing, privatization and commercialization of products for the sector. Although the growth of these groups in basic education seems to us a recent phenomenon in peripheral countries such as Brazil, its diffusion is closely linked to higher education conglomerates and other sectors of the economy forming oligopolies, which began to expand in the 1990s with strong state support and through political reforms that redefined its role, transforming it into a fundamental agent in the formation of guidelines to boost the incorporation of neoliberal logic. This expansion occurred through the objectification of education, commodifying it and transforming students into consumer clients. Financial power combined with the neo-liberalization of state public policies allowed the profusion of social exclusion, the increase of individuals without access to basic services, deindustrialization, automation, capital volatility and the indetermination of the economy; in addition, this process causes capital to be valued and devalued at rates never seen before, which together generates various impacts such as the precariousness of work. Understanding the connection between these processes, which engender the economy, allows us to see their consequences in labor relations and in the territory. In this sense, it is necessary to analyze the geographic-economic context and the role of the facilitating agents of this process, which can give us clues about the ongoing transformations and the directions of education in the national and even international scenario since this process is linked to the multiple scales of financial globalization. Therefore, the present research has the general objective of analyzing the socio-spatial impacts of financialization and the formation of oligopolies in Brazilian basic education. For this, the survey of laws, data, and public policies on the subject in question was used as a methodology. As a methodology, the work was based on some data from these companies available on websites for investors. Survey of information from global and national companies that operate in Brazilian basic education. In addition to mapping the expansion of educational oligopolies using public data on the location of schools. With this, the research intends to provide information about the ongoing commodification process in the country. Discuss the consequences of the oligopolization of education, considering the impacts that financialization can bring to teaching work.

Keywords: financialization, oligopolies, education, Brazil

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Authors: Hannah Dean

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The growth ideology, and its association with progress, is an important construct in the narrative of modernity. This ideology is embedded in neoclassical economic growth theory which conceptualises growth as linear and predictable, and the entrepreneur as a rational economic manager. This conceptualisation has been critiqued for reinforcing the managerial discourse in entrepreneurship studies. Despite these critiques, both the neoclassical growth theory and its adjacent managerial discourse dominate entrepreneurship studies notably the literature on female entrepreneurs. The latter is the focus of this paper. Given this emphasis on growth, female entrepreneurs are portrayed as problematic because their growth lags behind their male counterparts. This image which ignores the complexity and diversity of female entrepreneurs’ experience persists in the literature due to the lack of studies that analyse the process and contextual factors surrounding female entrepreneurs’ experience. This study aims to address the subordination of female entrepreneurs by questioning the hegemonic logic of economic growth and the managerial discourse as a true representation for the entrepreneurial experience. This objective is achieved by drawing on Schumpeter’s theorising and narrative inquiry. This exploratory study undertakes in depth interviews to gain insights into female entrepreneurs’ experience and the impact of the economic growth model and the managerial discourse on their performance. The narratives challenge a number of assumptions about female entrepreneurs. The participants occupied senior positions in the corporate world before setting up their businesses. This is at odds with much writing which assumes that women underperform because they leave their career without gaining managerial experience to achieve work-life balance. In line with Schumpeter, who distinguishes the entrepreneur from the manager, the participants’ main function was innovation. They did not believe that the managerial paradigm governing their corporate careers was applicable to their entrepreneurial experience. Formal planning and managerial rationality can hinder their decision making process. The narratives point to the gap between the two worlds which makes stepping into entrepreneurship a scary move. Schumpeter argues that the entrepreneurial process is evolutionary and that failure is an integral part of it. The participants’ entrepreneurial process was in fact irregular. The performance of new combinations was not always predictable. They therefore relied on their initiative. The inhibition to deploy these traits had an adverse effect on business growth. The narratives also indicate that over-reliance on growth threaten the business survival as it faces competing pressures. The study offers theoretical and empirical contributions to (female) entrepreneurship studies by presenting Schumpeter’s theorising as an alternative theoretical framework to the neoclassical economic growth theory. The study also reduces entrepreneurs’ vulnerability by making them aware of the negative influence that the linear growth model and the managerial discourse hold upon their performance. The study has implications for policy makers as it generates new knowledge that incorporates the current social and economic changes in the context of entrepreneurs that can no longer be sustained by the linear growth models especially in the current economic climate.

Keywords: economic growth, female entrepreneurs, managerial discourse, Schumpeter

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Authors: Mukul Sharma, Madhusmita Das, Sundeep Chaitanya Vedithi

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Leprosy is a chronic human disease caused by Mycobacterium leprae, that cannot be cultured in vitro. Though treatable with multidrug therapy (MDT), recently, bacteria reported resistance to multiple antibiotics. Targeting DNA replication and repair pathways can serve as the foundation of developing new anti-leprosy drugs. Due to the absence of an axenic culture medium for the propagation of M. leprae, studying cellular processes, especially those belonging to DNA repair pathways, is challenging. Genomic understanding of M. Leprae harbors several protein-coding genes with no previously assigned function known as 'hypothetical proteins'. Here, we report identification and expression of known and hypothetical DNA repair genes from a human skin biopsy and mouse footpads that are involved in base excision repair, direct reversal repair, and SOS response. Initially, a bioinformatics approach was employed based on sequence similarity, identification of known protein domains to screen the hypothetical proteins in the genome of M. leprae, that are potentially related to DNA repair mechanisms. Before testing on clinical samples, pure stocks of bacterial reference DNA of M. leprae (NHDP63 strain) was used to construct standard graphs to validate and identify lower detection limit in the qPCR experiments. Primers were designed to amplify the respective transcripts, and PCR products of the predicted size were obtained. Later, excisional skin biopsies of newly diagnosed untreated, treated, and drug resistance leprosy cases from SIHR & LC hospital, Vellore, India were taken for the extraction of RNA. To determine the presence of the predicted transcripts, cDNA was generated from M. leprae mRNA isolated from clinically confirmed leprosy skin biopsy specimen across all the study groups. Melting curve analysis was performed to determine the integrity of the amplification and to rule out primer‑dimer formation. The Ct values obtained from qPCR were fitted to standard curve to determine transcript copy number. Same procedure was applied for M. leprae extracted after processing a footpad of nude mice of drug sensitive and drug resistant strains. 16S rRNA was used as positive control. Of all the 16 genes involved in BER, DR, and SOS, differential expression pattern of the genes was observed in terms of Ct values when compared to human samples; this was because of the different host and its immune response. However, no drastic variation in gene expression levels was observed in human samples except the nth gene. The higher expression of nth gene could be because of the mutations that may be associated with sequence diversity and drug resistance which suggests an important role in the repair mechanism and remains to be explored. In both human and mouse samples, SOS system – lexA and RecA, and BER genes AlkB and Ogt were expressing efficiently to deal with possible DNA damage. Together, the results of the present study suggest that DNA repair genes are constitutively expressed and may provide a reference for molecular diagnosis, therapeutic target selection, determination of treatment and prognostic judgment in M. leprae pathogenesis.

Keywords: DNA repair, human biopsy, hypothetical proteins, mouse footpads, Mycobacterium leprae, qPCR

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Authors: Imdad Ullah Khan, Yongseok Yoon, Kyeung Uk Choi, Kwang Rae Jo, Namyul Kim, Eunbee Lee, Wan Hee Kim, Oh-Kyeong Kweon

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The primary spinal cord injury (SCI) causes mechanical damage to the neurons and blood vessels. It leads to secondary SCI, which activates multiple pathological pathways, which expand neuronal damage at the injury site. It is characterized by vascular disruption, ischemia, excitotoxicity, oxidation, inflammation, and apoptotic cell death. It causes nerve demyelination and disruption of axons, which perpetuate a loss of impulse conduction through the injured spinal cord. It also leads to the production of myelin inhibitory molecules, which with a concomitant formation of an astroglial scar, impede axonal regeneration. The pivotal role regarding the neuronal necrosis is played by oxidation and inflammation. During an early stage of spinal cord injury, there occurs an abundant expression of reactive oxygen species (ROS) due to defective mitochondrial metabolism and abundant migration of phagocytes (macrophages, neutrophils). ROS cause lipid peroxidation of the cell membrane, and cell death. Abundant migration of neutrophils, macrophages, and lymphocytes collectively produce pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1β), matrix metalloproteinase, superoxide dismutase, and myeloperoxidases which synergize neuronal apoptosis. Therefore, it is crucial to control inflammation and oxidation injury to minimize the nerve cell death during secondary spinal cord injury. Therefore, in response to oxidation and inflammation, heme oxygenase-1 (HO-1) is induced by the resident cells to ameliorate the milieu. In the meanwhile, neurotrophic factors are induced to promote neuroregeneration. However, it seems that anti-stress enzyme (HO-1) and neurotrophic factor (BDNF) do not significantly combat the pathological events during secondary spinal cord injury. Therefore, optimum healing can be induced if anti-inflammatory and neurotrophic factors are administered in a higher amount through an exogenous source. During the first experiment, the inflammation and neuroregeneration were selectively targeted. HO-1 expressing MSCs (HO-1 MSCs) and BDNF expressing MSCs (BDNF MSC) were co-transplanted in one group (combination group) of dogs with subacute spinal cord injury to selectively control the expression of inflammatory cytokines by HO-1 and induce neuroregeneration by BDNF. We compared the combination group with the HO-1 MSCs group, BDNF MSCs group, and GFP MSCs group. We found that the combination group showed significant improvement in functional recovery. It showed increased expression of neural markers and growth-associated proteins (GAP-43) than in other groups, which depicts enhanced neuroregeneration/neural sparing due to reduced expression of pro-inflammatory cytokines such as TNF-alpha, IL-6 and COX-2; and increased expression of anti-inflammatory markers such as IL-10 and HO-1. Histopathological study revealed reduced intra-parenchymal fibrosis in the injured spinal cord segment in the combination group than in other groups. Thus it was concluded that selectively targeting the inflammation and neuronal growth with the combined use of HO-1 MSCs and BDNF MSCs more favorably promote healing of the SCI. HO-1 MSCs play a role in controlling the inflammation, which favors the BDNF induced neuroregeneration at the injured spinal cord segment of dogs.

Keywords: HO-1 MSCs, BDNF MSCs, neuroregeneration, inflammation, anti-inflammation, spinal cord injury, dogs

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Authors: Tamar Lin, Nufar Buchshtab, Yifat Elharar, Julian Nicenboim, Rotem Edgar, Iddo Weiner, Lior Zelcbuch, Ariel Cohen, Sharon Kredo-Russo, Inbar Gahali-Sass, Naomi Zak, Sailaja Puttagunta, Merav Bassan

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Background: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder that is characterized by dry skin and flares of eczematous lesions and intense pruritus. Multiple lines of evidence suggest that AD is associated with increased colonization by Staphylococcus aureus, which contributes to disease pathogenesis through the release of virulence factors that affect both keratinocytes and immune cells, leading to disruption of the skin barrier and immune cell dysfunction. The aim of the current study is to develop a bacteriophage-based product that specifically targets S. aureus. Methods: For the discovery of phage, environmental samples were screened on 118 S. aureus strains isolated from skin samples, followed by multiple enrichment steps. Natural phages were isolated, subjected to Next-generation Sequencing (NGS), and analyzed using proprietary bioinformatics tools for undesirable genes (toxins, antibiotic resistance genes, lysogeny potential), taxonomic classification, and purity. Phage host range was determined by an efficiency of plating (EOP) value above 0.1 and the ability of the cocktail to completely lyse liquid bacterial culture under different growth conditions (e.g., temperature, bacterial stage). Results: Sequencing analysis demonstrated that the 118 S. aureus clinical strains were distributed across the phylogenetic tree of all available Refseq S. aureus (~10,750 strains). Screening environmental samples on the S. aureus isolates resulted in the isolation of 50 lytic phages from different genera, including Silviavirus, Kayvirus, Podoviridae, and a novel unidentified phage. NGS sequencing confirmed the absence of toxic elements in the phages’ genomes. The host range of the individual phages, as measured by the efficiency of plating (EOP), ranged between 41% (48/118) to 79% (93/118). Host range studies in liquid culture revealed that a subset of the phages can infect a broad range of S. aureus strains in different metabolic states, including stationary state. Combining the single-phage EOP results of selected phages resulted in a broad host range cocktail which infected 92% (109/118) of the strains. When tested in vitro in a liquid infection assay, clearance was achieved in 87% (103/118) of the strains, with no evidence of phage resistance throughout the study (24 hours). A S. aureus host was identified that can be used for the production of all the phages in the cocktail at high titers suitable for large-scale manufacturing. This host was validated for the absence of contaminating prophages using advanced NGS methods combined with multiple production cycles. The phages are produced under optimized scale-up conditions and are being used for the development of a topical formulation (BX005) that may be administered to subjects with atopic dermatitis. Conclusions: A cocktail of natural phages targeting S. aureus was effective in reducing bacterial burden across multiple assays. Phage products may offer safe and effective steroid-sparing options for atopic dermatitis.

Keywords: atopic dermatitis, bacteriophage cocktail, host range, Staphylococcus aureus

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Authors: Sumeyra Yakar, Emine Enise Yakar

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Iran presents itself as Islamic, first and foremost, and thus, it can be said that sharī’a is the political and social centre of the states. However, actual practice reveals distinct interpretations and understandings of the sharī’a. The research can be categorised inside the framework of logic in Islamic law and theology. The first task of this paper will be to identify how the sharī’a is understood in Iran by mapping out how the judges apply the law in their respective jurisdictions. The attention will then move from a simple description of the diversity of sharī’a understandings to the question of how that diversity relates to social concepts and cultures. This, of course, necessitates a brief exploration of Iran’s historical background which will also allow for an understanding of sectarian influences and the significance of certain events. The main purpose is to reach an understanding of the process of applying sources to formulate solutions which are in accordance with sharī’a and how religious education is pursued in order to become official judges. Ultimately, this essay will explore the attempts to gain an understanding by linking the practices to the secondary sources of Islamic law. It is important to emphasise that these cultural components of Islamic law must be compatible with the aims of Islamic law and their fundamental sources. The sharī’a consists of more than just legal doctrines (fiqh) and interpretive activities (ijtihād). Its contextual and theoretical framework reveals a close relationship with cultural and historical elements of society. This has meant that its traditional reproduction over time has relied on being embedded into a highly particular form of life. Thus, as acknowledged by pre-modern jurists, the sharī’a encompasses a comprehensive approach to the requirements of justice in legal, historical and political contexts. In theological and legal areas that have the specific authority of tradition, Iran adheres to Shīa’ doctrine, and this explains why the Shīa’ religious establishment maintains a dominant position in matters relating to law and the interpretation of sharī’a. The statements and interpretations of the tradition are distinctly different from sunnī interpretations, and so the use of different sources could be understood as the main reason for the discrepancies in the application of sharī’a between Iran and other Muslim countries. The sharī’a has often accommodated prevailing customs; moreover, it has developed legal mechanisms to all for its adaptation to particular needs and circumstances in society. While jurists may operate within the realm of governance and politics, the moral authority of the sharī’a ensures that these actors legitimate their actions with reference to God’s commands. The Iranian regime enshrines the principle of vilāyāt-i faqīh (guardianship of the jurist) which enables jurists to solve the conflict between law as an ideal system, in theory, and law in practice. The paper aims to show how the religious, educational system works in harmony with the governmental authorities with the concept of vilāyāt-i faqīh in Iran and contributes to the creation of religious custom in the society.

Keywords: guardianship of the jurist (vilāyāt-i faqīh), imitation (taqlīd), seminaries (hawza), Shi’i jurisprudence

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Authors: Shuo Li, Yannick Coffinier, Chann Lagadec, Fabrizio Cleri, Katsuhiko Nishiguchi, Akira Fujiwara, Soo Hyeon Kim, Nicolas Clément

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The need for single cell detection and analysis techniques has increased in the past decades because of the heterogeneity of individual living cells, which increases the complexity of the pathogenesis of malignant tumors. In the search for early cancer detection, high-precision medicine and therapy, the technologies most used today for sensitive detection of target analytes and monitoring the variation of these species are mainly including two types. One is based on the identification of molecular differences at the single-cell level, such as flow cytometry, fluorescence-activated cell sorting, next generation proteomics, lipidomic studies, another is based on capturing or detecting single tumor cells from fresh or fixed primary tumors and metastatic tissues, and rare circulating tumors cells (CTCs) from blood or bone marrow, for example, dielectrophoresis technique, microfluidic based microposts chip, electrochemical (EC) approach. Compared to other methods, EC sensors have the merits of easy operation, high sensitivity, and portability. However, despite various demonstrations of low limits of detection (LOD), including aptamer sensors, arrayed EC sensors for detecting single-cell have not been demonstrated. In this work, a new technique based on 20-nm-thick nanopillars array to support cells and keep them at ideal recognition distance for redox-labeled aptamers grafted on the surface. The key advantages of this technology are not only to suppress the false positive signal arising from the pressure exerted by all (including non-target) cells pushing on the aptamers by downward force but also to stabilize the aptamer at the ideal hairpin configuration thanks to a confinement effect. With the first implementation of this technique, a LOD of 13 cells (with5.4 μL of cell suspension) was estimated. In further, the nanosupported cell technology using redox-labeled aptasensors has been pushed forward and fully integrated into a single-cell electrochemical aptasensor array. To reach this goal, the LOD has been reduced by more than one order of magnitude by suppressing parasitic capacitive electrochemical signals by minimizing the sensor area and localizing the cells. Statistical analysis at the single-cell level is demonstrated for the recognition of cancer cells. The future of this technology is discussed, and the potential for scaling over millions of electrodes, thus pushing further integration at sub-cellular level, is highlighted. Despite several demonstrations of electrochemical devices with LOD of 1 cell/mL, the implementation of single-cell bioelectrochemical sensor arrays has remained elusive due to their challenging implementation at a large scale. Here, the introduced nanopillar array technology combined with redox-labeled aptamers targeting epithelial cell adhesion molecule (EpCAM) is perfectly suited for such implementation. Combining nanopillar arrays with microwells determined for single cell trapping directly on the sensor surface, single target cells are successfully detected and analyzed. This first implementation of a single-cell electrochemical aptasensor array based on Brownian-fluctuating redox species opens new opportunities for large-scale implementation and statistical analysis of early cancer diagnosis and cancer therapy in clinical settings.

Keywords: bioelectrochemistry, aptasensors, single-cell, nanopillars

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