Search results for: artificial intelligence and genetic algorithms

Authors: Henning Lahmann, Benjamyn I. Scott, Bart Custers

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Suboptimal adoption of AI in defence organisations carries risks for the protection of the freedom, safety, and security of society. Despite the vast opportunities that defence AI-technology presents, there are also a variety of ethical, legal, and societal concerns. To ensure the successful use of AI technology by the military, ethical, legal, and societal aspects (ELSA) need to be considered, and their concerns continuously addressed at all levels. This includes ELSA considerations during the design, manufacturing and maintenance of AI-based systems, as well as its utilisation via appropriate military doctrine and training. This raises the question how defence organisations can remain strategically competitive and at the edge of military innovation, while respecting the values of its citizens. This paper will explain the set-up and share preliminary results of a 4-year research project commissioned by the National Research Council in the Netherlands on the ethical, legal, and societal aspects of AI in defence. The project plans to develop a future-proof, independent, and consultative ecosystem for the responsible use of AI in the defence domain. In order to achieve this, the lab shall devise a context-dependent methodology that focuses on the ‘analysis’, ‘design’ and ‘evaluation’ of ELSA of AI-based applications within the military context, which include inter alia unmanned aircraft. This is bolstered as the Lab also recognises and complements the existing methods in regards to human-machine teaming, explainable algorithms, and value-sensitive design. Such methods will be modified for the military context and applied to pertinent case-studies. These case-studies include, among others, the application of autonomous robots (incl. semi- autonomous) and AI-based methods against cognitive warfare. As the perception of the application of AI in the military context, by both society and defence personnel, is important, the Lab will study how these perceptions evolve and vary in different contexts. Furthermore, the Lab will monitor – as they may influence people’s perception – developments in the global technological, military and societal spheres. Although the emphasis of the research project is on different forms of AI in defence, it focuses on several case studies. One of these case studies is on unmanned aircraft, which will also be the focus of the paper. Hence, ethical, legal, and societal aspects of unmanned aircraft in the defence domain will be discussed in detail, including but not limited to privacy issues. Typical other issues concern security (for people, objects, data or other aircraft), privacy (sensitive data, hindrance, annoyance, data collection, function creep), chilling effects, PlayStation mentality, and PTSD.

Keywords: autonomous weapon systems, unmanned aircraft, human-machine teaming, meaningful human control, value-sensitive design

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Authors: Minghui Zhang, Sirine Fkaier, Sabri Fernana, Svetlana Kiseleva, Denis Kiselev

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The real-time identification of bacteria and fungi is difficult because they emit much weaker signals than pollen. In 2020, Plair developed Rapid-E+, which extends abilities of Rapid-E to detect smaller bioaerosols such as bacteria and fungal spores with diameters down to 0.3 µm, while keeping the similar or even better capability for measurements of large bioaerosols like pollen. Rapid-E+ enables simultaneous measurements of (1) time-resolved, polarization and angle dependent Mie scattering patterns, (2) fluorescence spectra resolved in 16 channels, and (3) fluorescence lifetime of individual particles. Moreover, (4) it provides 2D Mie scattering images which give the full information on particle morphology. The parameters of every single bioaerosol aspired into the instrument are subsequently analysed by machine learning. Firstly, pure species of microbes, e.g., Bacillus subtilis (a species of bacteria), and Penicillium chrysogenum (a species of fungal spores), were aerosolized in a bioaerosol chamber for Rapid-E+ training. Afterwards, we tested microbes under different concentrations. We used several steps of data analysis to classify and identify microbes. All single particles were analysed by the parameters of light scattering and fluorescence in the following steps. (1) They were treated with a smart filter block to get rid of non-microbes. (2) By classification algorithm, we verified the filtered particles were microbes based on the calibration data. (3) The probability threshold (defined by the user) step provides the probability of being microbes ranging from 0 to 100%. We demonstrate how Rapid-E+ identified simultaneously microbes based on the results of Bacillus subtilis (bacteria) and Penicillium chrysogenum (fungal spores). By using machine learning, Rapid-E+ achieved identification precision of 99% against the background. The further classification suggests the precision of 87% and 89% for Bacillus subtilis and Penicillium chrysogenum, respectively. The developed algorithm was subsequently used to evaluate the performance of microbe classification and quantification in real-time. The bacteria and fungi were aerosolized again in the chamber with different concentrations. Rapid-E+ can classify different types of microbes and then quantify them in real-time. Rapid-E+ enables classifying different types of microbes and quantifying them in real-time. Rapid-E+ can identify pollen down to species with similar or even better performance than the previous version (Rapid-E). Therefore, Rapid-E+ is an all-in-one instrument which classifies and quantifies not only pollen, but also bacteria and fungi. Based on the machine learning platform, the user can further develop proprietary algorithms for specific microbes (e.g., virus aerosols) and other aerosols (e.g., combustion-related particles that contain polycyclic aromatic hydrocarbons).

Keywords: bioaerosols, laser-induced fluorescence, Mie-scattering, microorganisms

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Authors: Miguel Contreras, David Long, Will Bachman

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Background: Microscopy plays a central role in cell and developmental biology. In particular, fluorescence microscopy can be used to visualize specific cellular components and subsequently quantify their morphology through development of virtual-cell models for study of effects of mechanical forces on cells. However, there are challenges with these imaging experiments, which can make it difficult to quantify cell morphology: inconsistent results, time-consuming and potentially costly protocols, and limitation on number of labels due to spectral overlap. To address these challenges, the objective of this project is to develop an automatic computational machine learning pipeline to predict cellular components morphology for virtual-cell generation based on fluorescence cell membrane confocal z-stacks. Methods: Registered confocal z-stacks of nuclei and cell membrane of endothelial cells, consisting of 20 images each, were obtained from fluorescence confocal microscopy and normalized through software pipeline for each image to have a mean pixel intensity value of 0.5. An open source machine learning algorithm, originally developed to predict fluorescence labels on unlabeled transmitted light microscopy cell images, was trained using this set of normalized z-stacks on a single CPU machine. Through transfer learning, the algorithm used knowledge acquired from its previous training sessions to learn the new task. Once trained, the algorithm was used to predict morphology of nuclei using normalized cell membrane fluorescence images as input. Predictions were compared to the ground truth fluorescence nuclei images. Results: After one week of training, using one cell membrane z-stack (20 images) and corresponding nuclei label, results showed qualitatively good predictions on training set. The algorithm was able to accurately predict nuclei locations as well as shape when fed only fluorescence membrane images. Similar training sessions with improved membrane image quality, including clear lining and shape of the membrane, clearly showing the boundaries of each cell, proportionally improved nuclei predictions, reducing errors relative to ground truth. Discussion: These results show the potential of pre-trained machine learning algorithms to predict cell morphology using relatively small amounts of data and training time, eliminating the need of using multiple labels in immunofluorescence experiments. With further training, the algorithm is expected to predict different labels (e.g., focal-adhesion sites, cytoskeleton), which can be added to the automatic machine learning pipeline for direct input into Principal Component Analysis (PCA) for generation of virtual-cell mechanical models.

Keywords: cell morphology prediction, computational machine learning, fluorescence microscopy, virtual-cell models

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Authors: Takaaki Nemoto

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Case presentation: A 69-year-old Japanese man presented with a low-grade fever and fatigue that had persisted for one month. The patient had an aortic dissection on the aortic arch 13 years prior, an abdominal aortic aneurysm seven years prior, and an aortic dissection on the distal aortic arch one year prior, which were all treated with artificial blood-vessel replacement surgery. Laboratory tests revealed an inflammatory response (CRP 7.61 mg/dl), high serum creatinine (Cr 1.4 mg/dL), and elevated transaminase (AST 47 IU/L, ALT 45 IU/L). The patient was admitted to our hospital on suspicion of prosthetic vascular graft infection. Following further workups on the inflammatory response, an enhanced chest computed tomography (CT) and a non-enhanced chest DWI (MRI) were performed. The patient was diagnosed with a pulmonary fistula and a prosthetic vascular graft infection on the distal aortic arch. After admission, the patient was administered Ceftriaxion and Vancomycine for 10 days, but his fever and inflammatory response did not improve. On day 13 of hospitalization, a lung fistula repair surgery and an omental filling operation were performed, and Meropenem and Vancomycine were administered. The fever and inflammatory response continued, and therefore we took repeated blood cultures. M. fortuitum was detected in a blood culture on day 16 of hospitalization. As a result, we changed the treatment regimen to Amikacin (400 mg/day), Meropenem (2 g/day), and Cefmetazole (4 g/day), and the fever and inflammatory response began to decrease gradually. We performed a test of sensitivity for Mycobacterium fortuitum, and found that the MIC was low for fluoroquinolone antibacterial agent. The clinical course was good, and the patient was discharged after a total of 8 weeks of intravenous drug administration. At discharge, we changed the treatment regimen to Levofloxacin (500 mg/day) and Clarithromycin (800 mg/day), and prescribed these two drugs as a long life suppressive therapy. Discussion: There are few cases of prosthetic vascular graft infection caused by mycobacteria, and a standard therapy remains to be established. For prosthetic vascular graft infections, it is ideal to provide surgical and medical treatment in parallel, but in this case, surgical treatment was difficult and, therefore, a conservative treatment was chosen. We attempted to increase the treatment success rate of this refractory disease by conducting a susceptibility test for mycobacteria and treating with different combinations of antimicrobial agents, which was ultimately effective. With our treatment approach, a good clinical course was obtained and continues at the present stage. Conclusion: Although prosthetic vascular graft infection resulting from mycobacteria is a refractory infectious disease, it may be curative to administer appropriate antibiotics based on the susceptibility test in addition to surgical treatment.

Keywords: prosthetic vascular graft infection, lung fistula, Mycobacterium fortuitum, conservative treatment

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Authors: Waleed Omri

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With the growth of the small business sector in emerging markets, developing a better understanding of what drives 'day-to-day' entrepreneurial activities has become an important issue for academicians and practitioners. Innovation, as an entrepreneurial behavior, revolves around individuals who creatively engage in new organizational efforts. In a similar vein, the innovation behaviors and processes at the organizational member level are central to any corporate entrepreneurship strategy. Despite the broadly acknowledged importance of entrepreneurship and innovation at the individual level in the establishment of successful ventures, the literature lacks evidence on how entrepreneurs can effectively harness their skills and knowledge in the workplace. The existing literature illustrates that religion can impact the day-to-day work behavior of entrepreneurs, managers, and employees. Religious beliefs and practices could affect daily entrepreneurial activities by fostering mental abilities and traits such as creativity, intelligence, and self-efficacy. In the present study, we define religious capital as a set of personal and intangible resources, skills, and competencies that emanate from an individual’s religious values, beliefs, practices, and experiences and may be used to increase the quality of economic activities. Religious beliefs and practices give individuals a religious satisfaction, which can lead them to perform better in the workplace. In addition, religious ethics and practices have been linked to various positive employee outcomes in terms of organizational change, job satisfaction, and entrepreneurial intensity. As investigations of their consequences beyond direct task performance are still scarce, we explore if religious capital plays a role in entrepreneurs’ innovative behavior. In sum, this study explores the determinants of individual entrepreneurial behavior by investigating the relationship between religious capital and entrepreneurs’ innovative behavior in the context of small businesses. To further explain and clarify the religious capital-innovative behavior link, the present study proposes a model to examine the mediating role of entrepreneurial creativity. We use both Islamic work ethics (IWE) and Islamic religious practices (IRP) to measure Islamic religious capital. We use structural equation modeling with a robust maximum likelihood estimation to analyze data gathered from 289 Tunisian small businesses and to explore the relationships among the above-described variables. In line with the theory of planned behavior, only religious work ethics are found to increase the innovative behavior of small businesses’ owner-managers. Our findings also clearly demonstrate that the connection between religious capital-related variables and innovative behavior is better understood if the influence of entrepreneurial creativity, as a mediating variable of the aforementioned relationship, is taken into account. By incorporating both religious capital and entrepreneurial creativity into the innovative behavior analysis, this study provides several important practical implications for promoting innovation process in small businesses.

Keywords: entrepreneurial behavior, small business, religion, creativity

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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: 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: 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: Andrew Fox, Qingping Yang, Yuanhong Zhao, Tao Zhang

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Furniture is a very significant subdivision of architecture and its inherent interior design activities. The furniture industry has developed from an artisan-driven craft industry, whose forerunners saw themselves manifested in their crafts and treasured a sense of pride in the creativity of their designs, these days largely reduced to an anonymous collective mass-produced output. Although a very conservative industry, there is great potential for the implementation of collaborative digital technologies allowing a reconfigured artisan experience to be reawakened in a new and exciting form. The furniture manufacturing industry, in general, has been slow to adopt new methodologies for a design using artificial and rule-based generative design. This tardiness has meant the loss of potential to enhance its capabilities in producing sustainable, flexible, and mass customizable ‘right first-time’ designs. This paper aims to demonstrate the concept methodology for the creation of alternative and inspiring aesthetic structures for robot-based additive manufacturing (RBAM). These technologies can enable the economic creation of previously unachievable structures, which traditionally would not have been commercially economic to manufacture. The integration of these technologies with the computing power of generative design provides the tools for practitioners to create concepts which are well beyond the insight of even the most accomplished traditional design teams. This paper aims to address the problem by introducing generative design methodologies employing the Autodesk Fusion 360 platform. Examination of the alternative methods for its use has the potential to significantly reduce the estimated 80% contribution to environmental impact at the initial design phase. Though predominantly a design methodology, generative design combined with RBAM has the potential to leverage many lean manufacturing and quality assurance benefits, enhancing the efficiency and agility of modern furniture manufacturing. Through a case study examination of a furniture artifact, the results will be compared to a traditionally designed and manufactured product employing the Ecochain Mobius product life cycle analysis (LCA) platform. This will highlight the benefits of both generative design and robot-based additive manufacturing from an environmental impact and manufacturing efficiency standpoint. These step changes in design methodology and environmental assessment have the potential to revolutionise the design to manufacturing workflow, giving momentum to the concept of conceiving a pre-industrial model of manufacturing, with the global demand for a circular economy and bespoke sustainable design at its heart.

Keywords: robot, manufacturing, generative design, sustainability, circular econonmy, product life cycle assessment, furniture

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Authors: Zheng Wang, Zhenhong Li, Jon Mills

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Ground-based synthetic aperture radar (GBSAR) represents a powerful remote sensing tool for deformation monitoring towards various geohazards, e.g. landslides, mudflows, avalanches, infrastructure failures, and the subsidence of residential areas. Unlike spaceborne SAR with a fixed revisit period, GBSAR data can be acquired with an adjustable temporal resolution through either continuous or discontinuous operation. However, challenges arise from processing high temporal-resolution continuous GBSAR data, including the extreme cost of computational random-access-memory (RAM), the delay of displacement maps, and the loss of temporal evolution. Moreover, repositioning errors between discontinuous campaigns impede the accurate measurement of surface displacements. Therefore, a versatile package with two complete chains is developed in this study in order to process both continuous and discontinuous GBSAR data and address the aforementioned issues. The first chain is based on a small-baseline subset concept and it processes continuous GBSAR images unit by unit. Images within a window form a basic unit. By taking this strategy, the RAM requirement is reduced to only one unit of images and the chain can theoretically process an infinite number of images. The evolution of surface displacements can be detected as it keeps temporarily-coherent pixels which are present only in some certain units but not in the whole observation period. The chain supports real-time processing of the continuous data and the delay of creating displacement maps can be shortened without waiting for the entire dataset. The other chain aims to measure deformation between discontinuous campaigns. Temporal averaging is carried out on a stack of images in a single campaign in order to improve the signal-to-noise ratio of discontinuous data and minimise the loss of coherence. The temporal-averaged images are then processed by a particular interferometry procedure integrated with advanced interferometric SAR algorithms such as robust coherence estimation, non-local filtering, and selection of partially-coherent pixels. Experiments are conducted using both synthetic and real-world GBSAR data. Displacement time series at the level of a few sub-millimetres are achieved in several applications (e.g. a coastal cliff, a sand dune, a bridge, and a residential area), indicating the feasibility of the developed GBSAR data processing package for deformation monitoring of a wide range of scientific and practical applications.

Keywords: ground-based synthetic aperture radar, interferometry, small baseline subset algorithm, deformation monitoring

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Authors: Lena Lapidot, Amir Amnon, Rita Nosenko, Veitsman Ella, Cohen-Ezra Oranit, Davidov Yana, Segev Shlomo, Koren Omry, Safran Michal, Ben-Ari Ziv

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Introduction: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related mortality worldwide. Liver Cirrhosis is the main predisposing risk factor for the development of HCC. The factor(s) influencing disease progression from Cirrhosis to HCC remain unknown. Gut microbiota has recently emerged as a major player in different liver diseases, however its association with HCC is still a mystery. Moreover, there might be an important association between the gut microbiota, nutrition, life style and the progression of Cirrhosis and HCC. The aim of our study was to characterize the gut microbial signature in association with life style and nutrition of patients with Cirrhosis, HCC-Cirrhosis and healthy controls. Design: Stool samples were collected from 95 individuals (30 patients with HCC, 38 patients with Cirrhosis and 27 age, gender and BMI-matched healthy volunteers). All participants answered lifestyle and Food Frequency Questionnaires. 16S rRNA sequencing of fecal DNA was performed (MiSeq Illumina). Results: There was a significant decrease in alpha diversity in patients with Cirrhosis (qvalue=0.033) and in patients with HCC-Cirrhosis (qvalue=0.032) compared to healthy controls. The microbiota of patients with HCC-cirrhosis compared to patients with Cirrhosis, was characterized by a significant overrepresentation of Clostridium (pvalue=0.024) and CF231 (pvalue=0.010) and lower expression of Alphaproteobacteria (pvalue=0.039) and Verrucomicrobia (pvalue=0.036) in several taxonomic levels: Verrucomicrobiae, Verrucomicrobiales, Verrucomicrobiaceae and the genus Akkermansia (pvalue=0.039). Furthermore, we performed an analysis of predicted metabolic pathways (Kegg level 2) that resulted in a significant decrease in the diversity of metabolic pathways in patients with HCC-Cirrhosis (qvalue=0.015) compared to controls, one of which was amino acid metabolism. Furthermore, investigating the life style and nutrition habits of patients with HCC-Cirrhosis, we found significant correlations between intake of artificial sweeteners and Verrucomicrobia (qvalue=0.12), High sugar intake and Synergistetes (qvalue=0.021) and High BMI and the pathogen Campylobacter (qvalue=0.066). Furthermore, overweight in patients with HCC-Cirrhosis modified bacterial diversity (qvalue=0.023) and composition (qvalue=0.033). Conclusions: To the best of the our knowledge, we present the first report of the gut microbial composition in patients with HCC-Cirrhosis, compared with Cirrhotic patients and healthy controls. We have demonstrated in our study that there are significant differences in the gut microbiome of patients with HCC-cirrhosis compared to Cirrhotic patients and healthy controls. Our findings are even more pronounced because the significantly increased bacteria Clostridium and CF231 in HCC-Cirrhosis weren't influenced by diet and lifestyle, implying this change is due to the development of HCC. Further studies are needed to confirm these findings and assess causality.

Keywords: Cirrhosis, Hepatocellular carcinoma, life style, liver disease, microbiome, nutrition

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Authors: Azam Fazelpour, Saeed Reza Dehghani, Vlastimil Masek, Yuri S. Muzychka

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The study uses a novel image analysis based on thermal imaging to detect temperature contours created on salt ice surface during transient phenomena. Thermal cameras detect objects by using their emissivities and IR radiance. The ice surface temperature is not uniform during transient processes. The temperature starts to increase from the boundary of ice towards the center of that. Thermal cameras are able to report temperature changes on the ice surface at every individual moment. Various contours, which show different temperature areas, appear on the ice surface picture captured by a thermal camera. Identifying the exact boundary of these contours is valuable to facilitate ice surface temperature analysis. Image processing techniques are used to extract each contour area precisely. In this study, several pictures are recorded while the temperature is increasing throughout the ice surface. Some pictures are selected to be processed by a specific time interval. An image segmentation method is applied to images to determine the contour areas. Color thermal images are used to exploit the main information. Red, green and blue elements of color images are investigated to find the best contour boundaries. The algorithms of image enhancement and noise removal are applied to images to obtain a high contrast and clear image. A novel edge detection algorithm based on differences in the color of the pixels is established to determine contour boundaries. In this method, the edges of the contours are obtained according to properties of red, blue and green image elements. The color image elements are assessed considering their information. Useful elements proceed to process and useless elements are removed from the process to reduce the consuming time. Neighbor pixels with close intensities are assigned in one contour and differences in intensities determine boundaries. The results are then verified by conducting experimental tests. An experimental setup is performed using ice samples and a thermal camera. To observe the created ice contour by the thermal camera, the samples, which are initially at -20° C, are contacted with a warmer surface. Pictures are captured for 20 seconds. The method is applied to five images ,which are captured at the time intervals of 5 seconds. The study shows the green image element carries no useful information; therefore, the boundary detection method is applied on red and blue image elements. In this case study, the results indicate that proposed algorithm shows the boundaries more effective than other edges detection methods such as Sobel and Canny. Comparison between the contour detection in this method and temperature analysis, which states real boundaries, shows a good agreement. This color image edge detection method is applicable to other similar cases according to their image properties.

Keywords: color image processing, edge detection, ice contour boundary, salt ice, thermal image

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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

Procedia PDF Downloads 394

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

Procedia PDF Downloads 280

Authors: Nir Nissim, Ran Yahalom, Tomer Lancewiki, Yuval Elovici, Boaz Lerner

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Background: Attackers increasingly take advantage of innocent users who tend to use USB devices casually, assuming these devices benign when in fact they may carry an embedded malicious behavior or hidden malware. USB devices have many properties and capabilities that have become the subject of malicious operations. Many of the recent attacks targeting individuals, and especially organizations, utilize popular and widely used USB devices, such as mice, keyboards, flash drives, printers, and smartphones. However, current detection tools, techniques, and solutions generally fail to detect both the known and unknown attacks launched via USB devices. Significance: We propose USBWARE, a project that focuses on the vulnerabilities of USB devices and centers on the development of a comprehensive detection framework that relies upon a crucial attack repository. USBWARE will allow researchers and companies to better understand the vulnerabilities and attacks associated with USB devices as well as providing a comprehensive platform for developing detection solutions. Methodology: The framework of USBWARE is aimed at accurate detection of both known and unknown USB-based attacks by a process that efficiently enhances the framework's detection capabilities over time. The framework will integrate two main security approaches in order to enhance the detection of USB-based attacks associated with a variety of USB devices. The first approach is aimed at the detection of known attacks and their variants, whereas the second approach focuses on the detection of unknown attacks. USBWARE will consist of six independent but complimentary detection modules, each detecting attacks based on a different approach or discipline. These modules include novel ideas and algorithms inspired from or already developed within our team's domains of expertise, including cyber security, electrical and signal processing, machine learning, and computational biology. The establishment and maintenance of the USBWARE’s dynamic and up-to-date attack repository will strengthen the capabilities of the USBWARE detection framework. The attack repository’s infrastructure will enable researchers to record, document, create, and simulate existing and new USB-based attacks. This data will be used to maintain the detection framework’s updatability by incorporating knowledge regarding new attacks. Based on our experience in the cyber security domain, we aim to design the USBWARE framework so that it will have several characteristics that are crucial for this type of cyber-security detection solution. Specifically, the USBWARE framework should be: Novel, Multidisciplinary, Trusted, Lightweight, Extendable, Modular and Updatable and Adaptable. Major Findings: Based on our initial survey, we have already found more than 23 types of USB-based attacks, divided into six major categories. Our preliminary evaluation and proof of concepts showed that our detection modules can be used for efficient detection of several basic known USB attacks. Further research, development, and enhancements are required so that USBWARE will be capable to cover all of the major known USB attacks and to detect unknown attacks. Conclusion: USBWARE is a crucial detection framework that must be further enhanced and developed.

Keywords: USB, device, cyber security, attack, detection

Procedia PDF Downloads 368

Authors: A. G. Akhundov

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Issues of obtaining unbiased data on the status of pipeline systems of oil- and oil product transportation become especially important when laying and operating pipelines under severe nature and climatic conditions. The essential attention is paid here to researching exogenous processes and their impact on linear facilities of the pipeline system. Reliable operation of pipelines under severe nature and climatic conditions, timely planning and implementation of compensating measures are only possible if operation conditions of pipeline systems are regularly monitored, and changes of permafrost soil and hydrological operation conditions are accounted for. One of the main reasons for emergency situations to appear is the geodynamic factor. Emergency situations are proved by the experience to occur within areas characterized by certain conditions of the environment and to develop according to similar scenarios depending on active processes. The analysis of natural and technical systems of main pipelines at different stages of monitoring gives a possibility of making a forecast of the change dynamics. The integration of GIS technologies, traditional means of geotechnical monitoring (in-line inspection, geodetic methods, field observations), and remote methods (aero-visual inspection, aero photo shooting, air and ground laser scanning) provides the most efficient solution of the problem. The united environment of geo information system (GIS) is a comfortable way to implement the monitoring system on the main pipelines since it provides means to describe a complex natural and technical system and every element thereof with any set of parameters. Such GIS enables a comfortable simulation of main pipelines (both in 2D and 3D), the analysis of situations and selection of recommendations to prevent negative natural or man-made processes and to mitigate their consequences. The specifics of such systems include: a multi-dimensions simulation of facilities in the pipeline system, math modelling of the processes to be observed, and the use of efficient numeric algorithms and software packets for forecasting and analyzing. We see one of the most interesting possibilities of using the monitoring results as generating of up-to-date 3D models of a facility and the surrounding area on the basis of aero laser scanning, data of aerophotoshooting, and data of in-line inspection and instrument measurements. The resulting 3D model shall be the basis of the information system providing means to store and process data of geotechnical observations with references to the facilities of the main pipeline; to plan compensating measures, and to control their implementation. The use of GISs for geotechnical monitoring of pipeline systems is aimed at improving the reliability of their operation, reducing the probability of negative events (accidents and disasters), and at mitigation of consequences thereof if they still are to occur.

Keywords: databases, 3D GIS, geotechnical monitoring, pipelines, laser scaning

Procedia PDF Downloads 166

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: Jayashree And Gajjam

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Intellectual humility (IH) is defined as a virtuous mean between intellectual arrogance and intellectual self-diffidence by the ‘Doxastic Account of IH’ studied, researched and developed by western scholars not earlier than 2015 at the University of Edinburgh. Ancient Indian philosophical texts or the Upanisads written in the Sanskrit language during the later Vedic period (circa 600-300 BCE) have long addressed the virtue of being humble in several stories and narratives. The current research paper questions and revisits these character traits in an Indian context following an experimental method. Based on the subjective reports of more than 400 Indian teenagers and adults, it argues that while a few traits of IH (such as trustworthiness, respectfulness, intelligence, politeness, etc.) are panhuman and pancultural, a few are not. Some attributes of IH (such as proper pride, open-mindedness, awareness of own strength, etc.) may be taken for arrogance by the Indian population, while other qualities of Intellectual Diffidence such as agreeableness, surrendering can be regarded as the characteristic of IH. The paper then gives the reasoning for this discrepancy that can be traced back to the ancient Indian (Upaniṣadic) teachings that are still prevalent in many Indian families and still anchor their views on IH. The name Upanisad itself means ‘sitting down near’ (to the Guru to gain the Supreme knowledge of the Self and the Universe and setting to rest ignorance) which is equivalent to the three traits among the BIG SEVEN characterized as IH by the western scholars viz. ‘being a good listener’, ‘curious to learn’, and ‘respect to other’s opinion’. The story of Satyakama Jabala (Chandogya Upanisad 4.4-8) who seeks the truth for several years even from the bull, the fire, the swan and waterfowl, suggests nothing but the ‘need for cognition’ or ‘desire for knowledge’. Nachiketa (Katha Upanisad), a boy with a pure mind and heart, follows his father’s words and offers himself to Yama (the God of Death) where after waiting for Yama for three days and nights, he seeks the knowledge of the mysteries of life and death. Although the main aim of these Upaniṣadic stories is to give the knowledge of life and death, the Supreme reality which can be identical with traits such as ‘curious to learn’, one cannot deny that they have a lot more to offer than mere information about true knowledge e.g., ‘politeness’, ‘good listener’, ‘awareness of own limitations’, etc. The possible future scope of this research includes (1) finding other socio-cultural factors that affect the ideas on IH such as age, gender, caste, type of education, highest qualification, place of residence and source of income, etc. which may be predominant in current Indian society despite our great teachings of the Upaniṣads, and (2) to devise different measures to impart IH in Indian children, teenagers, and younger adults for the harmonious future. The current experimental research can be considered as the first step towards these goals.

Keywords: ethics and virtue epistemology, Indian philosophy, intellectual humility, upaniṣadic texts in ancient India

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Authors: Tomasz Grzes, Maciej Kopczynski, Jaroslaw Stepaniuk

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The rough sets theory developed by Prof. Z. Pawlak is one of the tools that can be used in the intelligent systems for data analysis and processing. Banking, medicine, image recognition and security are among the possible fields of utilization. In all these fields, the amount of the collected data is increasing quickly, but with the increase of the data, the computation speed becomes the critical factor. Data reduction is one of the solutions to this problem. Removing the redundancy in the rough sets can be achieved with the reduct. A lot of algorithms of generating the reduct were developed, but most of them are only software implementations, therefore have many limitations. Microprocessor uses the fixed word length, consumes a lot of time for either fetching as well as processing of the instruction and data; consequently, the software based implementations are relatively slow. Hardware systems don’t have these limitations and can process the data faster than a software. Reduct is the subset of the decision attributes that provides the discernibility of the objects. For the given decision table there can be more than one reduct. Core is the set of all indispensable condition attributes. None of its elements can be removed without affecting the classification power of all condition attributes. Moreover, every reduct consists of all the attributes from the core. In this paper, the hardware implementation of the two-stage greedy algorithm to find the one reduct is presented. The decision table is used as an input. Output of the algorithm is the superreduct which is the reduct with some additional removable attributes. First stage of the algorithm is calculating the core using the discernibility matrix. Second stage is generating the superreduct by enriching the core with the most common attributes, i.e., attributes that are more frequent in the decision table. Described above algorithm has two disadvantages: i) generating the superreduct instead of reduct, ii) additional first stage may be unnecessary if the core is empty. But for the systems focused on the fast computation of the reduct the first disadvantage is not the key problem. The core calculation can be achieved with a combinational logic block, and thus add respectively little time to the whole process. Algorithm presented in this paper was implemented in Field Programmable Gate Array (FPGA) as a digital device consisting of blocks that process the data in a single step. Calculating the core is done by the comparators connected to the block called 'singleton detector', which detects if the input word contains only single 'one'. Calculating the number of occurrences of the attribute is performed in the combinational block made up of the cascade of the adders. The superreduct generation process is iterative and thus needs the sequential circuit for controlling the calculations. For the research purpose, the algorithm was also implemented in C language and run on a PC. The times of execution of the reduct calculation in a hardware and software were considered. Results show increase in the speed of data processing.

Keywords: data reduction, digital systems design, field programmable gate array (FPGA), reduct, rough set

Procedia PDF Downloads 191

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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Authors: H. Mayton, X. Yan, A. G. Taylor

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Infested tomato seeds were used to investigate the influence of Xanthomonas euvesicatoria on germination and seed to seedling transmission in a controlled environment and greenhouse assays in an effort to develop effective seed treatments and characterize seed borne transmission of bacterial leaf spot of tomato. Bacterial leaf spot of tomato, caused by four distinct Xanthomonas species, X. euvesicatoria, X. gardneri, X. perforans, and X. vesicatoria, is a serious disease worldwide. In the United States, disease prevention is expensive for commercial growers in warm, humid regions of the country, and crop losses can be devastating. In this study, four different infested tomato seed lots were extracted from tomato fruits infected with bacterial leaf spot from a field in New York State in 2017 that had been inoculated with X. euvesicatoria. In addition, vacuum infiltration at 61 kilopascals for 1, 5, 10, and 15 minutes and seed soaking for 5, 10, 15, and 30 minutes with different bacterial concentrations were used to artificially infest seed in the laboratory. For controlled environment assays, infested tomato seeds from the field and laboratory were placed othe n moistened blue blotter in square plastic boxes (10 cm x 10 cm) and incubated at 20/30 ˚C with an 8/16 hour light cycle, respectively. Infested tomato seeds from the field and laboratory were also planted in small plastic trays in soil (peat-lite medium) and placed in the greenhouse with 24/18 ˚C day and night temperatures, respectively, with a 14-hour photoperiod. Seed germination was assessed after eight days in the laboratory and 14 days in the greenhouse. Polymerase chain reaction (PCR) using the hrpB7 primers (RST65 [5’- GTCGTCGTTACGGCAAGGTGGTG-3’] and RST69 [5’-TCGCCCAGCGTCATCAGGCCATC-3’]) was performed to confirm presence or absence of the bacterial pathogen in seed lots collected from the field and in germinating seedlings in all experiments. For infested seed lots from the field, germination was lowest (84%) in the seed lot with the highest level of bacterial infestation (55%) and ranged from 84-98%. No adverse effect on germination was observed from artificially infested seeds for any bacterial concentration and method of infiltration when compared to a non-infested control. Germination in laboratory assays for artificially infested seeds ranged from 82-100%. In controlled environment assays, 2.5 % were PCR positive for the pathogen, and in the greenhouse assays, no infected seedlings were detected. From these experiments, X. euvesicatoria does not appear to adversely influence germination. The lowest rate of germination from field collected seed may be due to contamination with multiple pathogens and saprophytic organisms as no effect of artificial bacterial seed infestation in the laboratory on germination was observed. No evidence of systemic movement from seed to seedling was observed in the greenhouse assays; however, in the controlled environment assays, some seedlings were PCR positive. Additional experiments are underway with green fluorescent protein-expressing isolates to further characterize seed to seedling transmission of the bacterial leaf spot pathogen in tomato.

Keywords: bacterial leaf spot, seed germination, tomato, Xanthomonas euvesicatoria

Procedia PDF Downloads 114

Authors: Nasser Koleini Mamaghani, Sara Mostowfi

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The complexity of public space design makes it difficult for designers to simultaneously consider all issues for thorough decision-making. Among public spaces, the public space around people’s house is the most prominent space that affects and impacts people’s daily life. Considering recreational public spaces in cities, their main purpose would be to design for experiences that enable a deep feeling of peace and a moment of being away from the hectic daily life. Respecting human emotions and restoring natural environments, although difficult and to some extent out of reach, are key issues for designing such spaces. In this paper we propose to analyse the structure of recreational public spaces and the related emotional impressions. Furthermore, we suggest investigating how these structures influence people’s choice for public spaces by using differential semantics. According to Kansei methodology, in order to evaluate a situation appropriately, the assessment variables must be adapted to the user’s mental scheme. This means that the first step would have to be the identification of a space’s conceptual scheme. In our case study, 32 Kansei words and 4 different locations, each with a different sensual experience, were selected. The 4 locations were all parks in the city of Tehran (Iran), each with a unique structure and artifacts such as a fountain, lighting, sculptures, and music. It should be noted that each of these parks has different combination and structure of environmental and artificial elements like: fountain, lightning, sculpture, music (sound) and so forth. The first one was park No.1, a park with natural environment, the selected space was a fountain with motion light and sculpture. The second park was park No.2, in which there are different styles of park construction: ways from different countries, the selected space was traditional Iranian architecture with a fountain and trees. The third one was park No.3, the park with modern environment and spaces, and included a fountain that moved according to music and lighting. The fourth park was park No.4, the park with combination of four elements: water, fire, earth, wind, the selected space was fountains squirting water from the ground up. 80 participant (55 males and 25 females) aged from 20-60 years participated in this experiment. Each person filled the questionnaire in the park he/she was in. Five-point semantic differential scale was considered to determine the relation between space details and adjectives (kansei words). Received data were analyzed by multivariate statistical technique (factor analysis using SPSS statics). Finally the results of this analysis are criteria as inspiration which can be used in future space designing for creating pleasant feeling in users.

Keywords: environmental design, differential semantics, Kansei engineering, subjective preferences, space

Procedia PDF Downloads 384

Authors: Roberta Pecoraro

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The focus of this work was to investigate the potential toxic effect of titanium dioxide-reduced graphene oxide (TiO₂-rGO) nanocomposites on nauplii of microcrustacean Artemia sp. In order to assess the nanocomposite’s toxicity, a short-term test was performed by exposing nauplii to solutions containing TiO₂-rGO. To prepare titanium dioxide-reduced graphene oxide (TiO₂-rGO) nanocomposites, a green procedure based on solar photoreduction was proposed; it allows to obtain the photocatalysts by exploiting the photocatalytic properties of titania activated by the solar irradiation in order to avoid the high temperatures and pressures required for the standard hydrothermal synthesis. Powders of TiO₂-rGO supplied by the Department of Chemical Sciences (University of Catania) are indicated as TiO₂-rGO at 1% and TiO₂-rGO at 2%. Starting from a stock solution (1mg rGO-TiO₂/10 ml ASPM water) of each type, we tested four different concentrations (serial dilutions ranging from 10⁻¹ to 10⁻⁴ mg/ml). All the solutions have been sonicated for 12 min prior to use. Artificial seawater (called ASPM water) was prepared to guarantee the hatching of the cysts and to maintain nauplii; the durable cysts used in this study, marketed by JBL (JBL GmbH & Co. KG, Germany), were hydrated with ASPM water to obtain nauplii (instar II-III larvae). The hatching of the cysts was carried out in the laboratory by immersing them in ASPM water inside a 500 ml beaker and keeping them constantly oxygenated thanks to an aerator for the insufflation of microbubble air: after 24-48 hours, the cysts hatched, and the nauplii appeared. The nauplii in the second and third stages of development were collected one-to-one, using stereomicroscopes, and transferred into 96-well microplates where one nauplius per well was added. The wells quickly have been filled with 300 µl of each specific concentration of the solution used, and control samples were incubated only with ASPM water. Replication was performed for each concentration. Finally, the microplates were placed on an orbital shaker, and the tests were read after 24 and 48 hours from inoculating the solutions to assess the endpoint (immobility/death) for the larvae. Nauplii that appeared motionless were counted as dead, and the percentages of mortality were calculated for each treatment. The results showed a low percentage of immobilization both for TiO₂-rGO at 1% and TiO₂-rGO at 2% for all concentrations tested: for TiO₂-rGO at 1% was below 12% after 24h and below 15% after 48h; for TiO₂-rGO at 2% was below 8% after 24h and below 12% after 48h. According to other studies in the literature, the results have not shown mortality nor toxic effects on the development of larvae after exposure to rGO. Finally, it is important to highlight that the TiO₂-rGO catalysts were tested in the solar photodegradation of a toxic herbicide (2,4-Dichlorophenoxyacetic acid, 2,4-D), obtaining a high percentage of degradation; therefore, this alternative approach could be considered a good strategy to obtain performing photocatalysts.

Keywords: Nauplii, photocatalytic properties, reduced GO, short-term toxicity test, titanium dioxide

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Authors: Fabiana Franceschi, Martha Cobo, Manuel Figueredo

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Bogotá, the capital of Colombia, is its largest city and one of the most polluted in Latin America due to the fast economic growth over the last ten years. Bogotá has been affected by high pollution events which led to the high concentration of PM10 and NO2, exceeding the local 24-hour legal limits (100 and 150 g/m3 each). The most important pollutants in the city are PM10 and PM2.5 (which are associated with respiratory and cardiovascular problems) and it is known that their concentrations in the atmosphere depend on the local meteorological factors. Therefore, it is necessary to establish a relationship between the meteorological variables and the concentrations of the atmospheric pollutants such as PM10, PM2.5, CO, SO2, NO2 and O3. This study aims to determine the interrelations between meteorological variables and air pollutants in Bogotá, using data mining techniques. Data from 13 monitoring stations were collected from the Bogotá Air Quality Monitoring Network within the period 2010-2015. The Principal Component Analysis (PCA) algorithm was applied to obtain primary relations between all the parameters, and afterwards, the K-means clustering technique was implemented to corroborate those relations found previously and to find patterns in the data. PCA was also used on a per shift basis (morning, afternoon, night and early morning) to validate possible variation of the previous trends and a per year basis to verify that the identified trends have remained throughout the study time. Results demonstrated that wind speed, wind direction, temperature, and NO2 are the most influencing factors on PM10 concentrations. Furthermore, it was confirmed that high humidity episodes increased PM2,5 levels. It was also found that there are direct proportional relationships between O3 levels and wind speed and radiation, while there is an inverse relationship between O3 levels and humidity. Concentrations of SO2 increases with the presence of PM10 and decreases with the wind speed and wind direction. They proved as well that there is a decreasing trend of pollutant concentrations over the last five years. Also, in rainy periods (March-June and September-December) some trends regarding precipitations were stronger. Results obtained with K-means demonstrated that it was possible to find patterns on the data, and they also showed similar conditions and data distribution among Carvajal, Tunal and Puente Aranda stations, and also between Parque Simon Bolivar and las Ferias. It was verified that the aforementioned trends prevailed during the study period by applying the same technique per year. It was concluded that PCA algorithm is useful to establish preliminary relationships among variables, and K-means clustering to find patterns in the data and understanding its distribution. The discovery of patterns in the data allows using these clusters as an input to an Artificial Neural Network prediction model.

Keywords: air pollution, air quality modelling, data mining, particulate matter

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Authors: Ryan A. Black, Stacey A. McCaffrey

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Over the past few decades, great strides have been made towards improving the science in the measurement of psychological constructs. Item Response Theory (IRT) has been the foundation upon which statistical models have been derived to increase both precision and accuracy in psychological measurement. These models are now being used widely to develop and refine tests intended to measure an individual's level of academic achievement, aptitude, and intelligence. Recently, the field of clinical psychology has adopted IRT models to measure psychopathological phenomena such as depression, anxiety, and addiction. Because advances in IRT measurement models are being made so rapidly across various fields, it has become quite challenging for psychologists and other behavioral scientists to keep abreast of the most recent developments, much less learn how to employ and decide which models are the most appropriate to use in their line of work. In the same vein, IRT measurement models vary greatly in complexity in several interrelated ways including but not limited to the number of item-specific parameters estimated in a given model, the function which links the expected response and the predictor, response option formats, as well as dimensionality. As a result, inferior methods (a.k.a. Classical Test Theory methods) continue to be employed in efforts to measure psychological constructs, despite evidence showing that IRT methods yield more precise and accurate measurement. To increase the use of IRT methods, this study endeavors to provide a comprehensive overview of binary IRT models; that is, measurement models employed on test data consisting of binary response options (e.g., correct/incorrect, true/false, agree/disagree). Specifically, this study will cover the most basic binary IRT model, known as the 1-parameter logistic (1-PL) model dating back to over 50 years ago, up until the most recent complex, 4-parameter logistic (4-PL) model. Binary IRT models will be defined mathematically and the interpretation of each parameter will be provided. Next, all four binary IRT models will be employed on two sets of data: 1. Simulated data of N=500,000 subjects who responded to four dichotomous items and 2. A pilot analysis of real-world data collected from a sample of approximately 770 subjects who responded to four self-report dichotomous items pertaining to emotional consequences to alcohol use. Real-world data were based on responses collected on items administered to subjects as part of a scale-development study (NIDA Grant No. R44 DA023322). IRT analyses conducted on both the simulated data and analyses of real-world pilot will provide a clear demonstration of how to construct, evaluate, and compare binary IRT measurement models. All analyses will be performed using the new IRT procedure in SAS 9.4. SAS code to generate simulated data and analyses will be available upon request to allow for replication of results.

Keywords: instrument development, item response theory, latent trait theory, psychometrics

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Authors: Ahmad S. Darwish, Tarek Lemaoui, Hanifa Taher, Inas M. AlNashef, Fawzi Banat

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This research reports a systematic top-down approach for designing neoteric hydrophobic solvents –particularly, deep eutectic solvents (DES) and ionic liquids (IL)– as furfural extractants from aqueous media for the application of sustainable biomass conversion. The first stage of the framework entailed screening 32 neoteric solvents to determine their efficacy against toluene as the application’s conventional benchmark for comparison. The selection criteria for the best solvents encompassed not only their efficiency in extracting furfural but also low viscosity and minimal toxicity levels. Additionally, for the DESs, their natural origins, availability, and biodegradability were also taken into account. From the screening pool, two neoteric solvents were selected: thymol:decanoic acid 1:1 (Thy:DecA) and trihexyltetradecyl phosphonium bis(trifluoromethylsulfonyl) imide [P₁₄,₆,₆,₆][NTf₂]. These solvents outperformed the toluene benchmark, achieving efficiencies of 94.1% and 97.1% respectively, compared to toluene’s 81.2%, while also possessing the desired properties. These solvents were then characterized thoroughly in terms of their physical properties, thermal properties, critical properties, and cross-contamination solubilities. The selected neoteric solvents were then extensively tested under various operating conditions, and an exceptional stable performance was exhibited, maintaining high efficiency across a broad range of temperatures (15–100 °C), pH levels (1–13), and furfural concentrations (0.1–2.0 wt%) with a remarkable equilibrium time of only 2 minutes, and most notably, demonstrated high efficiencies even at low solvent-to-feed ratios. The durability of the neoteric solvents was also validated to be stable over multiple extraction-regeneration cycles, with limited leachability to the aqueous phase (≈0.1%). Moreover, the extraction performance of the solvents was then modeled through machine learning, specifically multiple non-linear regression (MNLR) and artificial neural networks (ANN). The models demonstrated high accuracy, indicated by their low absolute average relative deviations with values of 2.74% and 2.28% for Thy:DecA and [P₁₄,₆,₆,₆][NTf₂], respectively, using MNLR, and 0.10% for Thy:DecA and 0.41% for [P₁₄,₆,₆,₆][NTf₂] using ANN, highlighting the significantly enhanced predictive accuracy of the ANN. The neoteric solvents presented herein offer noteworthy advantages over traditional organic solvents, including their high efficiency in both extraction and regeneration processes, their stability and minimal leachability, making them particularly suitable for applications involving aqueous media. Moreover, these solvents are more environmentally friendly, incorporating renewable and sustainable components like thymol and decanoic acid. This exceptional efficacy of the newly developed neoteric solvents signifies a significant advancement, providing a green and sustainable alternative for furfural production from biowaste.

Keywords: sustainable biomass conversion, furfural extraction, ionic liquids, deep eutectic solvents

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Authors: Erik Vassøy Olsen, Hirpa G. Lemu

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Inspired by the Formula-1 competition, IMechE (Institute of Mechanical Engineers) and Formula SAE (Society of Mechanical Engineers) organize annual competitions for University and College students worldwide to compete with a single-seat race car they have designed and built. The design of the chassis or the frame is a key component of the competition because the weight and stiffness properties are directly related with the performance of the car and the safety of the driver. In addition, a reduced weight of the chassis has a direct influence on the design of other components in the car. Among others, it improves the power to weight ratio and the aerodynamic performance. As the power output of the engine or the battery installed in the car is limited to 80 kW, increasing the power to weight ratio demands reduction of the weight of the chassis, which represents the major part of the weight of the car. In order to reduce the weight of the car, ION Racing team from the University of Stavanger, Norway, opted for a monocoque design. To ensure fulfilment of the above-mentioned requirements of the chassis, the monocoque design should provide sufficient torsional stiffness and absorb the impact energy in case of a possible collision. The study reported in this article is based on the requirements for Formula Student competition. As part of this study, diverse mechanical tests were conducted to determine the mechanical properties and performances of the monocoque design. Upon a comprehensive theoretical study of the mechanical properties of sandwich composite materials and the requirements of monocoque design in the competition rules, diverse tests were conducted including 3-point bending test, perimeter shear test and test for absorbed energy. The test panels were homemade and prepared with an equivalent size of the side impact zone of the monocoque, i.e. 275 mm x 500 mm so that the obtained results from the tests can be representative. Different layups of the test panels with identical core material and the same number of layers of carbon fibre were tested and compared. Influence of the core material thickness was also studied. Furthermore, analytical calculations and numerical analysis were conducted to check compliance to the stated rules for Structural Equivalency with steel grade SAE/AISI 1010. The test results were also compared with calculated results with respect to bending and torsional stiffness, energy absorption, buckling, etc. The obtained results demonstrate that the material composition and strength of the composite material selected for the monocoque design has equivalent structural properties as a welded frame and thus comply with the competition requirements. The developed analytical calculation algorithms and relations will be useful for future monocoque designs with different lay-ups and compositions.

Keywords: composite material, Formula student, ION racing, monocoque design, structural equivalence

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Authors: Rasha Waheeb, Bjorn Andersen, Rafa Shakir

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Purpose The purpose of this study is to avoid delays that occur in emergency reconstruction projects especially in post disaster circumstances whether if they were natural or manmade due to their particular national and humanitarian importance. We presented a theoretical and practical concepts for projects management in the field of construction industry that deal with a range of global and local trails. This study aimed to identify the factors of effective delay in construction projects in Iraq that affect the time and the specific quality cost, and find the best solutions to address delays and solve the problem by setting parameters to restore balance in this study. 30 projects were selected in different areas of construction were selected as a sample for this study. Design/methodology/approach This study discusses the reconstruction strategies and delay in time and cost caused by different delay factors in some selected projects in Iraq (Baghdad as a case study).A case study approach was adopted, with thirty construction projects selected from the Baghdad region, of different types and sizes. Project participants from the case projects provided data about the projects through a data collection instrument distributed through a survey. Mixed approach and methods were applied in this study. Mathematical data analysis was used to construct models to predict delay in time and cost of projects before they started. The artificial neural networks analysis was selected as a mathematical approach. These models were mainly to help decision makers in construction project to find solutions to these delays before they cause any inefficiency in the project being implemented and to strike the obstacles thoroughly to develop this industry in Iraq. This approach was practiced using the data collected through survey and questionnaire data collection as information form. Findings The most important delay factors identified leading to schedule overruns were contractor failure, redesigning of designs/plans and change orders, security issues, selection of low-price bids, weather factors, and owner failures. Some of these are quite in line with findings from similar studies in other countries/regions, but some are unique to the Iraqi project sample, such as security issues and low-price bid selection. Originality/value we selected ANN’s analysis first because ANN’s was rarely used in project management , and never been used in Iraq to finding solutions for problems in construction industry. Also, this methodology can be used in complicated problems when there is no interpretation or solution for a problem. In some cases statistical analysis was conducted and in some cases the problem is not following a linear equation or there was a weak correlation, thus we suggested using the ANN’s because it is used for nonlinear problems to find the relationship between input and output data and that was really supportive.

Keywords: construction projects, delay factors, emergency reconstruction, innovation ANN, post disasters, project management

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Authors: Juan S. Mantilla, Peter Thomson

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Seismic events may result in discomfort on occupants of the buildings, structural damage or even buildings collapse. Traditional design aims to reduce dynamic response of structures by increasing stiffness, thus increasing the construction costs and the design forces. Structural control systems arise as an alternative to reduce these dynamic responses. A commonly used control systems in buildings are the passive friction dampers, which adds energy dissipation through damping mechanisms induced by sliding friction between their surfaces. Passive friction dampers are usually implemented on the diagonal of braced buildings, but such devices have the disadvantage that are optimal for a range of sliding force and out of that range its efficiency decreases. The above implies that each passive friction damper is designed, built and commercialized for a specific sliding/clamping force, in which the damper shift from a locked state to a slip state, where dissipates energy through friction. The risk of having a variation in the efficiency of the device according to the sliding force is that the dynamic properties of the building can change as result of many factor, even damage caused by a seismic event. In this case the expected forces in the building can change and thus considerably reduce the efficiency of the damper (that is designed for a specific sliding force). It is also evident than when a seismic event occurs the forces in each floor varies in the time what means that the damper's efficiency is not the best at all times. Semi-Active Friction devices adapt its sliding force trying to maintain its motion in the slipping phase as much as possible, because of this, the effectiveness of the device depends on the control strategy used. This paper deals with the development and performance evaluation of a low cost Semiactive Variable Friction Damper (SAVFD) in reduced scale to reduce vibrations of structures subject to earthquakes. The SAVFD consist in a (1) hydraulic brake adapted to (2) a servomotor which is controlled with an (3) Arduino board and acquires accelerations or displacement from (4) sensors in the immediately upper and lower floors and a (5) power supply that can be a pair of common batteries. A test structure, based on a Benchmark structure for structural control, was design and constructed. The SAVFD and the structure are experimentally characterized. A numerical model of the structure and the SAVFD is developed based on the dynamic characterization. Decentralized control algorithms were modeled and later tested experimentally using shaking table test using earthquake and frequency chirp signals. The controlled structure with the SAVFD achieved reductions greater than 80% in relative displacements and accelerations in comparison to the uncontrolled structure.

Keywords: earthquake response, friction damper, semiactive control, shaking table

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Authors: Mei Chen, Yingping Hou, Michelle Hao, Soheil Aghamohammadzadeh, Esteban Terzo, Roger Clark, Vijay Modur

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Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genetic skin condition characterized by skin tearing and unremitting blistering upon minimal trauma. Repeated blistering, fibrosis, and scarring lead to aggressive squamous cell carcinoma later in life. RDEB is caused by mutations in the COL7A1 gene encoding collagen type VII (C7), the major component of anchoring fibrils mediating epidermis-dermis adherence. Nonsense mutations in the COL7A1 gene of a subset of RDEB patients leads to premature termination codons (PTC). Similarly, most Junctional Epidermolysis Bullosa (JEB) cases are caused by nonsense mutations in the LAMB3 gene encoding the β3 subunit of laminin 332. Currently, there is an unmet need for the treatment of RDEB and JEB. Zikani Therapeutics has discovered an array of macrocyclic compounds with ring structures similar to macrolide antibiotics that can facilitate readthrough activity of nonsense mutations in the COL7A1 and LAMB3 genes by acting as Ribosome Modulating Agents (RMAs). The medicinal chemistry synthetic advancements of these macrocyclic compounds have allowed targeting the human ribosome while preserving the structural elements responsible for the safety and pharmacokinetic profile of clinically used macrolide antibiotics. Methods: C7 expression was used as a measure of readthrough activity by immunoblot assays in two primary human fibroblasts from RDEB patients (R578X/R578X and R163X/R1683X-COL7A1). Similarly, immunoblot assays in C325X/c.629-12T > A-LAMB3 keratinocytes were used to measure readthrough activity for JEB. The relative readthrough activity of each compound was measured relative to Gentamicin. An imaging-based fibroblast migration assay was used as an assessment of C7 functionality in RDEB-fibroblasts over 16-20 hrs. The incubation period for the above experiments was 48 hrs for RDEB fibroblasts and 72 hours for JEB keratinocytes. Results: 9 RMAs demonstrated increased protein expression in both patient RDEB fibroblasts. The highest readthrough activity at tested concentrations without cytotoxicities increased protein expression up to 179% of Gentamicin (400 µg/ml), with favored readthrough activity in R163X/R1683X-COL7A1 fibroblasts. Concurrent with protein expression, fibroblast hypermotility phenotype observed in RDEB was rescued by reducing motility by ~35% to WT levels (the same level as 690 µM Gentamicin treated cells). Laminin β3 expression was also shown to be increased by 6 RMAs in keratinocytes to 33-83% of (400 µg/ml) Gentamicin. Conclusions: To date, 9 RMAs have been identified that enhance the expression of functional C7 in a mutation-dependent manner in two different RDEB patient fibroblast backgrounds (R578X/R578X and R163X/R1683X-COL7A1). A further 6 RMAs have been identified that enhance the readthrough of C325X-LAMB3 in JEB patient keratinocytes. Based on the clinical trial conducted by us with topical gentamycin in 2017, Zikani’s RMAs achieve clinically significant levels of read-through for the treatment of recessive dystrophic and Junctional Epidermolysis Bullosa.

Keywords: epidermolysis bullosa, nonsense mutation, readthrough, ribosome modulation

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