Search results for: genetic transformation

Authors: Timur S. Zaripov, Artur K. Gilfanov, Sergei S. Sazhin, Steven M. Begg, Morgan R. Heikal

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The calculation of the concentration of inertial droplets in complex flows is encountered in the modelling of numerous engineering and environmental phenomena; for example, fuel droplets in internal combustion engines and airborne pollutant particles. The results of recent research, focused on the development of methods for calculating concentration and their implementation in the commercial CFD code, ANSYS Fluent, is presented here. The study is motivated by the investigation of the mixture preparation processes in internal combustion engines with direct injection of fuel sprays. Two methods are used in our analysis; the Fully Lagrangian method (also known as the Osiptsov method) and the Eulerian approach. The Osiptsov method predicts droplet concentrations along path lines by solving the equations for the components of the Jacobian of the Eulerian-Lagrangian transformation. This method significantly decreases the computational requirements as it does not require counting of large numbers of tracked droplets as in the case of the conventional Lagrangian approach. In the Eulerian approach the average droplet velocity is expressed as a function of the carrier phase velocity as an expansion over the droplet response time and transport equation can be solved in the Eulerian form. The advantage of the method is that droplet velocity can be found without solving additional partial differential equations for the droplet velocity field. The predictions from the two approaches were compared in the analysis of the problem of a dilute gas-droplet flow around an infinitely long, circular cylinder. The concentrations of inertial droplets, with Stokes numbers of 0.05, 0.1, 0.2, in steady-state and transient laminar flow conditions, were determined at various Reynolds numbers. In the steady-state case, flows with Reynolds numbers of 1, 10, and 100 were investigated. It has been shown that the results predicted using both methods are almost identical at small Reynolds and Stokes numbers. For larger values of these numbers (Stokes — 0.1, 0.2; Reynolds — 10, 100) the Eulerian approach predicted a wider spread in concentration in the perturbations caused by the cylinder that can be attributed to the averaged droplet velocity field. The transient droplet flow case was investigated for a Reynolds number of 200. Both methods predicted a high droplet concentration in the zones of high strain rate and low concentrations in zones of high vorticity. The maxima of droplet concentration predicted by the Osiptsov method was up to two orders of magnitude greater than that predicted by the Eulerian method; a significant variation for an approach widely used in engineering applications. Based on the results of these comparisons, the Osiptsov method has resulted in a more precise description of the local properties of the inertial droplet flow. The method has been applied to the analysis of the results of experimental observations of a liquid gasoline spray at representative fuel injection pressure conditions. The preliminary results show good qualitative agreement between the predictions of the model and experimental data.

Keywords: internal combustion engines, Eulerian approach, fully Lagrangian approach, gasoline fuel sprays, droplets and particle concentrations

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Authors: Su Mon Saw, Joe Rothnagel

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Short open reading frames (sORFs) located in 5’UTR of mRNAs are known as uORFs. Characterization of uORF-encoded peptides (uPEPs) i.e., a subset of short open reading frame encoded peptides (sPEPs) and their translation regulation lead to understanding of causes of genetic disease, proteome complexity and development of treatments. Existence of uORFs within cellular proteome could be detected by LC-MS/MS. The ability of uORF to be translated into uPEP and achievement of uPEP identification will allow uPEP’s characterization, structures, functions, subcellular localization, evolutionary maintenance (conservation in human and other species) and abundance in cells. It is hypothesized that a subset of sORFs are translatable and that their encoded sPEPs are functional and are endogenously expressed contributing to the eukaryotic cellular proteome complexity. This project aimed to investigate whether sORFs encode functional peptides. Liquid chromatography-mass spectrometry (LC-MS) and bioinformatics were thus employed. Due to probable low abundance of sPEPs and small in sizes, the need for efficient peptide enrichment strategies for enriching small proteins and depleting the sub-proteome of large and abundant proteins is crucial for identifying sPEPs. Low molecular weight proteins were extracted using SDS-PAGE from Human Embryonic Kidney (HEK293) cells and Strong Cation Exchange Chromatography (SCX) from secreted HEK293 cells. Extracted proteins were digested by trypsin to peptides, which were detected by LC-MS/MS. The MS/MS data obtained was searched against Swiss-Prot using MASCOT version 2.4 to filter out known proteins, and all unmatched spectra were re-searched against human RefSeq database. ProteinPilot v5.0.1 was used to identify sPEPs by searching against human RefSeq, Vanderperre and Human Alternative Open Reading Frame (HaltORF) databases. Potential sPEPs were analyzed by bioinformatics. Since SDS PAGE electrophoresis could not separate proteins <20kDa, this could not identify sPEPs. All MASCOT-identified peptide fragments were parts of main open reading frame (mORF) by ORF Finder search and blastp search. No sPEP was detected and existence of sPEPs could not be identified in this study. 13 translated sORFs in HEK293 cells by mass spectrometry in previous studies were characterized by bioinformatics. Identified sPEPs from previous studies were <100 amino acids and <15 kDa. Bioinformatics results showed that sORFs are translated to sPEPs and contribute to proteome complexity. uPEP translated from uORF of SLC35A4 was strongly conserved in human and mouse while uPEP translated from uORF of MKKS was strongly conserved in human and Rhesus monkey. Cross-species conserved uORFs in association with protein translation strongly suggest evolutionary maintenance of coding sequence and indicate probable functional expression of peptides encoded within these uORFs. Translation of sORFs was confirmed by mass spectrometry and sPEPs were characterized with bioinformatics.

Keywords: bioinformatics, HEK293 cells, liquid chromatography-mass spectrometry, ProteinPilot, Strong Cation Exchange Chromatography, SDS-PAGE, sPEPs

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Authors: Liou Shyhnan, Chia Han Yang

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The study aims to investigate the promotion of innovation in the development of cultural and creative industries (CCI) and apply research on culture and creativity to this promotion. Using the research perspectives of culture and creativity as the starting points, this study has examined the challenges, trends, and opportunities that have emerged from the development of the CCI until the present. It is found that a definite context of cause and effect exist between them, and that a homologous theoretical basis can be used to understand and interpret them. Based on the characteristics of the aforementioned challenges and trends, this study has compiled two main theoretical systems for conducting research on culture and creativity: (i) reciprocal process between creativity and culture, and (ii) a mechanism for innovation involving multicultural convergence. Both theoretical systems were then used as the foundation to arrive at possible research propositions relating to the two developmental systems. This was respectively done through identification of the theoretical context through a literature review, and interviews and observations of actual case studies within Taiwan’s CCI. In so doing, the critical factors that can address the aforementioned challenges and trends were discovered. Our results indicated that, for reciprocal process between creativity and culture, we recognize that culture serves as creative resources in cultural and creative industries. According to shared consensus, culture provides symbolic meanings and emotional attachment for products and experiences offered by CCI. Besides, different cultures vary in their effects on creativity processes and standards, thus engendering distinctive preferences for and evaluations of the creative expressions and experiences of CCIs. In addition, we identify that creativity serves as the engine for driving the continuation and rebirth of cultures. Accounting for the core of culture, the employment of technology, design, and business facilitates the transformation and innovation mechanism for promoting culture continuity. In addition, with cultural centered, the digital technology, design thinking, and business model are critical constitutes of the innovation mechanism to promote the cultural continuity. Regarding cultural preservation and regeneration of local spaces and folk customs, we argue that the preservation and regeneration of local spaces and cultural cultures must embody the interactive experiences of present-day life. And cultural space and folk custom would regenerate with interact and experience in modern life. Regarding innovation mechanism for multicultural convergence, we propose that innovative stakeholders from different disciplines (e.g., creators, designers, engineers, and marketers) in CCIs rely on the establishment of a cocreation mechanism to promote interdisciplinary interaction. Furthermore, CCI development needs to develop a cocreation mechanism for enhancing the interdisciplinary collaboration among CCI innovation stakeholders. We further argue multicultural mixing would enhance innovation in developing CCI, and assuming an open and mutually enlightening attitude to enrich one another’s cultures in the multicultural exchanges under globalization will create diversity in homogenous CCIs. Finally, for promoting innovation in developing cultural and creative industries, we further propose a model for joint knowledge creation that can be established for enhancing the mutual reinforcement of theoretical and practical research on culture and creativity.

Keywords: culture and creativity, innovation, cultural and creative industries, cultural mixing

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Authors: Arsyam Mawardi, Sony Suhandono, Azzania Fibriani, Fifi Fitriyah Masduki

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Malaria is an infectious disease caused by Plasmodium sp. This disease has a high prevalence in Indonesia, especially in Jayapura. The vaccine that is currently being developed has not been effective in overcoming malaria. This is due to the high polymorphism in the Plasmodium genome especially in areas that encode Plasmodium surface proteins. Merozoite Surface Protein 1 (MSP1) Plasmodium falciparum is a surface protein that plays a role in the invasion process in human erythrocytes through the interaction of Glycophorin A protein receptors and sialic acid in erythrocytes with Reticulocyte Binding Proteins (RBP) and Duffy Adhesion Protein (DAP) ligands in merozoites. MSP1 can be targeted to be a specific antigen and predicted epitope area which will be used for the development of diagnostic and malaria vaccine therapy. MSP1 consists of 17 blocks, each block is dimorphic, and has been marked as the K1 and MAD20 alleles. Exceptions only in block 2, because it has 3 alleles, among others K1, MAD20 and RO33. These polymorphisms cause allelic variations and implicate the severity of patients infected P. falciparum. In addition, polymorphism of MSP1 in Jayapura isolates has not been reported so it is interesting to be further identified and projected as a specific antigen. Therefore, in this study, we analyzed the allele polymorphism as well as detected the MSP1 epitope antigen candidate on block 2 P. falciparum. Clinical samples of selected malaria patients followed the consecutive sampling method, examining malaria parasites with blood preparations on glass objects observed through a microscope. Plasmodium DNA was isolated from the blood of malarial positive patients. The block 2 MSP1 gene was amplified using PCR method and cloned using the pGEM-T easy vector then transformed to TOP'10 E.coli. Positive colonies selection was performed with blue-white screening. The existence of target DNA was confirmed by PCR colonies and DNA sequencing methods. Furthermore, DNA sequence analysis was done through alignment and formation of a phylogenetic tree using MEGA 6 software and insilico analysis using IEDB software to predict epitope candidate for P. falciparum. A total of 15 patient samples have been isolated from Plasmodium DNA. PCR amplification results show the target gene size about ± 1049 bp. The results of MSP1 nucleotide alignment analysis reveal that block 2 MSP1 genes derived from the sample of malarial patients were distributed in four different allele family groups, K1 (7), MAD20 (1), RO33 (0) and MSP1_Jayapura (10) alleles. The most commonly appears of the detected allele is MSP1_Jayapura single allele. There was no significant association between sex variables, age, the density of parasitemia and alel variation (Mann Whitney, U > 0.05), while symptomatic signs have a significant difference as a trigger of detectable allele variation (U < 0.05). In this research, insilico study shows that there is a new epitope antigen candidate from the MSP1_Jayapura allele and it is predicted to be recognized by B cells with 17 amino acid lengths in the amino acid sequence 187 to 203.

Keywords: epitope candidate, insilico analysis, MSP1 P. falciparum, polymorphism

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Authors: Anthony F. Peressini

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The concept of race has recently come prominently back into discussion in the context of medicine and medical science, along with renewed effort to biologize racial concepts. This paper argues that this renewed effort to biologize race by way of medicine and population genetics fail on their own terms, and more importantly, that the philosophical project of biologizing race ought to be recognized for what it is—a retrograde racial project—and abandoned. There is clear agreement that standard racial categories and concepts cannot be grounded in the old way of racial naturalism, which understand race as a real, interest-independent biological/metaphysical category in which its members share “physical, moral, intellectual, and cultural characteristics.” But equally clear is the very real and pervasive presence of racial concepts in individual and collective consciousness and behavior, and so it remains a pressing area in which to seek deeper understanding. Recent philosophical work has endeavored to reconcile these two observations by developing a “thin” conception of race, grounded in scientific concepts but without the moral and metaphysical content. Such “thin,” science-based analyses take the “commonsense” or “folk” sense of race as it functions in contemporary society as the starting point for their philosophic-scientific projects to biologize racial concepts. A “philosophic-scientific analysis” is a special case of the cornerstone of analytic philosophy: a conceptual analysis. That is, a rendering of a concept into the more perspicuous concepts that constitute it. Thus a philosophic-scientific account of a concept is an attempt to work out an analysis of a concept that makes use of empirical science's insights to ground, legitimate and explicate the target concept in terms of clearer concepts informed by empirical results. The focus in this paper is on three recent philosophic-scientific cases for retaining “race” that all share this general analytic schema, but that make use of “medical necessity,” population genetics, and human genetic clustering, respectively. After arguing that each of these three approaches suffers from internal difficulties, the paper considers the general analytic schema employed by such biologizations of race. While such endeavors are inevitably prefaced with the disclaimer that the theory to follow is non-essentialist and non-racialist, the case will be made that such efforts are not neutral scientific or philosophical projects but rather are what sociologists call a racial project, that is, one of many competing efforts that conjoin a representation of what race means to specific efforts to determine social and institutional arrangements of power, resources, authority, etc. Accordingly, philosophic-scientific biologizations of race, since they begin from and condition their analyses on “folk” conceptions, cannot pretend to be “prior to” other disciplinary insights, nor to transcend the social-political dynamics involved in formulating theories of race. As a result, such traditional philosophical efforts can be seen to be disciplinarily parochial and to address only a caricature of a large and important human problem—and thereby further contributing to the unfortunate isolation of philosophical thinking about race from other disciplines.

Keywords: population genetics, ontology of race, race-based medicine, racial formation theory, racial projects, racism, social construction

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Authors: Neil Fourati

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Collaboration between public and private stakeholders for agricultural development are today lacking in Tunisia. The last dictatorship witnessed by the country has deteriorated the necessary trust between the state and small farmers for the realization of development projects, in particular in the interior, disadvantaged regions of the country. These regions, where the youth unemployment rate is above 30%, have been the heart of the uprising that preceded the revolution. The transitional period that the country is going through since 2011 is an opportunity for the emergence of new governance systems in the context of the decentralization. The latter is recognized in the 2nd Tunisian Republic constitution as the basis of regional management. Civil society participation to the decision-making process is considered as a mean to identify measures that are more coherent with local populations’ needs. The development of agriculture and food value chains in rural areas is relevant within the framework of the implementation of new decisions systems that require public-private collaborations. These new systems can lead to actions in favor of improving living conditions of rural populations. The diverisification of activities around agriculture can be a solution for job creation and local value creation. The project for the promotion of sustainable agriculture and rural development in Tunisia has designed and implemented a multi-stakeholder dialogue process for the development of local value chains platforms in disadvantaged areas of the country. The platforms gather public and private organizations ; as well civil society organizations ; that intervene in a locality in relation to the production transformation or product’s commercialization. The role of these platforms is to formulate realize and evaluate collaborative actions or projects for the promotion of the concerned product and territory. The dialogue process steps allow to create the necessary collaboration conditions in order to promote viable collectivities, dynamic economies and healthy environments. Effectively, the dialogue process steps allow to identify the local leaders. These leaders recognize the development constraints and opportunities. They deal with key and gathering subjects around the collaborative projects or actions. They take common decisions in order to create effective coalitions for the implementation of common actions. The plateforms realize quick success so as to build trust. The project has supported the formulation of 22 collaborative projects. Seven priority collaborative projects have been realized. Each collaborative project includes 3 parts : the signature of the collaboration conventions between public and private organizations, investment in the relevant material in order to increase productivity and the quality of local and products and finally management and technical training in favour of producers’ organizations for the promotion of local products. The implementation of this process has enabled to enhance the capacities of collaboration between local actors : producers, traders, processors and support structures from public sector and civil society. It also allowed to improve the efficiency and relevance of actions and measures for agriculture and rural development programs. Thus, the process for the development of local value chain platform is a basis for sustainable development of agriculture.

Keywords: governance, public private collaboration, rural development, value chains

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Authors: Evren Aysev Denec

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As an urban settlement dating as early as 8000 years and the capital for Byzantine and Ottoman empires; İstanbul has been a significant global city throughout history. The most drastic changes in the macro form of Istanbul have taken place in the last seven decades; starting from 1950’s with rapid industrialization and population growth; pacing up after the 1980’s with the efforts of integration to the global capitalist system; reaching to a climax in the 2000’s with the adaptation of a neoliberal urban regime. Today, the rate of urbanization together with land speculation and real estate investment has been growing enormously. Every inch of urban land is conceptualized as a commodity to be capitalized. This neoliberal mindset has many controversial implementations, from the privatization of public land to the urban transformation of historic neighbourhoods and consumption of natural resources. The planning decisions concerning the city have been mainly top down initiations; conceptualising historical, cultural and natural heritage as commodities to be capitalised and consumed in favour of creating rent value. One of the most crucial implementations of this neoliberal urban regime is the project of establishing a ‘new city’ around northern Istanbul; together with a number of large-scale infrastructural projects such as the Third Bosporus Bridge; a new highway system, a Third Airport Project and a secondary Bosporus project called the ‘Canal Istanbul’. Urbanizing northern Istanbul is highly controversial as this area consists of major natural resources of the city; being the northern forests, water supplies and wildlife; which are bound to be destroyed to a great extent following the implementations. The construction of the third bridge and the third airport has begun in 2013, despite environmental objections and protests. Over five hundred thousand trees are planned be cut for solely the construction of the bridge and the Northern Marmara Motorway. Yet the real damage will be the urbanization of the forest area; irreversibly corrupting the natural resources and attracting millions of additional population towards Istanbul. Furthermore, these projects lack an integrated planning scope as the plans prepared for Istanbul are constantly subjected to alterations forced by the central government. Urban interventions mentioned above are executed despite the rulings of Istanbul Environmental plan, due to top down planning decisions. Instead of an integrated action plan that prepares for the future of the city, Istanbul is governed by partial plans and projects that are issued by a profit based agenda; supported by legal alterations and laws issued by the central government. This paper aims to discuss the ongoing implementations with regards to northern Istanbul; claiming that they are not merely infrastructural interventions but parts of a greater neoliberal urbanization strategy. In the course of the study, firstly a brief account on the northern forests of Istanbul will be presented. Then, the projects will be discussed in detail, addressing how the current planning schemes deal with the natural heritage of the city. Lastly, concluding remarks on how the implementations could affect the future of Istanbul will be presented.

Keywords: Istanbul, urban design, urban planning, natural resources

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Authors: Banafsheh Nikmehr, Mohsen Bahrami, Yueqiang Song, Anuradha Koduru, Ayse K. Vuruskan, Hongkun Lu, Mallory Pitts, Tolga B. Mesen, Tamer M. Yalcinkaya

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The number of people who receive in vitro fertilization (IVF) treatment has increased on a startling trajectory over the past two decades. Despite advances in this field, particularly the introduction of intracytoplasmic sperm injection (ICSI) and the preimplantation genetic screening (PGS), the IVF success remains low. A major factor contributing to IVF failure is embryonic aneuploidy (abnormal chromosome content), which often results in miscarriage and birth defects. Although PGS is often used as the standard diagnostic tool to identify aneuploid embryos, it is an invasive approach that could affect the embryo development, and yet inaccessible to many patients due its high costs. As such, there is a clear need for a non-invasive cost-effective approach to identify euploid embryos for single embryo transfer (SET). The reported differences between morphokinetic behaviors of aneuploid and euploid embryos has shown promise to address this need. However, current literature is inconclusive and further research is urgently needed to translate current findings into clinical diagnostics. In this ongoing study, we found significant differences between morphokinetic behaviors of euploid and aneuploid embryos that provides important insights and reaffirms the promise of such behaviors for developing non-invasive methodologies. Methodology—A total of 242 embryos (euploid: 149, aneuploid: 93) from 74 patients who underwent IVF treatment in Carolinas Fertility Clinics in Winston-Salem, NC, were analyzed. All embryos were incubated in an EmbryoScope incubator. The patients were randomly selected from January 2019 to June 2021 with most patients having both euploid and aneuploid embryos. All embryos reached the blastocyst stage and had known PGS outcomes. The ploidy assessment was done by a third-party testing laboratory on day 5-7 embryo biopsies. The morphokinetic variables of each embryo were measured by the EmbryoViewer software (Uniesense FertiliTech) on time-lapse images using 7 focal depths. We compared the time to: pronuclei fading (tPNf), division to 2,3,…,9 cells (t2, t3,…,t9), start of embryo compaction (tSC), Morula formation (tM), start of blastocyst formation (tSC), blastocyst formation (tB), and blastocyst expansion (tEB), as well as intervals between them (e.g., c23 = t3 – t2). We used a mixed regression method for our statistical analyses to account for the correlation between multiple embryos per patient. Major Findings— The average age of the patients was 35.04 yrs. The average patient age associated with euploid and aneuploid embryos was not different (P = 0.6454). We found a significant difference in c45 = t5-t4 (P = 0.0298). Our results indicated this interval on average lasts significantly longer for aneuploid embryos - c45(aneuploid) = 11.93hr vs c45(euploid) = 7.97hr. In a separate analysis limited to embryos from the same patients (patients = 47, total embryos=200, euploid=112, aneuploid=88), we obtained the same results (P = 0.0316). The statistical power for this analysis exceeded 87%. No other variable was different between the two groups. Conclusion— Our results demonstrate the importance of morphokinetic variables as potential biomarkers that could aid in non-invasively characterizing euploid and aneuploid embryos. We seek to study a larger population of embryos and incorporate the embryo quality in future studies.

Keywords: IVF, embryo, euploidy, aneuploidy, morphokinteic

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Authors: Julia Kapr, Andrea Rossi, Haribaskar Ramachandran, Marius Pollet, Ilka Egger, Selina Dangeleit, Katharina Koch, Jean Krutmann, Ellen Fritsche

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It is widely acknowledged that animal models do not always represent human disease. Especially human brain development is difficult to model in animals due to a variety of structural and functional species-specificities. This causes significant discrepancies between predicted and apparent drug efficacies in clinical trials and their subsequent failure. Emerging alternatives based on 3D in vitro approaches, such as human brain spheres or organoids, may in the future reduce and ultimately replace animal models. Here, we present a human induced pluripotent stem cell (hiPSC)-based 3D neural in a vitro disease model for the Cockayne Syndrome B (CSB). CSB is a rare hereditary disease and is accompanied by severe neurologic defects, such as microcephaly, ataxia and intellectual disability, with currently no treatment options. Therefore, the aim of this study is to investigate the molecular and cellular defects found in neural hiPSC-derived CSB models. Understanding the underlying pathology of CSB enables the development of treatment options. The two CSB models used in this study comprise a patient-derived hiPSC line and its isogenic control as well as a CSB-deficient cell line based on a healthy hiPSC line (IMR90-4) background thereby excluding genetic background-related effects. Neurally induced and differentiated brain sphere cultures were characterized via RNA Sequencing, western blot (WB), immunocytochemistry (ICC) and multielectrode arrays (MEAs). CSB-deficiency leads to an altered gene expression of markers for autophagy, focal adhesion and neural network formation. Cell migration was significantly reduced and electrical activity was significantly increased in the disease cell lines. These data hint that the cellular pathologies is possibly underlying CSB. By induction of autophagy, the migration phenotype could be partially rescued, suggesting a crucial role of disturbed autophagy in defective neural migration of the disease lines. Altered autophagy may also lead to inefficient mitophagy. Accordingly, disease cell lines were shown to have a lower mitochondrial base activity and a higher susceptibility to mitochondrial stress induced by rotenone. Since mitochondria play an important role in neurotransmitter cycling, we suggest that defective mitochondria may lead to altered electrical activity in the disease cell lines. Failure to clear the defective mitochondria by mitophagy and thus missing initiation cues for new mitochondrial production could potentiate this problem. With our data, we aim at establishing a disease adverse outcome pathway (AOP), thereby adding to the in-depth understanding of this multi-faced disorder and subsequently contributing to alternative drug development.

Keywords: autophagy, disease modeling, in vitro, pluripotent stem cells

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Authors: Simone Raimondi De Souza, Glaucia Maria Moraes De Oliveira, Ronir Raggio Luiz, Glorimar Rosa

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Introduction: Obesity is among the main risk factors for cardiovascular disease (CVD). Genesis is multifactorial, including genetic, hormonal and environmental factors disorders, among which inadequate feeding pattern, for which nutritional counseling strategies have proven effective. The consumption of beta-glucans (soluble fibers that reportedly promote satiety) present in oat bran can be an effective strategy for preventing and treating obesity. Other benefits have been observed with oat bran consumption, such as reduction of hypercholesterolemia and hyperglycemia, two other risk factors for CVD. Objectives: To analyze the effect of oat bran consumption associated with nutritional counseling in reducing body mass index (BMI), blood cholesterol, glucose profile, waist and neck circumference in obese individuals, and to evaluate the change in eating pattern. Methods: clinical trial, randomized, double-blind, placebo-controlled, lasting 90 days with adults of both genders, with BMI ≥30kg/m2. The study was approved by the Ethics in Research involving human beings in a public institute of cardiology, in Rio de Janeiro, Brazil. Individuals were invited to participate and accepted formally by signing the Terms of Consent. Participants were randomized into oat bran group (gOB) or placebo group (gPCB) and received, respectively: morning prepared consisting of 40g oat bran, 30g of skimmed milk powder and 1g sweetener sucralose; refined flour 40g rice, 30g of milk powder and 1g sweetener sucralose. The Ten Steps to Healthy Eating, of Brazilian Ministry of Health were used to support the nutritional counseling. Variables analyzed: gender; age; BMI, waist circumference (WC) neck circumference (NC); systolic blood pressure (SBP); diastolic blood pressure (DBP); food consumption, total cholesterol (TC), LDL-cholesterol (LDL-c), HDL-cholesterol (HDL-c), non-HDL cholesterol (nHDLc), triglycerides (TG), fasting glucose (FG), fasting insulin (FI) and HOMA-IR. Dietary intake was assessed by 24-hour dietary recall. The Diet Quality Index revised for the Brazilian population (IQD-R) assessed quality of feeding pattern. Statistical analyzes were performed using SPSS version 21, considering statistically significant p-value less than 0.05. Results: A total of 38 participants were included, age = 50 ± 7,6years, 63% women. 19 subjects were placed in gOB and 19 in gPCB. After intervention, statistically significant reductions were observed in the following parameters: in gOB: IQD-R, TC, LDL-c, nHDL-c, FI, SBP, DBP, BMI, WC, NC; in gPCB: IQD-R, LDL-c, SBP, DBP, BMI, WC, NC. No statistically significant differences were observed in the results between groups. Conclusion: Our results reinforce nutritional counseling as important strategy for prevention and treatment of obesity and suggest that inclusion of oat bran in daily diet can bring additional benefits controlling risk factors for CVD. More studies are needed to establish all benefits of oat bran to human health as well as the ideal daily dose for consumption.

Keywords: oat bran, cardiovascular disease, nutritional counseling, obesity

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Authors: Nisha Sharma, Mili Kaur, Ashutosh Halder, Seema Kaushal, Manoj Kumar, Manish Jain

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Purpose: To investigate microRNAs (miRNA) as an epigenomic etiological factor in idiopathic non-obstructive azoospermia (NOA). In order to achieve the same, an association was seen between occupational exposure to radiation, thermal, and chemical factors and idiopathic cases of non-obstructive azoospermia, and later, testicular differential miRNA expression profiling was done in exposure group NOA cases. Method: It is a prospective study in which 200 apparent idiopathic male factor infertility cases, who have been advised to undergo testicular fine needle aspiration (FNA) evaluation, are recruited. A detailed occupational history was taken to understand the possible type of exposure due to the nature and duration of work. A total of 26 patients were excluded upon XY-FISH and Yq microdeletion tests due to the presence of genetic causes of infertility, 6 hypospermatogeneis (HS), six Sertoli cell-only syndrome (SCOS), and six normospermatogeneis patients testicular FNA samples were used for RNA isolation followed by small RNA sequencing and nCounter miRNA expression analysis. Differential miRNA expression profile of HS and SCOS patients was done. A web-based tool, miRNet, was used to predict the interacting compounds or chemicals using the shortlisted miRNAs with high fold change. The major limitation encountered in this study was the insufficient quantity of testicular FNA sample used for total RNA isolation, which resulted in a low yield and RNA integrity number (RIN) value. Therefore, the number of RNA samples admissible for differential miRNA expression analysis was very small in comparison to the total number of patients recruited. Results: Differential expression analysis revealed 69 down-regulated and 40 up-regulated miRNAs in HS and 66 down-regulated and 33 up-regulated miRNAs in SCOS in comparison to normospermatogenesis controls. The miRNA interaction analysis using the miRNet tool showed that the differential expression profiles of HS and SCOS patients were associated with arsenic trioxide, bisphenol-A, calcium sulphate, lithium, and cadmium. These compounds are reproductive toxins and might be responsible for miRNA-mediated epigenetic deregulation leading to NOA. The association between occupational risk factor exposure and the non-exposure group of NOA patients was not statistically significant, with ꭓ2 (3, N= 178) = 6.70, p= 0.082. The association between individual exposure groups (radiation, thermal, and chemical) and various sub-types of NOA is also not significant, with ꭓ2 (9, N= 178) = 15.06, p= 0.089. Functional analysis of HS and SCOS patients' miRNA profiles revealed some important miR-family members in terms of male fertility. The miR-181 family plays a role in the differentiation of spermatogonia and spermatocytes, as well as the transcriptional regulation of haploid germ cells. The miR-34 family is expressed in spermatocytes and round spermatids and is involved in the regulation of SSCs differentiation. Conclusion: The reproductive toxins might adopt the miRNA-mediated mechanism of disease development in idiopathic cases of NOA. Chemical compound induced; miRNA-mediated epigenetic deregulation can give a future perspective on the etiopathogenesis of the disease.

Keywords: microRNA, non-obstructive azoospermia (NOA), occupational exposure, hypospermatogenesis (HS), Sertoli cell only syndrome (SCOS)

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Authors: Kamyar Tolouei, Ehsan Moosavi

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In open-pit mines, the long-term production scheduling optimization problem (LTPSOP) is a complicated problem that contains constraints, large datasets, and uncertainties. Uncertainty in the output is caused by several geological, economic, or technical factors. Due to its dimensions and NP-hard nature, it is usually difficult to find an ideal solution to the LTPSOP. The optimal schedule generally restricts the ore, metal, and waste tonnages, average grades, and cash flows of each period. Past decades have witnessed important measurements of long-term production scheduling and optimal algorithms since researchers have become highly cognizant of the issue. In fact, it is not possible to consider LTPSOP as a well-solved problem. Traditional production scheduling methods in open-pit mines apply an estimated orebody model to produce optimal schedules. The smoothing result of some geostatistical estimation procedures causes most of the mine schedules and production predictions to be unrealistic and imperfect. With the expansion of simulation procedures, the risks from grade uncertainty in ore reserves can be evaluated and organized through a set of equally probable orebody realizations. In this paper, to synthesize grade uncertainty into the strategic mine schedule, a stochastic integer programming framework is presented to LTPSOP. The objective function of the model is to maximize the net present value and minimize the risk of deviation from the production targets considering grade uncertainty simultaneously while satisfying all technical constraints and operational requirements. Instead of applying one estimated orebody model as input to optimize the production schedule, a set of equally probable orebody realizations are applied to synthesize grade uncertainty in the strategic mine schedule and to produce a more profitable and risk-based production schedule. A mixture of metaheuristic procedures and mathematical methods paves the way to achieve an appropriate solution. This paper introduced a hybrid model between the augmented Lagrangian relaxation (ALR) method and the metaheuristic algorithm, the Harris Hawks optimization (HHO), to solve the LTPSOP under grade uncertainty conditions. In this study, the HHO is experienced to update Lagrange coefficients. Besides, a machine learning method called Random Forest is applied to estimate gold grade in a mineral deposit. The Monte Carlo method is used as the simulation method with 20 realizations. The results specify that the progressive versions have been considerably developed in comparison with the traditional methods. The outcomes were also compared with the ALR-genetic algorithm and ALR-sub-gradient. To indicate the applicability of the model, a case study on an open-pit gold mining operation is implemented. The framework displays the capability to minimize risk and improvement in the expected net present value and financial profitability for LTPSOP. The framework could control geological risk more effectively than the traditional procedure considering grade uncertainty in the hybrid model framework.

Keywords: grade uncertainty, metaheuristic algorithms, open-pit mine, production scheduling optimization

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Authors: Fang Bin Guo, Emma Roberts, Haibin Du, Yonggang Wang, Yu Chen, Xiuli Ge

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This paper explores the findings so far from a major externally-funded project which operates internationally in China, Germany and the UK. The research team is working in the context of the redevelopment of post-industrial sites in China and how these might be platforms for creative enterprises and thereby, the economy and welfare to flourish. Results from the project are anticipated to inform urban design policies in China and possibly farther afield. The research has utilised ethnographic studies and participatory design methods to investigate alternative strategies for sustainable urban renewal of China’s post-industrial areas. Additionally, it has undertaken comparative studies of successful examples of European and Chinese urban regeneration cases. The international cross-disciplinary team has been seeking different opportunities for developing relevant creative industries whilst retaining cultural and industrial heritage. This paper will explore the research conducted so far by the team and offer initial findings. Findings point out the development challenges of cities respecting the protection of local culture/heritages, history of the industries and transformation of the local economies. The preliminary results and pilot analysis of the current research have demonstrated that local government policyholders, business investors/developers and creative industry practitioners are the three major stakeholders that will impact city revitalisations. These groups are expected to work together with asynchronous vision in order for redevelopments to be successful. Meanwhile, local geography, history, culture, politics, economy and ethnography have been identified as important factors that impact on project design and development during urban transformations. Data is being processed from the team’s research conducted across the focal Western and Chinese cities. This has provided theoretical guidance and practical support to the development of significant experimental projects. Many were re-examined with a more international perspective, and adjustments have been based on the conclusions of the research. The observations and research are already generating design solutions in terms of ascertaining essential site components, layouts, visual design and practical facilities for regenerated sites. Two significant projects undertaken by this project team have been nominated by the central Chinese government as the most successful exemplars. They have been listed as outstanding national industry heritage projects; in particular, one of them was nominated by ArchDaily as Building of the Year 2019, and so this project outcome has made a substantial contribution to research and innovation. In summary, this paper will outline the funded project, discuss the work conducted so far, and pinpoint the initial discoveries. It will detail the future steps and indicate how these will impact on national and local governments in China, designers, local citizens and building users.

Keywords: cultural & industrial heritages, ethnographic research, participatory design, regeneration of post-industrial sites, sustainable

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Authors: Yuna Lee

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In the current policy process, there has been a growing interest in more open approaches that incorporate creativity and innovation based on the forecasting groups composed by the public and experts together into scientific data-driven foresight methods to implement more effective policymaking. Especially, citizen participation as collective intelligence in policymaking with design and deep scale of innovation at the global level has been developed and human-centred design thinking is considered as one of the most promising methods for strategic foresight. Yet, there is a lack of a common theoretical foundation for a comprehensive approach for the current situation of and post-COVID-19 era, and substantial changes in policymaking practice are insignificant and ongoing with trial and error. This project hypothesized that rigorously developed policy systems and tools that support strategic foresight by considering the public understanding could maximize ways to create new possibilities for a preferable future, however, it must involve a better understating of Behavioural Insights, including individual and cultural values, profit motives and needs, and psychological motivations, for implementing holistic and multilateral foresight and creating more positive possibilities. To what extent is the policymaking system theoretically possible that incorporates the holistic and comprehensive foresight and policy process implementation, assuming that theory and practice, in reality, are different and not connected? What components and environmental conditions should be included in the strategic foresight system to enhance the capacity of decision from policymakers to predict alternative futures, or detect uncertainties of the future more accurately? And, compared to the required environmental condition, what are the environmental vulnerabilities of the current policymaking system? In this light, this research contemplates the question of how effectively policymaking practices have been implemented through the synthesis of scientific, technology-oriented innovation with the strategic design for tackling complex societal challenges and devising more significant insights to make society greener and more liveable. Here, this study conceptualizes the notions of a new collaborative way of strategic foresight that aims to maximize mutual benefits between policy actors and citizens through the cooperation stemming from evolutionary game theory. This study applies mixed methodology, including interviews of policy experts, with the case in which digital transformation and strategic design provided future-oriented solutions or directions to cities’ sustainable development goals and society-wide urgent challenges such as COVID-19. As a result, artistic and sensual interpreting capabilities through strategic design promote a concrete form of ideas toward a stable connection from the present to the future and enhance the understanding and active cooperation among decision-makers, stakeholders, and citizens. Ultimately, an improved theoretical foundation proposed in this study is expected to help strategically respond to the highly interconnected future changes of the post-COVID-19 world.

Keywords: policymaking, strategic design, sustainable innovation, evolution of cooperation

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Authors: Till Gramberg, Erwin Gross, Christoph Birenbaum

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This paper presents the approach of the Easy2IoT research project. Easy2IoT aims to enable companies in the prefabrication sheet metal and sheet metal processing industry to enter the Industrial Internet of Things (IIoT) with a low-threshold and cost-effective approach. It focuses on the development of physical hardware and software to easily capture machine activities from on a sawing machine, benefiting various stakeholders in the SME value chain, including machine operators, tool manufacturers and service providers. The methodological approach of Easy2IoT includes an in-depth requirements analysis and customer interviews with stakeholders along the value chain. Based on these insights, actions, requirements and potential solutions for smart services are derived. The focus is on providing actionable recommendations, competencies and easy integration through no-/low-code applications to facilitate implementation and connectivity within production networks. At the core of the project is a novel, non-invasive measurement and analysis system that can be easily deployed and made IIoT-ready. This system collects machine data without interfering with the machines themselves. It does this by non-invasively measuring the tension on a sawing machine. The collected data is then connected and analyzed using artificial intelligence (AI) to provide smart services through a platform-based application. Three Smart Services are being developed within Easy2IoT to provide immediate benefits to users: Wear part and product material condition monitoring and predictive maintenance for sawing processes. The non-invasive measurement system enables the monitoring of tool wear, such as saw blades, and the quality of consumables and materials. Service providers and machine operators can use this data to optimize maintenance and reduce downtime and material waste. Optimize Overall Equipment Effectiveness (OEE) by monitoring machine activity. The non-invasive system tracks machining times, setup times and downtime to identify opportunities for OEE improvement and reduce unplanned machine downtime. Estimate CO2 emissions for connected machines. CO2 emissions are calculated for the entire life of the machine and for individual production steps based on captured power consumption data. This information supports energy management and product development decisions. The key to Easy2IoT is its modular and easy-to-use design. The non-invasive measurement system is universally applicable and does not require specialized knowledge to install. The platform application allows easy integration of various smart services and provides a self-service portal for activation and management. Innovative business models will also be developed to promote the sustainable use of the collected machine activity data. The project addresses the digitalization gap between large enterprises and SME. Easy2IoT provides SME with a concrete toolkit for IIoT adoption, facilitating the digital transformation of smaller companies, e.g. through retrofitting of existing machines.

Keywords: smart services, IIoT, IIoT-platform, industrie 4.0, big data

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Authors: Orit Wolf

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Classical music performance is undergoing a profound transformation, marked by a confluence of technological advancements and evolving cultural dynamics. This academic paper explores the multifaceted changes and challenges faced by classical music performance, considering the impact of artificial intelligence (AI) along with other vital factors shaping this evolution. In the contemporary era, classical music is experiencing shifts in performance practices. This paper delves into these changes, emphasizing the need for adaptability within the classical music world. From repertoire selection and concert formats to artistic expression, performers and institutions navigate a delicate balance between tradition and innovation. We explore how these changes impact the authenticity and vitality of classical music performances. Furthermore, the influence of AI in the classical music concert world cannot be underestimated. AI technologies are making inroads into various aspects, from composition assistance to rehearsal and live performances. This paper examines the transformative effects of AI, considering how it enhances precision, adaptability, and creative exploration for musicians. We explore the implications for composers, performers, and the overall concert experience while addressing ethical concerns and creative opportunities. In addition to AI, there is the importance of cross-genre interactions within the classical music sphere. Mash-ups and collaborations with artists from diverse musical backgrounds are redefining the boundaries of classical music and creating works that resonate with a wider and more diverse audience. The benefits of cross-pollination in classical music seem crucial, offering a fresh perspective to listeners. As an active concert artist, Orit Wolf will share how the expectations of classical music audiences are evolving. Modern concertgoers seek not only exceptional musical performances but also immersive experiences that may involve technology, multimedia, and interactive elements. This paper examines how classical musicians and institutions are adapting to these changing expectations, using technology and innovative concert formats to deliver a unique and enriched experience to their audiences. As these changes and challenges reshape the classical music world, the need for a harmonious coexistence of tradition, technology, and innovation becomes evident. Musicians, composers, and institutions are striving to find a balance that ensures classical music remains relevant in a rapidly changing cultural landscape while maintaining the value it brings to compositions and audiences. This paper, therefore, aims to explore the evolving trends in classical music performance. It considers the influence of AI as one element within the broader context of change, highlighting the necessity of adaptability, cross-genre interactions, and a response to evolving audience expectations. By doing so, the classical music world can navigate this transformative period while preserving its timeless traditions and adding value to both performers and listeners. Orit Wolf, an international concert pianist, fulfils her vision to bring this music in new ways to mass audiences and will share her personal and professional experience as an artist who goes on stage and makes disruptive concerts.

Keywords: cross culture collaboration, music performance and ai, classical music in the digital age, classical concerts, innovation and technology, performance innovation, audience engagement in classical concerts

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Authors: Wen Liu, Errol Haarhoff, Lee Beattie

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In 2010, New Zealand’s central government re-organise the local governments arrangements in Auckland, New Zealand by amalgamating its previous regional council and seven supporting local government units into a single unitary council, the Auckland Council. The Auckland Council is charged with providing local government services to approximately 1.5 million people (a third of New Zealand’s total population). This includes addressing Auckland’s strategic urban growth management and setting its urban planning policy directions for the next 40 years. This is expressed in the first ever spatial plan in the region – the Auckland Plan (2012). The Auckland plan supports implementing a compact city model by concentrating the larger part of future urban growth and development in, and around, existing and proposed transit centres, with the intention of Auckland to become globally competitive city and achieving ‘the most liveable city in the world’. Turning that vision into reality is operatized through the statutory land use plan, the Auckland Unitary Plan. The Unitary plan replaced the previous regional and local statutory plans when it became operative in 2016, becoming the ‘rule book’ on how to manage and develop the natural and built environment, using land use zones and zone standards. Common to the broad range of literature on urban growth management, one significant issue stands out about intensification. The ‘gap’ between strategic planning and what has been achieved is evident in the argument for the ‘compact’ urban form. Although the compact city model may have a wide range of merits, the extent to which these are actualized largely rely on how intensification actually is delivered. The transformation of the rhetoric of the residential intensification model into reality is of profound influence, yet has enjoyed limited empirical analysis. In Auckland, the establishment of the Auckland Plan set up the strategies to deliver intensification into diversified arenas. Nonetheless, planning policy itself does not necessarily achieve the envisaged objectives, delivering the planning system and high capacity to enhance and sustain plan implementation is another demanding agenda. Though the Auckland Plan provides a wide ranging strategic context, its actual delivery is beholden on the Unitary Plan. However, questions have been asked if the Unitary Plan has the necessary statutory tools to deliver the Auckland Plan’s policy outcomes. In Auckland, there is likely to be continuing tension between the strategies for intensification and their envisaged objectives, and made it doubtful whether the main principles of the intensification strategies could be realized. This raises questions over whether the Auckland Plan’s policy goals can be achieved in practice, including delivering ‘quality compact city’ and residential intensification. Taking Auckland as an example of traditionally sprawl cities, this article intends to investigate the efficacy plan making and implementation directed towards higher density development. This article explores the process of plan development, plan making and implementation frameworks of the first ever spatial plan in Auckland, so as to explicate the objectives and processes involved, and consider whether this will facilitate decision making processes to realize the anticipated intensive urban development.

Keywords: urban intensification, sustainable development, plan making, governance and implementation

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Authors: Rania Raouf Sedky

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Adaptive architecture relates to buildings specifically designed to adapt to their residents and their environments. To design a biologically adaptive system, we can observe how living creatures in nature constantly adapt to different external and internal stimuli to be a great inspiration. The issue is not just how to create a system that is capable of change but also how to find the quality of change and determine the incentive to adapt. The research examines the possibilities of transforming spaces using the human body as an active tool. The research also aims to design and build an effective dynamic structural system that can be applied on an architectural scale and integrate them all into the creation of a new adaptive system that allows us to conceive a new way to design, build and experience architecture in a dynamic manner. The main objective was to address the possibility of a reciprocal transformation between the user and the architectural element so that the architecture can adapt to the user, as the user adapts to architecture. The motivation is the desire to deal with the psychological benefits of an environment that can respond and thus empathize with human emotions through its ability to adapt to the user. Adaptive affiliations of kinematic structures have been discussed in architectural research for more than a decade, and these issues have proven their effectiveness in developing kinematic structures, responsive and adaptive, and their contribution to 'smart architecture'. A wide range of strategies have been used in building complex kinetic and robotic systems mechanisms to achieve convertibility and adaptability in engineering and architecture. One of the main contributions of this research is to explore how the physical environment can change its shape to accommodate different spatial displays based on the movement of the user’s body. The main focus is on the relationship between materials, shape, and interactive control systems. The intention is to develop a scenario where the user can move, and the structure interacts without any physical contact. The soft form of shifting language and interaction control technology will provide new possibilities for enriching human-environmental interactions. How can we imagine a space in which to construct and understand its users through physical gestures, visual expressions, and response accordingly? How can we imagine a space whose interaction depends not only on preprogrammed operations but on real-time feedback from its users? The research also raises some important questions for the future. What would be the appropriate structure to show physical interaction with the dynamic world? This study concludes with a strong belief in the future of responsive motor structures. We imagine that they are developing the current structure and that they will radically change the way spaces are tested. These structures have obvious advantages in terms of energy performance and the ability to adapt to the needs of users. The research highlights the interface between remote sensing and a responsive environment to explore the possibility of an interactive architecture that adapts to and responds to user movements. This study ends with a strong belief in the future of responsive motor structures. We envision that it will improve the current structure and that it will bring a fundamental change to the way in which spaces are tested.

Keywords: adaptive architecture, interactive architecture, responsive architecture, tensegrity

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Authors: Ronald Orth, Johanna Haunschild, Sara Tsog

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The bioeconomy is an inter- and cross-disciplinary field covering a large number and wide scope of existing and emerging technologies. It has a great potential to contribute to the transformation process of industry landscape and ultimately drive the economy towards sustainability. However, bioeconomy per se is not necessarily sustainable and technology should be seen as an enabler rather than panacea to all our ecological, social and economic issues. Therefore, to draw and maximize benefits from bioeconomy in terms of sustainability, we propose that innovative activities should encompass not only novel technologies and bio-based new materials but also multifocal innovations. For multifocal innovation endeavors, innovation management plays a substantial role, as any innovation emerges in a complex iterative process where communication and knowledge exchange among relevant stake holders has a pivotal role. The knowledge generation and innovation are although at the core of transition towards a more sustainable bio-based economy, to date, there is a significant lack of concepts and models that approach bioeconomy from the innovation management approach. The aim of this paper is therefore two-fold. First, it inspects the role of transformative approach in the adaptation of bioeconomy that contributes to the environmental, ecological, social and economic sustainability. Second, it elaborates the importance of technology and innovation management as a tool for smooth, prompt and effective transition of firms to the bioeconomy. We conduct a qualitative literature study on the sustainability challenges that bioeconomy entails thus far using Science Citation Index and based on grey literature, as major economies e.g. EU, USA, China and Brazil have pledged to adopt bioeconomy and have released extensive publications on the topic. We will draw an example on the forest based business sector that is transforming towards the new green economy more rapidly as expected, although this sector has a long-established conventional business culture with consolidated and fully fledged industry. Based on our analysis we found that a successful transition to sustainable bioeconomy is conditioned on heterogenous and contested factors in terms of stakeholders , activities and modes of innovation. In addition, multifocal innovations occur when actors from interdisciplinary fields engage in intensive and continuous interaction where the focus of innovation is allocated to a field of mutually evolving socio-technical practices that correspond to the aims of the novel paradigm of transformative innovation policy. By adopting an integrated and systems approach as well as tapping into various innovation networks and joining global innovation clusters, firms have better chance of creating an entire new chain of value added products and services. This requires professionals that have certain capabilities and skills such as: foresight for future markets, ability to deal with complex issues, ability to guide responsible R&D, ability of strategic decision making, manage in-depth innovation systems analysis including value chain analysis. Policy makers, on the other hand, need to acknowledge the essential role of firms in the transformative innovation policy paradigm.

Keywords: bioeconomy, innovation and technology management, multifocal innovation, sustainability, transformative innovation policy

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Authors: Mariam Khaled, Noha Farag, Ghada Mohamed Abdel Salam, Khaled Abu-Aisha, Mohamed El-Azizi

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Gastric and colorectal cancers are among the most frequent causes of cancer-associated mortalities in Africa. They have been considered as a global public health concern, as nearly one million new cases are reported per year. IL-1β is a pro-inflammatory cytokine-produced by activated macrophages and monocytes- and a member of the IL-1 family. The inactive IL-1β precursor is cleaved and activated by caspase-1 enzyme, which itself is activated by the assembly of intracellular structures defined as NLRP3 (Nod Like receptor P3) inflammasomes. Activated IL-1β stimulates the Interleukin-1 receptor type-1 (IL-1R1), which is responsible for the initiation of a signal transduction pathway leading to cell proliferation. It has been proven that the IL-1β gene is a highly polymorphic gene in which single nucleotide polymorphisms (SNPs) may affect its expression. It has been previously reported that SNPs including base transitions between C and T at positions, -511 (C-T; dbSNP: rs16944) and -31 (C-T; dbSNP: rs1143627), from the transcriptional start site, contribute to the pathogenesis of gastric and colorectal cancers by affecting IL-1β levels. Altered production of IL-1β due to such polymorphisms is suspected to stimulate an amplified inflammatory response and promote Epithelial Mesenchymal Transition leading to malignancy. Allele frequency distribution of the IL-1β-31 and -511 SNPs, in different populations, and their correlation to the incidence of gastric and colorectal cancers, has been intriguing to researchers worldwide. The current study aims to investigate allele distributions of the IL-1β SNPs among gastric and colorectal cancers Egyptian patients. In order to achieve to that, 89 Biopsy and surgical specimens from the antrum and corpus mucosa of chronic gastritis subjects and gastric and colorectal carcinoma patients was collected for DNA extraction followed by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). The amplified PCR products of IL-1β-31C > T and IL-1β-511T > C were digested by incubation with the restriction endonuclease enzymes ALu1 and Ava1. Statistical analysis was carried out to determine the allele frequency distribution in the three studied groups. Also, the effect of the IL-1β -31 and -511 SNPs on nuclear factor binding was analyzed using Fluorescence Electrophoretic Mobility Shift Assay (EMSA), preceded by nuclear factor extraction from gastric and colorectal tissue samples and LPS stimulated monocytes. The results of this study showed that a significantly higher percentage of Egyptian gastric cancer patients have a homozygous CC genotype at the IL-1β-31 position and a heterozygous TC genotype at the IL-1β-511 position. Moreover, a significantly higher percentage of the colorectal cancer patients have a homozygous CC genotype at the IL-1β-31 and -511 positions as compared to the control group. In addition, the EMSA results showed that IL-1β-31C/T and IL-1β-511T/C SNPs do not affect nuclear factor binding. Results of this study suggest that the IL-1β-31 C/T and IL-1β-511 T/C may be correlated to the incidence of gastric cancer in Egyptian patients; however, similar findings couldn’t be proven in the colorectal cancer patients group for the IL-1β-511 T/C SNP. This is the first study to investigate IL-1β -31 and -511 SNPs in the Egyptian population.

Keywords: colorectal cancer, Egyptian patients, gastric cancer, interleukin-1β, single nucleotide polymorphisms

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Authors: Javad Jozaei, Rob G. Bell, Paula Blackett, Scott A. Stephens

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In the last few decades, Social Vulnerability Assessment (SVA) has been a favoured means in evaluating the susceptibility of social systems to drivers of change, including climate change and natural disasters. However, the application of SVA to inform responsive and practical strategies to deal with uncertain climate change impacts has always been challenging, and typically agencies resort back to conventional risk/vulnerability assessment. These challenges include complex nature of social vulnerability concepts which influence its applicability, complications in identifying and measuring social vulnerability determinants, the transitory social dynamics in a changing environment, and unpredictability of the scenarios of change that impacts the regime of vulnerability (including contention of when these impacts might emerge). Research suggests that the conventional quantitative approaches in SVA could not appropriately address these problems; hence, the outcomes could potentially be misleading and not fit for addressing the ongoing uncertain rise in risk. The second phase of New Zealand’s Resilience to Nature’s Challenges (RNC2) is developing a forward-looking vulnerability assessment framework and methodology that informs the decision-making and policy development in dealing with the changing coastal systems and accounts for complex dynamics of New Zealand’s coastal systems (including socio-economic, environmental and cultural). Also, RNC2 requires the new methodology to consider plausible drivers of incremental and unknowable changes, create mechanisms to enhance social and community resilience; and fits the New Zealand’s multi-layer governance system. This paper aims to analyse the conventional approaches and methodologies in SVA and offer recommendations for more responsive approaches that inform adaptive decision-making and policy development in practice. The research adopts a qualitative research design to examine different aspects of the conventional SVA processes, and the methods to achieve the research objectives include a systematic review of the literature and case study methods. We found that the conventional quantitative, reductionist and deterministic mindset in the SVA processes -with a focus the impacts of rapid stressors (i.e. tsunamis, floods)- show some deficiencies to account for complex dynamics of social-ecological systems (SES), and the uncertain, long-term impacts of incremental drivers. The paper will focus on addressing the links between resilience and vulnerability; and suggests how resilience theory and its underpinning notions such as the adaptive cycle, panarchy, and system transformability could address these issues, therefore, influence the perception of vulnerability regime and its assessment processes. In this regard, it will be argued that how a shift of paradigm from ‘specific resilience’, which focuses on adaptive capacity associated with the notion of ‘bouncing back’, to ‘general resilience’, which accounts for system transformability, regime shift, ‘bouncing forward’, can deliver more effective strategies in an era characterised by ongoing change and deep uncertainty.

Keywords: complexity, social vulnerability, resilience, transformation, uncertain risks

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Authors: Sachin Mulmi Shrestha, Xin Fang, Hui Ye, Lihua Ren, Qinghua Ji, Ruihua Shi

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Background: Esophageal squamous cell carcinoma (ESCC) is a tumor arising from esophageal epithelial cells and is one of the major disease subtype in Asian countries, including China. Esophageal cancer is the 7th highest incidence based on the 2020 data of GLOBOCAN. The pathogenesis of cancer is still not well understood as many molecular and genetic basis of esophageal carcinogenesis has yet to be clearly elucidated. Circular RNAs are RNA molecules that are formed by back-splicing covalently joined 3′- and 5′-endsrather than canonical splicing, and recent data suggest circular RNAs could sponge miRNAs and are enriched with functional miRNA binding sites. Hence, we studied the mechanism of circular RNA, its biological function, and the relationship between microRNA in the carcinogenesis of ESCC. Methods: 4 pairs of normal and esophageal cancer tissues were collected in Zhongda hospital, affiliated to Southeast University, and high-throughput RNA sequencing was done. The result revealed that circ_0032746 was upregulated, and thus we selected circ_0032746 for further study. The backsplice junction of circRNA was validated by sanger sequence, and stability was determined by RNASE R assay. The binding site of circRNA and microRNA was predicted by circinteractome,mirandaand RNAhybrid database. Furthermore, circRNA was silenced by siRNA and then by lentivirus. The regulatory axis of circ0032746/miR4270 was validated by shRNA, mimic, and inhibitor transfection. Then, in vitro experiments were performed to assess the role of circ0032746 on proliferation (CCK-8 assay and colon formation assay), migration and invasion (Transewell assay), and apoptosis of ESCC. Results: The upregulated circ0032746 was validated in 9 pairs of tissues and 5 types of cell lines by qPCR, which showed high expression and was statistically significant (P<0.005) ). Upregulated circ0032746 was silenced by shRNA, which showed significant knockdown in KYSE 30 and TE-1 cell lines expression compared to control. Nuclear and cytoplasmic mRNA fraction experiment displayed the cytoplasmic location of circ0032746. The sponging of miR4270 was validated by co-transfection of sh-circ0032746 and mimic or inhibitor. Transfection with mimic showed the decreased expression of circ_0032746, whereas inhibitor inhibited the result. In vitro experiments showed that silencing of circ_0032746 inhibited the proliferation, migration, and invasion compared to the negative control group. The apoptosis was seen higher in a knockdown group than in the control group. Furthermore, 11 common mircoRNA target mRNAs were predicted by Targetscan, MirTarbase, and miRanda database, which may further play role in the pathogenesis. Conclusion: Our results showed that novel circ_0032746 is upregulated in ESCC and plays role in itsoncogenicity. Silencing of circ_0032746 inhibits the proliferation and migration of ESCC whereas increases the apoptosis of cancer cells. Hence, circ0032746 acts as an oncogene in ESCC by sponging with miR4270 and could be a potential biomarker in the diagnosis of ESCC in the future.

Keywords: circRNA, esophageal squamous cell carcinoma, microRNA, upregulated

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Authors: Tiziana Ferrero-Regis, Marissa Lindquist

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Circular Economy (CE) is increasingly seen as the reorganisation of production and consumption, and cities are acknowledged as the sources of many ecological and social problems; at the same time, they can be re-imagined through an ecologically and socially resilient future. The concept of the CE has received pointed critiques for its techno-deterministic orientation, focus on science and transformation by the policy. At the heart of our local re-imagining of the CE into circularity through contact zones there is the acknowledgment of collective, spontaneous and shared imaginations of alternative and sustainable futures through the creation of networks of community initiatives that are transformative, creating opportunities that simultaneously make cities rich and enrich humans. This paper presents a mapping project of the fashion and textile ecosystem in Brisbane, Queensland, Australia. Brisbane is currently the most aspirational city in Australia, as its population growth rate is the highest in the country. Yet, Brisbane is considered the least “fashion city” in the country. In contrast, the project revealed a greatly enhanced picture of distinct fashion and textile clusters across greater Brisbane and the adjacency of key services that may act to consolidate CE community contact zones. Clusters to the north of Brisbane and several locales to the south are zones of a greater mix between public/social amenities, walkable zones and local transport networks with educational precincts, community hubs, concentration of small enterprises, designers, artisans and waste recovery centers that will help to establish knowledge of key infrastructure networks that will support enmeshing these zones together. The paper presents two case studies of independent designers who work on new and re-designed clothing through recovering pre-consumer textiles and that operate from within creative precincts. The first case is designer Nelson Molloy, who recently returned to the inner city suburb of West End with their Chasing Zero Design project. The area was known in the 1980s and 1990s for its alternative lifestyle with creative independent production, thrifty clothing shops, alternative fashion and a socialist agenda. After 30 years of progressive gentrification of the suburb, which has dislocated many of the artists, designers and artisans, West End is seeing the return and amplification of clusters of artisans, artists, designers and architects. The other case study is Practice Studio, located in a new zone of creative growth, Bowen Hills, north of the CBD. Practice Studio combines retail with a workroom, offers repair and remaking services, becoming a point of reference for young and emerging Australian designers and artists. The paper demonstrates the spatial politics of the CE and the way in which new cultural capital is produced thanks to cultural specificities and resources. It argues for the recognition of contact zones that are created by local actors, communities and knowledge networks, whose grass-roots agency is fundamental for the co-production of CE’s systems of local governance.

Keywords: contact zones, circular citities, fashion and textiles, circular neighbourhoods, australia

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

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

Keywords: CRISPR, nanoparticles, brain diseases, administration routes

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Authors: Aathira Peedikaparambil Somasundaran

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The beginning of the 20th century marked the perios when a new generation of Lebanese radicals sowed the seeds for the second phase of Levant literary modernism, situated in the Levant. Beirut, during this era popularly fit every radical writer’s criterion owing to its weakened censorship and political control, despite the absence of a protective womb for the development of literary modernism, caused by the natively prevalent political unsettlement. The third stage of literary modernization, in which scholars used Western-inspired critical techniques to better understand their own cultures, coincides with the time period examined in this paper, which involved the international-inspired critical analysis of native cultural stimulants, which raised questions among Arab freethinking intellectuals. Locals who ventured outside recognised the difference between the West's progress and their own nations' stagnation. The awareness of such ‘gap of success’ aroused an ambition from journalists, authors, and proletarian revolutionaries who had studied in Europe, and finally developed enlightened ideas. Some Middle Eastern authors and artists only adopted current social and political frameworks after discovering western modernity. After learning about the upheavals that were happening in the West, these thinkers aspired to bring about equally broad drastic developments in their own country's social, political, and cultural milieu. These occurrences illustrate the increased power of migration to alter the cultural and literary scene in the Levant. The paper intends to discuss the different effects of migration that contributed to Levant literary modernism. The exploration of these factors as causes begins with addressing the politically influenced activism, that has always been a relevant part of Beirut, and then diving into the psychological effects of migration in the individuals of the society, which might have induced an accommodability to alien thoughts and ideas over time, as a coping mechanism. Nature or environmental stimuli, a common trigger for any creative output, often having the highest influence during travel will be identified and analysed to inspect the extent of its impact on the exchange of ideas that resulted in Levant modernism. The efficiency of both the stimulating component of travel and the diaspora of the indigenous, a by-product of travel in catalysing modernism in the Levant has to be proven in order to understand how migration indirectly affected the transmission and adoption of ideas in Levant literature. The paper will revisit the events revolving around these key players and platforms like Shir, to understand how the Lebanese literature, tied down in poetry drastically mutated under the leadership of Adonis, Yusuf et Khal, and other pioneers of Levant literary modernism. The conclision will identify the triggers that helped authors overcome personal and geographical barriers to unite the West and the Levant, and investigate the extent to which the bi-directional migration prompted a transformation in the local poetry. Consequently, the paper aims to shed light into the unique factor that provoked the shift in the literary scene of Twentieth century in the Middle East.

Keywords: literature, modernism, Middle East, levant, Beirut

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Authors: Haohua Zong, Marios Kotsonis

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Plasma synthetic jet actuator (PSJA) is a new concept of zero net mass flow actuator which utilizes pulsed arc/spark discharge to rapidly pressurize gas in a small cavity under constant-volume conditions. The unique combination of high exit jet velocity (>400 m/s) and high actuation frequency (>5 kHz) provides a promising solution for high-speed high-Reynolds-number flow control. This paper focuses on the performance of PSJA in repetitive working mode which is more relevant to future flow control applications. A two-electrodes PSJA (cavity volume: 424 mm3, orifice diameter: 2 mm) together with a capacitive discharge circuit (discharge energy: 50 mJ-110 mJ) is designed to enable repetitive operation. Time-Resolved Particle Imaging Velocimetry (TR-PIV) system working at 10 kHz is exploited to investigate the influence of discharge frequency on performance of PSJA. In total, seven cases are tested, covering a wide range of discharge frequencies (20 Hz-560 Hz). The pertinent flow features (shock wave, vortex ring and jet) remain the same for single shot mode and repetitive working mode. Shock wave is issued prior to jet eruption. Two distinct vortex rings are formed in one cycle. The first one is produced by the starting jet whereas the second one is related with the shock wave reflection in cavity. A sudden pressure rise is induced at the throat inlet by the reflection of primary shock wave, promoting the shedding of second vortex ring. In one cycle, jet exit velocity first increases sharply, then decreases almost linearly. Afterwards, an alternate occurrence of multiple jet stages and refresh stages is observed. By monitoring the dynamic evolution of exit velocity in one cycle, some integral performance parameters of PSJA can be deduced. As frequency increases, the jet intensity in steady phase decreases monotonically. In the investigated frequency range, jet duration time drops from 250 µs to 210 µs and peak jet velocity decreases from 53 m/s to approximately 39 m/s. The jet impulse and the expelled gas mass (0.69 µN∙s and 0.027 mg at 20 Hz) decline by 48% and 40%, respectively. However, the electro-mechanical efficiency of PSJA defined by the ratio of jet mechanical energy to capacitor energy doesn’t show significant difference (o(0.01%)). Fourier transformation of the temporal exit velocity signal indicates two dominant frequencies. One corresponds to the discharge frequency, while the other accounts for the alternation frequency of jet stage and refresh stage in one cycle. The alternation period (300 µs approximately) is independent of discharge frequency, and possibly determined intrinsically by the actuator geometry. A simple analytical model is established to interpret the alternation of jet stage and refresh stage. Results show that the dynamic response of exit velocity to a small-scale disturbance (jump in cavity pressure) can be treated as a second-order under-damping system. Oscillation frequency of the exit velocity, namely alternation frequency, is positively proportional to exit area, but inversely proportional to cavity volume and throat length. Theoretical value of alternation period (305 µs) agrees well with the experimental value.

Keywords: plasma, synthetic jet, actuator, frequency effect

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Authors: Faheema Khan

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To investigate the ability of sensitive and tolerant genotype of Glycine max to adapt to a saline environment in a field, we examined the growth performance, water relation and activities of antioxidant enzymes in relation to photosynthetic rate, chlorophyll a fluorescence, photosynthetic pigment concentration, protein and proline in plants exposed to salt stress. Ten soybean genotypes (Pusa-20, Pusa-40, Pusa-37, Pusa-16, Pusa-24, Pusa-22, BRAGG, PK-416, PK-1042, and DS-9712) were selected and grown hydroponically. After 3 days of proper germination, the seedlings were transferred to Hoagland’s solution (Hoagland and Arnon 1950). The growth chamber was maintained at a photosynthetic photon flux density of 430 μmol m−2 s−1, 14 h of light, 10 h of dark and a relative humidity of 60%. The nutrient solution was bubbled with sterile air and changed on alternate days. Ten-day-old seedlings were given seven levels of salt in the form of NaCl viz., T1 = 0 mM NaCl, T2=25 mM NaCl, T3=50 mM NaCl, T4=75 mM NaCl, T5=100 mM NaCl, T6=125 mM NaCl, T7=150 mM NaCl. The investigation showed that genotype Pusa-24, PK-416 and Pusa-20 appeared to be the most salt-sensitive. genotypes as inferred from their significantly reduced length, fresh weight and dry weight in response to the NaCl exposure. Pusa-37 appeared to be the most tolerant genotype since no significant effect of NaCl treatment on growth was found. We observed a greater decline in the photosynthetic variables like photosynthetic rate, chlorophyll fluorescence and chlorophyll content, in salt-sensitive (Pusa-24) genotype than in salt-tolerant Pusa-37 under high salinity. Numerous primers were verified on ten soybean genotypes obtained from Operon technologies among which 30 RAPD primers shown high polymorphism and genetic variation. The Jaccard’s similarity coefficient values for each pairwise comparison between cultivars were calculated and similarity coefficient matrix was constructed. The closer varieties in the cluster behaved similar in their response to salinity tolerance. Intra-clustering within the two clusters precisely grouped the 10 genotypes in sub-cluster as expected from their physiological findings.Salt tolerant genotype Pusa-37, was further analysed by 2-Dimensional gel electrophoresis to analyse the differential expression of proteins at high salt stress. In the Present study, 173 protein spots were identified. Of these, 40 proteins responsive to salinity were either up- or down-regulated in Pusa-37. Proteomic analysis in salt-tolerant genotype (Pusa-37) led to the detection of proteins involved in a variety of biological processes, such as protein synthesis (12 %), redox regulation (19 %), primary and secondary metabolism (25 %), or disease- and defence-related processes (32 %). In conclusion, the soybean plants in our study responded to salt stress by changing their protein expression pattern. The photosynthetic, biochemical and molecular study showed that there is variability in salt tolerance behaviour in soybean genotypes. Pusa-24 is the salt-sensitive and Pusa-37 is the salt-tolerant genotype. Moreover this study gives new insights into the salt-stress response in soybean and demonstrates the power of genomic and proteomic approach in plant biology studies which finally could help us in identifying the possible regulatory switches (gene/s) controlling the salt tolerant genotype of the crop plants and their possible role in defence mechanism.

Keywords: glycine max, salt stress, RAPD, genomic and proteomic variability

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Authors: Massimiliano Biagini, Marco Spinsanti, Gabriella De Angelis, Sara Tomei, Ilaria Ferlenghi, Maria Scarselli, Alessia Biolchi, Alessandro Muzzi, Brunella Brunelli, Silvana Savino, Marzia M. Giuliani, Isabel Delany, Paolo Costantino, Rino Rappuoli, Vega Masignani, Nathalie Norais

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The gram-negative bacterium Neisseria meningitidis serogroup B (MenB) is an exclusively human pathogen representing the major cause of meningitides and severe sepsis in infants and children but also in young adults. This pathogen is usually present in the 30% of healthy population that act as a reservoir, spreading it through saliva and respiratory fluids during coughing, sneezing, kissing. Among surface-exposed protein components of this diplococcus, factor H binding protein is a lipoprotein proved to be a protective antigen used as a component of the recently licensed Bexsero vaccine. fHbp is a highly variable meningococcal protein: to reflect its remarkable sequence variability, it has been classified in three variants (or two subfamilies), and with poor cross-protection among the different variants. Furthermore, the level of fHbp expression varies significantly among strains, and this has also been considered an important factor for predicting MenB strain susceptibility to anti-fHbp antisera. Different methods have been used to assess fHbp expression on meningococcal strains, however, all these methods use anti-fHbp antibodies, and for this reason, the results are affected by the different affinity that antibodies can have to different antigenic variants. To overcome the limitations of an antibody-based quantification, we developed a quantitative Mass Spectrometry (MS) approach. Selected Reaction Monitoring (SRM) recently emerged as a powerful MS tool for detecting and quantifying proteins in complex mixtures. SRM is based on the targeted detection of ProteoTypicPeptides (PTPs), which are unique signatures of a protein that can be easily detected and quantified by MS. This approach, proven to be highly sensitive, quantitatively accurate and highly reproducible, was used to quantify the absolute amount of fHbp antigen in total extracts derived from 105 clinical isolates, evenly distributed among the three main variant groups and selected to be representative of the fHbp circulating subvariants around the world. We extended the study at the genetic level investigating the correlation between the differential level of expression and polymorphisms present within the genes and their promoter sequences. The implications of fHbp expression on the susceptibility of the strain to killing by anti-fHbp antisera are also presented. To date this is the first comprehensive fHbp expression profiling in a large panel of Neisseria meningitidis clinical isolates driven by an antibody-independent MS-based methodology, opening the door to new applications in vaccine coverage prediction and reinforcing the molecular understanding of released vaccines.

Keywords: quantitative mass spectrometry, Neisseria meningitidis, vaccines, bexsero, molecular epidemiology

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Authors: Changhan Ouyang, Zhonglin Xie

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In response to proatherosclerotic factors such as oxidized lipids, or to therapeutic interventions such as angioplasty, stents, or bypass surgery, vascular smooth muscle cells (VSMCs) migrate from the media to the intima, resulting in intimal hyperplasia, restenosis, graft failure, or atherosclerosis. These proatherosclerotic factors also activate autophagy in VSMCs. However, the functional role of autophagy in vascular health and disease remains poorly understood. In the present study, we determined the role of autophagy in the regulation of VSMC migration. Autophagy activity in cultured human aortic smooth muscle cells (HASMCs) and mouse carotid arteries was measured by Western blot analysis of microtubule-associated protein 1 light chain 3 B (LC3B) and P62. The VSMC migration was determined by scratch wound assay and transwell migration assay. Ex vivo smooth muscle cell migration was determined using aortic ring assay. The in vivo SMC migration was examined by staining the carotid artery sections with smooth muscle alpha actin (alpha SMA) after carotid artery ligation. To examine the relationship between autophagy and neointimal hyperplasia, C57BL/6J mice were subjected to carotid artery ligation. Seven days after injury, protein levels of Atg5, Atg7, Beclin1, and LC3B drastically increased and remained higher in the injured arteries three weeks after the injury. In parallel with the activation of autophagy, vascular injury-induced neointimal hyperplasia as estimated by increased intima/media ratio. The en face staining of carotid artery showed that vascular injury enhanced alpha SMA staining in the intimal cells as compared with the sham operation. Treatment of HASMCs with platelet-derived growth factor (PDGF), one of the major factors for vascular remodeling in response to vascular injury, increased Atg7 and LC3 II protein levels and enhanced autophagosome formation. In addition, aortic ring assay demonstrated that PDGF treated aortic rings displayed an increase in neovessel formation compared with control rings. Whole mount staining for CD31 and alpha SMA in PDGF treated neovessels revealed that the neovessel structures were stained by alpha SMA but not CD31. In contrast, pharmacological and genetic suppression of autophagy inhibits VSMC migration. Especially, gene silencing of Atg7 inhibited VSMC migration induced by PDGF. Furthermore, three weeks after ligation, markedly decreased neointimal formation was found in mice treated with chloroquine, an inhibitor of autophagy. Quantitative morphometric analysis of the injured vessels revealed a marked reduction in the intima/media ratio in the mice treated with chloroquine. Conclusion: Autophagy activation increases VSMC migration while autophagy suppression inhibits VSMC migration. These findings suggest that autophagy suppression may be an important therapeutic strategy for atherosclerosis and intimal hyperplasia.

Keywords: autophagy, vascular smooth muscle cell, migration, neointimal formation

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Authors: Abiodun Amusan, Olugbenga Akinola, Kazeem Akano, María Hernández-Castañeda, Jenna Dick, Akintunde Sowunmi, Geoffrey Hart, Grace Gbotosho

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Introduction: Artemisinin-based Combination Therapy (ACTs) is the cornerstone malaria treatment option in most malaria-endemic countries. Unfortunately, the malaria control effort is constantly being threatened by resistance of Plasmodium falciparum to ACTs. The recent evidence of artemisinin resistance in East Africa and its possibility of spreading to other African regions portends an imminent health catastrophe. This study aimed at evaluating the occurrence, prevalence, and influence of artemisinin-resistance markers on treatment outcomes in Ibadan before and after post-adoption of artemisinin combination therapy (ACTs) in Nigeria in 2005. Method: The study involved day zero dry blood spot (DBS) obtained from malaria patients during retrospective (2000-2005) and prospective (2021) studies. A cohort in the prospective study received oral dihydroartemisinin-piperaquine and underwent a 42-day follow-up to observe treatment outcomes. Genomic DNA was extracted from the DBS samples using a QIAamp blood extraction kit. Fragments of P. falciparum kelch13 (Pfkelch13), P. falciparum coronin (Pfcoronin), P. falciparum multidrug resistance 2 (PfMDR2), and P. falciparum chloroquine resistance transporter (PfCRT) genes were amplified and sequenced on a sanger sequencing platform to identify artemisinin resistance-associated mutations. Mutations were identified by aligning sequenced data with reference sequences obtained from the National Center for Biotechnology Information. Data were analyzed using descriptive statistics and student t-tests. Results: Mean parasite clearance time (PCT) and fever clearance time (FCT) were 2.1 ± 0.6 days (95% CI: 1.97-2.24) and 1.3 ± 0.7 days (95% CI: 1.1-1.6) respectively. Four mutations, K189T [34/53(64.2%)], R255K [2/53(3.8%)], K189N [1/53(1.9%)] and N217H [1/53(1.9%)] were identified within the N-terminal (Coiled-coil containing) domain of Pfkelch13. No artemisinin resistance-associated mutation usually found within the β-propeller domain of the Pfkelch13 gene was found in these analyzed samples. However, K189T and R255K mutations showed a significant correlation with longer parasite clearance time in the patients (P<0.002). The observed Pfkelch13 gene changes did not influence the baseline mean parasitemia (P = 0.44). P76S [17/100 (17%)] and V62M [1/100 (1%)] changes were identified in the Pfcoronin gene fragment without any influence on the parasitological parameters. No change was observed in the PfMDR2 gene, while no artemisinin resistance-associated mutation was found in the PfCRT gene. Furthermore, a sample each in the retrospective study contained the Pfkelch13 K189T and Pfcoronin P76S mutations. Conclusion: The study revealed absence of genetic-based evidence of artemisinin resistance in the study population at the time of study. The high frequency of K189T Pfkelch13 mutation and its correlation with increased parasite clearance time in this study may depict geographical variation of resistance mediators and imminent artemisinin resistance, respectively. The study also revealed an inherent potential of parasites to harbour drug-resistant genotypes before the introduction of ACTs in Nigeria.

Keywords: artemisinin resistance, plasmodium falciparum, Pfkelch13 mutations, Pfcoronin

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