Search results for: targeted covalent inhibitors (TCI)

Authors: Rashi Rajput, Manisha Singh

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Escitalopram oxalate (ETP), an FDA approved antidepressant drug from the category of SSRI (selective serotonin reuptake inhibitor) and is used in treatment of general anxiety disorder (GAD), major depressive disorder (MDD).When taken orally, it is metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT) in the liver with the help of enzymes CYP2C19, CYP3A4 and CYP2D6. Hence, causing side effects such as dizziness, fast or irregular heartbeat, headache, nausea etc. Therefore, targeted and sustained drug delivery will be a helpful tool for increasing its efficacy and reducing side effects. The present study is designed for formulating mucoadhesive nanoparticle formulation for the same Escitalopram loaded polymeric nanoparticles were prepared by ionic gelation method and characterization of the optimised formulation was done by zeta average particle size (93.63nm), zeta potential (-1.89mV), TEM (range of 60nm to 115nm) analysis also confirms nanometric size range of the drug loaded nanoparticles along with polydispersibility index of 0.117. In this research, we have studied the in vitro drug release profile for ETP nanoparticles, through a semi permeable dialysis membrane. The three important characteristics affecting the drug release behaviour were – particle size, ionic strength and morphology of the optimised nanoparticles. The data showed that on increasing the particle size of the drug loaded nanoparticles, the initial burst was reduced which was comparatively higher in drug. Whereas, the formulation with 1mg/ml chitosan in 1.5mg/ml tripolyphosphate solution showed steady release over the entire period of drug release. Then this data was further validated through mathematical modelling to establish the mechanism of drug release kinetics, which showed a typical linear diffusion profile in optimised ETP loaded nanoparticles.

Keywords: ionic gelation, mucoadhesive nanoparticle, semi-permeable dialysis membrane, zeta potential

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Authors: Mashael AlSalem

Abstract:

While research into language assessment has expanded in recent years, few if any studies to date have targeted the nature of thought processes used by teachers when constructing classroom-based assessment. This study reports on teachers’ conceptions of English grammar assessment and their classroom assessment practices in their Saudi higher educational facilities. A mixed-method approach using both qualitative and quantitative research instruments was employed to elicit teachers’ perceptions of English grammar assessment and their relationship to their current practices. Participants of the study included EFL teachers from 4 different educational facilities: King Saudi University, Princess Noura University, Imam Mouhamed Islamic University, and Institute of Public Administration. Data collection involved questionnaire (N=100), semi-structured interviews (N=30), retrospective thinking (N=20), and document analysis (N=20). Activity theory is used as an interpretive framework to explore and investigate the entire system of constructing classroom-based assessment. Preliminary findings reveal several similarities and differences between the participants’ stated beliefs and their current practices of assessing English grammar. Findings also showed that teacher participant’s beliefs about how English grammar should be assessed are influenced mostly by prior learning experience as well as their teaching instruction practices. Their practices, on the other hand, was more guided by educational policies and lack of teacher training in the field of assessment, among other factors. This research makes a significant contribution to knowledge in three different areas: it enriches the literature on language teacher cognition; it builds on the body of research on language classroom assessment, and it expands on the possibilities to use AC to investigate the relationship between teachers’ beliefs and practices.

Keywords: activity theory, classroom-based assessment, language teacher cognition, mixed method approach

Procedia PDF Downloads 128

Authors: Yaxin Bi, Peter Nicholl

Abstract:

The rapid advancement of Information and communication technologies (ICT) is extremely influencing every aspect of Higher Education. It has transformed traditional teaching, learning, assessment and feedback into a new era of Digital Education. This also introduces many challenges in capturing and understanding student engagement with their studies in Higher Education. The School of Computing at Ulster University has developed a Feedback And Notification (FAN) Online tool that has been used to send students links to personalized feedback on their submitted assessments and record students’ frequency of review of the shared feedback as well as the speed of collection. The feedback that the students initially receive is via a personal email directing them through to the feedback via a URL link that maps to the feedback created by the academic marker. This feedback is typically a Word or PDF report including comments and the final mark for the work submitted approximately three weeks before. When the student clicks on the link, the student’s personal feedback is viewable in the browser and they can view the contents. The FAN tool provides the academic marker with a report that includes when and how often a student viewed the feedback via the link. This paper presents an investigation into student engagement through analyzing the interaction timestamps and frequency of review by the student. We have proposed an approach to modeling interaction timestamps and use sentiment classification techniques to analyze the data collected over the last five years for a set of modules. The data studied is across a number of final years and second-year modules in the School of Computing. The paper presents the details of quantitative analysis methods and describes further their interactions with the feedback overtime on each module studied. We have projected the students into different groups of engagement based on sentiment analysis results and then provide a suggestion of early targeted intervention for the set of students seen to be under-performing via our proposed model.

Keywords: feedback, engagement, interaction modelling, sentiment analysis

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Authors: Ana Maria Girotti Sperandio, Jussara Conceição Guarnieri, Lauro Luiz Francisco Filho, Ana Claudia Martins Alves, Adriana Aparecida Carneiro Rosa

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The urban planning of a city should contemplate the construction of healthy spaces to provide quality of life for people. In a Brazilian municipality located 180 km from the capital of São Paulo with around 27,000 thousand inhabitants, the federal government made possible a program that allows the improvement of the quality of life of the inhabitants through the practice of physical activity. To describe health promotion strategies in the city that collaborate in the reduction of chronic non-communicable diseases (CDNT) and the improvement the quality of its residents. Considering the CDNT as a fundamental public health concern in different countries, the methodology of this work considered the different actions of health promotion that occurred in the city for the implementation of the Polo Health Academy with the objective of increasing the population's access to places that could develop targeted physical activities. As an instrument, it used records of participants of this academy such as: assessment sheets, evolution, photos, filming and daily reports of physical activities. Results: The implantation and implementation process of the Polo Health Academy in the city of Conchal / SP / Brazil was in accordance with the principles and values of the National Health Promotion Policy (PNaPS) in Brazil and with the city statute, that provides improvement in the quality of life of the Brazilian population. An increase was observed in the number of participants in different hours practicing physical activities in the territory linked to one of the five Health Units, showing the program provides that happiness and well-being to the students. The Brazilian health promotion policy, combined with the city’s development policy, provides the population with access to programs that stimulate the reduction of CDNTs, confirming the urban planning of a healthy city.

Keywords: health city, health promotion, physical activity, urban planning

Procedia PDF Downloads 190

Authors: Göksel Doğan, Murat Öztürk, Didar Tuğçe Karakulak, Mehmet Nurullah Orman, Nicolas Sylvius, Matthew Blades, Mustafa Sandıkçı, Cengiz Ünsal, Mehtap Kılıç Eren, Funda Kıral, Levent Karagenç

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Assisted reproduction is associated with impaired glucose metabolism in adulthood. miRNAs are key regulators of glucose metabolism. Whether embryo culture and/or transfer alters the expression of miRNAs and to what extent this process affects glucose metabolism remain largely unknown. The purpose of the present study was to examine the expression of miRNAs in the liver in mice obtained by the transfer of blastocysts. The study was comprised of an experimental (EG) and a control group (CG). EG was generated by embryo transfer to pseudo-pregnant females. Mice born from naturally ovulating females were used as the CG. Differential expression of miRNAs, blood glucose, plasma insulin, liver glycogen, and activities of some of the rate-limiting enzymes involved in glucose metabolism were determined at ten weeks of age. Blood glucose, plasma insulin, and glycogen concentrations were similar between the groups in both sexes. Activities of enzymes were similar among females. EG males had significantly less glucokinase and phosphofructokinase activity compared to CG males. None of the miRNAs were differentially expressed in males. On the other hand, miR-143-3p expression was upregulated in EG females. Expression of none of the genes targeted by miR143-3p differed between the groups. These results demonstrate that miR143-3p, a novel regulator of type 2 diabetes, is upregulated in mice generated by assisted reproduction in a sexually-dimorphic manner with no apparent effect on glucose and insulin levels at ten weeks of age. It remains to be determined if this process is associated with impaired glucose homeostasis in the long term.

Keywords: assisted reproduction, blastocyst, embryo culture, glucose metabolism, miR143-3p, oxygen

Procedia PDF Downloads 178

Authors: Jacob Seddlemeyer, Tahar Messadi, Hongmei Gu, Mahboobeh Hemmati

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The main purpose of this first tier of the study is to quantify and compare the embodied environmental impacts associated with alternative materials applied to Adohi Hall, a residence building at the University of Arkansas campus, Fayetteville, AR. This 200,000square foot building has5 stories builtwith mass timber and is compared to another scenario where the same edifice is built with a steel frame. Based on the defined goal and scope of the project, the materials respectivetothe respective to the two building options are compared in terms of Global Warming Potential (GWP), starting from cradle to the construction site, which includes the material manufacturing stage (raw material extract, process, supply, transport, and manufacture) plus transportation to the site (module A1-A4, based on standard EN 15804 definition). The consumedfossil fuels and emitted CO2 associated with the buildings are the major reason for the environmental impacts of climate change. In this study, GWP is primarily assessed to the exclusion of other environmental factors. The second tier of this work is to evaluate Tally’s performance in the decision-making process through the design phases, as well as determine its strengths and weaknesses. Tally is a Life Cycle Assessment (LCA) tool capable of conducting a cradle-to-grave analysis. As opposed to other software applications, Tally is specifically targeted at buildings LCA. As a peripheral application, this software tool is directly run within the core modeling application platform called Revit. This unique functionality causes Tally to stand out from other similar tools in the building sector LCA analysis. The results of this study also provide insights for making more environmentally efficient decisions in the building environment and help in the move forward to reduce Green House Gases (GHGs) emissions and GWP mitigation.

Keywords: comparison, GWP, LCA, materials, tally

Procedia PDF Downloads 223

Authors: Tina Sleiman

Abstract:

In the early 1970s, a graphics revolution - in quantity and quality - marked the youth publications sector in France. The increased interest in youth publications was supported with the emergence of youth libraries and major publishing houses. In parallel, the 'Agence de Cooperation Culturelle et Technique' (currently the International Organization of the Francophonie) was created, and several Arab countries had joined as members. In spite of political turmoil in the Middle East, French schools in Arab countries were still functioning and some even flourishing. This is a testament that French culture was, and still is, a major export to the region. This study focuses on the aesthetic value of the graphic styles that characterize French children’s books from the 1970s, and their personal value to Francophone people who have consumed these artifacts, in the Middle East. The first part of the study looks at the artifact itself: starting from the context of creation and consumption of these books, and continuing to the preservation and remaining collections. The aesthetic value is studied and compared to similar types of visuals of juxtaposed time periods. The second part examines the audience’s response to the visuals in terms of style recognition or identification, along with emotional significance or associations, and the personal value the artifacts might hold to their consumers. The methods of investigation consist of a literature review, a survey of book collections, and a visual questionnaire, supported by personal interviews. As an outcome, visual patterns will be identified: elements from 1970s children’s books reborn in contemporary youth-based publications. Results of the study shall inform us directly on the aesthetic and personal value of illustrated French children’s books in the Middle East, and indirectly on the capacity of youth-targeted design to create a long-term emotional response from its audience.

Keywords: children’s books, French visual culture, graphic style, publication design, revival

Procedia PDF Downloads 166

Authors: Hadjer Didouh, Mohammed Hadj Melliani, Izzeddine Sameut Bouhaik

Abstract:

Corrosion is a serious problem in industrial installations or metallic transport pipes. Corrosion is an interfacial process controlled by several parameters. The presence of microorganisms affects the kinetics of corrosion. This type of corrosion is often referred as bio-corrosion or corrosion influenced by microorganisms (MIC). The action of a microorganism or a bacterium is carried out by the formation of biofilm following its attachment to the metal surface. The formation of biofilm isolates the metal surface from its environment and allows the bacteria to control the parameters of the metal/bacteria interface. Biofilm formation by sulfate-reducing bacteria (SRB) X52 steel, poses substantial challenges in oil and gas industry SONATRACH of Algeria. This research delves into the complex attachment mechanisms employed by SRB biofilm on X52 carbon steel and investigates strategies for effective mitigation using biocides. The exploration commences by elucidating the underlying mechanisms facilitating SRB biofilm adhesion to X52 carbon steel, considering factors such as surface morphology, electrostatic interactions, and microbial extracellular substances. Advanced microscopy and spectroscopic techniques provide a support to the attachment processes, laying the foundation for targeted mitigation strategies. The use of 100 ppm of Moringa Oleifera extract biocide as a promising approach to control and prevent SRB biofilm formation on X52 carbon steel surfaces. Green extract undergo evaluation for their effectiveness in disrupting biofilm development while ensuring the integrity of the steel substrate. Systematic analysis is conducted on the biocide's impact on the biofilm's structural integrity, microbial viability, and overall attachment strength. This two-pronged investigation aims to deepen our comprehension of SRB biofilm dynamics and contribute to the development of effective strategies for mitigating its impact on X52 carbon steel.

Keywords: bio-corrosion, biofilm, attachement, metal/bacteria interface

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Authors: Melissa K. Hord, Stephen P. Whiteside

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With lifetime prevalence rates ranging from 6% to 15%, anxiety disorders are among the most common childhood mental health diagnoses. Anxiety disorders diagnosed in childhood generally show an unremitting course, lead to additional psychopathology and interfere with social, emotional, and academic development. Effective evidence-based treatments include cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRI’s). However, if anxious children receive any treatment, it is usually through primary care, typically consists of medication, and very rarely includes evidence-based psychotherapy. Despite the high prevalence of anxiety disorders, there have only been two independent research labs that have investigated long-term results for CBT treatment for all childhood anxiety disorders and two for specific anxiety disorders. Generally, the studies indicate that the majority of youth maintain gains up to 7.4 years after treatment. These studies have not been replicated. In addition, little is known about the additional mental health care received by these patients in the intervening years after anxiety treatment, which seems likely to influence maintenance of gains for anxiety symptoms as well as the development of additional psychopathology during the subsequent years. The original sample consisted of 335 children ages 7 to 17 years (mean 13.09, 53% female) diagnosed with an anxiety disorder in 2010. Medical record review included provider billing records for mental health appointments during the five years after anxiety treatment. The subsample for this study was classified into three groups: 64 children who received CBT in an anxiety disorders clinic, 56 who received treatment from a psychiatrist, and 10 who were seen in a primary care setting. Chi-square analyses resulted in significant differences in mental health care utilization across the five years after treatment. Youth receiving treatment in primary care averaged less than one appointment each year and the appointments continued at the same rate across time. Children treated by a psychiatrist averaged approximately 3 appointments in the first two years and 2 in the subsequent three years. Importantly, youth treated in the anxiety clinic demonstrated a gradual decrease in mental health appointments across time. The nuanced differences will be presented in greater detail. The results of the current study have important implications for developing dissemination materials to help guide parents when they are selecting treatment for their children. By including all mental health appointments, this study recognizes that anxiety is often comorbid with additional diagnoses and that receiving evidence-based treatment may have long-term benefits that are associated with improvements in broader mental health. One important caveat might be that the acuity of mental health influenced the level of care sought by patients included in this study; however, taking this possibility into account, it seems those seeking care in a primary care setting continued to require similar care at the end of the study, indicating little improvement in symptoms was experienced.

Keywords: anxiety, children, mental health, outcomes

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Authors: Isha Ranadive, Sonam Patel, Suresh Balakrishnan

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It has been observed that in lizards wound can be healed by either a scar free mechanism or by scarring. The animal model used to study both these healing processes was Northern House Gecko. In lizard, the tail when amputated heals by scar free mechanism which allows it to regenerate, the same is not seen when the limb is amputated. Proliferation, apoptosis, and angiogenesis are the main events which succeed an injury. We observed that proliferation of the cells beneath the wound epidermis was much higher in case of wound healing in tail. This could be because after the wound gets covered by the epithelium, it enters in to a cross-talk with the underlying mesenchyme to recruit a pool of blastemal cells which proliferate and later differentiate to form the lost part through epimorphic regeneration. This was substantiated by mRNA expression levels of various FGFs which facilitate the cross-talk and also by PCNA which is a marker for proliferation. Western blot result reaffirms the same notion. However, in case of the limb, the rate of apoptosis was more than proliferation as there are a lot of debris that needs to be removed. We came to this conclusion as we observed that p53 the apoptotic gene was highly upregulated in case of the scarred tissue. Further, we confirmed this result by checking the anti-apoptotic gene bcl2 and found it to be significantly down-regulated. As we noticed heightened proliferation in the case of scar-free wound healing in tail, angiogenesis was targeted for the study. This is because, when the cells are proliferating they require constant supply of blood and hence neo-vascularization is inevitable. It was observed that the marker of angiogenesis, VEGF, was expressed more during wound healing as compared to the resting stage of tail. Moreover, a high up-regulation was seen in KDR, a receptor of VEGF. Thus, this study reveals how proliferation, apoptosis, and angiogenesis play a key role in the scar-free as well as scarred wound healing.

Keywords: epimorphic regeneration, injury, northern house gecko, wound healing

Procedia PDF Downloads 241

Authors: Hai Zeng, Yisheng Li, Jincheng Huang, Chenghui Huang, Ying Zhang

Abstract:

Children are strong; the country strong, the development of children Basketball is a strategic advantage. Common forms of basketball equipment has been difficult to meet the needs of young children teaching the game of basketball, basketball development for 3-6 years old children in the form of appropriate teaching aids is a breakthrough basketball game teaching children bottlenecks, improve teaching critical path pleasure, but also the development of early childhood basketball a necessary requirement. In this study, literature, questionnaires, focus group interviews, comparative analysis, for domestic and foreign use of 12 kinds of basketball teaching aids (cloud computing MINI basketball, adjustable basketball MINI, MINI basketball court, shooting assist paw print ball, dribble goggles, dribbling machine, machine cartoon shooting, rebounding machine, against the mat, elastic belt, ladder, fitness ball), from fun and improve early childhood shooting technique, dribbling technology, as well as offensive and defensive rebounding against technology conduct research on conversion technology. The results show that by using appropriate forms of teaching children basketball aids, can effectively improve children's fun basketball game, targeted to improve a technology, different types of aids from different perspectives enrich the connotation of children basketball game. Recommended for children of color psychology, cartoon and environmentally friendly material production aids, and increase research efforts basketball aids children, encourage children to sports teachers aids applications.

Keywords: health and physical education field of curriculum outline, health fitness, sports and health curriculum reform, Taiwan, twelve years basic education

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Authors: Md. Rasel Mia, Ashik Billah

Abstract:

The empowerment of girls and youth in Bangladesh is a demanding issue in today's digital age, where online learning and education have become integral to personal and societal development. This abstract explores the critical importance of creating a secure online environment for girls and youth in Bangladesh, emphasizing the transformative impact it can have on their access to education and knowledge. Bangladesh, like many developing nations, faces gender inequalities in education and access to digital resources. The creation of a safe digital space not only mitigates the gender digital divide but also fosters an environment where girls and youth can thrive academically and professionally. This manuscript draws attention to the efforts through a mixed-method study to assess the current digital landscape in Bangladesh, revealing disparities in phone and internet access, online practices, and awareness of cyber security among diverse demographic groups. Moreover, the study unveils the varying levels of familial support and barriers encountered by girls and youth in their quest for digital literacy. It emphasizes the need for tailored training programs that address specific learning needs while also advocating for enhanced internet accessibility, safe online practices, and inclusive online platforms. The manuscript culminates in a call for collaborative efforts among stakeholders, including NGOs, government agencies, and telecommunications companies, to implement targeted interventions that bridge the gender digital divide and pave the way for a brighter, more equitable future for girls and youth in Bangladesh. In conclusion, this research highlights the undeniable significance of creating a safe digital space as a catalyst for the empowerment of girls and youth in Bangladesh, ensuring that they not only access but excel in the online space, thereby contributing to their personal growth and the advancement of society as a whole.

Keywords: collaboration, cyber security, digital literacy, digital resources, inclusiveness

Procedia PDF Downloads 55

Authors: Hadjer Didouh, Mohammed Hadj Melliani, Izzeddine Sameut Bouhaik

Abstract:

Corrosion is a serious problem in industrial installations or metallic transport pipes. Corrosion is an interfacial process controlled by several parameters. The presence of microorganisms affects the kinetics of corrosion. This type of corrosion is often referred to as bio-corrosion or corrosion influenced by microorganisms (MIC). The action of a microorganism or a bacterium is carried out by the formation of biofilm following its attachment to the metal surface. The formation of biofilm isolates the metal surface from its environment and allows the bacteria to control the parameters of the metal/bacteria interface. Biofilm formation by sulfate-reducing bacteria (SRB) X52 steel poses substantial challenges in the oil and gas industry SONATRACH of Algeria. This research delves into the complex attachment mechanisms employed by SRB biofilm on X52 carbon steel and investigates innovative strategies for effective mitigation using biocides. The exploration commences by elucidating the underlying mechanisms facilitating SRB biofilm adhesion to X52 carbon steel, considering factors such as surface morphology, electrostatic interactions, and microbial extracellular substances. Advanced microscopy and spectroscopic techniques provide support to the attachment processes, laying the foundation for targeted mitigation strategies. The use of 100 ppm of Moringa Oleifera extract biocide as a promising approach to control and prevent SRB biofilm formation on X52 carbon steel surfaces. Green extracts undergo evaluation for their effectiveness in disrupting biofilm development while ensuring the integrity of the steel substrate. Systematic analysis is conducted on the biocide's impact on the biofilm's structural integrity, microbial viability, and overall attachment strength. This two-pronged investigation aims to deepen our comprehension of SRB biofilm dynamics and contribute to the development of effective strategies for mitigating its impact on X52 carbon steel.

Keywords: attachment, bio-corrosion, biofilm, metal/bacteria interface

Procedia PDF Downloads 70

Authors: Fiona Curran-Cournane

Abstract:

Soil quality monitoring is a science-based soil management tool that assesses soil ecosystem health. A soil monitoring program in Auckland, New Zealand’s largest city, extends from 1995 to the present. The objective of this study was to firstly determine changes in soil parameters (basic soil properties and heavy metals) that were assessed from rural land in 1995-2000 and repeated in 2008-2012. The second objective was to determine differences in soil parameters across various land uses including native bush, rural (horticulture, pasture and plantation forestry) and urban land uses using soil data collected in more recent years (2009-2013). Across rural land, mean concentrations of Olsen P had significantly increased in the second sampling period and was identified as the indicator of most concern, followed by soil macroporosity, particularly for horticultural and pastoral land. Mean concentrations of Cd were also greatest for pastoral and horticultural land and a positive correlation existed between these two parameters, which highlights the importance of analysing basic soil parameters in conjunction with heavy metals. In contrast, mean concentrations of As, Cr, Pb, Ni and Zn were greatest for urban sites. Native bush sites had the lowest concentrations of heavy metals and were used to calculate a ‘pollution index’ (PI). The mean PI was classified as high (PI > 3) for Cd and Ni and moderate for Pb, Zn, Cr, Cu, As, and Hg, indicating high levels of heavy metal pollution across both rural and urban soils. From a land use perspective, the mean ‘integrated pollution index’ was highest for urban sites at 2.9 followed by pasture, horticulture and plantation forests at 2.7, 2.6, and 0.9, respectively. It is recommended that soil sampling continues over time because a longer spanning record will allow further identification of where soil problems exist and where resources need to be targeted in the future. Findings from this study will also inform policy and science direction in regional councils.

Keywords: heavy metals, pollution index, rural and urban land use, soil quality

Procedia PDF Downloads 372

Authors: M. Reza Roshandel, Tannaz Aghaei Badr, Batoul Khoundabi, Sara C. Lewis, Soroush Rais-Bahrami, John Sfakianos, Reza Mehrazin, Ash K. Tewari

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Introduction: Prostate biopsy is the most reliable diagnostic method for choosing the appropriate management of prostate cancer. However, discrepancies between Gleason grade groups (GG) of different biopsies remain a significant concern. This study aims to assess the association of the radiological factors with GG discrepancies in patients with index Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions, using radical prostatectomy (RP) specimens as the most accurate and informative pathology. Methods: This single-institutional retrospective study was performed on a total of 2289 consecutive prostate cancer patients with combined targeted and systematic prostate biopsy followed by radical prostatectomy (RP). The database was explored for patients with the index PI-RADS 3 lesions version 2 and 2.1. Cancers with PI-RADS 4 or 5 scoring were excluded from the study. Patient characteristics and radiologic features were analyzed by multivariable logistic regression. Number-density of lesions was defined as the number of lesions per prostatic volume. Results: Of the 151 prostate cancer cases with PI-RADS 3 index lesions, 27% and 17% had upgrades and downgrades at RP, respectively. Analysis of grade changes showed no significant associations between discrepancies and the number or the number density of PI-RADS 3 lesions. Moreover, the study showed no significant association of the GG changes with race, age, location of the lesions, or prostate volume. Conclusions: This study demonstrated that in PI-RADS 3 cancerous nodules, the chance of the pathology changes in the final pathology of RP specimens was low. Furthermore, having multiple PI-RADS 3 nodules did not change the conclusion, as the possibility of grade changes in patients with multiple nodules was similar to those with solitary lesions.

Keywords: prostate, adenocarcinoma, multiparametric MRI, Gleason score, robot-assisted surgery

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Authors: Jacinta Musyoka, Wesley Too

Abstract:

Cervical cancer is the second leading cause of cancer-related deaths in Kenya and the second most common cancer among women, yet preventable following prevention strategies put in place, which includes vaccination with Human Papilloma Virus Vaccine (HPPV) among the young adolescent girls. Kenya has the highest burden of cervical cancer and the leading cause of death among women of reproductive age and is a known frequent type of cancer amongst women. This is expected to double by 2025 if the necessary steps are not taken, which include vaccinating girls between the ages of 9 and 14 and screening women. Parental decision is critical in ensuring that their daughters receive this vaccine. Hence this study sought to establish parental willingness and factors associate with the acceptability to vaccine adolescent daughters against the human papilloma virus for cervical cancer prevention in Machakos County, Eastern Region of Kenya. Method: Cross-sectional study design utilizing a mixed methods approach was used to collect data from Nguluni Health Centre in Machakos County; Matungulu sub-county, Kenya. This study targeted all parents of adolescent girls seeking health care services in the Matungulu sub-county area who were aged 18 years and above. A total of 220 parents with adolescent girls aged 10-14 years were enrolled into the study after informed consent were sought. All ethical considerations were observed. Quantitative data were analyzed using Multivariate regression analysis, and thematic analysis was used for qualitative data related to perceptions of parents on HPVV. Results, conclusions, and recommendations- ongoing. We expect to report findings and articulate contributions based on the study findings in due course before October 2022

Keywords: adolescents, human papilloma virus, kenya, parents

Procedia PDF Downloads 106

Authors: Deyu Yuan

Abstract:

Discourse analysis as an interdisciplinary approach has more than 60-years-history since it was first named by Zellig Harris in 'Discourse Analysis' on Language in 1952. Ferdinand de Saussure differentiated the 'parole' from the 'langue' that established the principle of focusing on language but not speech. So the rising of discourse analysis can be seen as a discursive turn for the entire language research that closely related to the theory of Speech act. Critical discourse analysis becomes the mainstream of contemporary language research through drawing upon M. A. K. Halliday's socio-semiotic theory and Foucault, Barthes, Bourdieu's views on the sign, discourse, and ideology. So in contrast to general semiotics, social semiotics mainly focuses on parole and the application of semiotic theories to some applicable fields. The article attempts to discuss this applicable sociosemiotics and show the features of it that differ from the Saussurian and Peircian semiotics in four aspects: 1) the sign system is about meaning-generation resource in the social context; 2) the sign system conforms to social and cultural changes with the form of metaphor and connotation; 3) sociosemiotics concerns about five applicable principles including the personal authority principle, non-personal authority principle, consistency principle, model demonstration principle, the expertise principle to deepen specific communication; 4) the study of symbolic functions is targeted to the characteristics of ideational, interpersonal and interactional function in social communication process. Then the paper describes six features which characterize this sociosemiotics as applicable semiotics: social, systematic, usable interdisciplinary, dynamic, and multi-modal characteristics. Thirdly, the paper explores the multi-modal choices of sociosemiotics in the respects of genre, discourse, and style. Finally, the paper discusses the relationship between theory and practice in social semiotics and proposes a relatively comprehensive theoretical framework for social semiotics as applicable semiotics.

Keywords: discourse analysis, sociosemiotics, pragmatics, ideology

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Authors: Aparna Lal, Ashwin Swaminathan, Teisa Holani

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Background: Clostridium difficile infections (CDIs) have been on the rise globally. In Australia, rates of CDI in all States and Territories have increased significantly since mid-2011. Identifying risk factors for CDI in the community can help inform targeted interventions to reduce infection. Methods: We examine the role of neighbourhood socio-economic status, demography, testing practices and the number of residential aged care facilities on spatial patterns in CDI incidence in the Australian Capital Territory. Data on all tests conducted for CDI were obtained from ACT Pathology by postcode for the period 1st January 2004 through 31 December 2014. Distribution of age groups and the neighbourhood Index of Relative Socio-economic Advantage Disadvantage (IRSAD) were obtained from the Australian Bureau of Statistics 2011 National Census data. A Bayesian spatial conditional autoregressive model was fitted at the postcode level to quantify the relationship between CDI and socio-demographic factors. To identify CDI hotspots, exceedance probabilities were set at a threshold of twice the estimated relative risk. Results: CDI showed a positive spatial association with the number of tests (RR=1.01, 95% CI 1.00, 1.02) and the resident population over 65 years (RR=1.00, 95% CI 1.00, 1.01). The standardized index of relative socio-economic advantage disadvantage (IRSAD) was significantly negatively associated with CDI (RR=0.74, 95% CI 0.56, 0.94). We identified three postcodes with high probability (0.8-1.0) of excess risk. Conclusions: Here, we demonstrate geographic variations in CDI in the ACT with a positive association of CDI with socioeconomic disadvantage and identify areas with a high probability of elevated risk compared with surrounding communities. These findings highlight community-based risk factors for CDI.

Keywords: spatial, socio-demographic, infection, Clostridium difficile

Procedia PDF Downloads 317

Authors: Denis Duagi, Ben Carter, Maria Farrelly, Stephen Lisk, June S. L. Brown

Abstract:

Background: Adolescence represents a distinctive phase of development, and variables linked to this developmental period could affect the efficiency of prevention and treatment for depression and anxiety, as well as the long-term prognosis. The objectives of this study were to investigate the long-term effectiveness of psychosocial interventions for adolescents on depression and anxiety symptoms and to assess the influence of different intervention parameters on the long-term effects. Methods: Searches were carried out on the 11ᵗʰ of August 2022 using five databases (Cochrane Library, Embase, Medline, PsychInfo, Web of Science), as well as trial registers. Randomized controlled trials of psychosocial interventions targeting specifically adolescents were included if they assessed outcomes at 1-year post-intervention or more. The Cochrane risk of bias-2 quality assessment tool was used. The primary outcome was depression, and studies were pooled using a standardised mean difference, with an associated 95% confidence interval, p-value, and I². The study protocol was pre-registered (CRD42022348668). Findings: A total of 57 reports (n= 46,678 participants) were included in the review. Psychosocial interventions led to small reductions in depressive symptoms, with a standardised mean difference (SMD) at 1-year of -0.08 (95%CI -0.20, -0.03, p=0.002, I²=72%), 18-months SMD=-0.12, 95% CI -0.22, -0.01, p=0.03, I²=63%) and 2-years SMD=-0.12 (95% CI -0.20, -0.03, p=0.01, I²=68%). Sub-group analyses indicated that targeted interventions produced stronger effects, particularly when delivered by trained mental health professionals (K=18, SMD=-0.24, 95% CI -0.38, -0.10, p=0.001, I²=60%). No effects were detected for anxiety at any assessment. Conclusion: Psychosocial interventions specifically targeting adolescents were shown to have small but positive effects on depression symptoms but not anxiety symptoms, which were sustained for up to 2 years. These findings highlight the potential population-level preventive effects if such psychosocial interventions become widely implemented in accessible settings such as schools.

Keywords: psychosocial, adolescent, interventions, depression, anxiety, meta-analysis, randomized controlled trial

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Authors: Paras Agarwal

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Background: Initially believed to be rare, metastases to the eye are the most common ocular malignancy. The choroid’s high perfusion rate not only makes it the most susceptible ocular site for tumour seeding, but also promotes its growth. The cancers most frequently responsible for choroidal metastases originate from the breast and lung, although a significant proportion have unidentified primaries at the time of presentation. Case Presentation: This case report describes a 34 year old female presenting to the ophthalmology department with a one month history of painless distorted vision. On fundus examination, she was noted to have bilateral choroidal lesionsand subsequently underwent a comprehensive diagnostic work-up. The patient was diagnosed with metastatic pulmonary adenocarcinoma, despite lacking conventional risk factors. As she was found to have a mutation in EGFR, the patient was commenced on tyrosine-kinase inhibition with afatinib. The choroidal lesions regressed with a significant improvement in visual acuity and a dramatic anatomical reduction of the choroidal masses. Conclusions: Our case demonstrates the importance of considering metastases as a differential diagnosis for choroidal lesions. Appropriate and thorough history-taking, examination and investigations may be required in order to deduce the underlying cause. Our case is unusual in view of the choroidal lesion being the primary manifestation of metastatic lung cancer in a young patient with no known risk factors. Early recognition of choroidal metastases is important as it is often the first sign of tumour dissemination and will prompt earlier treatment with systemic medications such as chemotherapy, immunotherapy, targeted therapy or hormonal therapy. Our case report also demonstrates the efficacy of afatinib for the treatment of choroidal metastases, with morphological and functional improvements observed with regard to the choroidal metastatic tumour.

Keywords: choroidal neoplasm, choroidal naevus, pulmonary adenocarcinoma, metastases, lung cancer

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Authors: Youcef Serhane, Abdelkrim Bouzaza, Dominique Wolbert, Aymen Amin Assadi

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Throughout history, the use of chemical weapons is not exclusive to combats between army corps; some of these weapons are also found in very targeted intelligence operations (political assassinations), organized crime, and terrorist organizations. To improve the speed of action, important technological devices have been developed in recent years, in particular in the field of protection and decontamination techniques to better protect and neutralize a chemical threat. In order to assess certain protective, decontaminating technologies or to improve medical countermeasures, tests must be conducted. In view of the great toxicity of toxic chemical agents from (real) wars, simulants can be used, chosen according to the desired application. Here, we present an investigation about using a photocatalytic filtering reactor (PFR) for highly contaminated environments containing diethyl sulfide (DES). This target pollutant is used as a simulant of CWA, namely of Yperite (Mustard Gas). The influence of the inlet concentration (until high concentrations of DES (1200 ppmv, i.e., 5 g/m³ of air) has been studied. Also, the conversion rate was monitored under different relative humidity and different flow rates (respiratory flow - standards: ISO / DIS 8996 and NF EN 14387 + A1). In order to understand the efficacity of pollutant neutralization by PFR, a kinetic model based on the Langmuir–Hinshelwood (L–H) approach and taking into account the mass transfer step was developed. This allows us to determine the adsorption and kinetic degradation constants with no influence of mass transfer. The obtained results confirm that this small configuration of reactor presents an extremely promising way for the use of photocatalysis for treatment to deal with highly contaminated environments containing real chemical warfare agents. Also, they can give birth to an individual protection device (an autonomous cartridge for a gas mask).

Keywords: photocatalysis, photocatalytic filtering reactor, diethylsulfide, chemical warfare agents

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Authors: Shanika Y. Koreshi

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Sri Lanka housed the lingerie product development and manufacturing subsidiary to renowned brands such as La Senza, Marks & Spencer, H&M, Etam, Lane Bryant, and George. Over the last few years, they have produced local brands such as Amante to cater to the local and regional customers. Past research has identified factors such as quality, price, and design to be vital when marketing lingerie to consumers. However, there has been minimum research that looks into the ethnically targeted market and skin colour within the Asian population. Therefore, the main aim of the research was to identify whether consumer preference for lingerie is influenced by the skin tone of the model wearing it. Moreover, the secondary aim was to investigate if the consumer preference for lingerie is influenced by the consumer’s ethnic identification with the skin tone of the model. An experimental design was used to explore the above aims. The participants constituted of 66 females residing in the western province of Sri Lanka and were gathered via convenience sampling. Six computerized images of a real model were used in the study, and her skin tone was digitally manipulated to express three different skin tones (light, tan and dark). Consumer preferences were measured through a ranking order scale that was constructed via a focus group discussion and ethnic identity was measured by the Multigroup Ethnic Identity Measure-Revised. Wilcoxon signed-rank test, Friedman test, and chi square test of independence were carried out using SPSS version 20. The results indicated that majority of the consumers ethnically identified and preferred the tan skin over the light and dark skin tones. The findings support the existing literature that states there is a preference among consumers when models have a medium skin tone over a lighter skin tone. The preference for a tan skin tone in a model is consistent with the ethnic identification of the Sri Lankan sample. The study implies that lingerie brands should consider the model's skin tones when marketing the brand to different ethnic backgrounds.

Keywords: consumer preference, ethnic identification, lingerie, skin tone

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Authors: Lakhoua Najeh

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Introduction: In most situations, an industrial system already existing, conditioned by its history, its culture and its context are in difficulty facing the necessity to restructure itself in an organizational and technological environment in perpetual evolution. This is why all operations of restructuring first of all require a diagnosis based on a functional analysis. After a presentation of the functionality of a supervisory system for complex processes, we present the concepts of industrial automation and supervisory control and data acquisition (SCADA). Methods: This global analysis exploits the various available documents on the one hand and takes on the other hand in consideration the various testimonies through investigations, the interviews or the collective workshops; otherwise, it also takes observations through visits as a basis and even of the specific operations. The exploitation of this diagnosis enables us to elaborate the project of restructuring thereafter. Leaving from the system analysis for the restructuring of industrial systems, and after a technical diagnosis based on visits, an analysis of the various technical documents and management as well as on targeted interviews, a focusing retailing the various levels of analysis has been done according a general methodology. Results: The methodology adopted in order to contribute to the restructuring of industrial systems by its participative and systemic character and leaning on a large consultation a lot of human resources that of the documentary resources, various innovating actions has been proposed. These actions appear in the setting of the TQM gait requiring applicable parameter quantification and a treatment valorising some information. The new management environment will enable us to institute an information and communication system possibility of migration toward an ERP system. Conclusion: Technological advancements in process monitoring, control and industrial automation over the past decades have contributed greatly to improve the productivity of virtually all industrial systems throughout the world. This paper tries to identify the principles characteristics of a process monitoring, control and industrial automation in order to provide tools to help in the decision-making process.

Keywords: automation, supervision, SCADA, TQM

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Authors: Misganaw Ayele Gelaw

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This abstract presents an overview of agricultural investment in Ethiopia, with a focus on the Oromia Region. Ethiopia is a developing country that heavily relies on agriculture as a major contributor to its economic growth and employment. The Oromia Region, located in the central part of the country, is the largest region in Ethiopia and plays a significant role in the agricultural sector. The study aims to explore the current state of agricultural investment in the Oromia Region, focusing on the opportunities, challenges, and potential benefits that arise from such investments. It also highlights the key agricultural investment strategies and policies implemented by the Ethiopian government to attract domestic and foreign investors. To achieve these objectives, a comprehensive literature review and analysis of relevant reports, publications, and government policies will be conducted. The study will also incorporate qualitative and quantitative data collection methods, such as interviews, surveys, and statistical analysis, to provide a well-rounded understanding of agricultural investment dynamics in the Oromia Region. The findings of this study are expected to shed light on the impact of agricultural investments on local farmers, rural development, food security, income generation, and overall economic growth in the Oromia Region. It will also identify the key risk factors and potential mitigations associated with agricultural investment, offering recommendations to policymakers, investors, and stakeholders to improve the effectiveness and sustainability of investment efforts in the region. This abstract highlights the importance of agricultural investment in the Oromia Region and Ethiopia as a whole, as it strives to enhance productivity, increase farmers' income, and contribute to the country's long-term development goals. By understanding the challenges and opportunities associated with agricultural investment, policymakers and investors can develop targeted strategies to ensure inclusive and sustainable growth in the agricultural sector, leading to improved livelihoods and economic prosperity in the Oromia Region.

Keywords: agriculture, investment, agriculture policy, economy

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Authors: Josephine Emebiziogo Anene-Okeakwa

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This study investigates the challenges and opportunities for gender equality in vocational education in Awka South, Anambra State, Nigeria. Recognizing the critical role of vocational education in economic development, the research aims to evaluate the current state of gender equality, identify key barriers faced by female students, assess the impact of government policies, and explore opportunities for enhancing gender equality in this sector. Ten vocational schools within Awka South were randomly selected, and a total of 1,000 questionnaires were distributed among students, with 991 completed and returned, yielding a high response rate of 99.1%, and the retrieved data were analyzed using SPSS. The findings indicate significant gender disparities in vocational education enrollment and participation, with male students overwhelmingly outnumbering female students in most technical and engineering-related programs. Key barriers identified include cultural norms discouraging females from pursuing technical fields, economic constraints, lack of female role models, and social stereotypes regarding gender roles. Despite various government policies aimed at promoting gender equality, their implementation and effectiveness remain inadequate, as reflected in persistent gender disparities. However, opportunities for improving gender equality were identified, such as implementing gender-sensitive curricula, expanding mentorship programs for female students, and adopting best practices from other countries. The study recommends enhancing access to vocational training resources, implementing gender-sensitive curricula, expanding mentorship programs, and strengthening the implementation and monitoring of government policies. Addressing these challenges through targeted interventions is essential for achieving gender parity in vocational education, thereby empowering female students and contributing to Nigeria's socio-economic development.

Keywords: vocational education, gender equality, barriers, government policies

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Authors: Cliff Shunsheng Han

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Identifying the direct allergy cause that can be easily mitigated is the foundation to stop the allergy epidemic that has been started in the seventies. It has confirmed that the personal and social hygiene practices are associated with the allergy prevalence. But direct causes have been found, and proposed translational measures have not been effective. This study, assisted by a particular case of allergies, has seen the direct cause of allergies, developed a valid test resulted in lasting relief for allergies, and constructed theory describing general relationship between microbiota and host immune system. Saliva samples were collected from a subject for three years during which time the person experienced yearlong allergy, seasonal allergy, and remission of allergy symptoms. Bacterial DNA was extracted and 16S rRNA genes were profiled with Illumina sequencing technology. The analyzing results indicate that the possible direct cause of allergy is the lacking probiotic bacteria in the oral cavity, such as genera Streptococcus and Veilonella, that can produce metabolites to pacify immune system. Targeted promotion of those bacteria with a compound designed for them, has led to lasting remissions of allergic rhinitis. During the development of the translational measure, the subject's oral biofilm was completely destructed by a moderate fever due to an unrelated respiratory infection. The incident not only facilitated the development of the heat based microbiota reseeding procedure but also indicated a possible natural switch that subsequently increases the efficacy of the immune system previously restrained by metabolites from microbiota. These results lead to the proposal of a Theory of Negative Trigger (TNT) to describe the relationship between oral probiotics and immune system, in which probiotics are the negative trigger that will release the power of immune system when removed by fever or modern lifestyles. This study could open doors leading to further understanding of how the immune system functions under the influence of microbiota as well as validate simple traditional practices for healthy living.

Keywords: oral microbiome, allergy, immune system, infection

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Authors: Aurore Lechevallier, Mohend Chaouche, Jerome Soudier, Guillaume Renaudin

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The cement industry accounts for 8% of the global CO₂ emissions, and approximately 60% of these emissions are associated with the Portland cement clinker production from the decarbonization of limestone (CaCO3). Their impact on the greenhouse effect results in growing social awareness. Therefore, CO2 footprint becomes a product selection choice, and substituting Portland cement with a lower CO2-footprint alternative binder is sought. In this context, new hydraulic binders have been studied as a potential Ordinary Portland Cement substitute. Many of them are composed of iron oxides and aluminum oxides, present in the Ca₄Al₂-xFe₂+ₓO₁₀-like phase and forming Ca-LDH (i.e. AFM) as a hydration product. It has become essential to study the possible existence of Fe/Al AFM solid solutions to characterize the hydration process properly. Ca₂Al₂-xFex(OH)₆.X.nH₂O layered AFM samples intercalated with either nitrate or chloride X anions were synthesized based on the co-precipitation method under a nitrogen atmosphere to avoid the carbonation effect.AFM samples intercalated with carbonate anions were synthesized based on the anionic exchange process, using AFM-NO₃ as the source material. These three AFM samples were synthesized with varying Fe/Al molar ratios. The experimental conditions were optimized to make possible the formation of Al-AFM and Fe-AFM using the same parameters (namely pH value and salt concentration). Rietveld refinements were performed to demonstrate the existence of a solid solution between the two trivalent metallic end members. Spectroscopic analyses were used to confirm the intercalation of the targeted anion; secondary electron images were taken to analyze the AFM samples’ morphology, and energy dispersive X-ray spectroscopy (EDX) was carried out to determine the elemental composition of the AFM samples. Results of this study make it possible to quantify the Al/Fe ratio of the AFM phases precipitated in our hydraulic binder, thanks to the determined Vegard's law characteristic to the corresponding solid solutions

Keywords: AFm phase, iron-rich binder, low-carbon cement, solid solution

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Authors: Brigitta Bodnár, Lajos Kovács, Zoltán Kupihár

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The cancer cells require higher amount of nucleoside building blocks for their proliferation, therefore they have significantly higher uptake of nucleosides by the different nucleoside transporters. Therefore, the conjugation with nucleosides may significantly increase the efficiency and selectivity of potential active pharmaceutical ingredients. On the other hand, the advantage of using a nucleoside could be either the higher activity on targeted enzymes overrepresented in cancer cells or an enhanced cellular uptake of the bioconjugates in these cells compared to the healthy ones. This fact can be used to make the nucleosides, as targeting moieties covalently bound to anti-cancer drug molecules which can selectively accumulate in cancer cells. However, in order to form the nucleoside-drug conjugates, such nucleoside building blocks are needed, which can selectively be coupled to the drug molecules containing even a high number of diverse functional groups. One of the most selective conjugation techniques is the copper-catalyzed azide-alkyne click reaction that requires the presence of an alkyl group on one of the conjugated molecules and an azide group on the other. In case of nucleosides, the development of azide group is simpler for which the replacement of the 5'-hydroxy group is the most suitable. This transformation generally involves many side reactions and result in very low yields. In addition, during our experiments, the transformation of the 2'-deoxyguanosine to the corresponding 5'-deoxy-5’-azido-2’-deoxyguanosine could not be performed with any of the methods described in the literature. Therefore, we have tried to overcome these difficulties with not only using the traditional process based on the 2 step exchange of tosyl to azide, but also using the Mitsunobu reaction which requires only one step. However, this path proved to be unsuccessful in spite of the optimizing the reaction conditions. Finally, a method has been developed whereby the azide groups were incorporated into the 5’-position resulting in significantly better yields compared to all other previous methods, and we were able to produce all the four nucleoside derivatives.

Keywords: 5'-azidonucleosides, bioconjugate, click reaction, proliferation

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Authors: Bauta J., Raynaud C., Vaca-Medina G., Simon V., Roully A., Vandenbossche V.

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Sargassum is a brown algae, originally found in the Sargasso Sea, located in the Caribbean region and the Gulf of Mexico. The flow of Sargassum is becoming a critical environmental problem all over the Caribbean islands particularly. In Guadeloupe alone, around 80,000 tons of seaweed are stranded during the season. Since the appearance of the first waves of Sargassum algae, several measures have been taken to collect them to keep the beaches clean. Nevertheless, 90% of the collected algae are currently stored without recovery. The lack of research initiative demands a more in-depth exploration of Sargassum algae chemistry, targeted towards added value applications and their development. In this context, the aim of the study was to develop a biorefinery process to valorize Sargassum as a source of bioactive natural substances and as raw material to produce biomaterials simultaneously. The technology used was the twin-screw extrusion, which allows to achieve continuously in the same machine different unit fractionation operations. After the identification of the molecules of interest in Sargassum algae, different operating conditions of thermo-mechanical treatment were applied in a twin-screw extruder. The nature of the solvent, the configuration of the extruder, the screw profile, and the temperature profile were studied in order to fractionate the algal biomass and to allow the recovery of a bioactive liquid fraction of interest and a solid residue suitable for the production of biomaterials. Each bioactive liquid fraction was characterized and strategic ways of adding value were proposed. In parallel, the possibility of using the solid residue to produce biomaterials was studied by setting up Dynamic Vapour Sorption (DVS) and basic Pressure-Volume-Temperature (PVT) analyses. The solid residue was molded by compression cooking. The obtained materials were finally characterized mechanically. The results obtained were very comforting and gave some perspectives to find an interesting valorization for the Sargassum algae.

Keywords: seaweeds, twin-screw extrusion, fractionation, bioactive compounds, biomaterials, biomass

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

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

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

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