Search results for: CD8+ T cell responses

Authors: Spira A., Marabelle A., Kientop D., Moser E., Mumm J.

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Background: Both interleukin-2 (IL-2) and interleukin-10 (IL-10) have been extensively studied for their stimulatory function on T cells and their potential to obtain sustainable tumor control in RCC, melanoma, lung, and pancreatic cancer as monotherapy, as well as combination with PD-1 blockers, radiation, and chemotherapy. While approved, IL-2 retains significant toxicity, preventing its widespread use. The significant efforts undertaken to uncouple IL-2 toxicity from its anti-tumor function have been unsuccessful, and early phase clinical safety observed with PEGylated IL-10 was not met in a blinded Phase 3 trial. Deka Biosciences has engineered a novel molecule coupling wild-type IL-2 to a high affinity variant of Epstein Barr Viral (EBV) IL-10 via a scaffold (scFv) that binds to epidermal growth factor receptors (EGFR). This patented molecule, termed DK210 (EGFR), is retained at high levels within the tumor microenvironment for days after dosing. In addition to overlapping and non-redundant anti-tumor function, IL-10 reduces IL-2 mediated cytokine release syndrome risks and inhibits IL-2 mediated T regulatory cell proliferation. Methods: DK210 (EGFR) is being evaluated in an open-label, dose-escalation (Phase 1) study with 5 (0.025-0.3 mg/kg) monotherapy dose levels and (expansion cohorts) in combination with PD-1 blockers, or radiation or chemotherapy in patients with advanced solid tumors overexpressing EGFR. Key eligibility criteria include 1) confirmed progressive disease on at least one line of systemic treatment, 2) EGFR overexpression or amplification documented in histology reports, 3) at least a 4 week or 5 half-lives window since last treatment, and 4) excluding subjects with long QT syndrome, multiple myeloma, multiple sclerosis, myasthenia gravis or uncontrolled infectious, psychiatric, neurologic, or cancer disease. Plasma and tissue samples will be investigated for pharmacodynamic and predictive biomarkers and genetic signatures associated with IFN-gamma secretion, aiming to select subjects for treatment in Phase 2. Conclusion: Through successful coupling of wild-type IL-2 with a high affinity IL-10 and targeting directly to the tumor microenvironment, DK210 (EGFR) has the potential to harness IL-2 and IL-10’s known anti-cancer promise while reducing immunogenicity and toxicity risks enabling safe concomitant cytokine treatment with other anti-cancer modalities.

Keywords: cytokine, EGFR over expression, interleukine-2, interleukine-10, clinical trial

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Authors: Samuel N. Forjuoh, Marcia G. Ory, Jaewoong Won, Samuel D. Towne, Suojin Wang, Chanam Lee

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The public health burden of obesity is well established as is the influence of physical activity (PA) on the health and wellness of individuals who are obese. This study examined the influence of selected demographic, health, and socioenvironmental factors on the walking behaviors of middle-aged and older overweight and obese adults. Online and paper surveys were administered to community-dwelling overweight and obese adults aged ≥ 50 years residing in four cities in central Texas and seen by a family physician in the primary care clinic from October 2013 to June 2014. Descriptive statistics were used to characterize participants’ anthropometric and demographic data as well as their health conditions and walking, socioenvironmental, and more broadly defined PA behaviors. Then Pearson chi-square tests were used to assess differences between participants who reported walking the recommended ≥ 150 minutes for any purpose in a typical week as a proxy to meeting the U.S. Centers for Disease Control and Prevention’s PA guidelines and those who did not. Finally, logistic regression was used to predict walking the recommended ≥ 150 minutes for any purpose, controlling for covariates. The analysis was conducted in 2016. Of the total sample (n=253, survey response rate of 6.8%), the majority were non-Hispanic white (81.7%), married (74.5%), male (53.5%), and reported an annual household income of ≥ $50,000 (65.7%). Approximately, half were employed (49.6%), or had at least a college degree (51.8%). Slightly more than 1 in 5 (n=57, 22.5%) reported walking the recommended ≥150 minutes for any purpose in a typical week. The strongest predictors of walking the recommended ≥ 150 minutes for any purpose in a typical week in adjusted analysis were related to education and a high favorable perception of the neighborhood environment. Compared to those with a high school diploma or some college, participants with at least a college degree were five times as likely to walk the recommended ≥ 150 minutes for any purpose (OR=5.55, 95% CI=1.79-17.25). Walking the recommended ≥ 150 minutes for any purpose was significantly associated with participants who disagreed that there were many distracted drivers (e.g., on the cell phone while driving) in their neighborhood (OR=4.08, 95% CI=1.47-11.36) and those who agreed that there are sidewalks or protected walkways (e.g., walking trails) in their neighborhood (OR=3.55, 95% CI=1.10-11.49). Those employed were less likely to walk the recommended ≥ 150 minutes for any purpose compared to those unemployed (OR=0.31, 95% CI=0.11-0.85) as were those who reported some difficulty walking for a quarter of a mile (OR=0.19, 95% CI=0.05-0.77). Other socio-environmental factors such as having care-giver responsibilities for elders, someone to walk with, or a dog in the household as well as Walk Score™ were not significantly associated with walking the recommended ≥ 150 minutes for any purpose in a typical week. Neighborhood perception appears to be an important factor associated with the walking behaviors of middle-aged and older overweight and obese individuals. Enhancing the neighborhood environment (e.g., providing walking trails) may promote walking among these individuals.

Keywords: determinants of walking, obesity, older adults, physical activity

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Authors: Annalise Weckesser, Alex Wade, Clara Joergensen, Jerome Turner

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Introduction: Digital mobile technologies afford Generation M a number of opportunities in terms of communication, creativity and connectivity in their social interactions. Yet these young people’s use of such technologies is often the source of moral panic with accordant social anxiety especially prevalent in media representations of teen ‘sexting,’ or the sending of sexually explicit images via smartphones. Thus far, most responses to youth sexting have largely been ineffective or unjust with adult authorities sometimes blaming victims of non-consensual sexting, using child pornography laws to paradoxically criminalise those they are designed to protect, and/or advising teenagers to simply abstain from the practice. Prevention strategies are further skewed, with sex education initiatives often targeted at girls, implying that they shoulder the responsibility of minimising the risks associated with sexting (e.g. revenge porn and sexual predation). Purpose of Study: Despite increasing public interest and concern about ‘teen sexting,’ there remains a dearth of research with young people regarding their experiences of navigating sex and relationships in the current digital media landscape. Furthermore, young people's views on sexting are rarely solicited in the policy and educational strategies aimed at them. To address this research-policy-education gap, an interdisciplinary team of four researchers (from anthropology, media, sociology and education) have undertaken a peer-to-peer research project to co-create a sexual health intervention. Methods: In the winter of 2015-2016, the research team conducted serial group interviews with four cohorts of students (aged 13 to 15) from a secondary school in the West Midlands, UK. To facilitate open dialogue, girls and boys were interviewed separately, and each group consisted of no more than four pupils. The team employed a range of participatory techniques to elicit young people’s views on sexting, its consequences, and its interventions. A final focus group session was conducted with all 14 male and female participants to explore developing a peer-to-peer ‘safe sexting’ education intervention. Findings: This presentation will highlight the ongoing, ‘old school’ sexual double standards at work within this new digital frontier. In the sharing of ‘nudes’ (teens’ preferred term to ‘sexting’) via social media apps (e.g. Snapchat and WhatsApp), girls felt sharing images was inherently risky and feared being blamed and ‘slut-shamed.’ In contrast, boys were seen to gain in social status if they accumulated nudes of female peers. Further, if boys had nudes of themselves shared without consent, they felt they were expected to simply ‘tough it out.’ The presentation will also explore what forms of supports teens desire to help them in their day-to-day navigation of these digitally mediated, heteronormative performances of teen femininity and masculinity expected of them. Conclusion: This is the first research project, within UK, conducted with rather than about teens and the phenomenon of sexting. It marks a timely and important contribution to the nascent, but growing body of knowledge on gender, sexual politics and the digital mobility of sexual images created by and circulated amongst young people.

Keywords: teens, sexting, gender, sexual politics

Procedia PDF Downloads 238

Authors: Gunta Resevica, Nikita Zrelovs, Ivars Silamikelis, Ieva Kalnciema, Helvijs Niedra, Gunārs Lācis, Toms Bartulsons, Inga Moročko-Bičevska, Arturs Stalažs, Kristīne Drevinska, Andris Zeltins, Ina Balke

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Newly discovered viruses provide novel knowledge for basic phytovirus research, serve as tools for biotechnology and can be helpful in identification of epidemic outbreaks. Blackcurrant-associated rhabdovirus (BCaRV) have been discovered in USA germplasm collection samples from Russia and France. As it was reported in one accession originating from France it is unclear whether the material was already infected when it entered in the USA or it became infected while in collection in the USA. Due to that BCaRV was definite as non-EU viruses. According to ICTV classification BCaRV is representative of Blackcurrant betanucleorhabdovirus specie in genus Betanucleorhabdovirus (family Rhabdoviridae). Nevertheless, BCaRV impact on the host, transmission mechanisms and vectors are still unknown. In RNA-seq data pool from Ribes plants resistance gene study by high throughput sequencing (HTS) we observed differences between sample group gene transcript heat maps. Additional analysis of the whole data pool (total 393660492 of 150 bp long read pairs) by rnaSPAdes v 3.13.1 resulted into 14424 bases long contig with an average coverage of 684x with shared 99.5% identity to the previously reported first complete genome of BCaRV (MF543022.1) using EMBOSS Needle. This finding proved BCaRV presence in EU and indicated that it might be relevant pathogen. In this study leaf tissue from twelve asymptomatic blackcurrant cv. Mara Eglite plants (negatively tested for blackcurrant reversion virus (BRV)) from Dobele, Latvia (56°36'31.9"N, 23°18'13.6"E) was collected and used for total RNA isolation with RNeasy Plant Mini Kit with minor modifications, followed by plant rRNA removal by a RiboMinus Plant Kit for RNA-Seq. HTS libraries were prepared using MGI Easy RNA Directional Library Prep Set for 16 reactions to obtain 150 bp pair-end reads. Libraries were pooled, circularized and cleaned and sequenced on DNBSEQ-G400 using PE150 flow cell. Additionally, all samples were tested by RT-PCR, and amplicons were directly sequenced by Sanger-based method. The contig representing the genome of BCaRV isolate Mara Eglite was deposited at European Nucleotide Archive under accession number OU015520. Those findings indicate a second evidence on the presence of this particular virus in the EU and further research on BCaRV prevalence in Ribes from other geographical areas should be performed. As there are no information on BCaRV impact on the host this should be investigated, regarding the fact that mixed infections with BRV and nucleorhabdoviruses are reported.

Keywords: BCaRV, Betanucleorhabdovirus, Ribes, RNA-seq

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Authors: Yusuf Berkay Metinal, Gulden Gumusburun Ayalp

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

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

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Authors: Melanie Schinnerl, Dorothea Greiling

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In the context of the 2020 strategy, poverty and its fight returned to the center of national political efforts. This served as motivation for an Austrian research grant-funded project to focus on the under-researched local government level with the aim to identify municipal best-practice cases and to derive policy implications for Austria. Designing effective poverty reduction strategies is a complex challenge which calls for an integrated multi-actor in approach. Cities are increasingly confronted to combat poverty, even in rich EU-member states. By doing so cities face substantial demographic, cultural, economic and social challenges as well as changing welfare state regimes. Furthermore, there is a low willingness of (right-wing) governments to support the poor. Against this background, the research questions are: 1. How do local governments define poverty? 2. Who are the main risk groups and what are the most pressing problems when fighting urban poverty? 3. What is regarded as successful anti-poverty initiatives? 4. What is the underlying welfare state concept? To address the research questions a multi-method approach was chosen, consisting of a systematic literature analysis, a comprehensive document analysis, and expert interviews. For interpreting the data the project follows the qualitative-interpretive paradigm. Municipal approaches for reducing poverty are compared based on deductive, as well as inductive identified criteria. In addition to an intensive literature analysis, interviews (40) were conducted in Austria since the project started in March 2018. From the other countries, 14 responses have been collected, providing a first insight. Regarding the definition of poverty the EU SILC-definition as well as counting the persons who receive need-based minimum social benefits, the Austrian form of social welfare, are the predominant approaches in Austria. In addition to homeless people, single-parent families, un-skilled persons, long-term unemployed persons, migrants (first and second generation), refugees and families with at least 3 children were frequently mentioned. The most pressing challenges for Austrian cities are: expected reductions of social budgets, a great insecurity of the central government's social policy reform plans, the growing number of homeless people and a lack of affordable housing. Together with affordable housing, old-age poverty will gain more importance in the future. The Austrian best practice examples, suggested by interviewees, focused primarily on homeless, children and young people (till 25). Central government’s policy changes have already negative effects on programs for refugees and elderly unemployed. Social Housing in Vienna was frequently mentioned as an international best practice case, other growing cities can learn from. The results from Austria indicate a change towards the social investment state, which primarily focuses on children and labour market integration. The first insights from the other countries indicate that affordable housing and labor market integration are cross-cutting issues. Inherited poverty and old-age poverty seems to be more pressing outside Austria.

Keywords: anti-poverty policies, European cities, empirical study, social investment

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Authors: Keda Li, Hong Hu

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Auxetic materials, as an emerging artificial designed metamaterial has attracted growing attention due to their promising negative Poisson’s ratio behaviors and tunable properties. The conventional auxetic lattice structures for which the deformation process is governed by a bending-dominated mechanism have faced the limitation of poor mechanical performance for many potential engineering applications. Recently, both load-bearing and energy absorption capabilities have become a crucial consideration in auxetic structure design. This study reports the finite element analysis of a class of hexagonal double-arrowhead auxetic structures with enhanced stiffness and energy absorption performance. The structure design was developed by extending the traditional double-arrowhead honeycomb to a hexagon frame, the stretching-dominated deformation mechanism was determined according to Maxwell’s stability criterion. The finite element (FE) models of 2D lattice structures established with stainless steel material were analyzed in ABAQUS/Standard for predicting in-plane structural deformation mechanism, failure process, and compressive elastic properties. Based on the computational simulation, the parametric analysis was studied to investigate the effect of the structural parameters on Poisson’s ratio and mechanical properties. The geometrical optimization was then implemented to achieve the optimal Poisson’s ratio for the maximum specific energy absorption. In addition, the optimized 2D lattice structure was correspondingly converted into a 3D geometry configuration by using the orthogonally splicing method. The numerical results of 2D and 3D structures under compressive quasi-static loading conditions were compared separately with the traditional double-arrowhead re-entrant honeycomb in terms of specific Young's moduli, Poisson's ratios, and specified energy absorption. As a result, the energy absorption capability and stiffness are significantly reinforced with a wide range of Poisson’s ratio compared to traditional double-arrowhead re-entrant honeycomb. The auxetic behaviors, energy absorption capability, and yield strength of the proposed structure are adjustable with different combinations of joint angle, struts thickness, and the length-width ratio of the representative unit cell. The numerical prediction in this study suggests the proposed concept of hexagonal double-arrowhead structure could be a suitable candidate for the energy absorption applications with a constant request of load-bearing capacity. For future research, experimental analysis is required for the validation of the numerical simulation.

Keywords: auxetic, energy absorption capacity, finite element analysis, negative Poisson's ratio, re-entrant hexagonal honeycomb

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Authors: Wang Heng, Zhong Zhaoping, Guo Feihong, Wang Jia, Wang Xiaoyi

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Flow of gas and particles in fluidized beds is complex and chaotic, which is difficult to measure and analyze by experiments. Some bed materials with bad fluidized performance always fluidize with fluidized medium. The material and the fluidized medium are different in many properties such as density, size and shape. These factors make the dynamic process more complex and the experiment research more limited. Numerical simulation is an efficient way to describe the process of gas-solid flow in fluidized bed. One of the most popular numerical simulation methods is CFD-DEM, i.e., computational fluid dynamics-discrete element method. The shapes of particles are always simplified as sphere in most researches. Although sphere-shaped particles make the calculation of particle uncomplicated, the effects of different shapes are disregarded. However, in practical applications, the two-component systems in fluidized bed also contain sphere particles and non-sphere particles. Therefore, it is needed to study the two component flow of sphere particles and non-sphere particles. In this paper, the flows of mixing were simulated as the flow of molding biomass particles and quartz in fluidized bad. The integrated model was built on an Eulerian–Lagrangian approach which was improved to suit the non-sphere particles. The constructed methods of cylinder-shaped particles were different when it came to different numerical methods. Each cylinder-shaped particle was constructed as an agglomerate of fictitious small particles in CFD part, which means the small fictitious particles gathered but not combined with each other. The diameter of a fictitious particle d_fic and its solid volume fraction inside a cylinder-shaped particle α_fic, which is called the fictitious volume fraction, are introduced to modify the drag coefficient β by introducing the volume fraction of the cylinder-shaped particles α_cld and sphere-shaped particles α_sph. In a computational cell, the void ε, can be expressed as ε=1-〖α_cld α〗_fic-α_sph. The Ergun equation and the Wen and Yu equation were used to calculate β. While in DEM method, cylinder-shaped particles were built by multi-sphere method, in which small sphere element merged with each other. Soft sphere model was using to get the connect force between particles. The total connect force of cylinder-shaped particle was calculated as the sum of the small sphere particles’ forces. The model (size=1×0.15×0.032 mm3) contained 420000 sphere-shaped particles (diameter=0.8 mm, density=1350 kg/m3) and 60 cylinder-shaped particles (diameter=10 mm, length=10 mm, density=2650 kg/m3). Each cylinder-shaped particle was constructed by 2072 small sphere-shaped particles (d=0.8 mm) in CFD mesh and 768 sphere-shaped particles (d=3 mm) in DEM mesh. The length of CFD and DEM cells are 1 mm and 2 mm. Superficial gas velocity was changed in different models as 1.0 m/s, 1.5 m/s, 2.0m/s. The results of simulation were compared with the experimental results. The movements of particles were regularly as fountain. The effect of superficial gas velocity on cylinder-shaped particles was stronger than that of sphere-shaped particles. The result proved this present work provided a effective approach to simulation the flow of two component particles.

Keywords: computational fluid dynamics, discrete element method, fluidized bed, multiphase flow

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Authors: Tugba Altin

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In a time characterized by escalating climate change impacts, communities globally face extreme events with deep-reaching tangible and intangible consequences. At the intersection of these phenomena lies the profound impact on the cultural and emotional connections that individuals forge with their environments. This study casts a spotlight on the Lytton Creek Fire of 2021, showcasing it as an exemplar of both the visible destruction brought by such events and the more covert yet deeply impactful disturbances to place attachment (PA). Defined as the emotional and cognitive bond individuals form with their surroundings, PA is critical in comprehending how such catastrophic events reshape cultural identity and the bond with the land. Against the stark backdrop of the Lytton Creek Fire's devastation, the research seeks to unpack the multilayered dynamics of PA amidst the tangible wreckage and the intangible repercussions such as emotional distress and disrupted cultural landscapes. Delving deeper, it examines how affected populations renegotiate their affiliations with these drastically altered environments, grappling with both the tangible loss of their homes and the intangible challenges to solace, identity, and community cohesion. This exploration is instrumental in the broader climate change narrative, as it offers crucial insights into how these personal-place relationships can influence and shape climate adaptation and recovery strategies. Departing from traditional data collection methodologies, this study adopts an interpretive phenomenological approach enriched by hermeneutic insights and places the experiences of the Lytton community and its co-researchers at its core. Instead of conventional interviews, innovative methods like walking audio sessions and photo elicitation are employed. These techniques allow participants to immerse themselves back into the environment, reviving and voicing their memories and emotions in real-time. Walking audio captures reflections on spatial narratives after the trauma, whereas photo voices encapsulate the intangible emotions, presenting a visual representation of place-based experiences. Key findings emphasize the indispensability of addressing both the tangible and intangible traumas in community recovery efforts post-disaster. The profound changes to the cultural landscape and the subsequent shifts in PA underscore the need for holistic, culturally attuned, and emotionally insightful adaptation strategies. These strategies, rooted in the lived experiences and testimonies of the affected individuals, promise more resonant and effective recovery efforts. The research further contributes to climate change discourse, highlighting the intertwined pathways of tangible reconstruction and the essentiality of emotional and cultural rejuvenation. Furthermore, the use of participatory methodologies in this inquiry challenges traditional research paradigms, pointing to potential evolutionary shifts in qualitative research norms. Ultimately, this study underscores the need for a more integrative approach in addressing the aftermath of environmental disasters, ensuring that both physical and emotional rebuilding are given equal emphasis.

Keywords: place attachment, community recovery, disaster reponse, sensory responses, intangible traumas, visual methodologies

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Authors: Elena Maria Scalisi

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Currently, photodegradation by nanoparticles (NPs) is a common solution for wastewater treatment. Nanoparticles are efficient for removing organic and inorganic pollutants, heavy metals from wastewater and killing microorganisms through environmentally friendly. In this context, the major representative of photocatalytic technology for industrial wastewater treatment are TiO₂ nanoparticles (TiO₂-NPs). TiO₂-NPs have a strong catalytic activity that depends to their physicochemical properties. Thanks to their small size (between 1-100 nm), nanoparticles occupy less volume, then their surface area increases. The increase in the surface-to-volume ratio results in the increase of the particle surface energy, which improve their reactivity potential. However, these unique properties represent risks to the ecosystems and organisms when unintentionally TiO₂-NPs are release into the environment and absorbed by living organisms. Several studies confirm that there is a high level of interest concerning the safety of TiO₂-NPs in the aquatic environment, furthermore, ecotoxicological tools are useful to correctly evaluate their toxicity. In the current study, we aimed to characterize potential toxic effects of TiO₂-NP suspension to zebrafish during embryo-larval stages to evaluate parameters such as survival rates, malformation, hatching, the overall length of the larvae heartbeat, and biochemical biomarkers that reflect the acute toxicity and sublethal effects of TiO₂-NPs. Zebrafish embryos were exposed to titanium dioxide nanoparticles (TiO₂-NPs at 1mg/L, 2mg/L, and 4mg/L) from fertilization to the free swimming stage (144hpf). Every day, we recorded the toxicological endpoints, moreover, immunohistochemical analysis has been performed at the end of the exposure. In particular, we have evaluate the expression of the following biomarkers: Heat Shock Protein 70 (HSP70), Poly ADP-Ribose Polymerase-1 (PARP-1), Metallothioneins (MTs). Our results have shown that hatch ability, survival, and malformation rate were not affected by TiO₂ NPs at these exposure levels. However, TiO₂-NPs caused an increase of heartbeat and reduction of body length; at the same time, TiO₂-NPs have inducted the production of ROS and the expression of oxidative stress biomarkers HSP70 and PARP-1. Hight positivity for PARP-1 at all concentration tested was observed. As regards MT, positivity was found in the expression of this biomarker in the whole body of the embryo, with the exception of the end of the tail. Metallothioneins (MT) are biomarkers widely used in environmental monitoring programs for aquatic creatures. At the light of our results i.e. no death until the end of the experiment (144hpf), no malformation and expression of the biomarkers mentioned, it is evident that zebrafish larvae with their natural detoxification pathways are able to resist the presence of toxic substances and then they can tolerate the presence of metal concentrations. However, an excessive oxidative state can compromise cell function, therefore the uncontrolled release of nanoparticles into the environment is severe and must be constantly monitored.

Keywords: nanoparticles, embryo zebrafish, HSP70, PARP-1

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Authors: Kaaryn Cater

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People vary in how they perceive, process, and react to internal, external, social, and emotional environmental factors; some are more sensitive than others. Compassionate people have a highly reactive nervous system and are more impacted by positive and negative environmental conditions (Differential Susceptibility). Further, some sensitive individuals are disproportionately able to benefit from positive and supportive environments without necessarily suffering negative impacts in less supportive environments (Vantage Sensitivity). Environmental sensitivity is underpinned by physiological, genetic, and personality/temperamental factors, and the phenotypic expression of high sensitivity is Sensory Processing Sensitivity. The hallmarks of Sensory Processing Sensitivity are deep cognitive processing, emotional reactivity, high levels of empathy, noticing environmental subtleties, a tendency to observe new and novel situations, and a propensity to become overwhelmed when over-stimulated. Several educational advantages associated with high sensitivity include creativity, enhanced memory, divergent thinking, giftedness, and metacognitive monitoring. High sensitivity can also lead to some educational challenges, particularly managing multiple conflicting demands and negotiating low sensory thresholds. A mixed methods study was undertaken. In the first quantitative study, participants completed the Perceived Success in Study Survey (PSISS) and the Highly Sensitive Person Scale (HSPS-12). Inclusion criteria were current or previous postsecondary education experience. The survey was presented on social media, and snowball recruitment was employed (n=365). The Excel spreadsheets were uploaded to the statistical package for the social sciences (SPSS)26, and descriptive statistics found normal distribution. T-tests and analysis of variance (ANOVA) calculations found no difference in the responses of demographic groups, and Principal Components Analysis and the posthoc Tukey calculations identified positive associations between high sensitivity and three of the five PSISS factors. Further ANOVA calculations found positive associations between the PSISS and two of the three sensitivity subscales. This study included a response field to register interest in further research. Respondents who scored in the 70th percentile on the HSPS-12 were invited to participate in a semi-structured interview. Thirteen interviews were conducted remotely (12 female). Reflexive inductive thematic analysis was employed to analyse data, and a descriptive approach was employed to present data reflective of participant experience. The results of this study found that compassionate students prioritize work-life balance; employ a range of practical metacognitive study and self-care strategies; value independent learning; connect with learning that is meaningful; and are bothered by aspects of the physical learning environment, including lighting, noise, and indoor environmental pollutants. There is a dearth of research investigating sensitivity in the educational context, and these studies highlight the need to promote widespread education sector awareness of environmental sensitivity, and the need to include sensitivity in sector and institutional diversity and inclusion initiatives.

Keywords: differential susceptibility, highly sensitive person, learning, neurosensitivity, sensory processing sensitivity, vantage sensitivity

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Authors: S. Jayasinghe, W. G. D. Wickramasingha, V. Karunaratne, D. N. Karunaratne, A. Ekanayake

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Multi-drug resistant microbial pathogens are a serious global health problem, and hence, there is an urgent necessity for discovering new drug therapeutics. However, finding alternatives is a one of the biggest challenges faced by the global drug industry due to the spiraling high cost and serious side effects associated with modern medicine. On the other hand, plants and their secondary metabolites can be considered as good sources of scaffolds to provide structurally diverse bioactive compounds as potential therapeutic agents. 6β-hydroxy betunolic acid is a triterpenoid isolated from bark of Schumacheria castaneifolia which is an endemic plant to Sri Lanka which has shown antibacterial activity against both Staphylococcus aureus (ATCC 29213) and methicillin-resistant S. aureus with Minimum Inhibition Concentration (MIC) of 16 µg/ml. The objective of this study was to determine the anti-bacterial activity for the derivatives of 6β- hydroxy betunolic acid against standard strains of Staphylococcus aureus (ATCC 29213 and ATCC 25923), Enterococcus faecalis (ATCC 29212), Escherichia coli (ATCC 35218 and ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), carbepenemas produce Kebsiella pneumonia (ATCC BAA 1705) and carbepenemas non produce Kebsiella pneumonia (ATCC BAA 1706) and four stains of clinically isolated methicillin resistance S. aureus and Acinetobacter. Structural analogues of 6β-hydroxy betunolic acid were synthesized by modifying the carbonyl group at C-3 to obtain olefin and oxime, the hydroxyl group at C-6 position to a ketone, the carboxylic acid at C-17 to obtain amide and halo ester and the olefin group at C-20 position to obtain epoxide. Chemical structures of the synthesized analogues were confirmed with spectroscopic data and antibacterial activity was determined through broth micro dilution assay. Results revealed that 6β- hydroxy betunolic acid shows significant antibacterial activity only against the Gram positive strains and it was inactive against all the tested Gram negative strains for the tested concentration range. However, structural modifications into oxime and olefin at C-3, ketone at C-6 and epoxide at C-20 decreased its antibacterial activity against the gram positive organisms and it was totally lost with the both modifications at C-17 into amide and ester. These results concluded that the antibacterial activity of 6β- hydroxy betunolic acid and derivatives is predominantly depending on the cell wall difference of the bacteria and the presence of carboxylic acid at C-17 is highly important for the antibacterial activity against Gram positive organisms.

Keywords: antibacterial activity, 6β- hydroxy betunolic acid, broth micro dilution assay, structure activity relationship

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Authors: Abdulaziz Alakeel, Roaa Alamri, Abdulrahman Alomair, Mohammed Fouda

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Introduction: Ibrutinib is a selective, potent, and irreversible small-molecule inhibitor of Bruton's tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue (CYS-481) at the active site of Btk, leading to inhibition of Btk enzymatic activity. The drug is indicated to treat certain type of cancers such as mantle cell lymphoma (MCL), chronic lymphocytic leukaemia and Waldenström's macroglobulinaemia (WM). Cardiac failure is a condition referred to inability of heart muscle to pump adequate blood to human body organs. There are multiple types of cardiac failure including left and right-sided heart failure, systolic and diastolic heart failures. The aim of this review is to evaluate the risk of cardiac failure associated with the use of ibrutinib and to suggest regulatory recommendations if required. Methodology: Signal Detection team at the National Pharmacovigilance Center (NPC) of Saudi Food and Drug Authority (SFDA) performed a comprehensive signal review using its national database as well as the World Health Organization (WHO) database (VigiBase), to retrieve related information for assessing the causality between cardiac failure and ibrutinib. We used the WHO- Uppsala Monitoring Centre (UMC) criteria as standard for assessing the causality of the reported cases. Results: Case Review: The number of resulted cases for the combined drug/adverse drug reaction are 212 global ICSRs as of July 2020. The reviewers have selected and assessed the causality for the well-documented ICSRs with completeness scores of 0.9 and above (35 ICSRs); the value 1.0 presents the highest score for best-written ICSRs. Among the reviewed cases, more than half of them provides supportive association (four probable and 15 possible cases). Data Mining: The disproportionality of the observed and the expected reporting rate for drug/adverse drug reaction pair is estimated using information component (IC), a tool developed by WHO-UMC to measure the reporting ratio. Positive IC reflects higher statistical association while negative values indicates less statistical association, considering the null value equal to zero. The results of (IC=1.5) revealed a positive statistical association for the drug/ADR combination, which means “Ibrutinib” with “Cardiac Failure” have been observed more than expected when compared to other medications available in WHO database. Conclusion: Health regulators and health care professionals must be aware for the potential risk of cardiac failure associated with ibrutinib and the monitoring of any signs or symptoms in treated patients is essential. The weighted cumulative evidences identified from causality assessment of the reported cases and data mining are sufficient to support a causal association between ibrutinib and cardiac failure.

Keywords: cardiac failure, drug safety, ibrutinib, pharmacovigilance, signal detection

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Authors: Julia Gontar, Natalia Buderatskaya, Igor Ilyin, Olga Parnitskaya, Sergey Lavrynenko, Eduard Kapustin, Ekaterina Ilyina, Yana Lakhno

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Introduction: It is well known that oocytes obtained from older reproductive women have accumulated mitochondrial DNA mutations, which negatively affects the morphology of a developing embryo and may lead to the birth of a child with mitochondrial disease. Special techniques have been developed to allow a donor oocyte cytoplasmic transfer with the parents’ biological nuclear DNA retention. At the same time, it is important to understand whether the procedure affects the future embryonic chromosome sets as the nuclear DNA is the transfer subject in this new complex procedure. Material and Methods: From July 2015 to July 2016, the investigation was carried out in the Medical Centre IGR. 34 donor oocytes (group A) were used for the manipulation with the aim of donating cytoplasm: 21 oocytes were used for zygotes pronuclear transfer and oocytes 13 – for the spindle transfer. The mean age of the oocyte donors was 28.4±2.9 years. The procedure was performed using Nikon Ti Eclipse inverted microscope equipped with the micromanipulators Narishige system (Japan), Saturn 3 laser console (UK), Oosight imaging systems (USA). For the preimplantation genetic screening (PGS) blastocyst biopsy was performed, trophectoderm samples were diagnosed using fluorescent in situ hybridization on chromosomes 9, 13, 15, 16, 17, 18, 21, 22, X, Y. For comparison of morphological characteristics and euploidy, was chosen a group of embryos (group B) with the amount of 121 blastocysts obtained from 213 oocytes, which were gotten from the donor programs of assisted reproductive technologies (ART). Group B was not subjected to donor oocyte cytoplasmic transfer procedure and studied on the above mentioned chromosomes. Statistical analysis was carried out using the criteria t, x^2 at a significance levels p<0.05, p<0.01, p<0.001. Results: After the donor cytoplasm transfer process the amount of the third day developing embryos was 27 (79.4%). In this stage, the group B consisted of 189 (88.7%) developing embryos, and there was no statistically significant difference (SSD) between the two groups (p>0.05). After a comparative analysis of the morphological characteristics of the embryos on the fifth day, we also found no SSD among the studied groups (p>0.05): from 34 oocytes exposed to manipulation, 14 (41.2%) blastocysts was obtained, while the group B blastocyst yield was 56.8% (n=121) from 213 oocytes. The following results were obtained after PGS performing: in group A euploidy in studied chromosomes were 28.6%(n=4) blastocysts, whereas in group B this rate was 40.5%(n=49), 28.6%(n=4) and 21.5%(n=26) of mosaic embryos and 42.8%(n=6) and 38.0%(n=46) aneuploid blastocysts respectively were identified. None of these specified parameters had an SSD (p>0.05). But attention was drawn by the blastocysts in group A with identified mosaicism, which was chaotic without any cell having euploid chromosomal set, in contrast to the mosaic embryos in group B where identified chaotic mosaicism was only 2.5%(n=3). Conclusions: According to the obtained results, there is no direct procedural effect on the chromosome in embryos obtained following donor oocyte cytoplasmic transfer. Thus, the technology introduction will enhance the infertility treating effectiveness as well as avoiding having a child with mitochondrial disease.

Keywords: donor oocyte cytoplasmic transfer, embryos’ chromosome set, oocyte spindle transfer, pronuclear transfer

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Authors: Drago Bratkovic, Curtis Gravance, David Ketteridge, Ravi Krishnan, Michael Imperiale

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The mucopolysaccharidoses (MPSs) are a group of lysosomal storage diseases that have a common defect in the catabolism of glycosaminoglycans (GAGs). MPS I is the most common of the MPS diseases. Manifestations of MPS I include coarsening of facial features, corneal clouding, developmental delay, short stature, skeletal manifestations, hearing loss, cardiac valve disease, hepatosplenomegaly, and umbilical and inguinal hernias. Treatments for MPS I restore or activate the missing or deficient enzyme in the case of enzyme replacement therapy (ERT) and haematopoietic stem cell transplantation (HSCT). Pentosan polysulfate sodium (PPS) is a potential treatment to improve bone and joint manifestations of MPS I. The mechanisms of action of PPS that are relevant to the treatment of MPS I are the ability to: (i) Reduce systemic and accumulated GAG, (ii) Reduce inflammatory effects via the inhibition of NF-kB, resulting in the reduction in pro-inflammatory mediators. (iii) Reduce the expression of the pain mediator nerve growth factor in osteocytes from degenerating joints. (iv) Inhibit the cartilage degrading enzymes related to joint dysfunction in MPS I. PPS is being evaluated as an adjunctive therapy to ERT and/or HSCT in an open-label, single-centre, phase 2 study. Patients are ≥ 5 years of age with a diagnosis of MPS I and previously received HSCT and/or ERT. Three white, female, patients with MPS I-Hurler, ages 14, 15, and 19 years, and one, white male patient aged 15 years are enrolled. All were diagnosed at ≤2 years of age. All patients received HSCT ≤ 6 months after diagnosis. Two of the patients were treated with ERT prior to HSCT, and 1 patient received ERT commencing 3 months prior to HSCT. Two patients received 0.75mg/kg and 2 patients received 1.5mg/kg of PPS. PPS was well tolerated at doses of 0.75 and 1.5 mg/kg to 47 weeks of continuous dosing. Of the 19 adverse events (AEs), 2 were related to PPS. One AE was moderate (pre-syncope) and 1 was mild (injection site bruising), experienced in the same patient. All AEs were reported as mild or moderate. There have been no SAEs. One subject experienced a COVID-19 infection and PPS was interrupted. The MPS I signature GAG fragments, sulfated disaccharide and UA-HNAc S, tended to decrease in 3 patients from baseline through Week 25. Week 25 GAG data are pending for the 4th patient. Overall, most biomarkers (inflammatory, cartilage degeneration, and bone turnover) evaluated in the 3 patients with 25-week assessments have indicated either no change or a reduction in levels compared to baseline. In 3 patients, there was a trend toward improvement in the 2MWT from baseline to Week 48 with > 100% increase in 1 patient (01-201). In the 3 patients that had Week 48 assessments, patients and proxies reported improvement in PGIC, including “worthwhile difference” (n=1), or “made all the difference” (n=2).

Keywords: MPS I, pentosan polysulfate sodium, clinical study, 2MWT, QoL

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Authors: Maryline Vere, Wilma ten Ham-Baloyi, Lucy Ochola, Opeoluwa Oyedele, Lindsey Beyleveld, Siphokazi Tili, Takafira Mduluza, Paula E. Melariri

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Schistosomiasis, caused by Schistosoma (S.) haematobium and Schistosoma (S.) mansoni parasites poses a significant public health challenge in low-income regions. Diagnosis typically relies on identifying specific urine biomarkers such as haematuria, protein, and leukocytes for S. haematobium, while the Point-of-Care Circulating Cathodic Antigen (POC-CCA) assay is employed for detecting S. mansoni. Urinalysis and the POC-CCA assay are favoured for their rapid, non-invasive nature and cost-effectiveness. However, traditional diagnostic methods such as Kato-Katz and urine filtration lack sensitivity in low-transmission areas, which can lead to underreporting of cases and hinder effective disease control efforts. Therefore, in this study, urinalysis and the POC-CCA assay was utilised to diagnose schistosomiasis effectively among school-going children in Nelson Mandela Bay Municipality. This was a cross-sectional study with a total of 759 children, aged 5 to 14 years, who provided urine samples. Urinalysis was performed using urinary dipstick tests, which measure multiple parameters, including haematuria, protein, leukocytes, bilirubin, urobilinogen, ketones, pH, specific gravity and other biomarkers. Urinalysis was performed by dipping the strip into the urine sample and observing colour changes on specific reagent pads. The POC-CCA test was conducted by applying a drop of urine onto a cassette containing CCA-specific antibodies, and the presence of a visible test line indicated a positive result for S. mansoni infection. Descriptive statistics were used to summarize urine parameters, and Pearson correlation coefficients (r) were calculated to analyze associations among urine parameters using R software (version 4.3.1). Among the 759 children, the prevalence of S. haematobium using haematuria as a diagnostic marker was 33.6%. Additionally, leukocytes were detected in 21.3% of the samples, and protein was present in 15%. The prevalence of positive POC-CCA test results for S. mansoni was 3.7%. Urine parameters exhibited low to moderate associations, suggesting complex interrelationships. For instance, specific gravity and pH showed a negative correlation (r = -0.37), indicating that higher specific gravity was associated with lower pH. Weak correlations were observed between haematuria and pH (r = -0.10), bilirubin and ketones (r = 0.14), protein and bilirubin (r = 0.13), and urobilinogen and pH (r = 0.12). A mild positive correlation was found between leukocytes and blood (r = 0.23), reflecting some association between these inflammation markers. In conclusion, the study identified a significant prevalence of schistosomiasis among school-going children in Nelson Mandela Bay Municipality, with S. haematobium detected through haematuria and S. mansoni identified using the POC-CCA assay. The detection of leukocytes and protein in urine samples serves as critical biomarkers for schistosomiasis infections, reinforcing the presence of schistosomiasis in the study area when considered alongside haematuria. These urine parameters are indicative of inflammatory responses associated with schistosomiasis, underscoring the necessity for effective diagnostic methodologies. Such findings highlight the importance of comprehensive diagnostic assessments to accurately identify and monitor schistosomiasis prevalence and its associated health impacts. The significant burden of schistosomiasis in this population highlights the urgent need to develop targeted control interventions to effectively reduce its prevalence in the study area.

Keywords: schistosomiasis, urinalysis, haematuria, POC-CCA

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Authors: Nadarajah I. Ramesh

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Much of the research on stochastic point process models for rainfall has focused on Poisson cluster models constructed from either the Neyman-Scott or Bartlett-Lewis processes. The doubly stochastic Poisson process provides a rich class of point process models, especially for fine-scale rainfall modelling. This paper provides an account of recent development on this topic and presents the results based on some of the fine-scale rainfall models constructed from this class of stochastic point processes. Amongst the literature on stochastic models for rainfall, greater emphasis has been placed on modelling rainfall data recorded at hourly or daily aggregation levels. Stochastic models for sub-hourly rainfall are equally important, as there is a need to reproduce rainfall time series at fine temporal resolutions in some hydrological applications. For example, the study of climate change impacts on hydrology and water management initiatives requires the availability of data at fine temporal resolutions. One approach to generating such rainfall data relies on the combination of an hourly stochastic rainfall simulator, together with a disaggregator making use of downscaling techniques. Recent work on this topic adopted a different approach by developing specialist stochastic point process models for fine-scale rainfall aimed at generating synthetic precipitation time series directly from the proposed stochastic model. One strand of this approach focused on developing a class of doubly stochastic Poisson process (DSPP) models for fine-scale rainfall to analyse data collected in the form of rainfall bucket tip time series. In this context, the arrival pattern of rain gauge bucket tip times N(t) is viewed as a DSPP whose rate of occurrence varies according to an unobserved finite state irreducible Markov process X(t). Since the likelihood function of this process can be obtained, by conditioning on the underlying Markov process X(t), the models were fitted with maximum likelihood methods. The proposed models were applied directly to the raw data collected by tipping-bucket rain gauges, thus avoiding the need to convert tip-times to rainfall depths prior to fitting the models. One advantage of this approach was that the use of maximum likelihood methods enables a more straightforward estimation of parameter uncertainty and comparison of sub-models of interest. Another strand of this approach employed the DSPP model for the arrivals of rain cells and attached a pulse or a cluster of pulses to each rain cell. Different mechanisms for the pattern of the pulse process were used to construct variants of this model. We present the results of these models when they were fitted to hourly and sub-hourly rainfall data. The results of our analysis suggest that the proposed class of stochastic models is capable of reproducing the fine-scale structure of the rainfall process, and hence provides a useful tool in hydrological modelling.

Keywords: fine-scale rainfall, maximum likelihood, point process, stochastic model

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Authors: Amna Tariq Shah

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Amid the pandemic, the contemporary landscape has experienced accelerated growth in small business activities and an expanding digital marketplace, further exacerbating the issue of non-compliance among self-employed individuals through aggressive tax planning and evasion. This research seeks to address these challenges by developing strategic tax policies that promote voluntary compliance and improve taxpayer facilitation. The study employs the innovative MINDSPACE framework to examine three psychosocial factors—tax communication, tax literacy, and shaming—to optimize policy responses, address administrative shortcomings, and ensure adequate revenue collection for public goods and services. Preliminary findings suggest that incomprehensible communication from tax authorities drives individuals to seek alternative, potentially biased sources of tax information, thereby exacerbating non-compliance. Furthermore, the study reveals low tax literacy among Australian and Pakistani respondents, with many struggling to navigate complex tax processes and comprehend tax laws. Consequently, policy recommendations include simplifying tax return filing and enhancing pre-populated tax returns. In terms of shaming, the research indicates that Australians, being an individualistic society, may not respond well to shaming techniques due to privacy concerns. In contrast, Pakistanis, as a collectivistic society, may be more receptive to naming and shaming approaches. The study employs a mixed-method approach, utilizing interviews and surveys to analyze the issue in both jurisdictions. The use of mixed methods allows for a more comprehensive understanding of tax compliance behavior, combining the depth of qualitative insights with the generalizability of quantitative data, ultimately leading to more robust and well-informed policy recommendations. By examining evidence from opposite jurisdictions, namely a developed country (Australia) and a developing country (Pakistan), the study's applicability is enhanced, providing perspectives from two disparate contexts that offer insights from opposite ends of the economic, cultural, and social spectra. The non-comparative case study methodology offers valuable insights into human behavior, which can be applied to other jurisdictions as well. The application of the MINDSPACE framework in this research is particularly significant, as it introduces a novel approach to tax compliance behavior analysis. By integrating insights from behavioral economics, the framework enables a comprehensive understanding of the psychological and social factors influencing taxpayer decision-making, facilitating the development of targeted and effective policy interventions. This research carries substantial importance as it addresses critical challenges in tax compliance and administration, with far-reaching implications for revenue collection and the provision of public goods and services. By investigating the psychosocial factors that influence taxpayer behavior and utilizing the MINDSPACE framework, the study contributes invaluable insights to the field of tax policy. These insights can inform policymakers and tax administrators in developing more effective tax policies that enhance taxpayer facilitation, address administrative obstacles, promote a more equitable and efficient tax system, and foster voluntary compliance, ultimately strengthening the financial foundation of governments and communities.

Keywords: individual tax compliance behavior, psychosocial factors, tax non-compliance, tax policy

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Authors: Brooklyn Rushton, Michelle Rutty, Natalie Knowles, Daniel Scott

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As people are increasingly on the search for extraordinary experiences and connections with nature, adventure tourism is experiencing significant growth and providing tourists with life-changing experiences. Unlike built attraction-based tourism, adventure tourism relies entirely on natural heritage, which leaves communities dependent on adventure tourism extremely vulnerable to environmental and climatic changes. A growing body of evidence suggests that global climate change will influence the future of adventure tourism and mountain outdoor recreation opportunities on a global scale. Across Canada, more specifically, climate change is broadly anticipated to present risks for winter-snow sports, while opportunities are anticipated to arise for green season activities. These broad seasonal shifts do not account for the indirect impacts of climate change on adventure tourism, such as the cost of adaptation or the increase of natural hazards and the associated likelihood of accidents. While some research has examined the impact of climate change on natural environments that adventure tourism relies on, a very small body of research has specifically focused on guides’ perspectives or included hard adventure tourism activities. The guiding industry is unique, as guides are trained through an elegant blend of art and science to make decisions based on experience, observation, and intuition. While quantitative research can monitor change in natural environments, guides local knowledge can provide eye-witness accounts and outline what environmental changes mean for the future sustainability of adventure tourism. This research will capture the extensive knowledge of mountain guides to better understand the implications of climate change for mountain adventure and potential adaptive responses for the adventure tourism industry. This study uses a structured online survey with open and close-ended questions that will be administered using Qualtrics (an online survey platform). This survey is disseminated to current members of the Association of Canadian Mountain Guides (ACMG). Participation in this study will be exclusive to members of the ACMG operating in the outdoor guiding streams. The 25 survey questions are organized into four sections: demographic and professional operation (9 questions), physical change (4 questions), climate change perception (6 questions), and climate change adaptation (6 questions). How mountain guides perceive and respond to climate change is important knowledge for the future of the expanding adventure tourism industry. Results from this study are expected to provide important information to mountain destinations on climate change vulnerability and adaptive capacity. Expected results of this study include guides insight into: (1) experience-safety relevant observed physical changes in guided regions (i.e. glacial coverage, permafrost coverage, precipitation, temperature, and slope instability) (2) changes in hazards within the guiding environment (i.e. avalanches, rockfall, icefall, forest fires, flooding, and extreme weather events), (3) existing and potential adaptation strategies, and (4) key information and other barriers for adaptation. By gaining insight from the knowledge of mountain guides, this research can help the tourism industry at large understand climate risk and create adaptation strategies to ensure the resiliency of the adventure tourism industry.

Keywords: adventure tourism, climate change, environmental change, mountain hazards

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Authors: Joanna Gerszon, Aleksandra Rodacka

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In the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, protein and peptide aggregation processes play a vital role in contributing to the formation of intracellular and extracellular protein deposits. One of the major components of these deposits is the oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Therefore, the purpose of this research was to answer the question whether piceatannol, a stilbene derivative, counteracts and/or slows down oxidative stress-induced GAPDH aggregation. The study also aimed to determine if this natural occurring compound prevents unfavorable nuclear translocation of GAPDH in hippocampal cells. The isothermal titration calorimetry (ITC) analysis indicated that one molecule of GAPDH can bind up to 8 molecules of piceatannol (7.3 ± 0.9). As a consequence of piceatannol binding to the enzyme, the loss of activity was observed. Parallel with GAPDH inactivation the changes in zeta potential, and loss of free thiol groups were noted. Nevertheless, the ligand-protein binding does not influence the secondary structure of the GAPDH. Precise molecular docking analysis of the interactions inside the active center allowed to presume that these effects are due to piceatannol ability to assemble a covalent binding with nucleophilic cysteine residue (Cys149) which is directly involved in the catalytic reaction. Molecular docking also showed that simultaneously 11 molecules of ligand can be bound to dehydrogenase. Taking into consideration obtained data, the influence of piceatannol on level of GAPDH aggregation induced by excessive oxidative stress was examined. The applied methods (thioflavin-T binding-dependent fluorescence as well as microscopy methods - transmission electron microscopy, Congo Red staining) revealed that piceatannol significantly diminishes level of GAPDH aggregation. Finally, studies involving cellular model (Western blot analyses of nuclear and cytosolic fractions and confocal microscopy) indicated that piceatannol-GAPDH binding prevents GAPDH from nuclear translocation induced by excessive oxidative stress in hippocampal cells. In consequence, it counteracts cell apoptosis. These studies demonstrate that by binding with GAPDH, piceatannol blocks cysteine residue and counteracts its oxidative modifications, that induce oligomerization and GAPDH aggregation as well as it prevents hippocampal cells from apoptosis by retaining GAPDH in the cytoplasm. All these findings provide a new insight into the role of piceatannol interaction with GAPDH and present a potential therapeutic strategy for some neurological disorders related to GAPDH aggregation. This work was supported by the by National Science Centre, Poland (grant number 2017/25/N/NZ1/02849).

Keywords: glyceraldehyde-3-phosphate dehydrogenase, neurodegenerative disease, neuroprotection, piceatannol, protein aggregation

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Authors: Ching Shya Lee, Mohamed Kheireddine Aroua, Wan Mohd Ashri Wan Daud, Patrick Cognet, Yolande Peres, Mohammed Ajeel

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In recent years, with the decreasing supply of fossil fuel, renewable energy has received a significant demand. Biodiesel which is well known as vegetable oil based fatty acid methyl ester is an alternative fuel for diesel. It can be produced from transesterification of vegetable oils, such as palm oil, sunflower oil, rapeseed oil, etc., with methanol. During the transesterification process, crude glycerol is formed as a by-product, resulting in 10% wt of the total biodiesel production. To date, due to the fast growing of biodiesel production in worldwide, the crude glycerol supply has also increased rapidly and resulted in a significant price drop for glycerol. Therefore, extensive research has been developed to use glycerol as feedstock to produce various added-value chemicals, such as tartronic acid, mesoxalic acid, glycolic acid, glyceric acid, propanediol, acrolein etc. The industrial processes that usually involved are selective oxidation, biofermentation, esterification, and hydrolysis. However, the conversion of glycerol into added-value compounds by electrochemical approach is rarely discussed. Currently, the approach is mainly focused on the electro-oxidation study of glycerol under potentiostatic mode for cogenerating energy with other chemicals. The electro-organic synthesis study from glycerol under galvanostatic mode is seldom reviewed. In this study, the glycerol was converted into various added-value compounds by electrochemical method under galvanostatic mode. This work aimed to study the possible compounds produced from glycerol by electrochemical technique in a one-pot electrolysis cell. The electro-organic synthesis study from glycerol was carried out in a single compartment reactor for 8 hours, over the platinum cathode and anode electrodes under acidic condition. Various parameters such as electric current (1.0 A to 3.0 A) and reaction temperature (27 °C to 80 °C) were evaluated. The products obtained were characterized by using gas chromatography-mass spectroscopy equipped with an aqueous-stable polyethylene glycol stationary phase column. Under the optimized reaction condition, the glycerol conversion achieved as high as 95%. The glycerol was successfully converted into various added-value chemicals such as ethylene glycol, glycolic acid, glyceric acid, acetaldehyde, formic acid, and glyceraldehyde; given the yield of 1%, 45%, 27%, 4%, 0.7% and 5%, respectively. Based on the products obtained from this study, the reaction mechanism of this process is proposed. In conclusion, this study has successfully converted glycerol into a wide variety of added-value compounds. These chemicals are found to have high market value; they can be used in the pharmaceutical, food and cosmetic industries. This study effectively opens a new approach for the electrochemical conversion of glycerol. For further enhancement on the product selectivity, electrode material is an important parameter to be considered.

Keywords: biodiesel, glycerol, electrochemical conversion, galvanostatic mode

Procedia PDF Downloads 194

Authors: S. A. Bhat, Ahmad Arif, Muneeb U. Rehman, Manzoor R Mir, S. Bilal, Ishraq Hussain, H. M Khan, S. Shanaz, M. I Mir, Sabhiya Majid

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Background: Geologically Climatic conditions of the state range from sub-tropical (Jammu), temperate (Kashmir) to cold artic (Ladakh) zones, which exerts significant influence on its agro-climatic conditions. Gastrointestinal parasitism is a major problem in sheep production worldwide. Materials and Methods: The present study was to evaluate the resistance status of sheep breeds reared in Kashmir Valley for natural resistance against Haemonchus contortus by natural pasture challenge infection. Ten microsatellite markers were used in the study for evaluation of association of Ovar-MHC with parasitic resistance in association with biochemical and parasitological parameters. Following deworming, 500 animals were subjected to selected contaminated pastures in a vicinity of the livestock farms of SKUAST-K and Sheep Husbandry Kashmir. For each animal about 10-15 ml blood was collected aseptically for molecular and biochemical analysis. Weekly fecal samples (3g) were taken, directly from the rectum of all experimental animals and examined for Fecal egg count (FEC) with modified McMaster technique. Packed cell volume (PCV) was determined within 2-5 h of blood collection, all the biochemical parameters were determined in serum by semi automated analyzer. DNA was extracted from all the blood samples with phenol-chloroform method. Microsatellite analysis was done by denaturing sequencing gel electrophoresis Results: Overall sheep from Bakerwal breed followed by Corriediale breed performed relatively better in the trial; however difference between breeds remained low. Both significant (P<0.05) and non-significant differences with respect to resistance against haemonchosis were noted at different intervals in all the parameters.. All the animals were typed for the microsatellites INRA132, OarCP73, DRB1 (U0022), OLA-DQA2, BM1818, TFAP2A, HH56, BM1815, IL-3 and BM-1258. An association study including the effect of FEC, PCV, TSP, SA, LW, and the number of alleles within each marker was done. All microsatellite markers showed degree of heterozygosity of 0.72, 0.72, 0.75, 0.62, 0.84, 0.69, 0.66, 0.65, 0.73 and 0.68 respectively. Significant association between alleles and the parameters measured were only found for the OarCP73, OLA-DQA2 and BM1815 microsatellite marker. Standard alleles of the above markers showed significant effect on the TP, SA and body weight. The three sheep breeds included in the study responded differently to the nematode infection, which may be attributed to their differences in their natural resistance against nematodes. Conclusion: Our data confirms that some markers (OarCP73, OLA-DQA2 and BM1815) within Ovar-MHC are associated with phenotypic parameters of resistance and suggest superiority of Bakerwal sheep breed in natural resistance against Haemonchus contortus.

Keywords: Ovar-Mhc, ovine leukocyte antigen (OLA), sheep, parasitic resistance, Haemonchus contortus, phenotypic & genotypic markers

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Authors: Ayten Ekin Meşe, Selahattin Şentürk, Melike Duvanoğlu

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Petroleum refineries are a highly complex process industry with continuous production and high operating costs. Physical separation of crude oil starts with the crude oil distillation unit, continues with various conversion and purification units, and passes through many stages until obtaining the final product. To meet the desired product specification, process parameters are strictly followed. To be able to ensure the quality of distillates, routine analyses are performed in quality control laboratories based on appropriate international standards such as American Society for Testing and Materials (ASTM) standard methods and European Standard (EN) methods. The cut point of distillates in the crude distillation unit is very crucial for the efficiency of the upcoming processes. In order to maximize the process efficiency, the determination of the quality of distillates should be as fast as possible, reliable, and cost-effective. In this sense, an alternative study was carried out on the crude oil distillation unit that serves the entire refinery process. In this work, studies were conducted with three different crude oil distillates which are Light Straight Run Naphtha (LSRN), Heavy Straight Run Naphtha (HSRN), and Kerosene. These products are named after separation by the number of carbons it contains. LSRN consists of five to six carbon-containing hydrocarbons, HSRN consist of six to ten, and kerosene consists of sixteen to twenty-two carbon-containing hydrocarbons. Physical properties of three different crude distillation unit products (LSRN, HSRN, and Kerosene) were determined using Near-Infrared Spectroscopy with multivariate calibration. The absorbance spectra of the petroleum samples were obtained in the range from 10000 cm⁻¹ to 4000 cm⁻¹, employing a quartz transmittance flow through cell with a 2 mm light path and a resolution of 2 cm⁻¹. A total of 400 samples were collected for each petroleum sample for almost four years. Several different crude oil grades were processed during sample collection times. Extended Multiplicative Signal Correction (EMSC) and Savitzky-Golay (SG) preprocessing techniques were applied to FT-NIR spectra of samples to eliminate baseline shifts and suppress unwanted variation. Two different multivariate calibration approaches (Partial Least Squares Regression, PLS and Genetic Inverse Least Squares, GILS) and an ensemble model were applied to preprocessed FT-NIR spectra. Predictive performance of each multivariate calibration technique and preprocessing techniques were compared, and the best models were chosen according to the reproducibility of ASTM reference methods. This work demonstrates the developed models can be used for routine analysis instead of conventional analytical methods with over 90% accuracy.

Keywords: crude distillation unit, multivariate calibration, near infrared spectroscopy, data preprocessing, refinery

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Authors: Seyed Mehdi Seyed Alizadeh, Christoph Arns, Shane Latham

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Geomechanical characterization of rocks in detail and its possible implications on flow properties is an important aspect of reservoir characterization workflow. In order to gain more understanding of the microstructure evolution of reservoir rocks under stress a series of axisymmetric triaxial tests were performed on two different analogue rock samples. In-situ compression tests were coupled with high resolution micro-Computed Tomography to elucidate the changes in the pore/grain network of the rocks under pressurized conditions. Two outcrop sandstones were chosen in the current study representing a various cementation status of well-consolidated and weakly-consolidated granular system respectively. High resolution images were acquired while the rocks deformed in a purpose-built compression cell. A detailed analysis of the 3D images in each series of step-wise compression tests (up to the failure point) was conducted which includes the registration of the deformed specimen images with the reference pristine dry rock image. Digital Image Correlation (DIC) technique based on the intensity of the registered 3D subsets and particle tracking are utilized to map the displacement fields in each sample. The results suggest the complex architecture of the localized shear zone in well-cemented Bentheimer sandstone whereas for the weakly-consolidated Castlegate sandstone no discernible shear band could be observed even after macroscopic failure. Post-mortem imaging a sister plug from the friable rock upon undergoing continuous compression reveals signs of a shear band pattern. This suggests that for friable sandstones at small scales loading mode may affect the pattern of deformation. Prior to mechanical failure, the continuum digital image correlation approach can reasonably capture the kinematics of deformation. As failure occurs, however, discrete image correlation (i.e. particle tracking) reveals superiority in both tracking the grains as well as quantifying their kinematics (in terms of translations/rotations) with respect to any stage of compaction. An attempt was made to quantify the displacement field in compression using continuum Digital Image Correlation which is based on the reference and secondary image intensity correlation. Such approach has only been previously applied to unconsolidated granular systems under pressure. We are applying this technique to sandstones with various degrees of consolidation. Such element of novelty will set the results of this study apart from previous attempts to characterize the deformation pattern in consolidated sands.

Keywords: deformation mechanism, displacement field, shear behavior, triaxial compression, X-ray micro-CT

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Authors: Tomasz Borowski, Dawid Sołoducha, Agata Markowska-Szczupak, Aneta Wesołowska, Marian Kordas, Rafał Rakoczy

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Essential oils (EOs) are fragrant volatile oils obtained from plants. These are used for cooking (for flavor and aroma), cleaning, beauty (e.g., rosemary essential oil is used to promote hair growth), health (e.g. thyme essential oil cures arthritis, normalizes blood pressure, reduces stress on the heart, cures chest infection and cough) and in the food industry as preservatives and antioxidants. Rosemary and thyme essential oils are considered the most eminent herbs based on their history and medicinal properties. They possess a wide range of activity against different types of bacteria and fungi compared with the other oils in both in vitro and in vivo studies. However, traditional uses of EOs are limited due to rosemary and thyme oils in high concentrations can be toxic. In light of the accessible data, the following hypothesis was put forward: Low frequency rotating magnetic field (RMF) increases the antimicrobial potential of EOs. The aim of this work was to investigate the antimicrobial activity of commercial Salvia Rosmarinus L. and Thymus vulgaris L. essential oil from Polish company Avicenna-Oil under Rotating Magnetic Field (RMF) at f = 25 Hz. The self-constructed reactor (MAP) was applied for this study. The chemical composition of oils was determined by gas chromatography coupled with mass spectrometry (GC-MS). Model bacteria Escherichia coli K12 (ATCC 25922) was used. Minimum inhibitory concentrations (MIC) against E. coli were determined for the essential oils. Tested oils in very small concentrations were prepared (from 1 to 3 drops of essential oils per 3 mL working suspensions). From the results of disc diffusion assay and MIC tests, it can be concluded that thyme oil had the highest antibacterial activity against E. coli. Moreover, the study indicates the exposition to the RMF, as compared to the unexposed controls causing an increase in the efficacy of antibacterial properties of tested oils. The extended radiation exposure to RMF at the frequency f= 25 Hz beyond 160 minutes resulted in a significant increase in antibacterial potential against E. coli. Bacteria were killed within 40 minutes in thyme oil in lower tested concentration (1 drop of essential oils per 3 mL working suspension). Rapid decrease (>3 log) of bacteria number was observed with rosemary oil within 100 minutes (in concentration 3 drops of essential oils per 3 mL working suspension). Thus, a method for improving the antimicrobial performance of essential oil in low concentrations was developed. However, it still remains to be investigated how bacteria get killed by the EOs treated by an electromagnetic field. The possible mechanisms relies on alteration in the permeability of ionic channels in ionic channels in the bacterial cell walls that transport in the cells was proposed. For further studies, it is proposed to examine other types of essential oils and other antibiotic-resistant bacteria (ARB), which are causing a serious concern throughout the world.

Keywords: rotating magnetic field, rosemary, thyme, essential oils, Escherichia coli

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Authors: Jeanne Leblond, Warren Viricel, Amira Mbarek

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Although several products have reached the market, gene therapeutics are still in their first stages and require optimization. It is possible to improve their lacking efficiency by the use of carefully engineered vectors, able to carry the genetic material through each of the biological barriers they need to cross. In particular, getting inside the cell is a major challenge, because these hydrophilic nucleic acids have to cross the lipid-rich plasmatic and/or endosomal membrane, before being degraded into lysosomes. It takes less than one hour for newly endocytosed liposomes to reach highly acidic lysosomes, meaning that the degradation of the carried gene occurs rapidly, thus limiting the transfection efficiency. We propose to use a new pH-sensitive lipid able to change its conformation upon protonation at endosomal pH values, leading to the disruption of the lipidic bilayer and thus to the fast release of the nucleic acids into the cytosol. It is expected that this new pH-sensitive mechanism promote endosomal escape of the gene, thereby its transfection efficiency. The main challenge of this work was to design a preparation presenting fast-responding lipidic bilayer destabilization properties at endosomal pH 5 while remaining stable at blood pH value and during storage. A series of pH-sensitive lipids able to perform a conformational switch upon acidification were designed and synthesized. Liposomes containing these switchable lipids, as well as co-lipids were prepared and characterized. The liposomes were stable at 4°C and pH 7.4 for several months. Incubation with siRNA led to the full entrapment of nucleic acids as soon as the positive/negative charge ratio was superior to 2. The best liposomal formulation demonstrated a silencing efficiency up to 10% on HeLa cells, very similar to a commercial agent, with a lowest toxicity than the commercial agent. Using flow cytometry and microscopy assays, we demonstrated that drop of pH was required for the transfection efficiency, since bafilomycin blocked the transfection efficiency. Additional evidence was brought by the synthesis of a negative control lipid, which was unable to switch its conformation, and consequently exhibited no transfection ability. Mechanistic studies revealed that the uptake was mediated through endocytosis, by clathrin and caveolae pathways, as reported for previous lipid nanoparticle systems. This potent system was used for the treatment of hypercholesterolemia. The switchable lipids were able to knockdown PCSK9 expression on human hepatocytes (Huh-7). Its efficiency is currently evaluated on in vivo mice model of PCSK9 KO mice. In summary, we designed and optimized a new cationic pH-sensitive lipid for gene delivery. Its transfection efficiency is similar to the best available commercial agent, without the usually associated toxicity. The promising results lead to its use for the treatment of hypercholesterolemia on a mice model. Anticancer applications and pulmonary chronic disease are also currently investigated.

Keywords: liposomes, siRNA, pH-sensitive, molecular switch

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Authors: Aryati Yashadhana, Ted Fields Jnr., Wendy Fernando, Kelvin Brown, Godfrey Blitner, Francis Hayes, Ruby Stanley, Brian Donnelly, Bridgette Jerrard, Anthea Burnett, Anthony B. Zwi

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Indigenous Australians experience some of the worst health outcomes globally, with life expectancy being significantly poorer than those of non-Indigenous Australians. This is largely attributed to preventable diseases such as diabetes (prevalence 39% in Indigenous Australian adults > 55 years), which is attributed to a raised risk of diabetic visual impairment and cataract among Indigenous adults. Our study aims to explore the interface between structural and sociocultural determinants and human agency, in order to understand how they impact (1) accessibility of eye health and chronic disease services and (2) the potential for Indigenous patients to achieve positive clinical eye health outcomes. We used Participatory Action Research methods, and aimed to privilege the voices of Indigenous people through community collaboration. Semi-structured interviews (n=82) and patient focus groups (n=8) were conducted by Indigenous Community-Based Researchers (CBRs) with diabetic Indigenous adults (> 40 years) in four remote communities in Australia. Interviews (n=25) and focus groups (n=4) with primary health care clinicians in each community were also conducted. Data were audio recorded, transcribed verbatim, and analysed thematically using grounded theory, comparative analysis and Nvivo 10. Preliminary analysis occurred in tandem with data collection to determine theoretical saturation. The principal investigator (AY) led analysis sessions with CBRs, fostering cultural and contextual appropriateness to interpreting responses, knowledge exchange and capacity building. Identified themes were conceptualised into three spheres of influence: structural (health services, government), sociocultural (Indigenous cultural values, distrust of the health system, ongoing effects of colonialism and dispossession) and individual (health beliefs/perceptions, patient phenomenology). Permeating these spheres of influence were three core determinants: economic disadvantage, health literacy/education, and cultural marginalisation. These core determinants affected accessibility of services, and the potential for patients to achieve positive clinical outcomes at every level of care (primary, secondary, tertiary). Our findings highlight the clinical realities of institutionalised and structural inequities, illustrated through the lived experiences of Indigenous patients and primary care clinicians in the four sampled communities. The complex determinants surrounding inequity in health for Indigenous Australians, are entrenched through a longstanding experience of cultural discrimination and ostracism. Secure and long term funding of Aboriginal Community Controlled Health Services will be valuable, but are insufficient to address issues of inequity. Rather, working collaboratively with communities to build trust, and identify needs and solutions at the grassroots level, while leveraging community voices to drive change at the systemic/policy level are recommended.

Keywords: indigenous, Australia, culture, public health, eye health, diabetes, social determinants of health, sociology, anthropology, health equity, aboriginal and Torres strait islander, primary care

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Authors: Ran Goldblatt, Nicholas Jones, Jennifer Mannix, Brad Bottoms

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Accurate, complete, and up-to-date geospatial information is the foundation of successful disaster management. When the 2010 Haiti Earthquake struck, accurate and timely information on the distribution of critical infrastructure was essential for the disaster response community for effective search and rescue operations. Existing geospatial datasets such as Google Maps did not have comprehensive coverage of these features. In the days following the earthquake, many organizations released high-resolution satellite imagery, catalyzing a worldwide effort to map Haiti and support the recovery operations. Of these organizations, OpenStreetMap (OSM), a collaborative project to create a free editable map of the world, used the imagery to support volunteers to digitize roads, buildings, and other features, creating the most detailed map of Haiti in existence in just a few weeks. However, large portions of the island are still not fully covered by OSM. There is an increasing need for a tool to automatically identify which areas in Haiti, as well as in other countries vulnerable to disasters, that are not fully mapped. The objective of this project is to leverage different types of remote sensing measurements, together with machine learning approaches, in order to identify geographical areas where OSM coverage of building footprints is incomplete. Several remote sensing measures and derived products were assessed as potential predictors of OSM building footprints coverage, including: intensity of light emitted at night (based on VIIRS measurements), spectral indices derived from Sentinel-2 satellite (normalized difference vegetation index (NDVI), normalized difference built-up index (NDBI), soil-adjusted vegetation index (SAVI), urban index (UI)), surface texture (based on Sentinel-1 SAR measurements)), elevation and slope. Additional remote sensing derived products, such as Hansen Global Forest Change, DLR`s Global Urban Footprint (GUF), and World Settlement Footprint (WSF), were also evaluated as predictors, as well as OSM street and road network (including junctions). Using a supervised classification with a random forest classifier resulted in the prediction of 89% of the variation of OSM building footprint area in a given cell. These predictions allowed for the identification of cells that are predicted to be covered but are actually not mapped yet. With these results, this methodology could be adapted to any location to assist with preparing for future disastrous events and assure that essential geospatial information is available to support the response and recovery efforts during and following major disasters.

Keywords: disaster management, Haiti, machine learning, OpenStreetMap, remote sensing

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Authors: Ikele Chika Bright, Mgbenka Bernard Obialo, Ikele Chioma Faith

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Icthyophthiriasis is a prevalent protozoan (ectoparasite) mostly affecting cultured and aquarium fishes. The majority of the chemotherapeutants lack efficacy for completely eliminating Ich parasite without affecting the environment and they are not safe for human health. The present work is focused on the evaluating different immersion treatments of African catfish (Clarias gariepinus) infected with ichthyophthiriasis and treated with a non-chemical and environmental friendly parasiticides Moringa oleifera. A total number of 800 apparently healthy parasites free (examined) post juvenile catfish were obtained from a reputable farm, disinfected with potassium permanganate in a quarantine tank to remove any possible external parasites. The fish were further challenged with approximately 44,000 infective stages of theronts which were obtained through serial passages by cohabitation. Seven groups (A-G) of post Juvenile were used for the experiment which was carried out into three stages; Dips (60minutes), short term treatment (24-96h) and prolong bath treatment (0-15 days). The concentrations selected were dependent on the outcome of the LC50 of the plant material from which dose-dependent factors were used to select various concentrations of the treatment. In Dips treatment, group D-G were treated with 1,500mg/L, 2500mg/L., 3500mg/L and 4500mg/L, short-term treatment was treated with 150mg/L, 250mg/L, 350mg/L and 450mg/L and prolong bath was treated with 15mg/L, 25mg/L, 35mg/L and 45mg/L of the plant extract whereas group A, B and C were normal control, Ich- infested not treated and Ich- infested treated with standard drug (Acriflavin), respectively. The various types of treatment applied with corresponding concentrations showed almost complete elimination of the adult parasites (trophonts) both in the gills and the body smear, thereby making M. oleifera a potential parasiticides. There were serious pathological alterations in the skin and gills which are usually the main point for Ich parasites invasion but no significant morphological characteristics was noted among the treated groups subjected to different immersion treatment patterns. Epitheliocystis, aneurysm, oedema, hemorrhage, and localization of the adult parasite in the gills were the overall common observations made in the gills whereas degeneration of muscle fibre, dermatitis, hemorrhage, oedema, abscess formation and keratinisation were observed in the skin. However, there are no pathological changes in the control group. Moreover, biochemical parameters such as urea, creatinine, albumin., globulin, total protein, ALT, AST), blood chemistry (sodium, chloride, potassium, bicarbonate), antioxidants (CAT, SOD, GPx, LPO), enzymatic activities (myeloperoxidase, thioreadoxin reductase), Inflammatory response (C-reactive protein), Stress markers (lactate dehydrogenase), heamatological parameters (RBC, PCV, WBC, HB and differential count), lipid profile (total cholesterol, tryglycerides , high density lipoprotein and low density lipoprotein) all showed various significant (P<0.05) and no significant (P>0.05) responses among the Ich-infested fish treated under three immersion treatments. It is suggested that M. oleifera may serve as an alternatives to chemotherapeutants for control of Ichthyophthiriasis in African catfish Clarias gariepinus.

Keywords: Icthyophthirius multifilis, immersion treatment, pathophysiology, African catfish

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Authors: Paula I. Buonfiglio, Carlos David Bruque, Lucia Salatino, Vanesa Lotersztein, Sebastián Menazzi, Paola Plazas, Ana Belén Elgoyhen, Viviana Dalamón

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Hearing loss (HL) is the most prevalent sensorineural disorder affecting about 10% of the global population, with more than half due to genetic causes. About 1 in 500-1000 newborns present congenital HL. Most of the patients are non-syndromic with an autosomal recessive mode of inheritance. To date, more than 100 genes are related to HL. Therefore, the Whole-exome sequencing (WES) technique has become a cost-effective alternative approach for molecular diagnosis. Nevertheless, new challenges arise from the detection of novel variants, in particular missense changes, which can lead to a spectrum of genotype-to-phenotype correlations, which is not always straightforward. In this work, we aimed to identify the genetic causes of HL in isolated and familial cases by designing a multistep approach to analyze target genes related to hearing impairment. Moreover, we performed in silico and in vivo analyses in order to further study the effect of some of the novel variants identified in the hair cell function using the zebrafish model. A total of 650 patients were studied by Sanger Sequencing and Gap-PCR in GJB2 and GJB6 genes, respectively, diagnosing 15.5% of sporadic cases and 36% of familial ones. Overall, 50 different sequence variants were detected. Fifty of the undiagnosed patients with moderate HL were tested for deletions in STRC gene by Multiplex ligation-dependent probe amplification technique (MLPA), leading to 6% of diagnosis. After this initial screening, 50 families were selected to be analyzed by WES, achieving diagnosis in 44% of them. Half of the identified variants were novel. A missense variant in MYO6 gene detected in a family with postlingual HL was selected to be further analyzed. A protein modeling with AlphaFold2 software was performed, proving its pathogenic effect. In order to functionally validate this novel variant, a knockdown phenotype rescue assay in zebrafish was carried out. Injection of wild-type MYO6 mRNA in embryos rescued the phenotype, whereas using the mutant MYO6 mRNA (carrying c.2782C>A variant) had no effect. These results strongly suggest the deleterious effect of this variant on the mobility of stereocilia in zebrafish neuromasts, and hence on the auditory system. In the present work, we demonstrated that our algorithm is suitable for the sequential multigenic approach to HL in our cohort. These results highlight the importance of a combined strategy in order to identify candidate variants as well as the in silico and in vivo studies to analyze and prove their pathogenicity and accomplish a better understanding of the mechanisms underlying the physiopathology of the hearing impairment.

Keywords: diagnosis, genetics, hearing loss, in silico analysis, in vivo analysis, WES, zebrafish

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