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2313 An Evolutionary Perspective on the Role of Extrinsic Noise in Filtering Transcript Variability in Small RNA Regulation in Bacteria
Authors: Rinat Arbel-Goren, Joel Stavans
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Cell-to-cell variations in transcript or protein abundance, called noise, may give rise to phenotypic variability between isogenic cells, enhancing the probability of survival under stress conditions. These variations may be introduced by post-transcriptional regulatory processes such as non-coding, small RNAs stoichiometric degradation of target transcripts in bacteria. We study the iron homeostasis network in Escherichia coli, in which the RyhB small RNA regulates the expression of various targets as a model system. Using fluorescence reporter genes to detect protein levels and single-molecule fluorescence in situ hybridization to monitor transcripts levels in individual cells, allows us to compare noise at both transcript and protein levels. The experimental results and computer simulations show that extrinsic noise buffers through a feed-forward loop configuration the increase in variability introduced at the transcript level by iron deprivation, illuminating the important role that extrinsic noise plays during stress. Surprisingly, extrinsic noise also decouples of fluctuations of two different targets, in spite of RyhB being a common upstream factor degrading both. Thus, phenotypic variability increases under stress conditions by the decoupling of target fluctuations in the same cell rather than by increasing the noise of each. We also present preliminary results on the adaptation of cells to prolonged iron deprivation in order to shed light on the evolutionary role of post-transcriptional downregulation by small RNAs.Keywords: cell-to-cell variability, Escherichia coli, noise, single-molecule fluorescence in situ hybridization (smFISH), transcript
Procedia PDF Downloads 1642312 Development of an Electrochemical Aptasensor for the Detection of Human Osteopontin Protein
Authors: Sofia G. Meirinho, Luis G. Dias, António M. Peres, Lígia R. Rodrigues
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The emerging development of electrochemical aptasen sors has enabled the easy and fast detection of protein biomarkers in standard and real samples. Biomarkers are produced by body organs or tumours and provide a measure of antigens on cell surfaces. When detected in high amounts in blood, they can be suggestive of tumour activity. These biomarkers are more often used to evaluate treatment effects or to assess the potential for metastatic disease in patients with established disease. Osteopontin (OPN) is a protein found in all body fluids and constitutes a possible biomarker because its overexpression has been related with breast cancer evolution and metastasis. Currently, biomarkers are commonly used for the development of diagnostic methods, allowing the detection of the disease in its initial stages. A previously described RNA aptamer was used in the current work to develop a simple and sensitive electrochemical aptasensor with high affinity for human OPN. The RNA aptamer was biotinylated and immobilized on a gold electrode by avidin-biotin interaction. The electrochemical signal generated from the aptamer–target molecule interaction was monitored electrochemically using cyclic voltammetry in the presence of [Fe (CN) 6]−3/− as a redox probe. The signal observed showed a current decrease due to the binding of OPN. The preliminary results showed that this aptasensor enables the detection of OPN in standard solutions, showing good selectivity towards the target in the presence of others interfering proteins such as bovine OPN and bovine serum albumin. The results gathered in the current work suggest that the proposed electrochemical aptasensor is a simple and sensitive detection tool for human OPN and so, may have future applications in cancer disease monitoring.Keywords: osteopontin, aptamer, aptasensor, screen-printed electrode, cyclic voltammetry
Procedia PDF Downloads 4312311 The Ability of Consortium Wastewater Protozoan and Bacterial Species to Remove Chemical Oxygen Demand in the Presence of Nanomaterials under Varying pH Conditions
Authors: Anza-Vhudziki Mboyi, Ilunga Kamika, Maggy Momba
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The aim of this study was to ascertain the survival limit and capability of commonly found wastewater protozoan (Aspidisca sp, Trachelophyllum sp, and Peranema sp) and bacterial (Bacillus licheniformis, Brevibacillus laterosporus, and Pseudomonas putida) species to remove COD while exposed to commercial nanomaterials under varying pH conditions. The experimental study was carried out in modified mixed liquor media adjusted to various pH levels (pH 2, 7 and 10), and a comparative study was performed to determine the difference between the cytotoxicity effects of commercial zinc oxide (nZnO) and silver (nAg) nanomaterials (NMs) on the target wastewater microbial communities using standard methods. The selected microbial communities were exposed to lethal concentrations ranging from 0.015 g/L to 40 g/L for nZnO and from 0.015 g/L to 2 g/L for nAg for a period of 5 days of incubation at 30°C (100 r/min). Compared with the absence of NMs in wastewater mixed liquor, the relevant environmental concentration ranging between 10 µg/L and 100 µg/L, for both nZnO and nAg caused no adverse effects, but the presence of 20 g of nZnO/L and 0.65 g of nAg/L significantly inhibited microbial growth. Statistical evidence showed that nAg was significantly more toxic compared to nZnO, but there was an insignificant difference in toxicity between microbial communities and pH variations. A significant decrease in the removal of COD by microbial populations was observed in the presence of NMs with a moderate correlation of r = 0.3 to r = 0.7 at all pH levels. It was evident that there was a physical interaction between commercial NMs and target wastewater microbial communities; although not quantitatively assessed, cell morphology and cell death were observed. Such phenomena suggest the high resilience of the microbial community, but it is the accumulation of NMs that will have adverse effects on the performance in terms of COD removal.Keywords: bacteria, biological treatment, chemical oxygen demand (COD) and nanomaterials, consortium, pH, protozoan
Procedia PDF Downloads 3092310 A Systematic Categorization of Arguments against the Vision Zero Goal: A Literature Review
Authors: Henok Girma Abebe
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The Vision Zero is a long-term goal of preventing all road traffic fatalities and serious injuries which was first adopted in Sweden in 1997. It is based on the assumption that death and serious injury in the road system is morally unacceptable. In order to approach this end, vision zero has put in place strategies that are radically different from the traditional safety work. The vision zero, for instance, promoted the adoption of the best available technology to promote safety, and placed the ultimate responsibility for traffic safety on system designers. Despite Vision Zero’s moral appeal and its expansion to different safety areas and also parts of the world, important philosophical concerns related to the adoption and implementation of the vision zero remain to be addressed. Moreover, the vision zero goal has been criticized on different grounds. The aim of this paper is to identify and systematically categorize criticisms that have been put forward against vision zero. The findings of the paper are solely based on a critical analysis of secondary sources and snowball method is employed to identify the relevant philosophical and empirical literatures. Two general categories of criticisms on the vision zero goal are identified. The first category consists of criticisms that target the setting of vision zero as a ‘goal’ and some of the basic assumptions upon which the goal is based. Among others, the goal of achieving zero fatalities and serious injuries, together with vision zero’s lexicographical prioritization of safety has been criticized as unrealistic. The second category consists of criticisms that target the strategies put in place to achieve the goal of zero fatalities and serious injuries. For instance, Vision zero’s responsibility ascription for road safety and its rejection of cost-benefit analysis in the formulation and adoption of safety measures has both been criticized as counterproductive. In this category also falls the criticism that Vision Zero safety measures tend to be too paternalistic. Significant improvements have been recorded in road safety work since the adoption of vision zero, however, for the vision zero to even succeed more, it is important that issues and criticisms of philosophical nature associated with it are identified and critically dealt with.Keywords: criticisms, systems approach, traffic safety, vision zero
Procedia PDF Downloads 3012309 Calculation of Secondary Neutron Dose Equivalent in Proton Therapy of Thyroid Gland Using FLUKA Code
Authors: M. R. Akbari, M. Sadeghi, R. Faghihi, M. A. Mosleh-Shirazi, A. R. Khorrami-Moghadam
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Proton radiotherapy (PRT) is becoming an established treatment modality for cancer. The localized tumors, the same as undifferentiated thyroid tumors are insufficiently handled by conventional radiotherapy, while protons would propose the prospect of increasing the tumor dose without exceeding the tolerance of the surrounding healthy tissues. In spite of relatively high advantages in giving localized radiation dose to the tumor region, in proton therapy, secondary neutron production can have significant contribution on integral dose and lessen advantages of this modality contrast to conventional radiotherapy techniques. Furthermore, neutrons have high quality factor, therefore, even a small physical dose can cause considerable biological effects. Measuring of this neutron dose is a very critical step in prediction of secondary cancer incidence. It has been found that FLUKA Monte Carlo code simulations have been used to evaluate dose due to secondaries in proton therapy. In this study, first, by validating simulated proton beam range in water phantom with CSDA range from NIST for the studied proton energy range (34-54 MeV), a proton therapy in thyroid gland cancer was simulated using FLUKA code. Secondary neutron dose equivalent of some organs and tissues after the target volume caused by 34 and 54 MeV proton interactions were calculated in order to evaluate secondary cancer incidence. A multilayer cylindrical neck phantom considering all the layers of neck tissues and a proton beam impinging normally on the phantom were also simulated. Trachea (accompanied by Larynx) had the greatest dose equivalent (1.24×10-1 and 1.45 pSv per primary 34 and 54 MeV protons, respectively) among the simulated tissues after the target volume in the neck region.Keywords: FLUKA code, neutron dose equivalent, proton therapy, thyroid gland
Procedia PDF Downloads 4252308 A Corpus-Based Study on the Styles of Three Translators
Authors: Wang Yunhong
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The present paper is preoccupied with the different styles of three translators in their translating a Chinese classical novel Shuihu Zhuan. Based on a parallel corpus, it adopts a target-oriented approach to look into whether and what stylistic differences and shifts the three translations have revealed. The findings show that the three translators demonstrate different styles concerning their word choices and sentence preferences, which implies that identification of recurrent textual patterns may be a basic step for investigating the style of a translator.Keywords: corpus, lexical choices, sentence characteristics, style
Procedia PDF Downloads 2682307 Effect of Oxygen Ion Irradiation on the Structural, Spectral and Optical Properties of L-Arginine Acetate Single Crystals
Authors: N. Renuka, R. Ramesh Babu, N. Vijayan
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Ion beams play a significant role in the process of tuning the properties of materials. Based on the radiation behavior, the engineering materials are categorized into two different types. The first one comprises organic solids which are sensitive to the energy deposited in their electronic system and the second one comprises metals which are insensitive to the energy deposited in their electronic system. However, exposure to swift heavy ions alters this general behavior. Depending on the mass, kinetic energy and nuclear charge, an ion can produce modifications within a thin surface layer or it can penetrate deeply to produce long and narrow distorted area along its path. When a high energetic ion beam impinges on a material, it causes two different types of changes in the material due to the columbic interaction between the target atom and the energetic ion beam: (i) inelastic collisions of the energetic ion with the atomic electrons of the material; and (ii) elastic scattering from the nuclei of the atoms of the material, which is extremely responsible for relocating the atoms of matter from their lattice position. The exposure of the heavy ions renders the material return to equilibrium state during which the material undergoes surface and bulk modifications which depends on the mass of the projectile ion, physical properties of the target material, its energy, and beam dimension. It is well established that electronic stopping power plays a major role in the defect creation mechanism provided it exceeds a threshold which strongly depends on the nature of the target material. There are reports available on heavy ion irradiation especially on crystalline materials to tune their physical and chemical properties. L-Arginine Acetate [LAA] is a potential semi-organic nonlinear optical crystal and its optical, mechanical and thermal properties have already been reported The main objective of the present work is to enhance or tune the structural and optical properties of LAA single crystals by heavy ion irradiation. In the present study, a potential nonlinear optical single crystal, L-arginine acetate (LAA) was grown by slow evaporation solution growth technique. The grown LAA single crystal was irradiated with oxygen ions at the dose rate of 600 krad and 1M rad in order to tune the structural and optical properties. The structural properties of pristine and oxygen ions irradiated LAA single crystals were studied using Powder X- ray diffraction and Fourier Transform Infrared spectral studies which reveal the structural changes that are generated due to irradiation. Optical behavior of pristine and oxygen ions irradiated crystals is studied by UV-Vis-NIR and photoluminescence analyses. From this investigation we can concluded that oxygen ions irradiation modifies the structural and optical properties of LAA single crystals.Keywords: heavy ion irradiation, NLO single crystal, photoluminescence, X-ray diffractometer
Procedia PDF Downloads 2542306 Practices of Waterwise Circular Economy in Water Protection: A Case Study on Pyhäjärvi, SW Finland
Authors: Jari Koskiaho, Teija Kirkkala, Jani Salminen, Sarianne Tikkanen, Sirkka Tattari
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Here, phosphorus (P) loading to the lake Pyhäjärvi (SW Finland) was reviewed, load reduction targets were determined, and different measures of waterwise circular economy to reach the targets were evaluated. In addition to the P loading from the lake’s catchment, there is a significant amount of internal P loading occurring in the lake. There are no point source emissions into the lake. Thus, the most important source of external nutrient loading is agriculture. According to the simulations made with LLR-model, the chemical state of the lake is at the border of the classes ‘Satisfactory’ and ‘Good’. The LLR simulations suggest that a reduction of some hundreds of kilograms in annual P loading would be needed to reach an unquestionably ‘Good’ state. Evaluation of the measures of the waterwise circular economy suggested that they possess great potential in reaching the target P load reduction. If they were applied extensively and in a versatile, targeted manner in the catchment, their combined effect would reach the target reduction. In terms of cost-effectiveness, the waterwise measures were ranked as follows: The best: Fishing, 2nd best: Recycling of vegetation of reed beds, wetlands and buffer zones, 3rd best: Recycling field drainage waters stored in wetlands and ponds for irrigation, 4th best: Controlled drainage and irrigation, and 5th best: Recycling of the sediments of wetlands and ponds for soil enrichment. We also identified various waterwise nutrient recycling measures to decrease the P content of arable land. The cost-effectiveness of such measures may be very good. Solutions are needed to Finnish water protection in general, and particularly for regions like lake Pyhäjärvi catchment with intensive domestic animal production, of which the ‘P-hotspots’ are a crucial issue.Keywords: circular economy, lake protection, mitigation measures, phosphorus
Procedia PDF Downloads 1062305 Understanding the Heart of the Matter: A Pedagogical Framework for Apprehending Successful Second Language Development
Authors: Cinthya Olivares Garita
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Untangling language processing in second language development has been either a taken-for-granted and overlooked task for some English language teaching (ELT) instructors or a considerable feat for others. From the most traditional language instruction to the most communicative methodologies, how to assist L2 learners in processing language in the classroom has become a challenging matter in second language teaching. Amidst an ample array of methods, strategies, and techniques to teach a target language, finding a suitable model to lead learners to process, interpret, and negotiate meaning to communicate in a second language has imposed a great responsibility on language teachers; committed teachers are those who are aware of their role in equipping learners with the appropriate tools to communicate in the target language in a 21stcentury society. Unfortunately, one might find some English language teachers convinced that their job is only to lecture students; others are advocates of textbook-based instruction that might hinder second language processing, and just a few might courageously struggle to facilitate second language learning effectively. Grounded on the most representative empirical studies on comprehensible input, processing instruction, and focus on form, this analysis aims to facilitate the understanding of how second language learners process and automatize input and propose a pedagogical framework for the successful development of a second language. In light of this, this paper is structured to tackle noticing and attention and structured input as the heart of processing instruction, comprehensible input as the missing link in second language learning, and form-meaning connections as opposed to traditional grammar approaches to language teaching. The author finishes by suggesting a pedagogical framework involving noticing-attention-comprehensible-input-form (NACIF based on their acronym) to support ELT instructors, teachers, and scholars on the challenging task of facilitating the understanding of effective second language development.Keywords: second language development, pedagogical framework, noticing, attention, comprehensible input, form
Procedia PDF Downloads 292304 Variational Explanation Generator: Generating Explanation for Natural Language Inference Using Variational Auto-Encoder
Authors: Zhen Cheng, Xinyu Dai, Shujian Huang, Jiajun Chen
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Recently, explanatory natural language inference has attracted much attention for the interpretability of logic relationship prediction, which is also known as explanation generation for Natural Language Inference (NLI). Existing explanation generators based on discriminative Encoder-Decoder architecture have achieved noticeable results. However, we find that these discriminative generators usually generate explanations with correct evidence but incorrect logic semantic. It is due to that logic information is implicitly encoded in the premise-hypothesis pairs and difficult to model. Actually, logic information identically exists between premise-hypothesis pair and explanation. And it is easy to extract logic information that is explicitly contained in the target explanation. Hence we assume that there exists a latent space of logic information while generating explanations. Specifically, we propose a generative model called Variational Explanation Generator (VariationalEG) with a latent variable to model this space. Training with the guide of explicit logic information in target explanations, latent variable in VariationalEG could capture the implicit logic information in premise-hypothesis pairs effectively. Additionally, to tackle the problem of posterior collapse while training VariaztionalEG, we propose a simple yet effective approach called Logic Supervision on the latent variable to force it to encode logic information. Experiments on explanation generation benchmark—explanation-Stanford Natural Language Inference (e-SNLI) demonstrate that the proposed VariationalEG achieves significant improvement compared to previous studies and yields a state-of-the-art result. Furthermore, we perform the analysis of generated explanations to demonstrate the effect of the latent variable.Keywords: natural language inference, explanation generation, variational auto-encoder, generative model
Procedia PDF Downloads 1512303 Experimental and Theoretical Studies: Biochemical Properties of Honey on Type 2 Diabetes
Authors: Said Ghalem
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Honey is primarily composed of sugars: glucose and fructose. Depending honey, it's either fructose or glucose predominates. More the fructose concentration and the less the glycemic index (GI) is high. Thus, changes in the insulin response shows a decrease of the amount of insulin secreted at an increased fructose honey. Honey is also a compound that can reduce the lipid in the blood. Several studies on animals, but which remain to be checked in humans, have shown that the honey can have interesting effects when combined with other molecules: associated with Metformin (a medicine taken by diabetics), it shows the benefits and effects of diabetes preserves the tissue; associated ginger, it increases the antioxidant activity and thus avoids neurologic complications, neuropathic. Molecular modeling techniques are widely used in chemistry, biology, and the pharmaceutical industry. Most of the currently existing drugs target enzymes. Inhibition of DPP-4 is an important approach in the treatment of type 2 diabetes. We have chosen for the inhibition of DPP-4 the following molecules: Linagliptin (BI1356), Sitagliptin (Januvia), Vildagliptin, Saxagliptin, Alogliptin, and Metformin (Glucophage), that are involved in the disease management of type 2 diabetes and added to honey. For this, we used software Molecular Operating Environment. A Wistar rat study was initiated in our laboratory with a well-studied protocol; after sacrifice, according to international standards and respect for the animal This theoretical approach predicts the mode of interaction of a ligand with its target. The honey can have interesting effects when combined with other molecules, it shows the benefits and effects of honey preserves the tissue, it increases the antioxidant activity, and thus avoids neurologic complications, neuropathic or macrovascular. The organs, especially the kidneys of Wistar, shows that the parameters to renal function let us conclude that damages caused by diabetes are slightly perceptible than those observed without the addition of a high concentration of fructose honey.Keywords: honey, molecular modeling, DPP4 enzyme, metformin
Procedia PDF Downloads 982302 Model for Calculating Traffic Mass and Deceleration Delays Based on Traffic Field Theory
Authors: Liu Canqi, Zeng Junsheng
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This study identifies two typical bottlenecks that occur when a vehicle cannot change lanes: car following and car stopping. The ideas of traffic field and traffic mass are presented in this work. When there are other vehicles in front of the target vehicle within a particular distance, a force is created that affects the target vehicle's driving speed. The characteristics of the driver and the vehicle collectively determine the traffic mass; the driving speed of the vehicle and external variables have no bearing on this. From a physical level, this study examines the vehicle's bottleneck when following a car, identifies the outside factors that have an impact on how it drives, takes into account that the vehicle will transform kinetic energy into potential energy during deceleration, and builds a calculation model for traffic mass. The energy-time conversion coefficient is created from an economic standpoint utilizing the social average wage level and the average cost of motor fuel. Vissim simulation program measures the vehicle's deceleration distance and delays under the Wiedemann car-following model. The difference between the measured value of deceleration delay acquired by simulation and the theoretical value calculated by the model is compared using the conversion calculation model of traffic mass and deceleration delay. The experimental data demonstrate that the model is reliable since the error rate between the theoretical calculation value of the deceleration delay obtained by the model and the measured value of simulation results is less than 10%. The article's conclusion is that the traffic field has an impact on moving cars on the road and that physical and socioeconomic factors should be taken into account while studying vehicle-following behavior. The deceleration delay value of a vehicle's driving and traffic mass have a socioeconomic relationship that can be utilized to calculate the energy-time conversion coefficient when dealing with the bottleneck of cars stopping and starting.Keywords: traffic field, social economics, traffic mass, bottleneck, deceleration delay
Procedia PDF Downloads 672301 Use of an Insecticidal-Iridovirus Kinase towards the Development of Aphid-Resistant Plants
Authors: Saranya Ganapathy, Megha N. Parajulee, Michael San Francisco, Hong Zhang
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Insect pests are a serious threat to agricultural productivity. Use of chemical pesticides, the predominant control method thus far, has resulted in environmental damage, pest resurgence, and negative effects on non-target species. Genetically modified (GM) crops offer a promising alternative, and Bacillus thuringiensis endotoxin genes have played a major role in this respect. However, to overcome insect tolerance issues and to broaden the target range, it is critical to identify alternative-insecticidal toxins working through novel mechanisms. Our research group has identified a kinase from Chilo iridescent virus (CIV; Family Iridoviridae) that has insecticidal activity and designated it as ISTK (Iridovirus Serine/Threonine Kinase). A 35 kDa truncated form of ISTK, designated iridoptin, was obtained during expression and purification of ISTK in the yeast system. This yeast-expressed CIV toxin induced 50% mortality in cotton aphids and 100% mortality in green peach aphids (GPA). Optimized viral genes (o-ISTK and o-IRI) were stably transformed into the model plant, Arabidopsis. PCR analysis of genomic DNA confirmed the presence of the gene insert (oISTK/oIRI) in selected transgenic lines. The further screening was performed to identify the PCR positive lines that showed expression of respective toxins at the polypeptide level using Western blot analysis. The stable lines expressing either of these two toxins induced moderate to very high mortality in GPAs and significantly affected GPA development and fecundity. The aphicidal potential of these transgenic Arabidopsis lines will be presented.Keywords: Chilo iridescent virus, insecticidal toxin, iridoviruses, plant-incorporated protectants, serine/threonine kinase
Procedia PDF Downloads 2862300 Evaluation of Four Different DNA Targets in Polymerase Chain Reaction for Detection and Genotyping of Helicobacter pylori
Authors: Abu Salim Mustafa
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Polymerase chain reaction (PCR) assays targeting genomic DNA segments have been established for the detection of Helicobacter pylori in clinical specimens. However, the data on comparative evaluations of various targets in detection of H. pylori are limited. Furthermore, the frequencies of vacA (s1 and s2) and cagA genotypes, which are suggested to be involved in the pathogenesis of H. pylori in other parts of the world, are not well studied in Kuwait. The aim of this study was to evaluate PCR assays for the detection and genotyping of H. pylori by targeting the amplification of DNA targets from four genomic segments. The genomic DNA were isolated from 72 clinical isolates of H. pylori and tested in PCR with four pairs of oligonucleotides primers, i.e. ECH-U/ECH-L, ET-5U/ET-5L, CagAF/CagAR and Vac1F/Vac1XR, which were expected to amplify targets of various sizes (471 bp, 230 bp, 183 bp and 176/203 bp, respectively) from the genomic DNA of H. pylori. The PCR-amplified DNA were analyzed by agarose gel electrophoresis. PCR products of expected size were obtained with all primer pairs by using genomic DNA isolated from H. pylori. DNA dilution experiments showed that the most sensitive PCR target was 471 bp DNA amplified by the primers ECH-U/ECH-L, followed by the targets of Vac1F/Vac1XR (176 bp/203 DNA), CagAF/CagAR (183 bp DNA) and ET-5U/ET-5L (230 bp DNA). However, when tested with undiluted genomic DNA isolated from single colonies of all isolates, the Vac1F/Vac1XR target provided the maximum positive results (71/72 (99% positives)), followed by ECH-U/ECH-L (69/72 (93% positives)), ET-5U/ET-5L (51/72 (71% positives)) and CagAF/CagAR (26/72 (46% positives)). The results of genotyping experiments showed that vacA s1 (46% positive) and vacA s2 (54% positive) genotypes were almost equally associated with VaCA+/CagA- isolates (P > 0.05), but with VacA+/CagA+ isolates, S1 genotype (92% positive) was more frequently detected than S2 genotype (8% positive) (P< 0.0001). In conclusion, among the primer pairs tested, Vac1F/Vac1XR provided the best results for detection of H. pylori. The genotyping experiments showed that vacA s1 and vacA s2 genotypes were almost equally associated with vaCA+/cagA- isolates, but vacA s1 genotype had a significantly increased association with vacA+/cagA+ isolates.Keywords: H. pylori, PCR, detection, genotyping
Procedia PDF Downloads 1332299 Investigating the Flavin-Dependent Thymidylate Synthase (FDTS) Enzyme from Clostridioides Difficile (C. diff)
Authors: Sidra Shaw, Sarenna Shaw, Chae Joon Lee, Irimpan Mathews, Eric Koehn
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One of the biggest public health concerns of our time is increasing antimicrobial resistance. As of 2019, the CDC has documented more than 2.8 million serious antibiotic resistant infections in the United States. Currently, antibiotic resistant infections are directly implicated in over 750,000 deaths per year globally. On our current trajectory, British economist Jim O’Neill predicts that by 2050, an additional 10 million people (about half the population of New York) will die annually due to drug resistant infections. As a result, new biochemical pathways must be targeted to generate next generation antibiotic drugs that will be effective against drug resistant bacteria. One enticing target is the biosynthesis of DNA within bacteria, as few drugs interrupt this essential life process. Thymidylate synthase enzymes are essential for life as they catalyze the synthesis of a DNA building block, 2′-deoxythymidine-5′-monophosphate (dTMP). In humans, the thymidylate synthase enzyme (TSase) has been shown to be distinct from the flavin-dependent thymidylate synthase (FDTS) produced by many pathogenic bacteria. TSase and FDTS have distinct structures and mechanisms of catalysis, which should allow selective inhibition of FDTS over human TSase. Currently, C. diff is one of the most antibiotic resistant bacteria, and no drugs that target thymine biosynthesis exist for C. diff. Here we present the initial biochemical characterization of FDTS from C. diff. Specifically, we examine enzyme kinetics and binding features of this enzyme to determine the nature of interaction with ligands/inhibitors and understand the molecular mechanism of catalysis. This research will provide more insight into the targetability of the C. diff FDTS enzyme for novel antibiotic drugs.Keywords: flavin-dependent thymidylate synthase, FDTS, clostridioides difficile, C. diff, antibiotic resistance, DNA synthesis, enzyme kinetics, binding features
Procedia PDF Downloads 1042298 Boundary Feedback Stabilization of an Overhead Crane Model
Authors: Abdelhadi Elharfi
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A problem of boundary feedback (exponential) stabilization of an overhead crane model represented by a PDE is considered. For any $r>0$, the exponential stability at the desired decay rate $r$ is solved in semi group setting by a collocated-type stabiliser of a target system combined with a term involving the solution of an appropriate PDE.Keywords: feedback stabilization, semi group and generator, overhead crane system
Procedia PDF Downloads 4062297 Application of a Lighting Design Method Using Mean Room Surface Exitance
Authors: Antonello Durante, James Duff, Kevin Kelly
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The visual needs of people in modern work based buildings are changing. Self-illuminated screens of computers, televisions, tablets and smart phones have changed the relationship between people and the lit environment. In the past, lighting design practice was primarily based on providing uniform horizontal illuminance on the working plane, but this has failed to ensure good quality lit environments. Lighting standards of today continue to be set based upon a 100 year old approach that at its core, considers the task illuminance of the utmost importance, with this task typically being located on a horizontal plane. An alternative method focused on appearance has been proposed, as opposed to the traditional performance based approach. Mean Room Surface Exitance (MRSE) and Target-Ambient Illuminance Ratio (TAIR) are two new metrics proposed to assess illumination adequacy in interiors. The hypothesis is that these factors will be superior to the existing metrics used, which are horizontal illuminance led. For the six past years, research has examined this, within the Dublin Institute of Technology, with a view to determining the suitability of this approach for application to general lighting practice. Since the start of this research, a number of key findings have been produced that centered on how occupants will react to various levels of MRSE. This paper provides a broad update on how this research has progressed. More specifically, this paper will: i) Demonstrate how MRSE can be measured using HDR images technology, ii) Illustrate how MRSE can be calculated using scripting and an open source lighting computation engine, iii) Describe experimental results that demonstrate how occupants have reacted to various levels of MRSE within experimental office environments.Keywords: illumination hierarchy (IH), mean room surface exitance (MRSE), perceived adequacy of illumination (PAI), target-ambient illumination ratio (TAIR)
Procedia PDF Downloads 1872296 Mental Health Surveys on Community and Organizational Levels: Challenges, Issues, Conclusions and Possibilities
Authors: László L. Lippai
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In addition to the fact that mental health bears great significance to a particular individual, it can also be regarded as an organizational, community and societal resource. Within the Szeged Health Promotion Research Group, we conducted mental health surveys on two levels: The inhabitants of a medium-sized Hungarian town and students of a Hungarian university with a relatively big headcount were requested to participate in surveys whose goals were to define local government priorities and organization-level health promotion programmes, respectively. To facilitate professional decision-making, we defined three, pragmatically relevant, groups of the target population: the mentally healthy, the vulnerable and the endangered. In order to determine which group a person actually belongs to, we designed a simple and quick measurement tool, which could even be utilised as a smoothing method, the Mental State Questionnaire validity of the above three categories was verified by analysis of variance against psychological quality of life variables. We demonstrate the pragmatic significance of our method via the analyses of the scores of our two mental health surveys. On town level, during our representative survey in Hódmezővásárhely (N=1839), we found that 38.7% of the participants was mentally healthy, 35.3% was vulnerable, while 16.3% was considered as endangered. We were able to identify groups that were in a dramatic state in terms of mental health. For example, such a group consisted of men aged 45 to 64 with only primary education qualification and the ratios of the mentally healthy, vulnerable and endangered were 4.5, 45.5 and 50%, respectively. It was also astonishing to see to what a little extent qualification prevailed as a protective factor in the case of women. Based on our data, the female group aged 18 to 44 with primary education—of whom 20.3% was mentally healthy, 42.4% vulnerable and 37.3% was endangered—as well as the female group aged 45 to 64 with university or college degree—of whom 25% was mentally healthy, 51.3 vulnerable and 23.8% endangered—are to be handled as priority intervention target groups in a similarly difficult position. On organizational level, our survey involving the students of the University of Szeged, N=1565, provided data to prepare a strategy of mental health promotion for a university with a headcount exceeding 20,000. When developing an organizational strategy, it was important to gather information to estimate the proportions of target groups in which mental health promotion methods; for example, life management skills development, detection, psychological consultancy, psychotherapy, would be applied. Our scores show that 46.8% of the student participants were mentally healthy, 42.1% were vulnerable and 11.1% were endangered. These data convey relevant information as to the allocation of organizational resources within a university with a considerable headcount. In conclusion, The Mental State Questionnaire, as a valid smoothing method, is adequate to describe a community in a plain and informative way in the terms of mental health. The application of the method can promote the preparation, design and implementation of mental health promotion interventions.Keywords: health promotion, mental health promotion, mental state questionnaire, psychological well-being
Procedia PDF Downloads 2952295 Genetic Algorithm for In-Theatre Military Logistics Search-and-Delivery Path Planning
Authors: Jean Berger, Mohamed Barkaoui
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Discrete search path planning in time-constrained uncertain environment relying upon imperfect sensors is known to be hard, and current problem-solving techniques proposed so far to compute near real-time efficient path plans are mainly bounded to provide a few move solutions. A new information-theoretic –based open-loop decision model explicitly incorporating false alarm sensor readings, to solve a single agent military logistics search-and-delivery path planning problem with anticipated feedback is presented. The decision model consists in minimizing expected entropy considering anticipated possible observation outcomes over a given time horizon. The model captures uncertainty associated with observation events for all possible scenarios. Entropy represents a measure of uncertainty about the searched target location. Feedback information resulting from possible sensor observations outcomes along the projected path plan is exploited to update anticipated unit target occupancy beliefs. For the first time, a compact belief update formulation is generalized to explicitly include false positive observation events that may occur during plan execution. A novel genetic algorithm is then proposed to efficiently solve search path planning, providing near-optimal solutions for practical realistic problem instances. Given the run-time performance of the algorithm, natural extension to a closed-loop environment to progressively integrate real visit outcomes on a rolling time horizon can be easily envisioned. Computational results show the value of the approach in comparison to alternate heuristics.Keywords: search path planning, false alarm, search-and-delivery, entropy, genetic algorithm
Procedia PDF Downloads 3602294 One-Class Classification Approach Using Fukunaga-Koontz Transform and Selective Multiple Kernel Learning
Authors: Abdullah Bal
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This paper presents a one-class classification (OCC) technique based on Fukunaga-Koontz Transform (FKT) for binary classification problems. The FKT is originally a powerful tool to feature selection and ordering for two-class problems. To utilize the standard FKT for data domain description problem (i.e., one-class classification), in this paper, a set of non-class samples which exist outside of positive class (target class) describing boundary formed with limited training data has been constructed synthetically. The tunnel-like decision boundary around upper and lower border of target class samples has been designed using statistical properties of feature vectors belonging to the training data. To capture higher order of statistics of data and increase discrimination ability, the proposed method, termed one-class FKT (OC-FKT), has been extended to its nonlinear version via kernel machines and referred as OC-KFKT for short. Multiple kernel learning (MKL) is a favorable family of machine learning such that tries to find an optimal combination of a set of sub-kernels to achieve a better result. However, the discriminative ability of some of the base kernels may be low and the OC-KFKT designed by this type of kernels leads to unsatisfactory classification performance. To address this problem, the quality of sub-kernels should be evaluated, and the weak kernels must be discarded before the final decision making process. MKL/OC-FKT and selective MKL/OC-FKT frameworks have been designed stimulated by ensemble learning (EL) to weight and then select the sub-classifiers using the discriminability and diversities measured by eigenvalue ratios. The eigenvalue ratios have been assessed based on their regions on the FKT subspaces. The comparative experiments, performed on various low and high dimensional data, against state-of-the-art algorithms confirm the effectiveness of our techniques, especially in case of small sample size (SSS) conditions.Keywords: ensemble methods, fukunaga-koontz transform, kernel-based methods, multiple kernel learning, one-class classification
Procedia PDF Downloads 212293 Family Planning Programming for Youths and Adolescents in Nigeria
Authors: Ashimolowo Olubunmi
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Contraception use helps prevent pregnancy as well as health-related challenges, most especially among youths and girls. Our communities are bedeviled with many problems, including rape, defilement, neglect by the spouse, and intimate partner violence. Current interventions target only adults, with most facilities having youth and unfriendly adolescent services. To further support the need for this research, especially with our target beneficiaries, the partnership embarked on qualitative evidence-finding research through focus group discussions and in-depth-interview in Abeokuta and Ibadan (the capital cities of Ogun). The Focus Group Discussion (FGD) sessions were held in the state with adolescents (10-18 years) and young women (18-30 years). The result revealed that teenagers and youths who receive formal and sexual education on abstinence, and birth control methods, are likely to have healthier sexual behaviours through the promotion of abstinence and the use of condoms and other forms of contraceptives at their first intercourse, thereby protecting themselves against HIV/AIDs (Human Immunodeficiency Virus/Acquired immunodeficiency syndrome. The result further revealed that parents do not discuss issues around Adolescent and Sexual Reproductive Health (ASRH) with their adolescent girls, leading to gaps in knowledge of ASRH. Stakeholders’ involvement and trust are low. Respondents noted that there were few outreaches on ASRH and that youth-friendly adolescent centres are not common in the community. Respondents noted that there were few outreaches on ASRH organised within the community. Also, youth-friendly services were not common. There is a need to work with all stakeholders to promote those foundational life skills on pubertal changes, menstruation, and sexual life to prepare youths and girls for challenges ahead through sex education; we should work to institutionalize youth and adolescent-friendly Sexual and Reproductive Health (SRH) in our communities.Keywords: contraception, family planning, focus group discussion, adolescents
Procedia PDF Downloads 702292 The Role of Non-Governmental Organizations in Promoting Humanitarian Development: A Case Study in Saudi Arabia
Authors: Muamar Salameh, Rania Sinno
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Non-governmental organizations in Saudi Arabia play a vital role in promoting humanitarian development. Though this paper will emphasize this role and will provide a specific case study on the role of Prince Mohammad Bin Fahd Foundation for Humanitarian Development, yet many organizations do not provide transparent information for the accomplishments of the NGOs. This study will provide answers to the main research question regarding this role that NGOs play in promoting humanitarian development. The recent law regulating associations and foundations in Saudi Arabia was issued in December 2015 and went into effect March 2016. Any new association or foundation will need to follow these regulations. Though the registration, implementation, and workflow of the organizations still need major improvement and development, yet, the currently-registered organizations have several notable achievements. Most of these organizations adopt a centralized administration approach which in many cases still hinders progress and may be an obstacle in achieving and reaching a larger population of beneficiaries. A large portion of the existing organizations are charities, some of which have some sort of government affiliation. The laws and regulations limit registration of new organizations. Any violations to Islamic Sharia, contradictions to public order, breach to national unity, foreign and foreign-affiliation organizations prohibits any organization from registration. The lack of transparency in the operations and inner-working of NGOs in Saudi Arabia is apparent for the public. However, the regulations invoke full transparency with the governing ministry. This transparency should be available to the public and in specific to the target population that are eligible to benefit from the NGOs services. In this study, we will provide an extensive review of all related laws, regulations, policies and procedures related to all NGOs in the Eastern Province of Saudi Arabia. This review will include some examples of current NGOs, services and target population. The study will determine the main accomplishments of reputable NGOs that have impacted positively the Saudi communities. The results will highlight and concentrate on actions, services and accomplishments that achieve sustainable assistance in promoting humanitarian development and advance living conditions of target populations of the Saudi community. In particular, we will concentrate on a case study related to PMFHD; one of the largest foundations in the Eastern Province of Saudi Arabia. The authors have access to the data related to this foundation and have access to the foundation administration to gather, analyze and conclude the findings of this group. The study will also analyze whether the practices, budgets, services and annual accomplishments of the foundation have fulfilled the humanitarian role of the foundation while meeting the governmental requirements, with an analysis in the light of the new laws. The findings of the study show that great accomplishments for advancing and promoting humanitarian development in Saudi community and international communities have been achieved. Several examples will be included from several NGOs, with specific examples from PMFHD.Keywords: development, foundation, humanitarian, non-governmental organization, Saudi Arabia
Procedia PDF Downloads 2962291 Prospectivity Mapping of Orogenic Lode Gold Deposits Using Fuzzy Models: A Case Study of Saqqez Area, Northwestern Iran
Authors: Fanous Mohammadi, Majid H. Tangestani, Mohammad H. Tayebi
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This research aims to evaluate and compare Geographical Information Systems (GIS)-based fuzzy models for producing orogenic gold prospectivity maps in the Saqqez area, NW of Iran. Gold occurrences are hosted in sericite schist and mafic to felsic meta-volcanic rocks in this area and are associated with hydrothermal alterations that extend over ductile to brittle shear zones. The predictor maps, which represent the Pre-(Source/Trigger/Pathway), syn-(deposition/physical/chemical traps) and post-mineralization (preservation/distribution of indicator minerals) subsystems for gold mineralization, were generated using empirical understandings of the specifications of known orogenic gold deposits and gold mineral systems and were then pre-processed and integrated to produce mineral prospectivity maps. Five fuzzy logic operators, including AND, OR, Fuzzy Algebraic Product (FAP), Fuzzy Algebraic Sum (FAS), and GAMMA, were applied to the predictor maps in order to find the most efficient prediction model. Prediction-Area (P-A) plots and field observations were used to assess and evaluate the accuracy of prediction models. Mineral prospectivity maps generated by AND, OR, FAP, and FAS operators were inaccurate and, therefore, unable to pinpoint the exact location of discovered gold occurrences. The GAMMA operator, on the other hand, produced acceptable results and identified potentially economic target sites. The P-A plot revealed that 68 percent of known orogenic gold deposits are found in high and very high potential regions. The GAMMA operator was shown to be useful in predicting and defining cost-effective target sites for orogenic gold deposits, as well as optimizing mineral deposit exploitation.Keywords: mineral prospectivity mapping, fuzzy logic, GIS, orogenic gold deposit, Saqqez, Iran
Procedia PDF Downloads 1212290 Determinants of Customer Satisfaction: The case of Abyssinia Bank Customers in Addis Ababa Ethiopia
Authors: Yosef Ferede Bogale
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The purpose of this study was to evaluate the degree of customer satisfaction and the variables influencing it in the instance of the Bank of Abyssinia branches in the districts of Arada and Bole in Addis Ababa. The study was carried out utilizing a mixed research approach and a descriptive and explanatory research design in Addis Ababa, the capital city of Ethiopia. Both primary and secondary data were employed in this investigation. The study's target population consisted of 1000 of the bank's most prestigious clients. With a 93% response rate, 265 respondents from both genders in the active age group had higher levels of education and work experience and were in the active age group. Customers of the case bank under consideration comprised the study's target audience. The respondents, who belonged to both gender groups, were in the active age bracket with superior levels of education and work experience. As a result, this investigation discovered that the degree of client satisfaction was assigned a medium rating. Additionally given a middling rating were the company's image practices, employee competency, technology, and service quality. Further, the results also demonstrate that corporate image, employees’ competency, technology, and service quality all positively and significantly affect customer happiness. This study found that, to varying degrees, company image, technology, competence, and high-quality financial services will all improve consumer happiness. According to this report, banks should monitor customer satisfaction and service quality at least twice a year. This is because there is a growing movement among bank service providers for accountability, and measuring these factors is crucial. This study also recommends that banks make every effort to satisfy consumers' expectations to the highest level.Keywords: customer satisfaction, corporate image, quality service risk, banks
Procedia PDF Downloads 1242289 Determinants of Customer Satisfaction: The Case of Abyssinia Bank Customers in Addis Ababa Ethiopia
Authors: Yosef Ferede Bogale
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The purpose of this study was to evaluate the degree of customer satisfaction and the variables influencing it in the instance of the Bank of Abyssinia branches in the districts of Arada and Bole in Addis Ababa. The study was carried out utilizing a mixed research approach and a descriptive and explanatory research design in Addis Ababa, the capital city of Ethiopia. Both primary and secondary data were employed in this investigation. The study's target population consisted of 1000 of the bank's most prestigious clients. With a 93% response rate, 265 respondents from both genders in the active age group had higher levels of education and work experience and were in the active age group. Customers of the case bank under consideration comprised the study's target audience. The respondents, who belonged to both gender groups, were in the active age bracket with superior levels of education and work experience. As a result, this investigation discovered that the degree of client satisfaction was assigned a medium rating. Additionally given a middling rating were the company's image practices, employee competency, technology, and service quality. Further, the results also demonstrate that corporate image, employees’ competency, technology, and service quality all positively and significantly affect customer happiness. This study found that, to varying degrees, company image, technology, competence, and high-quality financial services will all improve consumer happiness. According to this report, banks should monitor customer satisfaction and service quality at least twice a year. This is because there is a growing movement among bank service providers for accountability, and measuring these factors is crucial. This study also recommends that banks make every effort to satisfy consumers' expectations to the highest level.Keywords: customer satisfaction, corporate image, quality services risk, bank
Procedia PDF Downloads 632288 A Trends Analysis of Yatch Simulator
Authors: Jae-Neung Lee, Keun-Chang Kwak
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This paper describes an analysis of Yacht Simulator international trends and also explains about Yacht. Examples of yacht Simulator using Yacht Simulator include image processing for totaling the total number of vehicles, edge/target detection, detection and evasion algorithm, image processing using SIFT (scale invariant features transform) matching, and application of median filter and thresholding.Keywords: yacht simulator, simulator, trends analysis, SIFT
Procedia PDF Downloads 4322287 Combinational Therapeutic Targeting of BRD4 and CDK7 Synergistically Induces Anticancer Effects in Hepatocellular Carcinoma
Authors: Xinxiu Li, Chuqian Zheng, Yanyan Qian, Hong Fan
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Objectives: In hepatocellular carcinoma (HCC), oncogenes are continuously and robustly transcribed due to aberrant expression of essential components of the trans-acting super-enhancers (SE) complex. Preclinical and clinical trials are now being conducted on small-molecule inhibitors that target core-transcriptional components, including as transcriptional bromodomain protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7), in a number of malignant tumors. This study aims to explore whether co-overexpression of BRD4 and CDK7 is a potential marker of worse prognosis and a combined therapeutic target in HCC. Methods: The expression pattern of BRD4 and CDK7 and their correlation with prognosis in HCC were analyzed by RNA sequencing data and survival data of HCC patients from TCGA and GEO datasets. The protein levels of BRD4 and CDK7 were determined by immunohistochemistry (IHC), and survival data of patients were analyzed using the Kaplan-Meier method. The mRNA expression levels of genes in HCC cell lines were evaluated by quantitative PCR (q-PCR). CCK-8 and colony formation assays were conducted to assess cell proliferation of HCC upon treatment with BRD4 inhibitor JQ1 or/and CDK7 inhibitor THZ1. Results: It was shown that BRD4 and CDK7 were often overexpressed in HCCs and were associated with poor prognosis of HCC by analyzing the TCGA and GEO datasets. BRD4 or CDK7 overexpression was related to a lower survival rate. It's interesting to note that co-overexpression of CDK7 and BRD4 was a worse prognostic factor in HCC. Treatment with JQ1 or THZ1 alone had an inhibitory effect on cell proliferation; however, when JQ1 and THZ1 were combined, there was a more notable suppression of cell growth. At the same time, the combined use of JQ1 and THZ1 synergistically suppresses the expression of HCC driver genes. Conclusion: Our research revealed that BRD4 and CDK7 coupled can be a useful biomarker in HCC prognosis and the combination of JQ1 and THZ1 can be a promising therapeutic therapy against HCC.Keywords: BRD4, CDK7, cell proliferation, combined inhibition
Procedia PDF Downloads 542286 Reallocation of Bed Capacity in a Hospital Combining Discrete Event Simulation and Integer Linear Programming
Authors: Muhammed Ordu, Eren Demir, Chris Tofallis
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The number of inpatient admissions in the UK has been significantly increasing over the past decade. These increases cause bed occupancy rates to exceed the target level (85%) set by the Department of Health in England. Therefore, hospital service managers are struggling to better manage key resource such as beds. On the other hand, this severe demand pressure might lead to confusion in wards. For example, patients can be admitted to the ward of another inpatient specialty due to lack of resources (i.e., bed). This study aims to develop a simulation-optimization model to reallocate the available number of beds in a mid-sized hospital in the UK. A hospital simulation model was developed to capture the stochastic behaviours of the hospital by taking into account the accident and emergency department, all outpatient and inpatient services, and the interactions between each other. A couple of outputs of the simulation model (e.g., average length of stay and revenue) were generated as inputs to be used in the optimization model. An integer linear programming was developed under a number of constraints (financial, demand, target level of bed occupancy rate and staffing level) with the aims of maximizing number of admitted patients. In addition, a sensitivity analysis was carried out by taking into account unexpected increases on inpatient demand over the next 12 months. As a result, the major findings of the approach proposed in this study optimally reallocate the available number of beds for each inpatient speciality and reveal that 74 beds are idle. In addition, the findings of the study indicate that the hospital wards will be able to cope with 14% demand increase at most in the projected year. In conclusion, this paper sheds a new light on how best to reallocate beds in order to cope with current and future demand for healthcare services.Keywords: bed occupancy rate, bed reallocation, discrete event simulation, inpatient admissions, integer linear programming, projected usage
Procedia PDF Downloads 1442285 The Impact of Australia's Skilled Migrant Selection System: A Case Study of Japanese Skilled Migrants and Their Families
Authors: Iori Hamada
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Australia's skilled migrant selection system is constantly changing its target skills and criteria according to the labour market demands. The government's intention to employ this highly selective market-driven selection system is to better target the skills needed in the economy, enable skilled migrants to be employed in industries that have the highest need, and consequently boost the economy and population. However, migration scholars have called this intention into question, arguing that the system is not making the best use of skilled migrants. This paper investigates the impact of recent reforms in Australian skilled migration system on skilled migrants' employment and related life conditions. Drawing on semi-structured qualitative interviews with Japanese skilled migrants in Australia, it argues that Australia’s skilled migrant selection system guarantees neither skilled migrants' employment nor successful transfer of their skills to the labour market. The findings show that Japanese skilled migrants are often unemployed or under-employed, although they intend to achieve upward occupational mobility. The interview data also reveal that male unemployment or under-employment status prompts some Japanese men to leave Australia and find a job that better matches their skills and qualifications in a new destination. Further, it finds that Japanese male skilled migrants who experience downward occupational mobility tend to continue to take a primary breadwinner role, which affects the distribution of paid and unpaid work within their families. There is a growing body of research investigating skilled migrants’ downward career mobility. However, little has been written on skilled Japanese migrants. Further, the work-family intersection is a 'hot public policy topic' in Australia and elsewhere. Yet, the existing studies focus almost exclusively on non-migrant families. This calls attention to the urgency of assessing the work-family lives of skilled migrants. This study fills these gaps, presenting additional insight into Japanese skilled migrants’ work and family in and beyond Australia.Keywords: Australia, employment, family, Japanese skilled migrants
Procedia PDF Downloads 1152284 Unifying RSV Evolutionary Dynamics and Epidemiology Through Phylodynamic Analyses
Authors: Lydia Tan, Philippe Lemey, Lieselot Houspie, Marco Viveen, Darren Martin, Frank Coenjaerts
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Introduction: Human respiratory syncytial virus (hRSV) is the leading cause of severe respiratory tract infections in infants under the age of two. Genomic substitutions and related evolutionary dynamics of hRSV are of great influence on virus transmission behavior. The evolutionary patterns formed are due to a precarious interplay between the host immune response and RSV, thereby selecting the most viable and less immunogenic strains. Studying genomic profiles can teach us which genes and consequent proteins play an important role in RSV survival and transmission dynamics. Study design: In this study, genetic diversity and evolutionary rate analysis were conducted on 36 RSV subgroup B whole genome sequences and 37 subgroup A genome sequences. Clinical RSV isolates were obtained from nasopharyngeal aspirates and swabs of children between 2 weeks and 5 years old of age. These strains, collected during epidemic seasons from 2001 to 2011 in the Netherlands and Belgium by either conventional or 454-sequencing. Sequences were analyzed for genetic diversity, recombination events, synonymous/non-synonymous substitution ratios, epistasis, and translational consequences of mutations were mapped to known 3D protein structures. We used Bayesian statistical inference to estimate the rate of RSV genome evolution and the rate of variability across the genome. Results: The A and B profiles were described in detail and compared to each other. Overall, the majority of the whole RSV genome is highly conserved among all strains. The attachment protein G was the most variable protein and its gene had, similar to the non-coding regions in RSV, more elevated (two-fold) substitution rates than other genes. In addition, the G gene has been identified as the major target for diversifying selection. Overall, less gene and protein variability was found within RSV-B compared to RSV-A and most protein variation between the subgroups was found in the F, G, SH and M2-2 proteins. For the F protein mutations and correlated amino acid changes are largely located in the F2 ligand-binding domain. The small hydrophobic phosphoprotein and nucleoprotein are the most conserved proteins. The evolutionary rates were similar in both subgroups (A: 6.47E-04, B: 7.76E-04 substitution/site/yr), but estimates of the time to the most recent common ancestor were much lower for RSV-B (B: 19, A: 46.8 yrs), indicating that there is more turnover in this subgroup. Conclusion: This study provides a detailed description of whole RSV genome mutations, the effect on translation products and the first estimate of the RSV genome evolution tempo. The immunogenic G protein seems to require high substitution rates in order to select less immunogenic strains and other conserved proteins are most likely essential to preserve RSV viability. The resulting G gene variability makes its protein a less interesting target for RSV intervention methods. The more conserved RSV F protein with less antigenic epitope shedding is, therefore, more suitable for developing therapeutic strategies or vaccines.Keywords: drug target selection, epidemiology, respiratory syncytial virus, RSV
Procedia PDF Downloads 413