Search results for: sterol regulatory element binding proteins

Authors: Khadse Saurabh, Talele Gokul, Surana Sanjay

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In an endeavor to find a new class of anti-inflammatory agents, a series of novel benzamides (ab1-ab16) were synthesized by utilizing some arylideneoxazolones (az1-az4) having 2-acetyloxyphenyl substitution on their second position. Structures of these synthesized compounds were confirmed by IR, 1H-NMR, 13C NMR, and HRMS. Among the tested benzamide compounds 3ab1, 3ab2, 3ab11, and 3ab16 showed promising anti-inflammatory activity with lessened propensity to cause gastro-intestinal hypermotility and ulceration when compared with standard Indomethacin. Virtual screening was performed by docking the designed compounds into the ATP binding site of COX-2 receptor to predict if these compounds have analogous binding mode to the COX-2 inhibitor.

Keywords: benzamides, anti-inflammatory, gastro-intestinal hypermotility, ulcerogenic activity, docking

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Authors: Alvaro Armenta-Ramade, Arturo Serrano-Santoyo, Veronica Rojas-Mendizabal, Roberto Conte-Galvan

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The availability and affordability of commercial off-the-shell products have brought a major impetus in the development of university projects related to the design, construction and launching of small satellites on a global scale. Universities in emerging economies as well as in least developed countries have been able to develop prototypes of small satellites (cubesats and cansats) with limited budgets. The experience gained in the development of small satellites gives rise to capacity building for designing more complex aerospace systems. This trend has significantly increased the pace and number of aerospace university projects around the world. In the case of Mexico, projects funded by different agencies have been very effective in accelerating the capacity building and technology transfer initiatives in the aerospace ecosystem. However, many of this initiatives have centered their efforts in technology development matters with minimum or no considerations of key regulatory issues related to frequency assignment, management and licensing, as well as launching requirements and measures of mitigation of space debris. These regulatory concerns are fundamental to accomplish successful missions that take into account the complete value chain of an aerospace project. The purpose of this paper is to develop a regulatory framework to support the efforts of educational institutions working on the development of small satellites in Mexico. We base our framework on recommendations from the International Telecommunications Union (ITU), the United Nations Office for Outer Space Affairs (UNOOSA) and other major actors of the Mexican regulatory ecosystem. In order to develop an integrated and cohesive framework, we draw on complexity science to identify the agents, their role and interactions. Our goal is to create a guiding instrument available both in print and online that can also be used in other regions of the world

Keywords: capacity building, complexity science, cubesats, space regulations, small satellites

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Authors: Olia Kanevskaia

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Standardization has been in the limelight of numerous academic studies. Typically described as ‘any set of technical specifications that either provides or is intended to provide a common design for a product or process’, standards do not only set quality benchmarks for products and services, but also spur competition and innovation, resulting in advantages for manufacturers and consumers. Their contribution to globalization and technology advancement is especially crucial in the Information and Communication Technology (ICT) and telecommunications sector, which is also characterized by a weaker state-regulation and expert-based rule-making. Most of the standards developed in that area are interoperability standards, which allow technological devices to establish ‘invisible communications’ and to ensure their compatibility and proper functioning. This type of standard supports a large share of our daily activities, ranging from traffic coordination by traffic lights to the connection to Wi-Fi networks, transmission of data via Bluetooth or USB and building the network architecture for the Internet of Things (IoT). A large share of ICT standards is developed in the specialized voluntary platforms, commonly referred to as Standards Development Organizations (SDOs), which gather experts from various industry sectors, private enterprises, governmental agencies and academia. The institutional architecture of these bodies can vary from semi-public bodies, such as European Telecommunications Standards Institute (ETSI), to industry-driven consortia, such as the Internet Engineering Task Force (IETF). The past decades witnessed a significant shift of standard setting to those institutions: while operating independently from the states regulation, they offer a rather informal setting, which enables fast-paced standardization and places technical supremacy and flexibility of standards above other considerations. Although technical norms and specifications developed by such nongovernmental platforms are not binding, they appear to create significant regulatory impact. In the United States (US), private voluntary standards can be used by regulators to achieve their policy objectives; in the European Union (EU), compliance with harmonized standards developed by voluntary European Standards Organizations (ESOs) can grant a product a free-movement pass. Moreover, standards can de facto manage the functioning of the market when other regulative alternatives are not available. Hence, by establishing (potentially) mandatory norms, SDOs assume regulatory functions commonly exercised by States and shape their own legal order. The purpose of this paper is threefold: First, it attempts to shed some light on SDOs’ institutional architecture, focusing on private, industry-driven platforms and comparing their regulatory frameworks with those of formal organizations. Drawing upon the relevant scholarship, the paper then discusses the extent to which the formulation of technological standards within SDOs constitutes a private legal order, operating in the shadow of governmental regulation. Ultimately, this contribution seeks to advise whether a state-intervention in industry-driven standard setting is desirable, and whether the increasing regulatory importance of SDOs should be addressed in legislation on standardization.

Keywords: private order, standardization, standard-setting organizations, transnational law

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Authors: Umamaheswari Shanmugam, Silvia Ronchi, Radu Vornicu

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Software, artificial intelligence, and machine learning can improve healthcare through innovative and advanced technologies that are able to use the large amount and variety of data generated during healthcare services every day. As we read the news, over 500 machine learning or other artificial intelligence medical devices have now received FDA clearance or approval, the first ones even preceding the year 2000. One of the big advantages of these new technologies is the ability to get experience and knowledge from real-world use and to continuously improve their performance. Healthcare systems and institutions can have a great benefit because the use of advanced technologies improves the same time efficiency and efficacy of healthcare. Software-defined as a medical device, is stand-alone software that is intended to be used for patients for one or more of these specific medical intended uses: - diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of a disease, any other health conditions, replacing or modifying any part of a physiological or pathological process–manage the received information from in vitro specimens derived from the human samples (body) and without principal main action of its principal intended use by pharmacological, immunological or metabolic definition. Software qualified as medical devices must comply with the general safety and performance requirements applicable to medical devices. These requirements are necessary to ensure high performance and quality and also to protect patients’ safety. The evolution and the continuous improvement of software used in healthcare must take into consideration the increase in regulatory requirements, which are becoming more complex in each market. The gap between these advanced technologies and the new regulations is the biggest challenge for medical device manufacturers. Regulatory requirements can be considered a market barrier, as they can delay or obstacle the device approval, but they are necessary to ensure performance, quality, and safety, and at the same time, they can be a business opportunity if the manufacturer is able to define in advance the appropriate regulatory strategy. The abstract will provide an overview of the current regulatory framework, the evolution of the international requirements, and the standards applicable to medical device software in the potential market all over the world.

Keywords: artificial intelligence, machine learning, SaMD, regulatory, clinical evaluation, classification, international requirements, MDR, 510k, PMA, IMDRF, cyber security, health care systems.

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Authors: M. Macchiaroli, L. Dolores, V. Pellecchia

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With the recent Resolution n. 580/2019/R/idr, the Italian Regulatory Authority for Energy, Networks, and Environment (ARERA) for the Urban Water Management has introduced, for water managements characterized by persistent critical issues regarding the planning and organization of the service and the implementation of the necessary interventions for the improvement of infrastructures and management quality, a new mechanism for determining tariffs: the regulatory scheme of Convergence. The aim of this regulatory scheme is the overcoming of the Water Service Divided in order to improve the stability of the local institutional structures, technical quality, contractual quality, as well as in order to guarantee transparency elements for Users of the Service. Convergence scheme presupposes the identification of the cost items to be considered in the tariff in parametric terms, distinguishing three possible cases according to the type of historical data available to the Manager. The study, in particular, focuses on operations that have neither data on tariff revenues nor data on operating costs. In this case, the Manager's Constraint on Revenues (VRG) is estimated on the basis of a reference benchmark and becomes the starting point for defining the structure of the tariff classes, in compliance with the TICSI provisions (Integrated Text for tariff classes, ARERA's Resolution n. 665/2017/R/idr). The proposed model implements the recent studies on optimization models for the definition of tariff classes in compliance with the constraints dictated by TICSI in the application of the Convergence mechanism, proposing itself as a support tool for the Managers and the local water regulatory Authority in the decision-making process.

Keywords: decision-making process, economic evaluation of projects, optimizing tools, urban water management, water tariff

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Authors: Samira Khalaji, , Fenneke Klein Jan, Kay-E. Gottschalk, Eugenia Makrantonaki, Karin Scharffetter-Kochanek

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Biological aging is a multi-dimensional process that takes place over a whole range of scales from the nanoscopic alterations within individual cells, over transformations in tissues and organs and to changes of the whole organism. On the single cell level, aging involves mutation of genes, differences in gene expression levels as well as altered posttranslational modifications of proteins. A variety of proteins is affected, including proteins of the cell cytoskeleton and migration machinery. Previous work quantified the expression of cytoskeleton proteins on the gene and protein levels in senescent and young fibroblasts. Their results show that senescent skin fibroblasts have an upregulated expression of the intermediate filament (IF) protein vimentin in contrast to actin and tubulin, which are downregulated. IFs play an important role in providing mechanical stability of cells. However, the mechanical properties of IFs depending on cellular senescence or age of the donor has not been studied so far. Hence, we employed passive microrheology on primary human dermal fibroblasts from female donors with age of 28 years (young) and 86 years (old) as model of in vivo aging and human normal dermal fibroblast from 11-year old male with CPD 17-35 (young) and CPD 58-59 (senescence) as a model of in vitro replicative senescence. In contrast to the expectations, our primary results show no significant differences in the viscoelastic properties of fibroblasts depending on age of the donor or cellular replicative senescence.

Keywords: aging, cytoskeleton, fibroblast, mechanical properties

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Authors: Dong Tran, Thanh Dac Van, Ly Le

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Hemagglutinin (HA) and Neuraminidase (NA) play an important role in host immune evasion across influenza virus evolution process. The correlation between HA and NA evolution in respect to epitopic evolution and drug interaction has yet to be investigated. In this study, combining of sequence to structure evolution and statistical analysis on epitopic/binding site specificity, we identified potential therapeutic features of HA and NA that show specific antibody binding site of HA and specific binding distribution within NA active site of current inhibitors. Our approach introduces the use of sequence variation and molecular interaction to provide an effective strategy in establishing experimental based distributed representations of protein-protein/ligand complexes. The most important advantage of our method is that it does not require complete dataset of complexes but rather directly inferring feature interaction from sequence variation and molecular interaction. Using correlated sequence analysis, we additionally identified co-evolved mutations associated with maintaining HA/NA structural and functional variability toward immunity and therapeutic treatment. Our investigation on the HA binding specificity revealed unique conserved stalk domain interacts with unique loop domain of universal antibodies (CR9114, CT149, CR8043, CR8020, F16v3, CR6261, F10). On the other hand, NA inhibitors (Oseltamivir, Zaninamivir, Laninamivir) showed specific conserved residue contribution and similar to that of NA substrate (sialic acid) which can be exploited for drug design. Our study provides an important insight into rational design and identification of novel therapeutics targeting universally recognized feature of influenza HA/NA.

Keywords: influenza virus, hemagglutinin (HA), neuraminidase (NA), sequence evolution

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Authors: Tawanda Mushiri, Charles Mbohwa

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The performance of door assembly is very significant for the vehicle design. In the present paper, the finite element method is used in the development processes of the door assembly. The stiffness, strength, modal characteristic, and anti-extrusion of a newly developed passenger vehicle door assembly are calculated and evaluated by several finite element analysis commercial software. The structural problems discovered by FE analysis have been modified and finally achieved the expected door structure performance target of this new vehicle. The issue in focus is to predict the performance of the door assembly by powerful finite element analysis software, and optimize the structure to meet the design targets. It is observed that this method can be used to forecast the performance of vehicle door efficiently when it’s designed. In order to reduce lead time and cost in the product development of vehicles more development will be made virtually.

Keywords: vehicle door, structure, strength, stiffness, modal characteristic, anti-extrusion, Finite Element Method

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Authors: Sweta Pandey, Samridhi Dhyani, Susmita Chaudhuri

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Klebsiella pneumoniae causes a wide range of infections, including urinary tract infections, sepsis, bacteremia, pneumonia, and liver abscesses. The emergence of multi-drug resistance in this bacterium led to a major setback for clinical management. WHO also endorsed a need for finding alternative therapy to antibiotics for the treatment of these infections. Development of vaccines and passive antibody therapy has been proven as a potent alternative to antibiotics in the case of MDR, XDR, and PDR Klebsiella infections. Siderophore receptors have been demonstrated to be overexpressed for the internalization of iron siderophore complexes during infections in most Gram-negative bacteria. For the present study, immune response to siderophore receptors to establish this protein as a potential immunogen for the development of therapeutic leads was explored. Clinical strains of Klebsiella pneumoniae were grown in iron-deficient conditions, and the iron-regulated outer membrane proteins were extracted and characterized through mass spectrometry for specific identification. The gene for identified protein was cloned in pET- 28a vector and expressed in E. coli. The native protein and the recombinant protein were isolated and purified and used as antigens for the generation of immune response in BALB/c mice. The native protein of Klebsiella pneumoniae grown in iron-deficient conditions was identified as FepA (Ferrienterobactin receptor) and other siderophore receptors. This 80 kDa protein generated an immune response in BALB/c mice. The antiserum from mice after subsequent booster doses was collected and showed binding with FepA protein in western blot and phagocytic uptake of the K. pneumoniae in the presence antiserum from immunized mice also observed from the animal studies after bacterial challenge post immunisation in mice have shown bacterial clearance. The antiserum from mice showed binding and clearance of the Klebsiella pneumoniae bacteria in vitro and in vivo. These antigens used for generating an active immune response in mice can further be used for therapeutic monoclonal antibody development against Klebsiella pneumoniae infections.

Keywords: antiserum, FepA, Klebsiella pneumoniae, multi drug resistance, siderophore receptor

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Authors: Tamer M. El-Messery

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By-products from sunflower oil extraction, such as sunflower cakes, are rich sources of proteins with desirable functional properties for the food industry. However, challenges such as sensory drawbacks and the presence of phenolic compounds have hindered their widespread use. In this study, sunflower protein concentrates were obtained from sunflower cakes using different ant-greening solvents (ascorbic acid (ASC) and N-acetylcysteine (NAC)), and their functional properties were evaluated. The color of extracted proteins ranged from dark green to yellow, where the using of ASC and NAC agents enhanced the color. The protein concentrates exhibited high solubility (>70%) and antioxidant activity, with hydrophobicity influencing emulsifying activity. Emulsions prepared with these proteins showed stability and microencapsulation efficiency. Incorporation of protein concentrates into low-fat whipping cream formulations increased overrun and affected color characteristics. Rheological studies demonstrated pseudoplastic behavior in whipped cream, influenced by shear rates and protein content. Overall, sunflower protein isolates showed promising functional properties, indicating their potential as valuable ingredients in food formulations.

Keywords: functional properties, sunflower protein concentrates, antioxidant capacity, ant-greening agents, low-fat whipping cream

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Authors: Shreya Sara Ittycheria, K. C. Sivakumar, Shijulal Nelson Sathi, Priya Srinivas

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hCG, a heterodimer composed of α and β subunits, is a peptide hormone having numerous biological functions. Although hCG is expressed by placenta during pregnancy, ectopic β-hCG secretion is observed in many non-trophoblastic tumors including that of breast. In-vitro and in-vivo studies done in the lab, have proved that BRCA1 defective cancers express β-hCG and when β-hCG is expressed or supplemented, it promotes tumor progression and exhibits resistance to carboplatin and ABT888, in such cancers but not in BRCA1 wild type cancers. In cancer cells, instead of binding to its regular receptor, LH-CGR, β-hCG binds with Transforming Growth Factor Receptor 2 (TGFβRII) and phosphorylates it resulting in faster tumor progression through the Smad signaling pathway. Targeting β-hCG could be a potential therapeutic strategy for managing BRCA1 defective cancers. Here, molecular docking and dynamic simulation studies were done to identify potential small molecule inhibitors against β-hCG as there are currently no such inhibitors reported. The binding sites of TGFβRII on β-hCG were identified from the top 10 predicted complexes from Z Dock. Virtual screening of selected commercially available small molecules from various libraries such as ZINC, NCI and Life Chemicals amounting to a total of 50,025 molecules were done. Four potential small molecule inhibitors were identified, RgcbPs-1, RgcbPs-2, RgcbPs-3 and RgcbPs-4 with binding affinities -60.778 kcal/mol, -45.447 kcal/mol, -65.2268 kcal/mol and -82.040 kcal/mol respectively. Further, 100ns Molecular Dynamics (MD) simulation showed that these molecules form stable complexes with β-hCG. RgcbPs-1 maintains hydrogen bonds with Q54, L52, Q46, C100, G36, C57, C38 residues, RgcbPs-2 maintains hydrogen bonds with A83 residue, RgcbPs-3 maintains hydrogen bonds with C57, Y58, R94, G101 residues and RgcbPs-4 maintains hydrogen bonds with G36, C38, T40, C57, D99, C100, G101 and L104 residues of β-hCG all of which coincide with the TGFβRII binding site on β-hCG. These results show that these two inhibitors could be used either singly or in combination for inhibiting β-hCG from binding to TGFβRII and thereby directly inhibiting the tumorigenesis pathway.

Keywords: β-hCG, breast cancer, dynamic simulations, molecular docking, small molecule inhibitors, virtual screening.

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Authors: Ahmed A. Mohamed Aly

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Ground movements induced from excavations is a major cause of deformation and damage to the adjacent buildings and utilities. With the increasing rate of construction work in urban area, this problem is growing more significant and has become the cause of numerous legal disputes. This problem is investigated numerically in the present study using finite element method. Five-story reinforced concrete building rests on raft foundation is idealized as two dimensional model. The building is considered to be constructed adjacent to excavation affected by an adjacent excavation in medium sand. Excavation is supported using sheet pile wall. Two dimensional plane strain program PLAXIS is used in this study. 15 nodes triangular element is used to idealize soil with Mohr-Coulomb model. Five nodes isoperimetric beam element is used to idealize sheet pile and building. Interface element is used to represent the contact between beam element and soil. Two parameters were studied, the first is the foundation depth and the second is the building distance from the excavation. Nodal displacements and elements straining actions were obtained and studied from the analyzed finite element model results.

Keywords: excavation, relative distance, effective stresses, lateral deformation, relative depth

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Authors: Amir Zeb, Shailima Rampogu, Minky Son, Ayoung Baek, Sang H. Yoon, Keun W. Lee

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Neurotoxic insults activate calpain, which in turn produces truncated p25 from p35. p25 forms hyperactivated Cdk5/p25 complex, and thereby induces severe neuropathological aberrations including hyperphosphorylated tau, neuroinflammation, apoptosis, and neuronal death. Inhibition of Cdk5/p25 complex alleviates aberrant phosphorylation of tau to mitigate AD pathology. PHA-793887 and Roscovitine have been investigated as selective inhibitors of Cdk5/p25 with IC50 values 5nM and 160nM, respectively, but their mechanistic studies remain unknown. Herein, computational simulations have explored the binding mode and interaction mechanism of PHA-793887 and Roscovitine with Cdk5/p25. Docking results suggested that PHA-793887 and Rsocovitine have occupied the ATP-binding site of Cdk5 and obtained highest docking (GOLD) score of 66.54 and 84.03, respectively. Furthermore, molecular dynamics (MD) simulation demonstrated that PHA-793887 and Roscovitine established stable RMSD of 1.09 Å and 1.48 Å with Cdk5/p25, respectively. Profiling of polar interactions suggested that each inhibitor formed hydrogen bonds (H-bond) with catalytic residues of Cdk5 and could remain stable throughout the molecular dynamics simulation. Additionally, binding free energy calculation by molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) suggested that PHA-793887 and Roscovitine had lowest binding free energies of -150.05 kJ/mol and -113.14 kJ/mol, respectively with Cdk5/p25. Free energy decomposition demonstrated that polar energy by H-bond between the Glu81 of Cdk5 and PHA-793887 is the essential factor to make PHA-793887 highly selective towards Cdk5/p25. Overall, this study provided substantial evidences to explore mechanistic interactions of the selective inhibitors of Cdk5/p25 and could be used as fundamental considerations in the development of structure-based selective inhibitors of Cdk5/p25.

Keywords: Cdk5/p25 inhibition, molecular modeling of Cdk5/p25, PHA-793887 and roscovitine, selective inhibition of Cdk5/p25

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Authors: Ahmed M. Hjazi, Bader M. Hjazi

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Protein 4.1 is a crucial component of complex interactions between the cytoskeleton and other junctional complex proteins. When the gene encoding this protein is altered, resulting in reduced expression, or when the protein is absent, the red cell undergoes a significant structural change. This research aims to achieve a deeper comprehension of the biochemical effects of red cell protein deficiency. A Tandem Mass Spectrometry Analysis (TMT-MS/MS) of patient cells lacking protein 4.1 compared to three healthy controls was achieved by the Proteomics Institute of the University of Bristol. The SDS-PAGE and Western blotting were utilized on the original patient sample and controls to partially confirm TMT MS/MS data analysis of the protein-4.1-deficient cells. Compared to healthy controls, protein levels in samples lacking protein 4.1 had a significantly higher concentration of proteins that probably originated from reticulocytes. This could occur if the patient has an elevated reticulocyte count. The increase in chaperone and reticulocyte-associated proteins was most notable in this study. This may result from elevated quantities of reticulocytes in patients with hereditary elliptocytosis.

Keywords: hereditary elliptocytosis, protein 4.1, red cells, tandem mass spectrometry data.

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Authors: Abul B. M. M. K. Islam, Nuria Lopez-Bigas, Elizaveta V. Benevolenskaya

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RBP2 has shown to be important for cell differentiation control through epigenetic mechanism. The main aim of the present study is genome-wide location analysis of human RBP2 isoforms that differ in a histone-binding domain by ChIPseq. It is conceivable that the larger isoform (LI) of RBP2, which contains a specific H3K4me3 interacting domain, differs from the smaller isoform (SI) in genomic location, may account for the observed diversity in RBP2 function. To distinguish the two RBP2 isoforms, we used the fact that the SI lacks the C-terminal PHD domain and hence used the antibodies detecting both RBP2 isoforms (AI) through a common central domain, and the antibodies detecting only LI but not SI, through a C-terminal PHD domain. Overall our analysis suggests that RBP2 occupies about 77 nucleotides and binds GC rich motifs of active genes, does not bind to centromere, telomere, or enhancer regions, and binding sites are conserved compare to random. A striking difference between the only-SI and only-LI is that a large number of only-SI peaks are located in CpG islands and close to TSS compared to only-LI peaks. Enrichment analysis of the related genes indicates that several oncogenic pathways and metabolic pathways/processes are significantly enriched among only-SI/AI targets, but not LI/only-LI peak’s targets.

Keywords: bioinformatics, cancer, ChIP-seq, KDM5A

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Authors: Ali Alshamrani

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This article aims to give a comprehensive and critical review of sukuk issuance in Saudi Arabia, and the extent to which the issuance of sukuk in Saudi Arabia is consistent with Shariah requirements. The article is divided into two sections. Accordingly, the first section of this article begins with an examination of sukuk in general, and includes the concept of sukuk, the basic principles of sukuk, common types of sukuk, and a critical analysis of the most important differences between sukuk and conventional bonds. The second section gives a critical analysis of how sukuk work in Saudi Arabia, offering the regulatory framework of the issuance of sukuk in the KSA, and the legal challenges from Shariah point of view, and provide recommendations to overcome these challenges.

Keywords: sukuk issuance, Shariah, Saudi Arabia, capital market authority

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Authors: Jay Ananth

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The drug discovery process currently requires numerous years of clinical testing as well as money just for a single drug to earn FDA approval. For drugs that even make it this far in the process, there is a very slim chance of receiving FDA approval, resulting in detrimental hurdles to drug accessibility. To minimize these inefficiencies, numerous studies have implemented computational methods, although few computational investigations have focused on a crucial feature of drugs: lipophilicity. Lipophilicity is a physical attribute of a compound that measures its solubility in lipids and is a determinant of drug efficacy. This project leverages Artificial Intelligence to predict the impact of a drug’s lipophilicity on its performance by accounting for factors such as binding affinity and toxicity. The model predicted lipophilicity and binding affinity in the validation set with very high R² scores of 0.921 and 0.788, respectively, while also being applicable to a variety of target receptors. The results expressed a strong positive correlation between lipophilicity and both binding affinity and toxicity. The model helps in both drug development and discovery, providing every pharmaceutical company with recommended lipophilicity levels for drug candidates as well as a rapid assessment of early-stage drugs prior to any testing, eliminating significant amounts of time and resources currently restricting drug accessibility.

Keywords: drug discovery, lipophilicity, ligand-receptor interactions, machine learning, drug development

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Authors: Alina Goldberg Cavalleri, Sara Franco Ortega, Nawaporn Onkokesung, Richard Dale, Melissa Brazier-Hicks, Robert Edwards

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Non-target site based resistance (NTSR) to herbicides in weeds is a polygenic trait associated with the upregulation of proteins involved in xenobiotic detoxification and translocation we have termed the xenome. Among the xenome proteins, ABC transporters play a key role in enhancing herbicide metabolism by effluxing conjugated xenobiotics from the cytoplasm into the vacuole. The importance of ABC transporters is emphasized by the fact that they often contribute to multidrug resistance in human cells and antibiotic resistance in bacteria. They also play a key role in insecticide resistance in major vectors of human diseases and crop pests. By surveying available databases, transcripts encoding ABCs have been identified as being enhanced in populations exhibiting NTSR in several weed species. Based on a transcriptomics data in black grass (Alopecurus myosuroides, Am), we have identified three proteins from the ABC-C subfamily that are upregulated in NTSR populations. ABC-C transporters are poorly characterized proteins in plants, but in Arabidopsis localize to the vacuolar membrane and have functional roles in transporting glutathionylated (GSH)-xenobiotic conjugates. We found that the up-regulation of AmABCs strongly correlates with the up-regulation of a glutathione transferase termed AmGSTU2, which can conjugate GSH to herbicides. The expression profile of the ABC transcripts was profiled in populations of black grass showing different degree of resistance to herbicides. This, together with a phylogenetic analysis, revealed that AmABCs cluster in different groups which might indicate different substrate and roles in the herbicide resistance phenotype in the different populations

Keywords: black grass, herbicide, resistance, transporters

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Authors: Abderrahim El Maslouhi

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The paper aims to analyze an often-overlooked dimension of global constitutionalism, which is the rise of the regulatory state and its impact on parliamentary dynamics in transition regimes. In contrast to Majone’s technocratic vision of convergence towards a single regulatory system based on competence and efficiency, national transpositions of regulatory governance and, in general, the relationship to global standards primarily depend upon a number of distinctive parameters. These include policy formation process, speed of change, depth of parliamentary tradition and greater or lesser vulnerability to the normative conditionality of donors, interstate groupings and transnational regulatory bodies. Based on a comparison between three post-Arab Spring countries -Morocco, Tunisia, and Egypt, whose constitutions have undergone substantive review in the period 2011-2014- and some European Union state members, the paper intends, first, to assess the degree of permeability to global constitutionalism in different contexts. A noteworthy divide emerges from this comparison. Whereas European constitutions still seem impervious to the lexicon of global constitutionalism, the influence of the latter is obvious in the recently drafted constitutions in Morocco, Tunisia, and Egypt. This is evidenced by their reference to notions such as ‘governance’, ‘regulators’, ‘accountability’, ‘transparency’, ‘civil society’, and ‘participatory democracy’. Second, the study will provide a contextual account of internal and external rationales underlying the constitutionalization of regulatory governance in the cases examined. Unlike European constitutionalism, where parliamentarism and the tradition of representative government function as a structural mechanism that moderates the de-parliamentarization effect induced by global constitutionalism, Arab constitutional transitions have led to a paradoxical situation; contrary to the public demands for further parliamentarization, the 2011 constitution-makers have opted for a de-parliamentarization pattern. This is particularly reflected in the procedures established by constitutions and regular legislation, to handle the interaction between lawmakers and regulatory bodies. Once the ‘constitutional’ and ‘independent’ nature of these agencies is formally endorsed, the birth of these ‘fourth power’ entities, which are neither elected nor directly responsible to elected officials, will raise the question of their accountability. Third, the paper shows that, even in the three selected countries, the de-parliamentarization intensity is significantly variable. By contrast to the radical stance of the Moroccan and Egyptian constituents who have shown greater concern to shield regulatory bodies from legislatures’ scrutiny, the Tunisian case indicates a certain tendency to provide lawmakers with some essential control instruments (e. g. exclusive appointment power, adversarial discussion of regulators’ annual reports, dismissal power, later held unconstitutional). In sum, the comparison reveals that the transposition of the regulatory state model and, more generally, sensitivity to the legal implications of global conditionality essentially relies on the evolution of real-world power relations at both national and international levels.

Keywords: Arab legislatures, de-parliamentarization, global constitutionalism, normative conditionality, regulatory state

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Authors: Mishari Khajah, Mohd. Elmuntasir Ahmed, Abdullah Al-Matouq, Farah Al-Ajeel, Fatemah Dashti, Ahmed Shishter

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The overall aim of this study was to monitor and evaluate the effluent quality of a reverse osmosis (RO) reject wastewater from the biggest wastewater treatment plant in the world that is using RO and ultrafiltration membranes in their processes to reclaim water for indirect potable water reuse from municipal wastewaters. The RO reject wastewater or brine included various contaminants that could harm the human health and the environment such as trace organics, organic matters, heavy metals, nutrients and pathogens. Unfortunately, there are no legally binding regulatory guidelines for brine management in Kuwait as many countries around the world. This study monitors and evaluate the RO reject wastewater (brine) generated from the Sulaibiya Wastewater Treatment Plant. Samples were collected and analyzed about 37 parameters for one-year period, twice a month, and compare it to Kuwait Environment Public Authority, KEPA. Results showed that the heavy metals parameters were above KEPA standards, which needs to be treated.

Keywords: domestic wastewater, management, potable water, RO reject wastewater, Sulaibiya wastewater treatment plant

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Authors: Carolina V. Viegas, Monique Gonçalves, Gisel Chenard Diaz, Yordanka Reyes Cruz, Donato Alexandre Gomes Aranda

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To develop the massive cultivation of microalgae, it is necessary to isolate and characterize the species, improving genetic tools in search of specific characteristics. Therefore, the detection, identification and quantification of the compounds that compose the Scenedesmus sp. were prerequisites to verify the potential of these microalgae. The main objective of this work was to carry out the characterization of Scenedesmus sp. as to the content of ash, carbohydrates, proteins and lipids as well as the determination of the composition of their lipid classes and main fatty acids. The biomass of Scenedesmus sp, showed 15,29 ± 0,23 % of ash and CaO (36,17 %) was the main component of this fraction, The total protein and carbohydrate content of the biomass was 40,74 ± 1,01 % and 23,37 ± 0,95 %, respectively, proving to be a potential source of proteins as well as carbohydrates for the production of ethanol via fermentation, The lipid contents extracted via Bligh & Dyer and in situ saponification were 8,18 ± 0,13 % and 4,11 ± 0,11 %, respectively. In the lipid extracts obtained via Bligh & Dyer, approximately 50 % of the composition of this fraction consists of fatty compounds, while the other half is composed of an unsaponifiable fraction composed mainly of chlorophylls, phytosterols and carotenes. From the lowest yield, it was possible to obtain a selectivity of 92,14 % for fatty components (fatty acids and fatty esters) confirmed through the infrared spectroscopy technique. The presence of polyunsaturated acids (~45 %) in the lipid extracts indicated the potential of this fraction as a source of nutraceuticals. The results indicate that the biomass of Scenedesmus sp, can become a promising potential source for obtaining polyunsaturated fatty acids, carotenoids and proteins as well as the simultaneous obtainment of different compounds of high commercial value.

Keywords: microalgae, Desmodesmus, lipid classes, fatty acid profile, proteins, carbohydrates

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Authors: Stephen Eyije Abechi, Casimir Emmanuel Gimba, Zaharaddeen Nasiru Garba, Sani Shamsudeen, David Ebuka Authur

Abstract:

Corrosion inhibition of mild steel in acid medium using Acalypha chamaedrifolia leaves extract as potential green inhibitor was investigated. Gravimetric (weight loss) technique was used for the corrosion studies. Mild steel coupons of 2cm × 1cm × 0.27 cm dimensions were exposed for varying durations of between 24 to 120 hours, in 1M HCl medium containing a varying concentrations of the leaves extract (0.25g/L, - 1.25g/L). The results show that corrosion rates dropped from a value of 0.49 mgcm-2hr-1 for the uninhibited medium to a value of 0.15 mgcm-2hr-1 for the inhibited medium of 1M HCl in 0.25 g/l of the extract. Values of corrosion inhibition efficiencies of 70.38-85.11% were observed as the concentration of the inhibitor were increased from 0.25g/L, - 1.25g/L. Corrosion Inhibition was found to increase with increase in immersion time and temperature. The magnitude of the Ea indicates that the interaction between the metal surface and the inhibitor was chemisorptions. The Adsorption process fit into the Langmuir isotherm model with a correlation coefficient of 0.97. Evidence from molecular dynamics model shows that Methyl stearate (Line 5) and (3Z, 13Z)-2-methyloctadeca-3,13-dien-1-ol (line 11) were found to have the highest binding energy of -197.69 ± 3.12 and-194.56 ± 10.04 in kcal/mol respectively. The binding energy of these compounds indicates that they would be a very good corrosion inhibitor for mild steel and other Fe related materials.

Keywords: binding energy, corrosion, inhibitor, langmuir isotherm, mild steel

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Authors: M. I. Tyletc, O. I. Podgornya, T. G. Shaposhnikova, S. V. Shabelnikov, A. G. Mittenberg, M. A. Daugavet

Abstract:

Ascidiacea is the most numerous class of the Tunicata subtype. These chordates' distinctive feature of the anatomical structure is a tunic consisting of cellulose fibrils, protein molecules, and single cells. The mechanisms of the tunic formation are not known in detail; tunic formation could be used as the model system for studying the interaction of cells with the extracellular matrix. Our model species is the ascidian Styela rustica, which is prevalent in benthic communities of the White Sea. As previously shown, the tunic formation involves morula blood cells, which contain the major 48 kDa protein p48. P48 participation in the tunic formation was proved using antibodies against the protein. The nature of the protein and its function remains unknown. The current research aims to determine the amino acid sequence of p48, as well as to clarify its role in the tunic formation. The peptides that make up the p48 amino acid sequence were determined by mass spectrometry. A search for peptides in protein sequence databases identified sequences homologous to p48 in Styela clava, Styela plicata, and Styela canopus. Based on sequence alignment, their level of similarity was determined as 81-87%. The correspondent sequence of ascidian Styela canopus was used for further analysis. The Styela rustica p48 sequence begins with a signal peptide, which could indicate that the protein is secretory. This is consistent with experimentally obtained data: the contents of morula cells secreted in the tunic matrix. The isoelectric point of p48 is 9.77, which is consistent with the experimental results of acid electrophoresis of morula cell proteins. However, the molecular weight of the amino acid sequence of ascidian Styela canopus is 103 kDa, so p48 of Styela rustica is a shorter homolog. The search for conservative functional domains revealed the presence of two Ca-binding EGF-like domains, thrombospondin (TSP1) and tyrosinase domains. The p48 peptides determined by mass spectrometry fall into the region of the sequence corresponding to the last two domains and have amino acid substitutions as compared to Styela canopus homolog. The tyrosinase domain (pfam00264) is known to be part of the phenoloxidase enzyme, which participates in melanization processes and the immune response. The thrombospondin domain (smart00209) interacts with a wide range of proteins, and is involved in several biological processes, including coagulation, cell adhesion, modulation of intercellular and cell-matrix interactions, angiogenesis, wound healing and tissue remodeling. It can be assumed that the tyrosinase domain in p48 plays the role of the phenoloxidase enzyme, and TSP1 provides a link between the extracellular matrix and cell surface receptors, and may also be responsible for the repair of the tunic. The results obtained are consistent with experimental data on p48. The domain organization of protein suggests that p48 is an enzyme involved in the tunic tunning and is an important regulator of the organization of the extracellular matrix.

Keywords: ascidian, p48, thrombospondin, tyrosinase, tunic, tunning

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Authors: Nikhil Agrawal, Adam A. Skelton

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Alzheimer’s disease (AD) is one of the most common forms of dementia, which is caused by misfolding and aggregation of amyloid beta (Aβ) peptides into amyloid-β fibrils (Aβ fibrils). To disrupt the remodeling of Aβ fibrils, a number of candidate molecules have been proposed. To study the molecular mechanisms of Aβ fibrils remodeling we performed a series of all-atom molecular dynamics simulations, a total time of 3µs, in explicit solvent. Several previously undiscovered candidate molecule-Aβ fibrils binding modes are unraveled; one of which shows the direct conformational change of the Aβ fibril by understanding the physicochemical factors responsible for binding and subsequent remodeling of Aβ fibrils by the candidate molecule, open avenues into structure-based drug design for AD can be opened.

Keywords: alzheimer’s disease, amyloid, MD simulations, misfolded protein

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Authors: S. Ghalem, M. Mesmoudi, I. Daoudand, H. Allali

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The nitrogen-containing bisphosphonates (N-BPs) are well established as the treatments of choice for disorders of excessive bone resorption, myeloma and bone metastases, and osteoporosis. They inhibit farnesyl pyrophosphate synthase (FFPS), a key enzyme in the mevalonate pathway, resulting in inhibition of the prenylation of small GTP-binding proteins in osteoclasts and disruption of their cytoskeleton, adhesion/spreading, and invasion of cancer cells. A very few examples for synthesis of α-amino bisphosphonates based on several amino acids are known from the literature. In the present work, esters of aminoacid react with ketophsophonate (or their analog acid or acyl) to afford the desired products, α-iminophosphonates. The reaction of imine with dimethyl phosphate in the presence of catalytic amount of I2 give ester of α-aminobisphosphonate as sole product in good yield. Finally, we used computational docking methods to predict how several α-aminobisphosphonates bind to FPPS and how R and X influence. Pamidronate, β-aminobisphosphonate already marketed, was used as reference. These results are of interest since they represent a new and simple way to sythesize α-aminobisphosphonates with a free COOH group increased by R2 functionalisable and opening up the possibility of using the molecular docking to facilitate the design of other, novel FFPS inhibitors.

Keywords: drug research, cancer, α-amino bisphosphonates, molecular docking

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Authors: Mohammadjavad Sotoudeheian, Soroush Nematollahi

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Crohn’s disease (CD) is a chronic gastrointestinal segment inflammation encompassing immune dysregulation in a genetically susceptible individual in response to the environmental triggers and interaction between the microbiome and immune system. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures and enteric fistulae. Increased production of Th1 and Th17-cell cytokines and defects in T-regulatory cells have been associated with CD. Th17-cells are essential for protection against extracellular pathogens, but their atypical activity can cause autoimmunity. Intrinsic defects in the control of programmed cell death in the mucosal T-cell compartment are strongly implicated in the pathogenesis of CD. The apoptosis defect in mucosal T-cells in CD has been endorsed as an imbalance of the Bcl-2 and the Bax. The immune system encounters foreign antigens through microbial colonization of mucosal surfaces or infections. In addition, FOSL downregulated IL-26 expression, a cytokine that marks inflammatory Th17-populations in patients suffering from CD. Furthermore, the expression of IL-23 is associated with the transcription factor primary leucine zipper transcription factor ATF-like (Batf). Batf-deficiency demonstrated the crucial role of Batf in colitis development. Batf and IL-23 mediate their effects by inducing IL-6 production. Strong association of IL-23R, Stat3, and Stat4 with IBD susceptibility point to a critical involvement of T-cells. IL-23R levels in transfer fistula were dependent on the AP-1 transcription factor JunB that additionally controlled levels of RORγt by facilitating DNA binding of Batf. T lymphocytes lacking JunB failed to induce IL-23- and Th17-mediated experimental colitis highlighting the relevance of JunB for the IL-23/ Th17 pathway. The absence of T-bet causes unrestrained Th17-cell differentiation. T-cells are central parts of immune-mediated colon fistula. Especially Th17-cells were highly prevalent in inflamed IBD tissues, as RORγt is effective in preventing colitis. Intraepithelial lymphocytes (IEL) contain unique T-cell subsets, including cells expressing RORγt. Increased activated Th17 and decreased T-regulatory cells in inflamed intestinal tissues had been seen. T-cells differentiate in response to many cytokines, including IL-1β, IL-6, IL-23, and TGF-β, into Th17-cells, a process which is critically dependent on the Batf. IL-23 promotes Th17-cell in the colon. Batf manages the generation of IL-23 induced IL-23R+ Th17-cells. Batf is necessary for TGF-β/IL-6-induced Th17-polarization. Batf-expressing T-cells are the core of T-cell-mediated colitis. The human-specific parts of three AP-1 transcription factors, FOSL1, FOSL2, and BATF, are essential during the early stages of Th17 differentiation. BATF supports the Th17 lineage. FOSL1, FOSL2, and BATF make possession of regulatory loci of genes in the Th17 lineage cascade. The AP1 transcription factor Batf is identified to control intestinal inflammation and seems to regulate pathways within lymphocytes, which could theoretically control the expression of several genes. It shows central regulatory properties over Th17-cell development and is intensely upregulated within IBD-affected tissues. Here, we demonstrated that targeting Batf in IBD appears as a therapeutic approach that reduces colitogenic T-cell activities during fistula formation while aiming to affect inflammation in the gut epithelial cells.

Keywords: immune system, Crohn’s Disease, BATF, T helper cells, Bcl, interleukin, FOSL

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Authors: Mohammad Reza Akhavan Khaleghi

Abstract:

This paper shows changes done to the Reduced Finite Element Method (RFEM) that its result will be the most powerful numerical method that has been proposed so far (some forms of this method are so powerful that they can approximate the most complex equations simply Laplace equation!). Finite Element Method (FEM) is a powerful numerical method that has been used successfully for the solution of the existing problems in various scientific and engineering fields such as its application in CFD. Many algorithms have been expressed based on FEM, but none have been used in popular CFD software. In this section, full monopoly is according to Finite Volume Method (FVM) due to better efficiency and adaptability with the physics of problems in comparison with FEM. It doesn't seem that FEM could compete with FVM unless it was fundamentally changed. This paper shows those changes and its result will be a powerful method that has much better performance in all subjects in comparison with FVM and another computational method. This method is not to compete with the finite volume method but to replace it.

Keywords: reduced finite element method, new computational package, new finite element formulation, new higher-order form, new isogeometric analysis

Procedia PDF Downloads 86

Authors: Daniel Zarzo Montes, Manuel Zarzo Castelló

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Proteins play a fundamental role in biology, but their structure is complex, and it is a challenge for teachers to conceptually explain the differences between their primary, secondary, tertiary, and quaternary structures. On the other hand, there are currently many computer programs to visualize the 3D structure of proteins, but they require advanced training and knowledge. Moreover, it becomes difficult to visualize the sequence of amino acids in these models, and how the protein conformation is reached. Given this drawback, a simple and instructive procedure is proposed in order to teach the protein structure to undergraduate and graduate students. For this purpose, insulin has been chosen because it is a protein that consists of 51 amino acids, a relatively small number. The methodology has consisted of the use of plastic atom models, which are frequently used in organic chemistry and biochemistry to explain the chirality of biomolecules. For didactic purposes, when the aim is to teach the biochemical foundations of proteins, a manipulative system seems convenient, starting from the chemical structure of amino acids. It has the advantage that the bonds between amino acids can be conveniently rotated, following the pattern marked by the 3D models. First, the 51 amino acids were modeled, and then they were linked according to the sequence of this protein. Next, the three disulfide bonds that characterize the stability of insulin have been established, and then the alpha-helix structure has been formed. In order to reach the tertiary 3D conformation of this protein, different interactive models available on the Internet have been visualized. In conclusion, the proposed methodology seems very suitable for biology and biochemistry students because they can learn the fundamentals of protein modeling by means of a manipulative procedure as a basis for understanding the functionality of proteins. This methodology would be conveniently useful for a biology or biochemistry laboratory practice, either at the pre-graduate or university level.

Keywords: protein structure, 3D model, insulin, biomolecule

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Authors: S. Kamil Akin, Turgut Acikara

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In recent years the world and our country has experienced several explosion events occurred due to terrorist attacks and accidents. In these explosion events many people have lost their lives and many buildings have been damaged. If structures were designed taking the blast loads into account, these results may not have happened or the casualties would have been less. In this thesis analysis of the protection walls have been conducted to prevent the building damage from blast loads. These analyzes was carried out for two different types of wall, concrete and reinforced concrete. Analyses were carried out on four different thicknesses of each wall element. In each wall element the stresses and displacements of the exposed surface due to the detonation charge has been calculated. The limit shear stress and displacement of the wall element according to their material properties has been taken into account. As the result of the analyses the standoff distances and TNT equivalent amount has been determined. According to equivalent TNT amounts and standoff distances the structural response of the protective wall elements has been observed. These structural responses have been observed by ABAQUS finite element package. Explosion loads were brought into effect to the protective wall element models by using the ABAQUS / CONWEP.

Keywords: blast loading, blast wave, TNT equivalent method, CONWEP, finite element analysis, detonation

Procedia PDF Downloads 414

Authors: Reham Khalaf-Nazzal, Imad Dweikat, Paula Gimenez, Iker Oyenarte, Alfonso Martinez-Cruz, Domonik Muller

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Metal cation transport mediator (CNNM) gene family comprises 4 isoforms that are expressed in various human tissues. Structurally, CNNMs are complex proteins that contain an extracellular N-terminal domain preceding a DUF21 transmembrane domain, a ‘Bateman module’ and a C-terminal cNMP-binding domain. Mutations in CNNM2 cause familial dominant hypomagnesaemia. Growing evidence highlights the role of CNNM2 in neurodevelopment. Mutations in CNNM2 have been implicated in epilepsy, intellectual disability, schizophrenia, and others. In the present study, we aim to elucidate the function of CNNM2 in the developing brain. Thus, we present the genetic origin of symptoms in two family cohorts. In the first family, three siblings of a consanguineous Palestinian family in which parents are first cousins, and consanguinity ran over several generations, presented a varying degree of intellectual disability, cone-rod dystrophy, and autism spectrum disorder. Exome sequencing and segregation analysis revealed the presence of homozygous pathogenic mutation in the CNNM2 gene, the parents were heterozygous for that gene mutation. Magnesium blood levels were normal in the three children and their parents in several measurements. They had no symptoms of hypomagnesemia. The CNNM2 mutation in this family was found to locate in the CBS1 domain of the CNNM2 protein. The crystal structure of the mutated CNNM2 protein was not significantly different from the wild-type protein, and the binding of AMP or MgATP was not dramatically affected. This suggests that the CBS1 domain could be involved in pure neurodevelopmental functions independent of its magnesium-handling role, and this mutation could have affected a protein partner binding or other functions in this protein. In the second family, another autosomal dominant CNNM2 mutation was found to run in a large family with multiple individuals over three generations. All affected family members had hypomagnesemia and hypermagnesuria. Oral supplementation of magnesium did not increase the levels of magnesium in serum significantly. Some affected members of this family have defects in fine motor skills such as dyslexia and dyslalia. The detected mutation is located in the N-terminal part, which contains a signal peptide thought to be involved in the sorting and routing of the protein. In this project, we describe heterogenous clinical phenotypes related to CNNM2 mutations and protein functions. In the first family, and up to the authors’ knowledge, we report for the first time the involvement of CNNM2 in retinal photoreceptor development and function. In addition, we report the presence of a neurophenotype independent of magnesium status related to the CNNM2 protein mutation. Taking into account the different modes of inheritance and the different positions of the mutations within CNNM2 and its different structural and functional domains, it is likely that CNNM2 might be involved in a wide spectrum of neuropsychiatric comorbidities with considerable varying phenotypes.

Keywords: magnesium transport, autosomal recessive, autism, neurodevelopment, CBS domain

Procedia PDF Downloads 124