Search results for: wear resistance
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 3521

Search results for: wear resistance

2381 Associations between Surrogate Insulin Resistance Indices and the Risk of Metabolic Syndrome in Children

Authors: Mustafa M. Donma, Orkide Donma

Abstract:

A well-defined insulin resistance (IR) is one of the requirements for the good understanding and evaluation of metabolic syndrome (MetS). However, underlying causes for the development of IR are not clear. Endothelial dysfunction also participates in the pathogenesis of this disease. IR indices are being determined in various obesity groups and also in diagnosing MetS. Components of MetS have been well established and used in adult studies. However, there are some ambiguities particularly in the field of pediatrics. The aims of this study were to compare the performance of fasting blood glucose (FBG), one of MetS components, with some other IR indices and check whether FBG may be replaced by some other parameter or ratio for a better evaluation of pediatric MetS. Five-hundred and forty-nine children were involved in the study. Five groups were constituted. Groups 109, 40, 100, 166, 110, 24 children were included in normal-body mass index (N-BMI), overweight (OW), obese (OB), morbid obese (MO), MetS with two components (MetS2) and MetS with three components (MetS3) groups, respectively. Age and sex-adjusted BMI percentiles tabulated by World Health Organization were used for the classification of obesity groups. MetS components were determined. Aside from one of the MetS components-FBG, eight measures of IR [homeostatic model assessment of IR (HOMA-IR), homeostatic model assessment of beta cell function (HOMA-%β), alanine transaminase-to-aspartate transaminase ratio (ALT/AST), alanine transaminase (ALT), insulin (INS), insulin-to-FBG ratio (INS/FBG), the product of fasting triglyceride and glucose (TyG) index, McAuley index] were evaluated. Statistical analyses were performed. A p value less than 0.05 was accepted as the statistically significance degree. Mean values for BMI of the groups were 15.7 kg/m2, 21.0 kg/m2, 24.7 kg/m2, 27.1 kg/m2, 28.7 kg/m2, 30.4 kg/m2 for N-BMI, OW, OB, MO, MetS2, MetS3, respectively. Differences between the groups were significant (p < 0.001). The only exception was MetS2-MetS3 couple, in spite of an increase detected in MetS3 group. Waist-to-hip circumference ratios significantly differed only for N-BMI vs, OB, MO, MetS2; OW vs MO; OB vs MO, MetS2 couples. ALT and ALT/AST did not differ significantly among MO-MetS2-MetS3. HOMA-%β differed only between MO and MetS2. INS/FBG, McAuley index and TyG were not significant between MetS2 and MetS3. HOMA-IR and FBG were not significant between MO and MetS2. INS was the only parameter, which showed statistically significant differences between MO-MetS2, MO-MetS3, and MetS2-MetS3. In conclusion, these findings have suggested that FBG presently considered as one of the five MetS components, may be replaced by INS during the evaluation of pediatric morbid obesity and MetS.

Keywords: children, insulin resistance indices, metabolic syndrome, obesity

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2380 Characterization of Kevlar 29 for Multifunction Applications

Authors: Doaa H. Elgohary, Dina M. Hamoda, S. Yahia

Abstract:

Technical textiles refer to textile materials that are engineered and designed to have specific functionalities and performance characteristics beyond their traditional use as apparel or upholstery fabrics. These textiles are usually developed for their unique properties such as strength, durability, flame retardancy, chemical resistance, waterproofing, insulation and other special properties. The development and use of technical textiles are constantly evolving, driven by advances in materials science, manufacturing technologies and the demand for innovative solutions in various industries. Kevlar 29 is a type of aramid fiber developed by DuPont. It is a high-performance material known for its exceptional strength and resistance to impact, abrasion, and heat. Kevlar 29 belongs to the Kevlar family, which includes different types of aramid fibers. Kevlar 29 is primarily used in applications that require strength and durability, such as ballistic protection, body armor, and body armor for military and law enforcement personnel. It is also used in the aerospace and automotive industries to reinforce composite materials, as well as in various industrial applications. Two different Kevlar samples were used coated with cooper lithium silicate (CLS); ten different mechanical and physical properties (weight, thickness, tensile strength, elongation, stiffness, air permeability, puncture resistance, thermal conductivity, stiffness, and spray test) were conducted to approve its functional performance efficiency. The influence of different mechanical properties was statistically analyzed using an independent t-test with a significant difference at P-value = 0.05. The radar plot was calculated and evaluated to determine the best-performing samples. The results of the independent t-test observed that all variables were significantly affected by yarn counts except water permeability, which has no significant effect. All properties were evaluated for samples 1 and 2, a radar chart was used to determine the best attitude for samples. The radar chart area was calculated, which shows that sample 1 recorded the best performance, followed by sample 2. The surface morphology of all samples and the coating materials was determined using a scanning electron microscope (SEM), also Fourier Transform Infrared Spectroscopy Measurement for the two samples.

Keywords: cooper lithium silicate, independent t-test, kevlar, technical textiles.

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2379 Enhancement of the Corrosion Resistance of Fastening System of Ballasted ‎Railway in Sandy Desert by Using Nano-Coating

Authors: Milad Alizadeh Galdiani, Navid Sabet, Mohamad Ali Mohit, Fatemeh Palizdar

Abstract:

Railway as one of the most important transportation modes, passes through ‎various areas with different conditions ‎inevitably, and in many countries such as ‎China, United States, Australia, and Iran, it passes through sandy ‎desert areas. One ‎of the main problems in these areas is the movement of sand, causing various ‎damages ‎to ballasted railway track such as corrosion in the railway fastening system. ‎The soil composition of some desert areas like Fahraj in Iran consists of sand ‎and ‎salt. Due to the movement of sand and corrosive ions of salt, the fastening system ‎of the railway is ‎corroded, which, in turn, reduces the thickness of the components ‎and their life span.‎ In this research, the Nano-coating for fastening system of ‎the railway is ‎introduced, and its performance has been investigated in both ‎laboratory and field tests. The Nano-coating of ‎the fastening system consists of zinc-rich, epoxy, polyurethane, and additive, which is produced through ‎Nano ‎technology. This layer covers the surface of the fastening system and ‎prohibits the chemical reactions, which result in ‎corrosion. The results of ‎Electrochemical Impedance Spectroscopy (EIS) ‎indicate that corrosion resistance ‎increases 315 times by using nano-coating, salt spray test results demonstrate that ‎nano-coated components remained intact after 1000 hours.‎

Keywords: ballasted railway, Nano-coating, railway fastening system, sandy desert

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2378 Isolation and Characterization of Ant-Salmonella Lactic Acid Bacteria from Dairy Products

Authors: Najie Hassanzade, Mohammad Rabbani Khorasgani

Abstract:

Dairy products have been regarded as the natural source of lactic acid bacteria with potential characteristics of probiotics; therefore, a lot of research and practical works have been carried out about the isolation of lactic acid bacteria (LAB) from dairy products, especially traditional yogurt and related products. Interest in traditional dairy products continues in the area of isolation of new LAB that can complement or replace currently used starters and/or that can be candidates as beneficial microorganisms for prevention or treatment purposes. In this perspective, such products are potentially good candidates for isolating new strains of probiotics. On the other hand, some infectious diseases such as salmonellosis have expressed resistance against many antibiotics; therefore, many attempts have been performed to use an alternative approach to overcome antibiotic resistance. The current research focuses on the isolation of LAB from dairy products, especially traditional dairy products and screening of them for anti-Salmonella activities. Twenty-five samples, including 15 sheep milk samples, one camel milk sample and seven cow milk samples from different areas of Iran and 2 yogurt samples from Herat, Afghanistan are collected. 20 bacteria are isolated by culturing the samples on MRS agar specific medium; among them 4 Lactobacillus strains, including 3L. plantarum strains and one L.gasseri strain, are identified by analyzing the biochemical tests and PCR tests in which 27F and 1492R primers are used. Then, their effects against Salmonella typhimurium using the well-diffusion method are evaluated.

Keywords: lactic acid bacteria, probiotics, dairy products Salmonella

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2377 The Pitfalls of Empowerment Initiatives in India: Overcoming Male Resistance to Women Empowerment Through Community Outreach, TVET, and Improved Sanitation

Authors: Christopher Coley, Srividya Sheshadri, Rao R. Bhavani

Abstract:

Empowering marginalized populations, especially women, with greater economic, social, and other leadership roles has been shown to have a profound effect on entire communities. There are discernible links between sustainable development, poverty reduction, and skill training for empowerment; however, one of the major challenges with implementing empowerment programs is to establish an understanding within the community that investing in women’s education carries the potential of high return for everyone. Effective strategies that can both empower women, and overcome the complex social issues normally faced, need to be developed and shared across stakeholders. Amrita University’s AMMACHI Labs, a research lab engaged in women empowerment through Technical Vocational Education and Training (TVET), has launched a new initiative, WE: Sanitation, a project aiming to train women to build their own toilets and promote healthy sanitation practices in rural villages across India. While in some cases, the community has come together and toilets are being built, there has been resistance by the community, especially men, in many places. This paper will explore the experiences of field workers and the initial results of the WE: Sanitation project, including observations on the trends of community dynamics, raise important questions for the direction of development work in general, and especially for sanitation projects in rural India.

Keywords: community-based development, gender dynamics, Indian sanitation, women empowerment, TVET

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2376 Solid Particle Erosion of Heat Treated TNB-V4 at Ambient and Elevated Temperatures

Authors: Muhammad Naveed, Richard Stechow, Sebastian Bolz, Katharina Hobusch, Sabine Weiß

Abstract:

Solid particle erosion has been identified as a critical wear phenomenon which takes place during operation of aeroengines in dusty environment. The present work discusses the erosion behavior of Ti-44.5Al-6.25Nb-0.8Mo-0.1B alloy (TNB-V4) which finds its application in low pressure gas turbines and can be used for high pressure compressors too. Prior to the erosion tests, the alloy was heat treated to improve the mechanical properties. Afterwards, specimens were eroded at impact angles of 30° and 90° at room and high temperatures (100 °C-400 °C). Volume loss and erosion behavior are studied through gravimetric analysis, whereas erosion mechanisms are characterized through scanning electron microscopy. The results indicate a clear difference in the erosion mechanism for different impact angles. The influence of the test temperature on the erosion behavior of the alloy is also discussed in the present contribution.

Keywords: solid particle erosion, gamma TiAl, TNB-V4, high temperature erosion

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2375 In Vivo Evaluation of the Therapeutic Effect on Intestinal Disorders by Thermophilic Streptococcus Isolated from Camel Milk

Authors: A. T. Laiche, M. L. Tlil, Benine B., S. Bechoua

Abstract:

The aim of this study is to isolate and select, from camel milk from El-Oued region in Algeria, a strains of lactic acid bacteria and possessing probiotic properties ; and to evaluate their potential effect on intestinal disorders in Wistar ratsmThe results relating to the selection of probiotic strains confirms that the Thermophilic streptococcus exhibits the best probiotic activity performance, with a resistance important to different degrees of pH and to bile salts, and a remarkable antibacterial activity and resistance to antibiotics compared to the other four isolated strains. In the in vivo study, diseases are induced in rats at the level of the digestive system, it was reported that the administration of Escherichia coli and castor oil caused an intestinal disorders. The microscopic observation of the histological section of the intestine showed a damaged intestinal structure and some symptoms of its irritation, including a decrease in the height of the villi and the presence of others destroyed cells, and after treatment with Streptococcus thermophilus, the microscopic observation of the cut of the histological section of the intestine showed almost complete disappearance of the mentioned symptoms, The dosage of the hematological parameters by complete blood count (CBC) is in agreement with the results of the histological sections.

Keywords: camel milk, probiotic, pathogenic bacteria, intestinal disorders, lactic acid bacteria

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2374 Insect Inducible Methanol Production in Plants for Insect Resistance

Authors: Gourav Jain, Sameer Dixit, Surjeet Kumar Arya, Praveen C. Verma

Abstract:

Plant cell wall plays a major role in defence mechanism against biotic and abiotic stress as it constitutes the physical barrier between the microenvironment and internal component of the cell. It is a complex structure composed of mostly carbohydrates among which cellulose and hemicelluloses are most abundant that is embedded in a matrix of pectins and proteins. Multiple enzymes have been reported which plays a vital role in cell wall modification, Pectin Methylesterase (PME) is one of them which catalyses the demethylesterification of homogalacturonans component of pectin which releases acidic pectin and methanol. As emitted methanol is toxic to the insect pest, we use PME gene for the better methanol production. In the current study we showed overexpression of PME gene isolated from Withania somnifera under the insect inducible promoter causes enhancement of methanol production at the time of insect feeds to plants, and that provides better insect resistance property. We found that the 85-90% mortality causes by transgenic tobacco in both chewing (Spodoptera litura larvae and Helicoverpa armigera) and sap-sucking (Aphid, mealybug, and whitefly) pest. The methanol content and emission level were also enhanced by 10-15 folds at different inducible time point interval (15min, 30min, 45min, 60min) which would be analysed by Purpald/Alcohol Oxidase method.

Keywords: methanol, Pectin methylesterase, inducible promoters, Purpald/Alcohol oxidase

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2373 Nonlinear Response of Infinite Beams on a Multilayer Tensionless Extensible Geosynthetic – Reinforced Earth Bed under Moving Load

Authors: K. Karuppasamy

Abstract:

In this paper analysis of an infinite beam resting on multilayer tensionless extensible geosynthetic reinforced granular fill - poor soil system overlying soft soil strata under moving the load with constant velocity is presented. The beam is subjected to a concentrated load moving with constant velocity. The upper reinforced granular bed is modeled by a rough membrane embedded in Pasternak shear layer overlying a series of compressible nonlinear Winkler springs representing the underlying the very poor soil. The multilayer tensionless extensible geosynthetic layer has been assumed to deform such that at the interface the geosynthetic and the soil have some deformation. Nonlinear behavior of granular fill and the very poor soil has been considered in the analysis by means of hyperbolic constitutive relationships. Governing differential equations of the soil foundation system have been obtained and solved with the help of appropriate boundary conditions. The solution has been obtained by employing finite difference method by means of Gauss-Siedel iterative scheme. Detailed parametric study has been conducted to study the influence of various parameters on the response of soil – foundation system under consideration by means of deflection and bending moment in the beam and tension mobilized in the geosynthetic layer. These parameters include the magnitude of applied load, the velocity of the load, damping, the ultimate resistance of the poor soil and granular fill layer. The range of values of parameters has been considered as per Indian Railways conditions. This study clearly observed that the comparisons of multilayer tensionless extensible geosynthetic reinforcement with poor foundation soil and magnitude of applied load, relative compressibility of granular fill and ultimate resistance of poor soil has significant influence on the response of soil – foundation system. However, for the considered range of velocity, the response has been found to be insensitive towards velocity. The ultimate resistance of granular fill layer has also been found to have no significant influence on the response of the system.

Keywords: infinite beams, multilayer tensionless extensible geosynthetic, granular layer, moving load and nonlinear behavior of poor soil

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2372 Assessment of Knowledge, Attitude and Perception of Drug Resistance in Rural Communities of ADA District, Central Ethiopia

Authors: Argaw Amare, Abbuna Fuffa, Stringer Andy

Abstract:

Improving public knowledge and changing their attitudes towards antibiotic use will be a crucial early strategy to contain Antibiotic resistance. The current study was undertaken from November 2015 to June 2016. A cross-sectional survey using a pretested questionnaire was conducted on 392 residents (330 male and 62 female) aged 18 and above. Participants were selected randomly. Data was analyzed using simple descriptive statistics; the Chi-square test was used to determine any significant difference. The majority of participants (81%) were farmers in their occupation. Most of the respondents (76%) were not able to define the difference between antimicrobials and antibiotics. Furthermore, (61%) of participants were not able to define what antibiotics and for what purpose they are used. Thirty-four percent of participants do not know the names of antibiotics they have used for their animals and for themselves. Nearly 68% have no knowledge about the disease they have been treated for. The majority of participants (73.5%) agree to complete their course of treatment even if they feel better. About 72.5% of participants disagree that antibiotics are safe and can be used to treat different diseases, without prescription. Most of the participants (95%) treat their animals after diagnosis; more than 80% of them agree to not purchase veterinary drugs from local traders. This study showed that the participants have poor knowledge and good attitude, with an average score of 41.3±16.1% and 79.6±16, respectively. Knowledge and attitude are significantly correlated (p<0.01). The participants in this study had a good attitude toward the rational use of antibiotics. Whereas they lack knowledge with regard to the kinds of antibiotics and the diseases they are prescribed for. Therefore, further educational interventions are necessary to improve their understanding of the antibiotics currently available and the major bacterial diseases they are prescribed.

Keywords: AMR, knoweledge, attitude, perception

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2371 Chemical, Structural and Mechanical Optimization of Zr-Based Bulk Metallic Glass for Biomedical Applications

Authors: Eliott Guérin, Remi Daudin, Georges Kalepsi, Alexis Lenain, Sebastien Gravier, Benoit Ter-Ovanessian, Damien Fabregue, Jean-Jacques Blandin

Abstract:

Due to interesting compromise between mechanical and corrosion properties, Zr-based BMGs are attractive for biomedical applications. However, the enhancement of their glass forming ability (GFA) is often achieved by addition of toxic elements like Ni or Be, which is of course a problem for such applications. Consequently, the development of Ni-free Be-free Zr-based BMGs is of great interest. We have developed a Zr-based (Ni and Be-free) amorphous metallic alloy with an elastic limit twice the one of Ti-6Al-4V. The Zr56Co28Al16 composition exhibits a yield strength close to 2 GPa and low Young’s modulus (close to 90 GPa) [1-2]. In this work, we investigated Niobium (Nb) addition through substitution of Zr up to 8 at%. Cobalt substitution has already been reported [3], but we chose Zr substitution to preserve the glass forming ability. In this case, we show that the glass forming ability for 5 mm diameters rods is maintained up to 3 at% of Nb substitution using suction casting in cooper moulds. Concerning the thermal stability, we measure a strong compositional dependence on the glass transition (Tg). Using DSC analysis (heating rate 20 K/min), we show that the Tg rises from 752 K for 0 at% of Nb to 759 K for 3 at% of Nb. Yet, the thermal range between Tg and the crystallisation temperature (Tx) remains almost unchanged from 33 K to 35 K. Uniaxial compression tests on 2 mm diameter pillars and 3 points bending (3PB) tests on 1 mm thick plates are performed to study the Nb addition on the mechanical properties and the plastic behaviour. With these tests, an optimal Nb concentration is found, improving both plasticity and fatigue resistance. Through interpretations of DSC measurements, an attempt is made to correlate the modifications of the mechanical properties with the structural changes. The optimized chemical, structural and mechanical properties through Nb addition are encouraging to develop the potential of this BMG alloy for biomedical applications. For this purpose, we performed polarisation, immersion and cytotoxicity tests. The figure illustrates the polarisation response of Zr56Co28Al16, Zr54Co28Al16Nb2 and TA6V as a reference after 2h of open circuit potential. The results show that the substitution of Zr by a small amount of Nb significantly improves the corrosion resistance of the alloy.

Keywords: metallic glasses, amorphous metal, medical, mechanical resistance, biocompatibility

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2370 Slurry Erosion Behaviour of Cryotreated SS316L Impeller Steel Used for Irrigation Pumps

Authors: Jagtar Singh, Kulwinder Singh

Abstract:

Slurry erosion is a type of erosion wherein material is removed from the target surface due to impingement of solid particles entrained in liquid medium. Slurry erosion performance of deep cryogenic treatment on impeller steel SS 316 L has been investigated. Slurry collected from an actual irrigation pump used as the abrasive media in an erosion test rig. An attempt has been made to study the effect of velocity of fluid and impingement angle by constant concentration (ppm) on the slurry erosion behavior of these cryotreated steels under different experimental conditions. The slurry erosion wear analysis of cryotreated and untreated steels was done. The slurry erosion performance of cryotreated SS 316L impeller steel has been found to superior to that of untreated steel. Metallurgical investigation, hardness as well as %age of carbide in both types of steel was also investigated.

Keywords: deep cryogenic treatment, impeller, Irrigation pumps SS316L, slurry erosion

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2369 Modelling of Phase Transformation Kinetics in Post Heat-Treated Resistance Spot Weld of AISI 1010 Mild Steel

Authors: B. V. Feujofack Kemda, N. Barka, M. Jahazi, D. Osmani

Abstract:

Automobile manufacturers are constantly seeking means to reduce the weight of car bodies. The usage of several steel grades in auto body assembling has been found to be a good technique to enlighten vehicles weight. This few years, the usage of dual phase (DP) steels, transformation induced plasticity (TRIP) steels and boron steels in some parts of the auto body have become a necessity because of their lightweight. However, these steels are martensitic, when they undergo a fast heat treatment, the resultant microstructure is essential, made of martensite. Resistance spot welding (RSW), one of the most used techniques in assembling auto bodies, becomes problematic in the case of these steels. RSW being indeed a process were steel is heated and cooled in a very short period of time, the resulting weld nugget is mostly fully martensitic, especially in the case of DP, TRIP and boron steels but that also holds for plain carbon steels as AISI 1010 grade which is extensively used in auto body inner parts. Martensite in its turn must be avoided as most as possible when welding steel because it is the principal source of brittleness and it weakens weld nugget. Thus, this work aims to find a mean to reduce martensite fraction in weld nugget when using RSW for assembling. The prediction of phase transformation kinetics during RSW has been done. That phase transformation kinetics prediction has been made possible through the modelling of the whole welding process, and a technique called post weld heat treatment (PWHT) have been applied in order to reduce martensite fraction in the weld nugget. Simulation has been performed for AISI 1010 grade, and results show that the application of PWHT leads to the formation of not only martensite but also ferrite, bainite and pearlite during the cooling of weld nugget. Welding experiments have been done in parallel and micrographic analyses show the presence of several phases in the weld nugget. Experimental weld geometry and phase proportions are in good agreement with simulation results, showing here the validity of the model.

Keywords: resistance spot welding, AISI 1010, modeling, post weld heat treatment, phase transformation, kinetics

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2368 A Novel Protein Elicitor Extracted From Lecanicillium lecanii Induced Resistance Against Whitefly, Bemisia tabaci in Cotton

Authors: Yusuf Ali Abdulle, Azhar Uddin Keerio

Abstract:

Background: Protein elicitors play a key role in signaling or displaying plant defense mechanisms and emerging as vital tools for bio-control of insects. This study was aimed at the characterization of the novel protein elicitor isolated from entomopathogenic fungi Lecanicillium lecanii (V3) strain and its activity against Whitefly, Bemisia tabaci in cotton. The sequence of purified elicitor protein showed 100% similarity with hypothetical protein LEL_00878 [Cordyceps confragosa RCEF 1005], GenBank no (OAA81333.1). This novel protein elicitor has 253 amino acid residues and 762bp with a molecular mass of 29 kDa. The protein recombinant was expressed in Escherichia coli using pET‐28a (+) plasmid. Effects of purified novel protein elicitor on Bemisia tabaci were determined at three concentrations of protein (i.e., 58.32, 41.22, 35.41 μg mL⁻¹) on cotton plants and were exposed to newly molted adult B.tabaci. Bioassay results showed a significant effect of the exogenous application of novel protein elicitor on B. tabaci in cotton. In addition, the gene expression analysis found a significant up-regulation of the major genes associated with salicylic acid (SA) and jasmonic acid (JA) linked plant defense pathways in elicitor protein-treated plants. Our results suggested the potential application of a novel protein elicitor derived from Lecanicillium lecanii as a future bio-intensive controlling approach against the whitefly, Bemisia tabaci.

Keywords: resistance, Lecanicillium lecanii, secondary metabolites, whitefly

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2367 LncRNA-miRNA-mRNA Networks Associated with BCR-ABL T315I Mutation in Chronic Myeloid Leukemia

Authors: Adenike Adesanya, Nonthaphat Wong, Xiang-Yun Lan, Shea Ping Yip, Chien-Ling Huang

Abstract:

Background: The most challenging mutation of the oncokinase BCR-ABL protein T315I, which is commonly known as the “gatekeeper” mutation and is notorious for its strong resistance to almost all tyrosine kinase inhibitors (TKIs), especially imatinib. Therefore, this study aims to identify T315I-dependent downstream microRNA (miRNA) pathways associated with drug resistance in chronic myeloid leukemia (CML) for prognostic and therapeutic purposes. Methods: T315I-carrying K562 cell clones (K562-T315I) were generated by the CRISPR-Cas9 system. Imatinib-treated K562-T315I cells were subjected to small RNA library preparation and next-generation sequencing. Putative lncRNA-miRNA-mRNA networks were analyzed with (i) DESeq2 to extract differentially expressed miRNAs, using Padj value of 0.05 as cut-off, (ii) STarMir to obtain potential miRNA response element (MRE) binding sites of selected miRNAs on lncRNA H19, (iii) miRDB, miRTarbase, and TargetScan to predict mRNA targets of selected miRNAs, (iv) IntaRNA to obtain putative interactions between H19 and the predicted mRNAs, (v) Cytoscape to visualize putative networks, and (vi) several pathway analysis platforms – Enrichr, PANTHER and ShinyGO for pathway enrichment analysis. Moreover, mitochondria isolation and transcript quantification were adopted to determine the new mechanism involved in T315I-mediated resistance of CML treatment. Results: Verification of the CRISPR-mediated mutagenesis with digital droplet PCR detected the mutation abundance of ≥80%. Further validation showed the viability of ≥90% by cell viability assay, and intense phosphorylated CRKL protein band being detected with no observable change for BCR-ABL and c-ABL protein expressions by Western blot. As reported by several investigations into hematological malignancies, we determined a 7-fold increase of H19 expression in K562-T315I cells. After imatinib treatment, a 9-fold increment was observed. DESeq2 revealed 171 miRNAs were differentially expressed K562-T315I, 112 out of these miRNAs were identified to have MRE binding regions on H19, and 26 out of the 112 miRNAs were significantly downregulated. Adopting the seed-sequence analysis of these identified miRNAs, we obtained 167 mRNAs. 6 hub miRNAs (hsa-let-7b-5p, hsa-let-7e-5p, hsa-miR-125a-5p, hsa-miR-129-5p, and hsa-miR-372-3p) and 25 predicted genes were identified after constructing hub miRNA-target gene network. These targets demonstrated putative interactions with H19 lncRNA and were mostly enriched in pathways related to cell proliferation, senescence, gene silencing, and pluripotency of stem cells. Further experimental findings have also shown the up-regulation of mitochondrial transcript and lncRNA MALAT1 contributing to the lncRNA-miRNA-mRNA networks induced by BCR-ABL T315I mutation. Conclusions: Our results have indicated that lncRNA-miRNA regulators play a crucial role not only in leukemogenesis but also in drug resistance, considering the significant dysregulation and interactions in the K562-T315I cell model generated by CRISPR-Cas9. In silico analysis has further shown that lncRNAs H19 and MALAT1 bear several complementary miRNA sites. This implies that they could serve as a sponge, hence sequestering the activity of the target miRNAs.

Keywords: chronic myeloid leukemia, imatinib resistance, lncRNA-miRNA-mRNA, T315I mutation

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2366 Energy Efficient Construction and the Seismic Resistance of Passive Houses

Authors: Vojko Kilar, Boris Azinović, David Koren

Abstract:

Recently, an increasing trend of passive and low-energy buildings transferring form non earthquake-prone to earthquake-prone regions has thrown out the question about the seismic safety of such buildings. The paper describes the most commonly used thermal insulating materials and the special details, which could be critical from the point of view of earthquake resistance. The most critical appeared to be the cases of buildings founded on the RC foundation slab lying on a thermal insulation (TI) layer made of extruded polystyrene (XPS). It was pointed out that in such cases the seismic response of such buildings might differ to response of their fixed based counterparts. The main parameters that need special designers’ attention are: the building’s lateral top displacement, the ductility demand of the superstructure, the foundation friction coefficient demand, the maximum compressive stress in the TI layer and the percentage of the uplifted foundation. The analyses have shown that the potentially negative influences of inserting the TI under the foundation slab could be expected only for slender high-rise buildings subjected to severe earthquakes. Oppositely it was demonstrated for the foundation friction coefficient demand which could exceed the capacity value yet in the case of low-rise buildings subjected to moderate earthquakes. Some suggestions to prevent the horizontal shifts are also given.

Keywords: earthquake response, extruded polystyrene (XPS), low-energy buildings, foundations on thermal insulation layer

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2365 When Psychology Meets Ecology: Cognitive Flexibility for Quarry Rehabilitation

Authors: J. Fenianos, C. Khater, D. Brouillet

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Ecological projects are often faced with reluctance from local communities hosting the project, especially when this project involves variation from preset ideas or classical practices. This paper aims at appreciating the contribution of environmental psychology through cognitive flexibility exercises to improve the acceptability of local communities in adopting more ecological rehabilitation scenarios. The study is based on a quarry site located in Bekaa- Lebanon. Four groups were considered with different levels of involvement, as follows: Group 1 is Training (T) – 50 hours of on-site training over 8 months, Group 2 is Awareness (A) – 2 hours of awareness raising session, Group 3 is Flexibility (F) – 2 hours of flexibility exercises and Group 4 is the Control (C). The results show that individuals in Group 3 (F) who followed flexibility sessions accept comparably the ecological rehabilitation option over the more classical one. This is also the case for the people in Group 1 (T) who followed a more time-demanding “on-site training”. Another experience was conducted on a second quarry site combining flexibility with awareness-raising. This research confirms that it is possible to reduce resistance to change thanks to a limited in-time intervention using cognitive flexibility. This methodological approach could be transferable to other environmental problems involving local communities and changes in preset perceptions.

Keywords: acceptability, ecological restoration, environmental psychology, Lebanon, local communities, resistance to change

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2364 Designing Self-Healing Lubricant-Impregnated Surfaces for Corrosion Protection

Authors: Sami Khan, Kripa Varanasi

Abstract:

Corrosion is a widespread problem in several industries and developing surfaces that resist corrosion has been an area of interest since the last several decades. Superhydrophobic surfaces that combine hydrophobic coatings along with surface texture have been shown to improve corrosion resistance by creating voids filled with air that minimize the contact area between the corrosive liquid and the solid surface. However, these air voids can incorporate corrosive liquids over time, and any mechanical faults such as cracks can compromise the coating and provide pathways for corrosion. As such, there is a need for self-healing corrosion-resistance surfaces. In this work, the anti-corrosion properties of textured surfaces impregnated with a lubricant have been systematically studied. Since corrosion resistance depends on the area and physico-chemical properties of the material exposed to the corrosive medium, lubricant-impregnated surfaces (LIS) have been designed based on the surface tension, viscosity and chemistry of the lubricant and its spreading coefficient on the solid. All corrosion experiments were performed in a standard three-electrode cell using iron, which readily corrodes in a 3.5% sodium chloride solution. In order to obtain textured iron surfaces, thin films (~500 nm) of iron were sputter-coated on silicon wafers textured using photolithography, and subsequently impregnated with lubricants. Results show that the corrosion rate on LIS is greatly reduced, and offers an over hundred-fold improvement in corrosion protection. Furthermore, it is found that the spreading characteristics of the lubricant are significant in ensuring corrosion protection: a spreading lubricant (e.g., Krytox 1506) that covers both inside the texture, as well as the top of the texture, provides a two-fold improvement in corrosion protection as compared to a non-spreading lubricant (e.g., Silicone oil) that does not cover texture tops. To enhance corrosion protection of surfaces coated with a non-spreading lubricant, pyramid-shaped textures have been developed that minimize exposure to the corrosive solution, and a consequent twenty-fold increased in corrosion protection is observed. An increase in viscosity of the lubricant scales with greater corrosion protection. Finally, an equivalent cell-circuit model is developed for the lubricant-impregnated systems using electrochemical impedance spectroscopy. Lubricant-impregnated surfaces find attractive applications in harsh corrosive environments, especially where the ability to self-heal is advantageous.

Keywords: lubricant-impregnated surfaces, self-healing surfaces, wettability, nano-engineered surfaces

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2363 Nd³⁺: Si₂N₂O (Sinoite) Phosphors for White Light Emitting Diodes

Authors: Alparslan A. Balta, Hilmi Yurdakul, Orkun Tunckan, Servet Turan, Arife Yurdakul

Abstract:

A silicon oxynitride (Si2N2O), the mineralogical name is “Sinoite”, reveals the outstanding physical, mechanical and thermal properties, e.g., good oxidation resistance at high temperatures, high fracture toughness with rod shape, high hardness, low theoretical density, good thermal shock resistance by low thermal expansion coefficient and high thermal conductivity. In addition, the orthorhombic crystal structure of Si2N2O allows accommodating the rare earth (RE) element atoms along the “c” axis due to existing large structural interstitial sites. Here, 0.02 to 0.12 wt. % Nd3+ doped Si2N2O samples were successfully synthesized by spark plasma sintering (SPS) method at 30MPa pressure and 1650oC temperature. Li2O was also utilized as a sintering additive to take advantage of low eutectic point during synthesizing. The specimens were characterized in detail by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and cathodoluminescence (CL) in SEM and photoluminescence (PL) spectroscopy. Based on the overall results, the Si2N2O phase was obtained above 90% by the SPS route. Furthermore, Nd3+: Si2N2O samples showed a very broad intense emission peak between 400-700 nm, which corresponds to white color. Therefore, this material can be considered as a promising candidate for white light-emitting diodes (WLEDs) purposes. This study was supported by TUBITAK under project number 217M667.

Keywords: neodymium, oxynitride, Si₂N₂O, WLEDs

Procedia PDF Downloads 113
2362 Neuron Efficiency in Fluid Dynamics and Prediction of Groundwater Reservoirs'' Properties Using Pattern Recognition

Authors: J. K. Adedeji, S. T. Ijatuyi

Abstract:

The application of neural network using pattern recognition to study the fluid dynamics and predict the groundwater reservoirs properties has been used in this research. The essential of geophysical survey using the manual methods has failed in basement environment, hence the need for an intelligent computing such as predicted from neural network is inevitable. A non-linear neural network with an XOR (exclusive OR) output of 8-bits configuration has been used in this research to predict the nature of groundwater reservoirs and fluid dynamics of a typical basement crystalline rock. The control variables are the apparent resistivity of weathered layer (p1), fractured layer (p2), and the depth (h), while the dependent variable is the flow parameter (F=λ). The algorithm that was used in training the neural network is the back-propagation coded in C++ language with 300 epoch runs. The neural network was very intelligent to map out the flow channels and detect how they behave to form viable storage within the strata. The neural network model showed that an important variable gr (gravitational resistance) can be deduced from the elevation and apparent resistivity pa. The model results from SPSS showed that the coefficients, a, b and c are statistically significant with reduced standard error at 5%.

Keywords: gravitational resistance, neural network, non-linear, pattern recognition

Procedia PDF Downloads 194
2361 Bacterial Diversity in Human Intestinal Microbiota and Correlations with Nutritional Behavior, Physiology, Xenobiotics Intake and Antimicrobial Resistance in Obese, Overweight and Eutrophic Individuals

Authors: Thais O. de Paula, Marjorie R. A. Sarmiento, Francis M. Borges, Alessandra B. Ferreira-Machado, Juliana A. Resende, Dioneia E. Cesar, Vania L. Silva, Claudio G. Diniz

Abstract:

Obesity is currently a worldwide public health threat, being considered a pandemic multifactorial disease related to the human gut microbiota (GM). Add to that GM is considered an important reservoir of antimicrobial resistance genes (ARG) and little is known on GM and ARG in obesity, considering the altered physiology and xenobiotics intake. As regional and social behavior may play important roles in GM modulation, and most of the studies are based on small sample size and various methodological approaches resulting in difficulties for data comparisons, this study was focused on the investigation of GM bacterial diversity in obese (OB), overweight (OW) and eutrophic individuals (ET) considering their nutritional, clinical and social characteristics; and comparative screening of AGR related to their physiology and xenobiotics intake. Microbial community was accessed by FISH considering phyla as a taxonomic level, and PCR-DGGE followed by dendrograms evaluation (UPGMA method) from fecal metagenome of 72 volunteers classified according to their body mass index (BMI). Nutritional, clinical, social parameters and xenobiotics intake were recorded for correlation analysis. The fecal metagenome was also used as template for PCR targeting 59 different ARG. Overall, 62% of OB were hypertensive, and 12% or 4% were, regarding the OW and ET individuals. Most of the OB were rated as low income (80%). Lower relative bacterial densities were observed in the OB compared to ET for almost all studied taxa (p < 0.05) with Firmicutes/Bacteroidetes ratio increased in the OB group. OW individuals showed a bacterial density representative of GM more likely to the OB. All the participants were clustered in 3 different groups based on the PCR-DGGE fingerprint patterns (C1, C2, C3), being OB mostly grouped in C1 (83.3%) and ET mostly grouped in C3 (50%). The cluster C2 showed to be transitional. Among 27 ARG detected, a cluster of 17 was observed in all groups suggesting a common core. In general, ARG were observed mostly within OB individuals followed by OW and ET. The ratio between ARG and bacterial groups may suggest that AGR were more related to enterobacteria. Positive correlations were observed between ARG and BMI, calories and xenobiotics intake (especially use of sweeteners). As with nutritional and clinical characteristics, our data may suggest that GM of OW individuals behave in a heterogeneous pattern, occasionally more likely to the OB or to the ET. Regardless the regional and social behaviors of our population, the methodological approaches in this study were complementary and confirmatory. The imbalance of GM over the health-disease interface in obesity is a matter of fact, but its influence in host's physiology is still to be clearly elucidated to help understanding the multifactorial etiology of obesity. Although the results are in agreement with observations that GM is altered in obesity, the altered physiology in OB individuals seems to be also associated to the increased xenobiotics intake and may interfere with GM towards antimicrobial resistance, as observed by the fecal metagenome and ARG screening. Support: FAPEMIG, CNPQ, CAPES, PPGCBIO/UFJF.

Keywords: antimicrobial resistance, bacterial diversity, gut microbiota, obesity

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2360 A Non-linear Damage Model For The Annulus Of the Intervertebral Disc Under Cyclic Loading, Including Recovery

Authors: Shruti Motiwale, Xianlin Zhou, Reuben H. Kraft

Abstract:

Military and sports personnel are often required to wear heavy helmets for extended periods of time. This leads to excessive cyclic loads on the neck and an increased chance of injury. Computational models offer one approach to understand and predict the time progression of disc degeneration under severe cyclic loading. In this paper, we have applied an analytic non-linear damage evolution model to estimate damage evolution in an intervertebral disc due to cyclic loads over decade-long time periods. We have also proposed a novel strategy for inclusion of recovery in the damage model. Our results show that damage only grows 20% in the initial 75% of the life, growing exponentially in the remaining 25% life. The analysis also shows that it is crucial to include recovery in a damage model.

Keywords: cervical spine, computational biomechanics, damage evolution, intervertebral disc, continuum damage mechanics

Procedia PDF Downloads 552
2359 Effect of Wind Braces to Earthquake Resistance of Steel Structures

Authors: H. Gokdemir

Abstract:

All structures are subject to vertical and lateral loads. Under these loads, structures make deformations and deformation values of structural elements mustn't exceed their capacity for structural stability. Especially, lateral loads cause critical deformations because of their random directions and magnitudes. Wind load is one of the lateral loads which can act in any direction and any magnitude. Although wind has nearly no effect on reinforced concrete structures, it must be considered for steel structures, roof systems and slender structures like minarets. Therefore, every structure must be able to resist wind loads acting parallel and perpendicular to any side. One of the effective methods for resisting lateral loads is assembling cross steel elements between columns which are called as wind bracing. These cross elements increases lateral rigidity of a structure and prevent exceeding of deformation capacity of the structural system. So, this means cross elements are also effective in resisting earthquake loads too. In this paper; Effects of wind bracing to earthquake resistance of structures are studied. Structure models (with and without wind bracing) are generated and these models are solved under both earthquake and wind loads with different seismic zone parameters. It is concluded by the calculations that; in low-seismic risk zones, wind bracing can easily resist earthquake loads and no additional reinforcement for earthquake loads is necessary. Similarly; in high-seismic risk zones, earthquake cross elements resist wind loads too.

Keywords: wind bracings, earthquake, steel structures, vertical and lateral loads

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2358 Akt: Isoform-Specific Regulation of Cellular Signaling in Cancer

Authors: Bhumika Wadhwa, Fayaz Malik

Abstract:

The serine/threonine protein kinase B (PKB) also known as Akt, is one of the multifaceted kinase in human kinome, existing in three isoforms. Akt plays a vital role in phosphoinositide 3-kinase (PI3K) mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. The functional significance of an individual isoform of Akt is not redundant in cancer cell proliferation and metastasis instead Akt isoforms play distinct roles during metastasis; thereby regulating EMT. This study aims to determine isoform specific functions of Akt in cancer. The results obtained suggest that Akt1 restrict tumor invasion, whereas Akt2 promotes cell migration and invasion by various techniques like MTT, wound healing and invasion assay. Similarly, qRT-PCR also revealed that Akt3 has shown promising results in promoting cancer cell migration. Contrary to pro-oncogenic properties attributed to Akt, it is to be understood how various isoforms of Akt compensates each other in the regulation of common pathways during cancer progression and drug resistance. In conclusion, this study aims to target selective isoforms which is essential to inhibit cancer. However, the question now is whether, and how much, Akt inhibition will be tolerated in the clinic remains to be answered and the experiments will have to address the question of which combinations of newly devised Akt isoform specific inhibitors exert a favourable therapeutic effect in in vivo models of cancer to provide the therapeutic window with minimal toxicity.

Keywords: Akt isoforms, cancer, drug resistance, epithelial mesenchymal transition

Procedia PDF Downloads 237
2357 A Study of the Resistance of Protective Glove Materials to Metalworking Fluids

Authors: Nguyen-Tri Phuong, Triki Ennouri, Gauvin Chantal, Tuduri Ludovic, Vu-Khanh Toan

Abstract:

Hand injuries due to mechanical hazards such as cuts and punctures are major risks and concerns for several occupational groups, particularly for workers in the metal manufacturing sector and mechanical automotive services. Personal protective equipment such as gloves or clothing is necessary for many professionals to protect against a variety of occupational hazards, which arise daily in their work environments. In many working places such as metal manufacturing or automotive services, mechanical hazards often occur together with industrial contaminants, particularly metalworking fluids (MWFs). The presence of these contaminants could modify the properties of gloves made from polymeric materials and thus increase the risk of hand injuries for workers. The focus of this study is to determine the swelling characteristics and the resistance of six polymer membranes when they are contaminated with several industrial metalworking fluids. These polymer membranes, commonly used in protective gloves, are nitrile, neoprene, vinyl, butyl, polyurethane and latex rubbers. Changes swelling index were continuously followed during the contamination procedure to compare the performance of each polymer under different conditions. The modification of the samples surface, tensile properties during the contamination process was also investigated. The effect of temperature on mechanical properties and morphology of material was also examined.

Keywords: metalworking fluid, swelling behavior, protective glove materials, elastomers

Procedia PDF Downloads 375
2356 Exploratory Tests on Structures Resistance during Forest Fires

Authors: Luis M. Ribeiro, Jorge Raposo, Ricardo Oliveira, David Caballero, Domingos X. Viegas

Abstract:

Under the scope of European project WUIWATCH a set of experimental tests on house vulnerability was performed in order to assess the resistance of selected house components during the passage of a forest fire. Among the individual elements most affected by the passage of a wildfire the windows are the ones with greater exposure. In this sense, a set of exploratory experimental tests was designed to assess some particular aspects related to the vulnerability of windows and blinds. At the same time, the importance of leaving them closed (as well as the doors inside a house) during a wild fire was explored in order to give some scientific background to guidelines for homeowners. Three sets of tests were performed: 1. Windows and blinds resistance to heat. Three types of protective blinds were tested (aluminium, PVC and wood) on 2 types of windows (single and double pane). The objective was to assess the structures resistance. 2. The influence of air flow on the transport of burning embers inside a house. A room was built to scale, and placed inside a wind tunnel, with one window and one door on opposite sides. The objective was to assess the importance of leaving an inside door opened on the probability of burning embers entering the room. 3. The influence of the dimension of openings on a window or door related to the probability of ignition inside a house. The objective was to assess the influence of different window openings in relation to the amount of burning particles that can enter a house. The main results were: 1. The purely radiative heat source provides 1.5 KW/m2 of heat impact in the structure, while the real fire generates 10 Kw/m2. When protected by the blind, the single pane window reaches 30ºC on both sides, and the double pane window has a differential of 10º from the side facing the heat (30ºC) and the opposite side (40ºC). Unprotected window constantly increases temperature until the end of the test. Window blinds reach considerably higher temperatures. PVC loses its consistency above 150ºC and melts. 2. Leaving the inside door closed results in a positive pressure differential of +1Pa from the outside to the inside, inhibiting the air flow. Opening the door in half or full reverts the pressure differential to -6 and -8 times respectively, favouring the air flow from the outside to the inside. The number of particles entering the house follows the same tendency. 3. As the bottom opening in a window increases from 0,5 cm to 4 cm the number of particles that enter the house per second also increases greatly. From 5 cm until 80cm there is no substantial increase in the number of entering particles. This set of exploratory tests proved to be an added value in supporting guidelines for home owners, regarding self-protection in WUI areas.

Keywords: forest fire, wildland urban interface, house vulnerability, house protective elements

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2355 Fabrication and Characterization of PPy/rGO|PPy/ZnO Composite with Varying Zno Concentration as Anode for Fuel Cell Applications

Authors: Bryan D. Llenarizas, Maria Carla F. Manzano

Abstract:

The rapid growth of electricity demand has led to a pursuit of alternative energy sources with high power output and not harmful to the environment. The fuel cell is a device that generates electricity via chemical reactions between the fuel and oxidant. Fuel cells have been known for decades, but the development of high-power output and durability was still one of the drawbacks of this energy source. This study investigates the potential of layer-by-layer composite for fuel cell applications. A two-electrode electrochemical cell was used for the galvanostatic electrochemical deposition method to fabricate a Polypyrrole/rGO|Polypyrrole/ZnO layer-by-layer composite material for fuel cell applications. In the synthesis, the first layer comprised 0.1M pyrrole monomer and 1mg of rGO, while the second layer had 0.1M pyrrole monomer and variations of ZnO concentration ranging from 0.08M up to 0.12M. A constant current density of 8mA/cm² was applied for 1 hour in fabricating each layer. Scanning electron microscopy (SEM) for the fabricated LBL material shows a globular surface with white spots. These white spots are the ZnO particles confirmed by energy-dispersive X-ray spectroscopy, indicating a successful deposition of the second layer onto the first layer. The observed surface morphology was consistent for each variation of ZnO concentrations. AC measurements were conducted to obtain the AC resistance of the fabricated film. Results show a decrease in AC resistance as the concentration of ZnO increases.

Keywords: anode, composite material, electropolymerization, fuel cell, galvanostatic, polypyrrole

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2354 Assessing the Risk of Condensation and Moisture Accumulation in Solid Walls: Comparing Different Internal Wall Insulation Options

Authors: David Glew, Felix Thomas, Matthew Brooke-Peat

Abstract:

Improving the thermal performance of homes is seen as an essential step in achieving climate change, fuel security, fuel poverty targets. One of the most effective thermal retrofits is to insulate solid walls. However, it has been observed that applying insulation to the internal face of solid walls reduces the surface temperature of the inner wall leaf, which may introduce condensation risk and may interrupt seasonal moisture accumulation and dissipation. This research quantifies the extent to which the risk of condensation and moisture accumulation in the wall increases (which can increase the risk of timber rot) following the installation of six different types of internal wall insulation. In so doing, it compares how risk is affected by both the thermal resistance, thickness, and breathability of the insulation. Thermal bridging, surface temperatures, condensation risk, and moisture accumulation are evaluated using hygrothermal simulation software before and after the thermal upgrades. The research finds that installing internal wall insulation will always introduce some risk of condensation and moisture. However, it identifies that risks were present prior to insulation and that breathable materials and insulation with lower resistance have lower risks than alternative insulation options. The implications of this may be that building standards that encourage the enhanced thermal performance of solid walls may be introducing moisture risks into homes.

Keywords: condensation risk, hygrothermal simulation, internal wall insulation, thermal bridging

Procedia PDF Downloads 139
2353 Green Technologies and Sustainability in the Care and Maintenance of Protective Textiles

Authors: R. Nayak, T. Panwar, R. Padhye

Abstract:

Protective textiles get soiled, stained and even worn during their use, which may not be usable after a certain period due to the loss of protective performance. They need regular cleaning and maintenance, which helps to extend the durability of the clothing, retains their useful properties and ensures that fresh clothing is ready to wear when needed. Generally, the cleaning processes used for various protective clothing include dry-cleaning (using solvents) or wet cleaning (using water). These cleaning processes can alter the fabric surface properties, dimensions, and physical, mechanical and performance properties. The technology of laundering and dry-cleaning has undergone several changes. Sustainable methods and products are available for faster, safer and improved cleaning of protective textiles. We performed a comprehensive and systematic review of green technologies and eco-friendly products for sustainable cleaning of protective textiles. Special emphasis is given on the care and maintenance procedures of protective textiles for protection from fire, bullets, chemical and other types of protective clothing.

Keywords: Sustainable cleaning, protective textiles, ecofriendly cleaning, ozone laundering, ultrasonic cleaning

Procedia PDF Downloads 220
2352 Constitutive Androstane Receptor (CAR) Inhibitor CINPA1 as a Tool to Understand CAR Structure and Function

Authors: Milu T. Cherian, Sergio C. Chai, Morgan A. Casal, Taosheng Chen

Abstract:

This study aims to use CINPA1, a recently discovered small-molecule inhibitor of the xenobiotic receptor CAR (constitutive androstane receptor) for understanding the binding modes of CAR and to guide CAR-mediated gene expression profiling studies in human primary hepatocytes. CAR and PXR are xenobiotic sensors that respond to drugs and endobiotics by modulating the expression of metabolic genes that enhance detoxification and elimination. Elevated levels of drug metabolizing enzymes and efflux transporters resulting from CAR activation promote the elimination of chemotherapeutic agents leading to reduced therapeutic effectiveness. Multidrug resistance in tumors after chemotherapy could be associated with errant CAR activity, as shown in the case of neuroblastoma. CAR inhibitors used in combination with existing chemotherapeutics could be utilized to attenuate multidrug resistance and resensitize chemo-resistant cancer cells. CAR and PXR have many overlapping modulating ligands as well as many overlapping target genes which confounded attempts to understand and regulate receptor-specific activity. Through a directed screening approach we previously identified a new CAR inhibitor, CINPA1, which is novel in its ability to inhibit CAR function without activating PXR. The cellular mechanisms by which CINPA1 inhibits CAR function were also extensively examined along with its pharmacokinetic properties. CINPA1 binding was shown to change CAR-coregulator interactions as well as modify CAR recruitment at DNA response elements of regulated genes. CINPA1 was shown to be broken down in the liver to form two, mostly inactive, metabolites. The structure-activity differences of CINPA1 and its metabolites were used to guide computational modeling using the CAR-LBD structure. To rationalize how ligand binding may lead to different CAR pharmacology, an analysis of the docked poses of human CAR bound to CITCO (a CAR activator) vs. CINPA1 or the metabolites was conducted. From our modeling, strong hydrogen bonding of CINPA1 with N165 and H203 in the CAR-LBD was predicted. These residues were validated to be important for CINPA1 binding using single amino-acid CAR mutants in a CAR-mediated functional reporter assay. Also predicted were residues making key hydrophobic interactions with CINPA1 but not the inactive metabolites. Some of these hydrophobic amino acids were also identified and additionally, the differential coregulator interactions of these mutants were determined in mammalian two-hybrid systems. CINPA1 represents an excellent starting point for future optimization into highly relevant probe molecules to study the function of the CAR receptor in normal- and pathophysiology, and possible development of therapeutics (for e.g. use for resensitizing chemoresistant neuroblastoma cells).

Keywords: antagonist, chemoresistance, constitutive androstane receptor (CAR), multi-drug resistance, structure activity relationship (SAR), xenobiotic resistance

Procedia PDF Downloads 265