Search results for: functional polymorphism

Authors: Malcolm Dinovitzer, Calvin Miller, Adam Hacker, Gabriel Wong, Zach Annen, Padmassun Rajakareyar, Jordan Mulvihill, Mostafa S.A. ElSayed

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The research work presented in this paper is developed by the Blended Wing Body (BWB) Unmanned Aerial Vehicle (UAV) team, a fourth-year capstone project at Carleton University Department of Mechanical and Aerospace Engineering. Here, a clean sheet UAV with BWB configuration is designed and optimized using Multiscale Design Optimization (MSDO) approach employing lattice materials taking into consideration design for additive manufacturing constraints. The BWB-UAV is being developed with a mission profile designed for surveillance purposes with a minimum payload of 1000 grams. To demonstrate the design methodology, a single design loop of a sample rib from the airframe is shown in details. This includes presentation of the conceptual design, materials selection, experimental characterization and residual thermal stress distribution analysis of additively manufactured materials, manufacturing constraint identification, critical loads computations, stress analysis and design optimization. A dynamic turbulent critical load case was identified composed of a 1-g static maneuver with an incremental Power Spectral Density (PSD) gust which was used as a deterministic design load case for the design optimization. 2D flat plate Doublet Lattice Method (DLM) was used to simulate aerodynamics in the aeroelastic analysis. The aerodynamic results were verified versus a 3D CFD analysis applying Spalart-Allmaras and SST k-omega turbulence to the rigid UAV and vortex lattice method applied in the OpenVSP environment. Design optimization of a single rib was conducted using topology optimization as well as MSDO. Compared to a solid rib, weight savings of 36.44% and 59.65% were obtained for the topology optimization and the MSDO, respectively. These results suggest that MSDO is an acceptable alternative to topology optimization in weight critical applications while preserving the functional requirements.

Keywords: blended wing body, multiscale design optimization, additive manufacturing, unmanned aerial vehicle

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Authors: Natalia Moreno-Castellanos, Amaia Rodriguez, Gema Frühbeck

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Introduction: In adipocytes, the cytoskeleton undergoes important expression and distribution in adipocytes rearrangements during adipogenesis and in obesity. Indeed, a role for these proteins in the regulation of adipocyte differentiation and response to insulin has been demonstrated. Recently, septins have been considered as new components of the cytoskeletal network that interact with other cytoskeletal elements (actin and tubulin) profoundly modifying their dynamics. However, these proteins have not been characterized as yet in adipose tissue. In this work, were examined the cellular, molecular and functional features of a member of this family, septin 11 (SEPT11), in adipocytes and evaluated the impact of obesity on the expression of this protein in human adipose tissue. Methods: Adipose gene and protein expression levels of SEPT11 were analysed in human samples. SEPT11 distribution was evaluated by immunocytochemistry, electronic microscopy, and subcellular fractionation techniques. GST-pull down, immunoprecipitation and a Yeast-Two Hybrid (Y2H) screening were used to identify the SEPT11 interactome. Gene silencing was employed to assess the role of SEPT11 in the regulation of insulin signaling and lipid metabolism in adipocytes. Results: SEPT11 is expressed in human adipocytes, and its levels increased in both omental and subcutaneous adipose tissue in obesity, with SEPT11 mRNA content positively correlating with parameters of insulin resistance in subcutaneous fat. In non-stimulated adipocytes, SEPT11 immunoreactivity showed a ring-like distribution at the cell surface and associated to caveolae. Biochemical analyses showed that SEPT11 interacted with the main component of caveolae, caveolin-1 (CAV1) as well as with the fatty acid-binding protein, FABP5. Notably, the three proteins redistributed and co-localized at the surface of lipid droplets upon exposure of adipocytes to oleate. In this line, SEPT11 silencing in 3T3-L1 adipocytes impaired insulin signaling and decreased insulin-induced lipogenesis. Conclusions: Those findings demonstrate that SEPT11 is a novel component of the adipocyte cytoskeleton that plays an important role in the regulation of lipid traffic, metabolism and can thus represent a potential biomarker of insulin resistance in obesity in adipocytes through its interaction with both CAV1 and FABP5.

Keywords: caveolae, lipid metabolism, obesity, septins

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Authors: Stacy Jarvis

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Databases such as JSTOR, RILM and WorldCat have been the main source and storage of literature in the music orb. The Reference Index to Music Literature is a bibliographic database of over 2.6 million citations to writings about music from over 70 countries. The Research Institute produces RILM for the Study of Music at the University of Buffalo. JSTOR is an e-library of academic journals, books, and primary sources. Database JSTOR helps scholars find, utilise, and build upon a vast range of literature through a powerful teaching and research platform. Another database, WorldCat, is the world's biggest library catalogue, assisting scholars in finding library materials online. An evaluation of these databases in the music sphere is conducted by looking into the description and intended use and finding similarities and differences among them. Through comparison, it is found that these aim to serve different purposes, though they have the same goal of providing and storing literature. Also, since each database has different parts of literature that it majors on, the intended use of the three databases is evaluated. This can be found in the description, scope, and intended uses section. These areas are crucial to the research as it addresses the functional or literature differences among the three databases. It is also found that these databases have different quantitative potentials. This is determined by addressing the year each database began collecting literature and the number of articles, periodicals, albums, conference proceedings, music, dissertations, digital media, essays collections, journal articles, monographs, online resources, reviews, and reference materials that can be found in each one of them. This can be found in the sections- description, scope and intended uses and the importance of the database in identifying literature on different topics. To compare the delivery of services to the users, the importance of databases in identifying literature on different topics is also addressed in the section -the importance of databases in identifying literature on different topics. Even though these databases are used in research, they all have disadvantages and advantages. This is addressed in the sections on advantages and disadvantages. This will be significant in determining which of the three is the best. Also, it will help address how the shortcomings of one database can be addressed by utilising two databases together while conducting research. It is addressed in the section- a combination of RILM and JSTOR. All this information revolves around the idea that a huge amount of quantitative and qualitative data can be found in the presented databases on music and digital content; however, each of the given databases has a different construction and material features contributing to the musical scholarship in its way.

Keywords: RILM, JSTOR, WorldCat, database, literature, research

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Authors: Gulsharat A. Baigonakova, Ekaterina S. Marchenko, Venera R. Luchsheva

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The preferred materials for bone grafting are titanium-nickel alloys. They have a porous, permeable structure similar to that of bone tissue, can withstand long-term physiological stress in the body, and retain the scaffolding function for bone tissue ingrowth. Despite the excellent functional properties of these alloys, there is a possibility of post-operative infectious complications that prevent the newly formed bone tissue from filling the spaces created in a timely manner and prolong the rehabilitation period of patients. In order to minimise such consequences, it is necessary to use biocompatible materials capable of simultaneously fulfilling the function of a long-term functioning implant and an osteoreplacement carrier saturated with drugs. Methods to modify the surface by saturation with bioactive substances, in particular macrocyclic compounds, for the controlled release of drugs, biologically active substances, and cells are becoming increasingly important. This work is dedicated to the functionalisation of the surface of porous titanium nickelide by the deposition of macrocyclic compounds in order to provide titanium nickelide with antibacterial activity and accelerated osteogenesis. The paper evaluates the effect of macrocyclic compound deposition methods on the continuity, structure, and cytocompatibility of the surface properties of porous titanium nickelide. Macrocyclic compounds were deposited on the porous surface of titanium nickelide under the influence of various physical effects. Structural research methods have allowed the evaluation of the surface morphology of titanium nickelide and the nature of the distribution of these compounds. The method of surface functionalisation of titanium nickelide influences the size of the deposited bioactive molecules and the nature of their distribution. The surface functionalisation method developed has enabled titanium nickelide to be deposited uniformly on the inner and outer surfaces of the pores, which will subsequently enable the material to be uniformly saturated with various drugs, including antibiotics and inhibitors. The surface-modified porous titanium nickelide showed high biocompatibility and low cytotoxicity in in vitro studies. The research was carried out with financial support from the Russian Science Foundation under Grant No. 22-72-10037.

Keywords: biocompatibility, NiTi, surface, porous structure

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Authors: Selam M. Tefera

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Soil constitutes a crucial component of rural and urban environments. This fact is making role of heavy and trace elements in the soil system an issue of global concern. Heavy metals constitute an ill-defined group of inorganic chemical hazards, whose main source is anthropogenic activities mainly related to fabrications. This accumulation of heavy metals soils can prove toxic to the environment. The application of biochar to soil is one way of immobilizing these contaminants through sorption by exploiting the high surface area of this material among its other essential properties. This research examined the ability of sugar cane straw, an organic waste material from sugar farm, derived biochar and ash to remediate soil contaminated with heavy metals mainly Chromium and Zinc from the effluent of electroplating industry. Biochar was produced by varying the temperature from 300 °C to 500 °C and ash at 700 °C. The highest yield (50%) was obtained at the lowest temperature (300 °C). The proximate analysis showed ash content of 42.8%, ultimate analysis with carbon content of 67.18%, the Hydrogen to Carbon ratio of 0.54 and the results from FTIR analysis disclosed the organic nature of biochar. Methylene blue absorption indicated its fine surface area and pore structure, which increases with severity of temperature. Biochar was mixed with soil with at a ration varying from 4% w/w to 10% w/w of soil, and the response variables were determined at a time interval of 150 days, 180 days, and 210 days. As for ash (10% w/w), the characterization was performed at incubation time of 210 days. The results of pH indicated that biochar (9.24) had a notable liming capacity of acidic soil (4.8) by increasing it to 6.89 whereas ash increased it to 7.5. The immobilization capacity of biochar was found to effected mostly by the highest production temperature (500 °C), which was 75.5% for chromium and 80.5% for nickel. In addition, ash was shown to possess an outstanding immobilization capacity of 95.5% and 90.5% for Chromium and Nickel, respectively. All in all, the results from these methods showed that biochar produced from this specific biomass possesses the typical functional groups that enable it to store carbon, the appropriate pH that could remediate acidic soil, a fine amount of macro and micro nutrients that would aid plant growth.

Keywords: biochar, biomass, heavy metal immobalization, soil remediation

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Authors: Daijun Chen

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Affordable housing is subsidized by the government to meet the housing demand of low and middle-income urban residents in the process of urbanization and to alleviate the housing inequality caused by market-based housing reforms. It is a recognized fact that the living conditions of the insured have been improved while constructing the subsidized housing. However, the choice of affordable housing is mostly in the suburbs, where the surrounding urban functions and infrastructure are incomplete, resulting in the spatial mismatch of "jobs-housing" in affordable housing. The main reason for this problem is that the residents of affordable housing are more sensitive to the spatial location of their residence, but their selectivity and controllability to the housing location are relatively weak, which leads to higher commuting costs. Their real cost of living has not been effectively reduced. In this regard, 92 subsidized housing communities in Nanjing, China, are selected as the research sample in this paper. The residents of the affordable housing and their commuting Spatio-temporal behavior characteristics are identified based on the LBS (location-based service) data. Based on the spatial mismatch theory, spatial mismatch indicators such as commuting distance and commuting time are established to measure the spatial mismatch degree of subsidized housing in different districts of Nanjing. Furthermore, the geographically weighted regression model is used to analyze the influencing factors of the spatial mismatch of affordable housing in terms of the provision of employment opportunities, traffic accessibility and supporting service facilities by using spatial, functional and other multi-source Spatio-temporal big data. The results show that the spatial mismatch of affordable housing in Nanjing generally presents a "concentric circle" pattern of decreasing from the central urban area to the periphery. The factors affecting the spatial mismatch of affordable housing in different spatial zones are different. The main reasons are the number of enterprises within 1 km of the affordable housing district and the shortest distance to the subway station. And the low spatial mismatch is due to the diversity of services and facilities. Based on this, a spatial optimization strategy for different levels of spatial mismatch in subsidized housing is proposed. And feasible suggestions for the later site selection of subsidized housing are also provided. It hopes to avoid or mitigate the impact of "spatial mismatch," promote the "spatial adaptation" of "jobs-housing," and truly improve the overall welfare level of affordable housing residents.

Keywords: affordable housing, spatial mismatch, commuting characteristics, spatial adaptation, welfare benefits

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Authors: Mahbuba Rahman, Sabri Boughorbel, Scott Presnell, Charlie Quinn, Darawan Rinchai, Damien Chaussabel, Nico Marr

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Collections of large-scale datasets made available in public repositories can be used to identify and fill gaps in biomedical knowledge. But first, these data need to be made readily accessible to researchers for analysis and interpretation. Here a collection of transcriptome datasets was made available to investigate the functional programming of human hematopoietic cells in early life. Thirty two datasets were retrieved from the NCBI Gene Expression Omnibus (GEO) and loaded in a custom, interactive web application called the Gene Expression browser (GXB), designed for visualization and query of integrated large-scale data. Multiple sample groupings and gene rank lists were created based on the study design and variables in each dataset. Web links to customized graphical views can be generated by users and subsequently be used to graphically present data in manuscripts for publication. The GXB tool also enables browsing of a single gene across datasets, which can provide information on the role of a given molecule across biological systems. The dataset collection is available online. As a proof-of-principle, one of the datasets (GSE25087) was re-analyzed to identify genes that are differentially expressed by regulatory T cells in early life. Re-analysis of this dataset and a cross-study comparison using multiple other datasets in the above mentioned collection revealed that PMCH, a gene encoding a precursor of melanin-concentrating hormone (MCH), a cyclic neuropeptide, is highly expressed in a variety of other hematopoietic cell types, including neonatal erythroid cells as well as plasmacytoid dendritic cells upon viral infection. Our findings suggest an as yet unrecognized role of MCH in immune regulation, thereby highlighting the unique potential of the curated dataset collection and systems biology approach to generate new hypotheses which can be tested in future mechanistic studies.

Keywords: early-life, GEO datasets, PMCH, interactive query, systems biology

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Authors: Olanrewaju O. Adeojo

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The constitutional system of government provides for the federating units of the Federal Republic of Nigeria, the States and the Local Councils under a governing structure of the Executive, the Legislature and the Judiciary with attendant distinct powers and spheres of influence. The legislative powers of the Federal Republic of Nigeria and of a State are vested in the National Assembly and House of Assembly of the State respectively. The Local council exercises legislative powers in clearly defined matters as provided by the Constitution. Though, the executive as constituted by the President and the Governor are charged with the powers of execution and administration, the legislature is empowered to ensure that such powers are duly exercised in accordance with the provisions of the Constitution. The vast areas do not make oversight functions indefinite and more importantly the purpose for the exercise of the powers are circumscribed. It include, among others, any matter with respect to which it has power to make laws. Indeed, the law provides for the competence of the legislature to procure evidence, examine all persons as witnesses, to summon any person to give evidence and to issue a warrant to compel attendance in matters relevant to the subject matter of its investigation. The exercise of functions envisaged by the Constitution seem to an extent to be literal because it lacks power of enforcing the outcome. Furthermore, the docility of the legislature is apparent in a situation where the agency or authority being called in to question is part of the branch of government to enforce sanctions. The process allows for cover up and obstruction of justice. The oversight functions are not functional in a situation where the executive is overbearing. The friction, that ensues, between the Legislature and the Executive in an attempt by the former to project the spirit of a constitutional mandate calls for concern. It is needless to state a power that can easily be frustrated. To an extent, the arm of government with coercive authority seems to have over shadowy effect over the laid down functions of the legislature. Recourse to adjudication by the Judiciary had not proved to be of any serious utility especially in a clime where the wheels of justice grinds slowly, as in Nigeria, due to the nature of the legal system. Consequently, the law and the Constitution, drawing lessons from other jurisdiction, need to insulate the legislative oversight from the vagaries of the executive. A strong and virile Constitutional Court that determines, within specific time line, issues pertaining to the oversight functions of the legislative power, is apposite.

Keywords: constitution, legislative, oversight, power

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Authors: Aleya Ferdausi, Meriel Jones, Anthony Halls

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The Amaryllidaceae genus Narcissus contains secondary metabolites, which are important sources of bioactive compounds such as pharmaceuticals indicating that their biological activity extends from the native plant to humans. Transcriptome analysis (RNA-seq) is an effective platform for the identification and functional characterization of candidate genes as well as to identify genes encoding uncharacterized enzymes. The biotechnological production of secondary metabolites in plant cell or organ cultures has become a tempting alternative to the extraction of whole plant material. The biochemical pathways for the production of secondary metabolites require primary metabolites to undergo a series of modifications catalyzed by enzymes such as cytochrome P450s, methyltransferases, glycosyltransferases, and acyltransferases. Differential gene expression analysis of Narcissus was obtained from two conditions, i.e. field and in vitro callus. Callus was obtained from modified MS (Murashige and Skoog) media supplemented with growth regulators and twin-scale explants from Narcissus cv. Carlton bulb. A total of 2153 differentially expressed transcripts were detected in Narcissus bulb and in vitro callus, and 78.95% of those were annotated. It showed the expression of genes involved in the biosynthesis of alkaloids were present in both conditions i.e. cytochrome P450s, O-methyltransferase (OMTs), NADP/NADPH dehydrogenases or reductases, SAM-synthetases or decarboxylases, 3-ketoacyl-CoA, acyl-CoA, cinnamoyl-CoA, cinnamate 4-hydroxylase, alcohol dehydrogenase, caffeic acid, N-methyltransferase, and NADPH-cytochrome P450s. However, cytochrome P450s and OMTs involved in the later stage of Amaryllidaceae alkaloids biosynthesis were mainly up-regulated in field samples. Whereas, the enzymes involved in initial biosynthetic pathways i.e. fructose biphosphate adolase, aminotransferases, dehydrogenases, hydroxyl methyl glutarate and glutamate synthase leading to the biosynthesis of precursors; tyrosine, phenylalanine and tryptophan for secondary metabolites were up-regulated in callus. The knowledge of probable genes involved in secondary metabolism and their regulation in different tissues will provide insight into the Narcissus plant biology related to alkaloid production.

Keywords: narcissus, callus, transcriptomics, secondary metabolites

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Authors: Oscar Orlando Ortiz Rodriguez, Raquel A. Villamizar-G, Alexander Araque

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There is a total of 1027 municipal development plants in Colombia, 70% of municipalities had Potable Water Treatment Plants (PWTPs) in urban areas and 20% in rural areas. These PWTPs are typically supplied by surface waters (mainly rivers) and resort to gravity, pumping and/or mixed systems to get the water from the catchment point, where the first stage of the potable water process takes place. Subsequently, a series of conventional methods are applied, consisting in a more or less standardized sequence of physicochemical and, sometimes, biological treatment processes which vary depending on the quality of the water that enters the plant. These processes require energy and chemical supplies in order to guarantee an adequate product for human consumption. Therefore, in this paper, we applied the environmental methodology of Life Cycle Assessment (LCA) to evaluate the environmental loads of a potable water treatment plant (PWTP) located in northeastern Colombia following international guidelines of ISO 14040. The different stages of the potable water process, from the catchment point through pumping to the distribution network, were thoroughly assessed. The functional unit was defined as 1 m³ of water treated. The data were analyzed through the database Ecoinvent v.3.01, and modeled and processed in the software LCA-Data Manager. The results allowed determining that in the plant, the largest impact was caused by Clarifloc (82%), followed by Chlorine gas (13%) and power consumption (4%). In this context, the company involved in the sustainability of the potable water service should ideally reduce these environmental loads during the potable water process. A strategy could be the use of Clarifloc can be reduced by applying coadjuvants or other coagulant agents. Also, the preservation of the hydric source that supplies the treatment plant constitutes an important factor, since its deterioration confers unfavorable features to the water that is to be treated. By concluding, treatment processes and techniques, bioclimatic conditions and culturally driven consumption behavior vary from region to region. Furthermore, changes in treatment processes and techniques are likely to affect the environment during all stages of a plant’s operation cycle.

Keywords: climate change, environmental impact, life cycle assessment, treated water

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Authors: Petr Slobodian, Pavel Riha, Jiri Matyas, Robert Olejnik, Nuri Karakurt

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Thermoelectric devices generate an electrical current when there is a temperature gradient between the hot and cold junctions of two dissimilar conductive materials typically n-type and p-type semiconductors. Consequently, also the polymeric semiconductors composed of polymeric matrix filled by different forms of carbon nanotubes with proper structural hierarchy can have thermoelectric properties which temperature difference transfer into electricity. In spite of lower thermoelectric efficiency of polymeric thermoelectrics in terms of the figure of merit, the properties as stretchability, flexibility, lightweight, low thermal conductivity, easy processing, and low manufacturing cost are advantages in many technological and ecological applications. Polyethylene-octene copolymer based highly elastic composites filled with multi-walled carbon nanotubes (MWCTs) were prepared by sonication of nanotube dispersion in a copolymer solution followed by their precipitation pouring into non-solvent. The electronic properties of MWCNTs were moderated by different treatment techniques such as chemical oxidation, decoration by Ag clusters or addition of low molecular dopants. In this concept, for example, the amounts of oxygenated functional groups attached on MWCNT surface by HNO₃ oxidation increase p-type charge carriers. p-type of charge carriers can be further increased by doping with molecules of triphenylphosphine. For partial altering p-type MWCNTs into less p-type ones, Ag nanoparticles were deposited on MWCNT surface and then doped with 7,7,8,8-tetracyanoquino-dimethane. Both types of MWCNTs with the highest difference in generated thermoelectric power were combined to manufacture polymeric based thermoelectric module generating thermoelectric voltage when the temperature difference is applied between hot and cold ends of the module. Moreover, it was found that the generated voltage by the thermoelectric module at constant temperature gradient was significantly affected when exposed to vapors of different volatile organic compounds representing then a self-powered thermoelectric sensor for chemical vapor detection.

Keywords: carbon nanotubes, polymer composites, thermoelectric materials, self-powered gas sensor

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Authors: Gabriela D. Silva, Rodrigo L. O. R. Cunha, Mauricio D. Coutinho-Neto

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In the last four decades the biological activities of selenium compounds has received great attention, particularly for hypervalent derivates from selenium (IV) used as enzyme inhibitors. The unregulated activity of cysteine proteases are related to the development of several pathologies, such as neurological disorders, cardiovascular diseases, obesity, rheumatoid arthritis, cancer and parasitic infections. These enzymes are therefore a valuable target for designing new small molecule inhibitors such as selenuranes. Even tough there has been advances in the synthesis and design of new selenuranes based inhibitors, little is known about their mechanism of action. It is a given that inhibition occurs through the reaction between the thiol group of the enzyme and the chalcogen atom. However, several open questions remain about the nature of the mechanism (associative vs. dissociative) and about the nature of the reactive species in solution under physiological conditions. In this work we performed a theoretical investigation on model systems to study the possible routes of substitution reactions. Nucleophiles may be present in biological systems, our interest is centered in the thiol groups from the cysteine proteases and the hydroxyls from the aqueous environment. We therefore expect this study to clarify the possibility of a route reaction in two stages, the first consisting of the substitution of chloro atoms by hydroxyl groups and then replacing these hydroxyl groups per thiol groups in selenuranes. The structures of selenuranes and nucleophiles were optimized using density function theory along the B3LYP functional and a 6-311+G(d) basis set. Solvent was treated using the IEFPCM method as implemented in the Gaussian 09 code. Our results indicate that hydrolysis from water react preferably with selenuranes, and then, they are replaced by the thiol group. It show the energy values of -106,0730423 kcal/mol for dople substituition by hydroxyl group and 96,63078511 kcal/mol for thiol group. The solvatation and pH reduction promotes this route, increasing the energy value for reaction with hydroxil group to -50,75637672 kcal/mol and decreasing the energy value for thiol to 7,917767189 kcal/mol. Alternative ways were analyzed for monosubstitution (considering the competition between Cl, OH and SH groups) and they suggest the same route. Similar results were obtained for aliphatic and aromatic selenuranes studied.

Keywords: chalcogenes, computational study, cysteine proteases, enzyme inhibitors

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Authors: Mateen A Khan, Taj Mohammad, Md. Imtaiyaz Hassan

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Alzheimer’s disease is characterized by the accumulation of the processing products of the amyloid beta peptide cleaved by amyloid precursor protein (APP). Iron increases the synthesis of amyloid beta peptides, which is why iron is present in Alzheimer's disease patients' amyloid plaques. Iron misregulation in the brain is linked to the overexpression of APP protein, which is directly related to amyloid-β aggregation in Alzheimer’s disease. The APP 5'-UTR region encodes a functional iron-responsive element (IRE) stem-loop that represents a potential target for modulating amyloid production. Targeted regulation of APP gene expression through the modulation of 5’-UTR sequence function represents a novel approach for the potential treatment of AD because altering APP translation can be used to improve both the protective brain iron balance and provide anti-amyloid efficacy. The molecular docking analysis of APP IRE RNA with eukaryotic translation initiation factors yields several models exhibiting substantial binding affinity. The finding revealed that the interaction involved a set of functionally active residues within the binding sites of eIF4F. Notably, APP IRE RNA and eIF4F interaction were stabilized by multiple hydrogen bonds with residues of APP IRE RNA and eIF4F. It was evident that APP IRE RNA exhibited a structural complementarity that tightly fit within binding pockets of eIF4F. The simulation studies further revealed the stability of the complexes formed between RNA and eIF4F, which is crucial for assessing the strength of these interactions and subsequent roles in the pathophysiology of Alzheimer’s disease. In addition, MD simulations would capture conformational changes in the IRE RNA and protein molecules during their interactions, illustrating the mechanism of interaction, conformational change, and unbinding events and how it may affect aggregation propensity and subsequent therapeutic implications. Our binding studies correlated well with the translation efficiency of APP mRNA. Overall, the outcome of this study suggests that the genomic modification and/or inhibiting the expression of amyloid protein by targeting APP IRE RNA can be a viable strategy to identify potential therapeutic targets for AD and subsequently be exploited for developing novel therapeutic approaches.

Keywords: Alzheimer's disease, Protein-RNA interaction analysis, molecular docking simulations, conformational dynamics, binding stability, binding kinetics, protein synthesis.

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Authors: Norhidayu Muhamad Zain

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Gelatin, a purified protein derived mostly from porcine and bovine sources, is used widely in food manufacturing, pharmaceutical, and cosmetic industries. However, the presence of any porcine-related products are strictly forbidden for Muslim and Jewish consumption. Therefore, analytical methods offering reliable results to differentiate the sources of gelatin are needed. The aim of this study was to differentiate the sources of gelatin (porcine and tilapia fish) using Fourier transform infrared- attenuated total reflection (FTIR-ATR) combined with two dimensional infrared (2DIR) correlation analysis. Porcine gelatin (PG) and tilapia fish gelatin (FG) samples were diluted in distilled water at concentrations ranged from 4-20% (w/v). The samples were then analysed using FTIR-ATR and 2DIR correlation software. The results showed a significant difference in the pattern map of synchronous spectra at the region of 1000 cm⁻¹ to 1100 cm⁻¹ between PG and FG samples. The auto peak at 1080 cm⁻¹ that attributed to C-O functional group was observed at high intensity in PG samples compared to FG samples. Meanwhile, two auto peaks (1080 cm⁻¹ and 1030 cm⁻¹) at lower intensity were identified in FG samples. In addition, using 2D correlation analysis, the original broad water OH bands in 1D IR spectra can be effectively differentiated into six auto peaks located at 3630, 3340, 3230, 3065, 2950 and 2885 cm⁻¹ for PG samples and five auto peaks at 3630, 3330, 3230, 3060 and 2940 cm⁻¹ for FG samples. Based on the rule proposed by Noda, the sequence of the spectral changes in PG samples is as following: NH₃⁺ amino acid > CH₂ and CH₃ aliphatic > OH stretch > carboxylic acid OH stretch > NH in secondary amide > NH in primary amide. In contrast, the sequence was totally in the opposite direction for FG samples and thus both samples provide different 2D correlation spectra ranged from 2800 cm-1 to 3700 cm⁻¹. This method may provide a rapid determination of gelatin source for application in food, pharmaceutical, and cosmetic products.

Keywords: 2 dimensional infrared (2DIR) correlation analysis, Fourier transform infrared- attenuated total reflection (FTIR-ATR), porcine gelatin, tilapia fish gelatin

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Authors: Shan Wang, Fahad Alhathal, Daniel Hobson

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User-centered design skills play an important role in crafting a positive and intuitive user experience for software applications. Embracing a user-centric design approach involves understanding the needs, preferences, and behaviors of the end-users throughout the design process. This mindset not only enhances the usability of the software but also fosters a deeper connection between the digital product and its users. This paper encompasses a 6-month knowledge exchange collaboration project between an academic institution and an external industry in 2023, aims to improve the user experience of a digital platform utilized for a knowledge management tool, to understand users' preferences for features, identify sources of frustration, and pinpoint areas for enhancement. This research conducted one of the most effective methods to implement user-centered design through co-design workshops for testing user onboarding experiences that involve the active participation of users in the design process. More specifically, in January 2023, we organized eight workshops with a diverse group of 11 individuals. Throughout these sessions, we accumulated a total of 11 hours of qualitative data in both video and audio formats. Subsequently, we conducted an analysis of user journeys, identifying common issues and potential areas for improvement. This analysis was pivotal in guiding the knowledge management software in prioritizing feature enhancements and design improvements. Employing a user-centered design thinking process, we developed a series of graphic design solutions in collaboration with the software management tool company. These solutions were targeted at refining onboarding user experiences, workplace interfaces, and interactive design. Some of these design solutions were translated into tangible interfaces for the knowledge management tool. By actively involving users in the design process and valuing their input, developers can create products that are not only functional but also resonate with the end-users, ultimately leading to greater success in the competitive software landscape. In conclusion, this paper not only contributes insights into designing onboarding user experiences for software within a co-design approach but also presents key theories on leveraging the user-centered design process in software design to enhance overall user experiences.

Keywords: user experiences, co-design, design process, knowledge management tool, user-centered design

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Authors: Paul Shize Li, Frank Alber

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A fundamental task of clinical genomics is to unravel the functions of genes and their associations with disorders. Although experimental biology has made efforts to discover and elucidate the molecular mechanisms of individual genes in the past decades, still about 40% of human genes have unknown functions, not to mention the diseases they may be related to. For those biologists who are interested in a particular gene with unknown functions, a powerful computational method tailored for inferring the functions and disease relevance of uncharacterized genes is strongly needed. Studies have shown that genes strongly linked to each other in multiple biological networks are more likely to have similar functions. This indicates that the densely connected subgraphs in multiple biological networks are useful in the functional and phenotypic annotation of uncharacterized genes. Therefore, in this work, we have developed an integrative network approach to identify the frequent local clusters, which are defined as those densely connected subgraphs that frequently occur in multiple biological networks and consist of the query gene that has few or no disease or function annotations. This is a local clustering algorithm that models multiple biological networks sharing the same gene set as a three-dimensional matrix, the so-called tensor, and employs the tensor-based optimization method to efficiently find the frequent local clusters. Specifically, massive public gene expression data sets that comprehensively cover dynamic, physiological, and environmental conditions are used to generate hundreds of gene co-expression networks. By integrating these gene co-expression networks, for a given uncharacterized gene that is of biologist’s interest, the proposed method can be applied to identify the frequent local clusters that consist of this uncharacterized gene. Finally, those frequent local clusters are used for function and disease annotation of this uncharacterized gene. This local tensor clustering algorithm outperformed the competing tensor-based algorithm in both module discovery and running time. We also demonstrated the use of the proposed method on real data of hundreds of gene co-expression data and showed that it can comprehensively characterize the query gene. Therefore, this study provides a new tool for annotating the uncharacterized genes and has great potential to assist clinical genomic diagnostics.

Keywords: local tensor clustering, query gene, gene co-expression network, gene annotation

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Authors: Christodoulakis Georgios, Kiourti Elisavet

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The Covid-19 pandemic has affected millions of people on a global scale, while lockdowns and quarantine measures were adopted periodically by a vast number of countries. These peculiar socio-historical conditions have led to the growth of participation in online environments. At the same time, the official educational bodies of many countries have been forced, for the first time at least for Greece and Cyprus, to switch to distance learning methods throughout the educational levels. However, this has not been done without issues, both in the technological and functional level, concerning the tools and the processes. Video games are the finest example of simulations of distance learning problem-solving environments. They incorporate different semiotic modes (e.g., a combination of image, sound, texts, gesture) while all this takes place in social and cultural constructed contexts. Players interact in the game environment in terms of spaces, objects, and actions in order to accomplish their goals, solve its problems, and win the game. In addition, players are engaging in layering literacies, which include combinations of independent and collaborative, digital and nondigital practices and spaces acting jointly to support meaning making, including interaction among and across texts and modalities (Abrams, 2017). From this point of view, players are engaged in collaborative, self-directed, and interest-based experiences by going back and forth and around gameplay. Within this context, this paper investigates the way Einstown, a greek serious video game, functions as an effective distance learning environment for teaching Greek as a second|foreign language to adults. The research methodology adopted is the case study approach using mixed methods. The participants were two adult women who are immigrants in Greece and who had zero gaming experience. The results of this research reveal that the videogame Einstown is, in fact, a digital environment of literacy through which the participants achieve active learning, cooperation, and engage in digital and non-digital literacy practices that result in improving the learning of specialized vocabulary presented throughout the gameplay.

Keywords: second/foreign language, vocabulary acquisition, literacy, serious video games

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Authors: Badriya Almutairi, Ashraf El-Hamalawi

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Wind energy technologies are considered to be among the most promising types of renewable energy sources due to the growing concerns over climate change and energy security. Kuwait is amongst the countries that began realising the consequences of climate change and the long-term economic and energy security situation, considering options when oil runs out. Added to this are the fluctuating oil prices, rapid increase in population, high electricity consumption and protection of the environment It began to make efforts in the direction of greener solutions for energy needs by looking for alternative forms of energy and assessing potential renewable energy resources, including wind and solar. The aim of this paper is to examine wind energy as an alternative renewable energy source in Kuwait, due to its availability and low cost, reducing the dependency on fossil fuels compared to other forms of renewable energy. This paper will present a life cycle assessment of onshore wind turbine systems in Kuwait, comprising 4 stages; goal and scope of the analysis, inventory analysis, impact assessment and interpretation of the results. It will also provide an assessment of potential renewable energy resources and technologies applied for power generation and the environmental benefits for Kuwait. An optimum location for a site (Shagaya) will be recommended for reasons such as high wind speeds, land availability and distance to the next grid connection, and be the focus of this study. The potential environmental impacts and resources used throughout the wind turbine system’s life-cycle are then analysed using a Life Cycle Assessment (LCA). The results show the total carbon dioxide (CO₂) emission for a turbine with steel pile foundations is greater than emissions from a turbine with concrete foundations by 18 %. The analysis also shows the average CO₂ emissions from electricity generated using crude oil is 645gCO₂/kWh and the carbon footprint per functional unit for a wind turbine ranges between 6.6 g/kWh to 10 g/kWh, an increase of 98%, thus providing cost and environmental benefits by creating a wind farm in Kuwait. Using a cost-benefit analysis, it was also found that the electricity produced from wind energy in Kuwait would cost 17.6fils/kWh (0.05834 $/kWh), which is less than the cost of electricity currently being produced using conventional methods at 22 fils/kW (0.07$/kWh), i.e., a reduction of 20%.

Keywords: CO₂ emissions, Kuwait, life cycle assessment, renewable energy, wind energy

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Authors: Milena Nanova, Radul Shishkov, Damyan Damov, Martin Georgiev

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This research paper presents an in-depth exploration of the use of generative design in urban residential architecture, with a dual focus on aligning aesthetic values with legal and environmental constraints. The study aims to demonstrate how generative design methodologies can innovate residential building designs that are not only legally compliant and environmentally conscious but also aesthetically compelling. At the core of our research is a specially developed generative design framework tailored for urban residential settings. This framework employs computational algorithms to produce diverse design solutions, meticulously balancing aesthetic appeal with practical considerations. By integrating site-specific features, urban legal restrictions, and environmental factors, our approach generates designs that resonate with the unique character of urban landscapes while adhering to regulatory frameworks. The paper places emphasis on algorithmic implementation of the logical constraint and intricacies in residential architecture by exploring the potential of generative design to create visually engaging and contextually harmonious structures. This exploration also contains an analysis of how these designs align with legal building parameters, showcasing the potential for creative solutions within the confines of urban building regulations. Concurrently, our methodology integrates functional, economic, and environmental factors. We investigate how generative design can be utilized to optimize buildings' performance, considering them, aiming to achieve a symbiotic relationship between the built environment and its natural surroundings. Through a blend of theoretical research and practical case studies, this research highlights the multifaceted capabilities of generative design and demonstrates practical applications of our framework. Our findings illustrate the rich possibilities that arise from an algorithmic design approach in the context of a vibrant urban landscape. This study contributes an alternative perspective to residential architecture, suggesting that the future of urban development lies in embracing the complex interplay between computational design innovation, regulatory adherence, and environmental responsibility.

Keywords: generative design, computational design, parametric design, algorithmic modeling

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Authors: Daniela Pisu

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The paper deals with the issue of territorial inequalities focused on the gap of the marginalization of inland areas with respect to the centrality of urban centers as they are subjected to an almost unstoppable demographic hemorrhage in a context marked by the tendency to depopulation such as the Sardinian territory, to which are added further and intense phenomena of de-anthropization. The research question is aimed at exploring the functionality of the interventions envisaged by the Piano Nazionale Ripresa Resilienza for the reduction of territorial imbalances in these areas to the extent that it is possible to identify policy strategies aimed at increasing the relational expertise of citizenship, functional to the consolidation of results in a long-term perspective. In order to answer this question, the qualitative case study on the Municipality of Ulàssai (province of Nuoro) is highlighted as the only winner on the island, with the Pilot Project ‘Where nature meets art’, intended for the cultural and social regeneration of small towns. The main findings, which emerged from the analysis of institutional sources and secondary data, highlight the socio-demographic fragility of the territory in the face of the active institutional commitment to make Ulàssai a smart community, starting from the enhancement of natural resources and the artistic heritage of fellow citizen Maria Lai. The findings drawn from the inspections and focus groups with the youth population present the aforementioned project as a generative opportunity for both the economic and social fabric, leveraging the public debates of the living labs, where the process of public communication becomes the main vector for the exercise of the rights of participatory democracy. The qualitative lunge leads to the conclusion that the repercussions envisaged by the PNRR in internal areas will be able to show their self-sustainable effect through colloquial administrations such as that of Ulàssai, capable of seeing in the interactive paradigm of public communication that natural process with which to reduce that historical sense of extraneousness attributed to the institution-citizenship relationship.

Keywords: social labs, smart community, depopulation, Sardinia, Piano Nazionale di Ripresa e Resilienza

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Authors: Andleeb Zahra, Itrat Rubab, Sumaira Malik, Amina Khan, Muhammad Jawad Khan, M. Qaiser Fatmi

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Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. Recent studies have highlighted the role of miRNA in disease pathology, indicating its potential use in an early diagnostic tool. miRNAs are small, double stranded, non-coding RNAs that regulate gene expression by deregulating mRNAs. miRNAs play important roles in modifying various cellular processes such as cell growth, differentiation, apoptosis, and immune response. Dis-regulated expression of miRNAs is known to affect the cell growth, and this may function as tumor suppressors or oncogenes in various cancers. Objectives: The main objectives of this study were to characterize the extracellular miRNAs involved in oral cancer (OC) to assist early detection of cancer as well as to propose a list of genes that can potentially be used as biomarkers of OC. We used gene expression data by microarrays already available in literature. Materials and Methods: In the first step, a total of 318 miRNAs involved in oral carcinoma were shortlisted followed by the prediction of their target genes. Simultaneously, the differentially expressed genes (DEGs) of oral carcinoma from all experiments were identified. The common genes between lists of DEGs of OC based on experimentally proven data and target genes of each miRNA were identified. These common genes are the targets of specific miRNA, which is involved in OC. Finally, a list of genes was generated which may be used as biomarker of OC. Results and Conclusion: In results, we included some of pathways in cancer to show the change in gene expression under the control of specific miRNA. Ingenuity pathway analysis (IPA) provided a list of major biomarkers like CDH2, CDK7 and functional enrichment analysis identified the role of miRNA in major pathways like cell adhesion molecules pathway affected by cancer. We observed that at least 25 genes are regulated by maximum number of miRNAs, and thereby, they can be used as biomarkers of OC. To better understand the role of miRNA with respect to their target genes further experiments are required, and our study provides a platform to better understand the miRNA-OC relationship at genomics level.

Keywords: biomarkers, gene expression, miRNA, oral carcinoma

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Authors: Sophio Kobauri, David Tugushi, Vladimir P. Torchilin, Ramaz Katsarava

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Hydrophobic / hydrophilically modified functional polymers are of high interest in modern biomedicine due to their ability to solubilize water-insoluble / poorly soluble (hydrophobic) drugs. Among the many approaches that are being developed in this direction, one of the most effective methods is the use of polymeric micelles (PMs) (micelles formed by amphiphilic block-copolymers) for solubilization of hydrophobic biologicals. For therapeutic purposes, PMs are required to be stable and biodegradable, although quite a few amphiphilic block-copolymers are described capable of forming stable micelles with good solubilization properties. For obtaining micelle-forming block-copolymers, polyethylene glycol (PEG) derivatives are desirable to use as hydrophilic shell because it represents the most popular biocompatible hydrophilic block and various hydrophobic blocks (polymers) can be attached to it. Although the construction of the hydrophobic core, due to the complex requirements and micelles structure development, is the very actual and the main problem for nanobioengineers. Considering the above, our research goal was obtaining biodegradable micelles for the solubilization of hydrophobic drugs and biologicals. For this purpose, we used biodegradable polymers– pseudo-proteins (PPs)(synthesized with naturally occurring amino acids and other non-toxic building blocks, such as fatty diols and dicarboxylic acids) as hydrophobic core since these polymers showed reasonable biodegradation rates and excellent biocompatibility. In the present study, we used the hydrophobic amino acid – L-phenylalanine (MW 4000-8000Da) instead of L-leucine. Amino-PEG (MW 2000Da) was used as hydrophilic fragments for constructing the suitable micelles. The molecular weight of PP (the hydrophobic core of micelle) was regulated by variation of used monomers ratios. Micelles were obtained by dissolving of synthesized amphiphilic polymer in water. The micelle-forming property was tested using dynamic light scattering (Malvern zetasizer NanoZSZEN3600). The study showed that obtaining amphiphilic block-copolymer form stable neutral micelles 100 ± 7 nm in size at 10mg/mL concentration, which is considered as an optimal range for pharmaceutical micelles. The obtained preliminary data allow us to conclude that the obtained micelles are suitable for the delivery of poorly water-soluble drugs and biologicals.

Keywords: amino acid – L-phenylalanine, pseudo-proteins, amphiphilic block-copolymers, biodegradable micelles

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Authors: Tarek Soliman Mostafa Soliman Al-Nana'i

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There are non-steady voiced augments in the Semitic languages, and in the morphological and structural augmentation, two sounds were augments in all Semitic languages at the level of the spoken language and two letters at the level of the written language, which are the hamza and the ta’. This research studies only the second of them; Therefore, we defined it as “The Voiceless Dental- alveolar common augment” (VDACA) to distinguish it from the glottal sound “Hamza”, first, middle, or last, in a noun or in a verb, in Arabic and its equivalent in the Semitic languages. What is meant by “VDACA” is the ta’ that is in addition to the root of the word at the morphological level: the word “voiceless” takes out the voiced sounds that we studied before, and the “dental- alveolar common augment” takes out the laryngeal sound of them, which is the “Hamza”: and the word “common” brings out the uncommon voiceless sounds, which are sīn, shīn, and hā’. The study is limited to the ta' alone among the Arabic sounds, and this title faced a problem in identifying it with the ta'. Because the designation of the ta is not the same in most Semitic languages. Hebrew, for example, has “tav” and is pronounced with the voiced fa (v), which is not in Arabic. It is called different names in other Semitic languages, such as “taw” or “tAu” in old Syriac. And so on. This goes hand in hand with the insistence on distance from the written level and the reference to the phonetic aspect in this study that is closely and closely linked to the morphological level. Therefore, the study is “morphophonemic”. What is meant by Semitic languages in this study are the following: Akkadian, Ugaritic, Hebrew, Syriac, Mandaean, Ge'ez, and Amharic. The problem of the study is the agreement or difference between these languages in the position of that augment, first, middle, or last. And in determining the distinguishing characteristics of each language from the other. As for the study methodology, it is determined by the comparative approach in Semitic languages, which is based on the descriptive approach for each language. The study is divided into an introduction, four sections, and a conclusion: Introduction: It included the subject of the study, its importance, motives, problem, methodology, and division. The first section: VDACA as a non-common phoneme. The second: VDACA as a common phoneme. The third: VDACA as a functional morpheme. The fourth section: Commentary and conclusion with the most important results. The positions of VDACA in Arabic and other Semitic languages, and in nouns and verbs, were limited to first, middle, and last. The research identified the individual addition, which is common with other augments, and the research proved that this augmentation is constant in all Semitic languages, but there are characteristics that distinguish each language from the other.

Keywords: voiceless -, dental- alveolar, augment, Arabic - semitic languages

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Authors: Aliaa Mahmoud Issa

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Green tea may provide an alternative treatment for many skin system disorders. Intrinsic or chronological aging represents the structural, functional, and metabolic changes in the skin, which depend on the passage of time per se. The aim of the present study is to compare the effect of green tea extract administration, in drinking water or topically, on the chronological changes of the old Swiss albino mice skin. A total number of forty Swiss albino female mice (Mus musculus) were used; thirty were old females, 50-52 weeks old and the remaining ten young females were about 10 weeks old. The skin of the back of all the studied mice was dehaired with a topical depilatory cream. Treatment with green tea extract was applied in two different ways: in the drinking water (0.5mg/ml/day) or topically, applied to the skin of the dorsal side (6mg/ml water). They were divided into four main groups each of 10 animals: Group I: young untreated, Group II: old untreated groups, Group III: tea-drinking (TD) group, and Group IV: topical tea (TT) group. The animals were euthanized after 3 and 6 weeks from the beginning of green tea extract treatment. The skin was subject to morphometric (epidermal, dermal, and stratum corneum thicknesses; collagen and elastin content) studies. The skin ultrastructure of the groups treated for 6 weeks with the green tea extract was also examined. The old mouse skin was compared to the young one to investigate the chronological changes of the tissue. The results revealed that the skin of mice treated with green tea extract, either topically or to less extent in drinking water, showed a reduction in the aging features manifested by a numerical but statistically insignificant improvement in the morphometric measurements. A remarkable amelioration in the ultrastructure of the old skin was also observed. Generally, green tea extract in the drinking water revealed inconsistent results. The topical application of green tea extract to the skin revealed that the epidermal, dermal and stratum corneum thicknesses and the elastin content, that were statistically significant, approach those of the young group. The ultrastructural study revealed the same observations. The disjunction of the lower epidermal keratinocytes was reduced. It could be concluded that the topical application of green tea extract to the skin of old mice showed improvement in reversing markers of skin system aging more than using the extract in the drinking water.

Keywords: aging, green tea extract, morphometry, skin, ultrastructure

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Authors: Zainab S. Ahmed, Mohammed S. Ali, Nadia A. Elshiekh, Sami Adam Ibrahim, Ghada M. El-Tayeb, Ahmed H. Elsadig, Rihab A. Omer, Sofia B. Mohamed

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Maple syrup urine (MSUD) is an autosomal recessive disease that causes a deficiency in the enzyme branched-chain alpha-keto acid (BCKA) dehydrogenase. The development of disease has been associated with SNPs in the DBT gene. Despite that, the computational analysis of SNPs in coding and noncoding and their functional impacts on protein level still remains unknown. Hence, in this study, we carried out a comprehensive in silico analysis of missense that was predicted to have a harmful influence on DBT structure and function. In this study, eight different in silico prediction algorithms; SIFT, PROVEAN, MutPred, SNP&GO, PhD-SNP, PANTHER, I-Mutant 2.0 and MUpo were used for screening nsSNPs in DBT including. Additionally, to understand the effect of mutations in the strength of the interactions that bind protein together the ELASPIC servers were used. Finally, the 3D structure of DBT was formed using Mutation3D and Chimera servers respectively. Our result showed that a total of 15 nsSNPs confirmed by 4 software (R301C, R376H, W84R, S268F, W84C, F276C, H452R, R178H, I355T, V191G, M444T, T174A, I200T, R113H, and R178C) were found damaging and can lead to a shift in DBT gene structure. Moreover, we found 7 nsSNPs located on the 2-oxoacid_dh catalytic domain, 5 nsSNPs on the E_3 binding domain and 3 nsSNPs on the Biotin Domain. So these nsSNPs may alter the putative structure of DBT’s domain. Furthermore, we detected all these nsSNPs are on the core residues of the protein and have the ability to change the stability of the protein. Additionally, we found W84R, S268F, and M444T have high significance, and they affected Leucine, Isoleucine, and Valine, which reduces or disrupt the function of BCKD complex, E2-subunit which the DBT gene encodes. In conclusion, based on our extensive in-silico analysis, we report 15 nsSNPs that have possible association with protein deteriorating and disease-causing abilities. These candidate SNPs can aid in future studies on Maple Syrup Urine Disease type II base in the genetic level.

Keywords: DBT gene, ELASPIC, in silico analysis, UCSF chimer

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Authors: Milda Nainyte, Viktoras Masevicius

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Biological methylation is a methyl group transfer from S-adenosyl-L-methionine (AdoMet) onto N-, C-, O- or S-nucleophiles in DNA, RNA, proteins or small biomolecules. The reaction is catalyzed by enzymes called AdoMet-dependent methyltransferases (MTases), which represent more than 3 % of the proteins in the cell. As a general mechanism, the methyl group from AdoMet replaces a hydrogen atom of nucleophilic center producing methylated DNA and S-adenosyl-L-homocysteine (AdoHcy). Recently, DNA methyltransferases have been used for the sequence-specific, covalent labeling of biopolymers. Two types of MTase catalyzed labeling of biopolymers are known, referred as two-step and one-step. During two-step labeling, an alkylating fragment is transferred onto DNA in a sequence-specific manner and then the reporter group, such as biotin, is attached for selective visualization using suitable chemistries of coupling. This approach of labeling is quite difficult and the chemical hitching does not always proceed at 100 %, but in the second step the variety of reporter groups can be selected and that gives the flexibility for this labeling method. In the one-step labeling, AdoMet analog is designed with the reporter group already attached to the functional group. Thus, the one-step labeling method would be more comfortable tool for labeling of biopolymers in order to prevent additional chemical reactions and selection of reaction conditions. Also, time costs would be reduced. However, effective AdoMet analog appropriate for one-step labeling of biopolymers and containing cleavable bond, required for reduction of PCR interferation, is still not known. To expand the practical utility of this important enzymatic reaction, cofactors with activated sulfonium-bound side-chains have been produced and can serve as surrogate cofactors for a variety of wild-type and mutant DNA and RNA MTases enabling covalent attachment of these chains to their target sites in DNA, RNA or proteins (the approach named methyltransferase-directed Transfer of Activated Groups, mTAG). Compounds containing hex-2-yn-1-yl moiety has proved to be efficient alkylating agents for labeling of DNA. Herein we describe synthetic procedures for the preparation of N-biotinoyl-N’-(pent-4-ynoyl)cystamine starting from the coupling of cystamine with pentynoic acid and finally attaching the biotin as a reporter group. The synthesis of the first AdoMet based cofactor containing a cleavable reporter group and appropriate for one-step labeling was developed.

Keywords: adoMet analogs, DNA alkylation, cofactor, methyltransferases

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Authors: Raphael Udeh, Luis García De Guadiana Romualdo, Xenia Dolje-Gore

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Background: Quite disturbing is the huge public health impact of COVID-19: As at today [25th March 2021, the COVID-19 global burden shows over 123 million cases and over 2.7 million deaths worldwide. Rationale: Recent evidence shows calprotectin’s potential as a therapeutic target, stating that tasquinimod, from the Quinoline-3-Carboxamide family is capable of blocking the interaction between calprotectin and TLR4. Hence preventing the cytokine release syndrome, that heralds the functional exhaustion in COVID-19. Early preclinical studies showed that tasquinimod inhibit tumor growth and prevent angiogenesis/cytokine storm. Phase I – III clinical studies in prostate cancer showed it has a good safety profile with good radiologic progression free survival but no effect on overall survival. Rationale/hypothesis: Strategic endeavors have been amplified globally to assess new therapeutic interventions for COVID-19 management – thus the clinical and antiviral efficacy of tasquinimod in COVID-19 remains to be explored. Hence the primary objective of this trial will be to evaluate the efficacy of tasquinimod in the treatment of adult patients with severe COVID-19 infections. Therefore, I hypothesise that among adults with COVID19 infection, tasquinimod will reduce the severe respiratory distress associated with COVID-19 compared to placebo, over a 28-day study period. Method: The setting is in Europe. Design – a randomized, placebo-controlled, phase II double-blinded trial. Trial lasts for 28 days from randomization, Tasquinimod capsule given as 0.5mg daily 1st fortnight, then 1mg daily 2nd fortnight. I0 outcome - assessed using six-point ordinal scale alongside eight 20 outcomes. 125 participants to be enrolled, data collection at baseline and subsequent data points, and safety reporting monitored via serological profile. Significance: This work could potentially establish tasquinimod as an effective and safe therapeutic agent for COVID-19 by reducing the severe respiratory distress, related time to recovery, time on oxygen/admission. It will also drive future research – as in larger multi-centre RCT.

Keywords: Calprotectin, COVID-19, Phase II Trial, Tasquinimod

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Authors: Olufunmilola A. Abiodun, Adegbola O. Dauda, Ayobami Ojo, Samson A. Oyeyinka

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Blighia sapida (Ackee) seed is a neglected and under-utilised crop. The fruit is cultivated for the aril which is used as meat substitute in soup while the seed is discarded. The seed is toxic due to the presence of hypoglycin which causes vomiting and death. The seed is shining black and bigger than the legume seeds. The seed contains high starch content which could serve as a cheap source of starch hereby reducing wastage of the crop during its season. Native starch had limitation in their use; therefore, modification of starch had been reported to improve the functional properties of starches. Therefore, this work determined the effect of modification on the properties of Blighia sapida seed starch. Blighia sapida seed was dehulled manually, milled and the starch extracted using standard method. The starch was subjected to modification using four methods (acid, alkaline, oxidized and acetylated methods). The morphological structure, form factor, granule size, amylose, swelling power, hypoglycin and pasting properties of the starches were determined. The structure of Blighia sapida using light microscope showed that the seed starch demonstrated an oval, round, elliptical, dome-shaped and also irregular shape. The form factors of the starch ranged from 0.32-0.64. Blighia sapida seed starches were smaller in granule sizes ranging from 2-6 µm. Acid modified starch had the highest amylose content (24.83%) and was significantly different ( < 0.05) from other starches. Blighia sapida seed starches showed a progressive increase in swelling power as temperature increased in native, acidified, alkalized, oxidized and acetylated starches but reduced with increasing temperature in pregelatinized starch. Hypoglycin A ranged from 3.89 to 5.74 mg/100 g with pregelatinized starch having the lowest value and alkalized starch having the highest value. Hypoglycin B ranged from 7.17 to 8.47 mg/100 g. Alkali-treated starch had higher peak viscosity (3973 cP) which was not significantly different (p > 0.05) from the native starch. Alkali-treated starch also was significantly different (p > 0.05) from other starches in holding strength value while acetylated starch had higher breakdown viscosity (1161.50 cP). Native starch was significantly different (p > 0.05) from other starches in final and setback viscosities. Properties of Blighia sapida modified starches showed that it could be used as a source of starch in food and other non-food industries and the toxic compound found in the starch was very low when compared to lethal dosage.

Keywords: Blighia sapida seed, modification, starch, hypoglycin

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Authors: Sabyasachi Behera, Shiv Kumar, Pramod Gautam, Anisur Rahman, Pawan Pathak, Rahul Bhadouria

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Background: The increasing proportion of population especially urban poor and vulnerable groups or groups with specific needs, with health indicators worse than their rural counterparts in India face various issues related with availability and quality of health care. The reasons are myriad, starting from information and awareness of the community, especially, in a scenario wherein the needs and challenges of floating and migrant urban populations remain poorly understood. Weak linkages between health care facilities and slum dwellers and vulnerable populations hinder the improvement of health services for urban poor. Method: To address this issue, TCIHC program is helping health department of Indore city of Madhya Pradesh to establish a referral mechanism with a dual approach: at both community and facility level. The former is based on the premise of ‘building social capital’, i.e. norms and networks within a community facilitating collective action, helps improve the demand and supply of health services at appropriate levels of care (Minus 2: Accredited Social Health Activist and Community Health Groups; Minus 1: Urban Health Nutrition Days; Zero: Urban Primary Health Center; Plus 1: secondary facility with BEmONC services; Plus 2: secondary facilities with CEmONC services; Plus 3: tertiary level facility) for the urban poor. The latter focuses on encouraging the provision of all services at various levels of service delivery points and stakeholders to function in a coordinated manner to ensure better health service availability and coverage in underserved slum areas. Results: This initiative has enhanced the utilization of community based, primary and secondary level services through defined referral pathways that are clearly known to a community dweller. Conclusion: An ideal referral mechanism should begin with referral at the community level wherein services of a frontline health care provider are accessed by them at their door-step, causing no delay in both understanding and decision on the health issues faced by them.

Keywords: levels of care, linkages, referral mechanism, service delivery

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Authors: Roberto Coppo, Francesca Orso, Daniela Dettori, Elena Quaglino, Lei Nie, Mehran M. Sadeghi, Daniela Taverna

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Malignant melanoma is currently the fifth most common cancer in the white population and it is fatal in its metastatic stage. Several research studies in recent years have provided evidence that cancer initiation and progression are driven by genetic alterations of the tumor and paracrine interactions between tumor and microenvironment. Scattered data show that the Endothelial and Smooth muscle cell-Derived Neuropilin-like molecule (ESDN) controls cell proliferation and movement of stroma and tumor cells. To investigate the role of ESDN in the tumor microenvironment during melanoma progression, murine melanoma cells (B16 or B16-F10) were injected in ESDN knockout mice in order to evaluate how the absence of ESDN in stromal cells could influence melanoma progression. While no effect was found on primary tumor growth, increased cell extravasation and lung metastasis formation was observed in ESDN knockout mice compared to wild type controls. In order to understand how cancer cells cross the endothelial barrier during metastatic dissemination in an ESDN-null microenvironment, structure, and permeability of lung blood vessels were analyzed. Interestingly, ESDN knockout mice showed structurally altered and more permeable vessels compared to wild type animals. Since cell surface molecules mediate the process of tumor cell extravasation, the expression of a panel of extravasation-related ligands and receptors was analyzed. Importantly, modulations of N-cadherin, E-selectin, ICAM-1 and VAP-1 were observed in ESDN knockout endothelial cells, suggesting the presence of a favorable tumor microenvironment which facilitates melanoma cell extravasation and metastasis formation in the absence of ESDN. Furthermore, a potential contribution of immune cells in tumor dissemination was investigated. An increased recruitment of macrophages in the lungs of ESDN knockout mice carrying subcutaneous B16-F10 tumors was found. In conclusion, our data suggest a functional role of ESDN in the tumor microenvironment during melanoma progression and the identification of the mechanisms that regulate tumor cell extravasation could lead to the development of new therapies to reduce metastasis formation.

Keywords: melanoma, tumor microenvironment, extravasation, cell surface molecules

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