Search results for: point mutations

Authors: Amandeep Thakur, Yi-Hsuan Chu, Chun-Hsu Pan, Kunal Nepali

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The transfer of ADP-ribose residues onto target substrates from nicotinamide adenine dinucleotide (NAD) (PARylation) is catalyzed by Poly (ADP-ribose) polymerases (PARPs). Amongst the PARP family members, the DNA damage response in cancer is majorly regulated by PARP1 and PARP2. The blockade of DNA repair by PARP inhibitors leads to the progression of DNA single-strand breaks (induced by some triggering factors) to double-strand breaks. Notably, PARP inhibitors are remarkably effective in cancers with defective homologous recombination repair (HRR). In particular, cancer cells with BRCA mutations are responsive to therapy with PARP inhibitors. The aforementioned requirement for PARP inhibitors to be effective confers a narrow activity spectrum to PARP inhibitors, which hinders their clinical applicability. Thus, the quest to expand the application horizons of PARP inhibitors beyond BRCA mutations is the need of the hour. Literature precedents reveal that HDAC inhibition induces BRCAness in cancer cells and can broaden the therapeutic scope of PARP inhibitors. Driven by such disclosures, dual inhibitors targeting both PARP and HDAC enzymes were designed by our research group to extend the efficacy of PARP inhibitors beyond BRCA-mutated cancers to cancers with induced BRCAness. The design strategy involved the installation of Veliparib, an investigational PARP inhibitor, as a surface recognition part in the HDAC inhibitor pharmacophore model. The chemical architecture of veliparib was deemed appropriate as a starting point for the generation of dual inhibitors by virtue of its size and structural flexibility. A validatory docking study was conducted at the outset to predict the binding mode of the designed dual modulatory chemical architectures. Subsequently, the designed chemical architectures were synthesized via a multistep synthetic route and evaluated for antitumor efficacy. Delightfully, one compound manifested impressive anti-leukemic effects (HL-60 cell lines) mediated via dual inhibition of PARP and class I HDACs. The outcome of the western blot analysis revealed that the compound could downregulate the expression levels of PARP1 and PARP2 and the HDAC isoforms (HDAC1, 2, and 3). Also, the dual PARP-HDAC inhibitor upregulated the protein expression of the acetyl histone H3, confirming its abrogation potential for class I HDACs. In addition, the dual modulator could arrest the cell cycle at the G0/G1 phase and induce autophagy. Further, polymer-based nanoformulation of the dual inhibitor was furnished to afford targeted delivery of the dual inhibitor at the cancer site. Transmission electron microscopy (TEM) results indicate that the nanoparticles were monodispersed and spherical. Moreover, the polymeric nanoformulation exhibited an appropriate particle size. Delightfully, pH-sensitive behavior was manifested by the polymeric nanoformulation that led to selective antitumor effects towards the HL-60 cell lines. In light of the magnificent anti-leukemic profile of the identified dual PARP-HDAC inhibitor, in-vivo studies (pharmacokinetics and pharmacodynamics) are currently being conducted. Notably, the optimistic findings of the aforementioned study have spurred our research group to initiate several medicinal chemistry campaigns to create bifunctional small molecule inhibitors addressing PARP as the primary target.

Keywords: PARP inhibitors, HDAC inhibitors, BRCA mutations, leukemia

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Authors: M. Altekin, R. F. Yükseler

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Geometrically nonlinear axisymmetric bending of a shallow spherical shell with a point support at the apex under linearly varying axisymmetric load was investigated numerically. The edge of the shell was assumed to be simply supported or clamped. The solution was obtained by the finite difference and the Newton-Raphson methods. The thickness of the shell was considered to be uniform and the material was assumed to be homogeneous and isotropic. Sensitivity analysis was made for two geometrical parameters. The accuracy of the algorithm was checked by comparing the deflection with the solution of point supported circular plates and good agreement was obtained.

Keywords: Bending, Nonlinear, Plate, Point support, Shell.

Procedia PDF Downloads 264

Authors: Liudmila Garzanova, Lidia Ananyeva, Olga Koneva, Olga Ovsyannikova, Oxana Desinova, Mayya Starovoytova, Rushana Shayahmetova, Anna Khelkovskaya-Sergeeva

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Objectives. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are associated with severe course, increased morbidity and mortality in systemic sclerosis (SSc). The aim of our study was to assess changes in CRP and ESR in SSc patients during long-term RTX therapy. Methods. This study included 113 patients with SSc. Mean age was 48.1±13 years, female-85%. The mean disease duration was 6±5 years. The diffuse cutaneous subset of the disease had 55% of patients. All pts had interstitial lung disease (ILD). All patients received prednisolone at a mean dose of 11.6±4.8 mg/day, and 53 of them - were immunosuppressants at inclusion. Patients received RTX due to the ineffectiveness of previous therapy for ILD. The parameters were evaluated over the periods: at baseline (point 0), 13±2.3 month (point 1, n=113), 42±14 month (point 2, n=80) and 79±6.5 month (point 3, n=25) after initiation of RTX therapy. Cumulative mean dose of RTX at point 1 = 1.7±0.6g, at point 2 = 3±1.5g, and at point 3 = 3.8±2.4g. The results are presented in the form of mean values, delta(Δ)-difference between the baseline parameter and follow-up point. Results. There was an improvement in studied parameters on RTX therapy. There was a significant decrease of ESR, CRP and activity index (EScSG-AI) at all observation points (p=0.001). In point 1: ΔCRP was 6.7 mg/l, ΔESR = 7.4 mm/h, ΔActivity index (EScSG-AI) = 1.7. In point 2: ΔCRP was 8.7 mg/l, ΔESR = 7.5 mm/h, ΔActivity index (EScSG-AI) = 1.9. In point 3: ΔCRP was 16.1 mg/l, ΔESR = 11 mm/h, ΔActivity index (EScSG-AI) = 2.1. Conclusion. There was a significant decrease in CRP and ESR during long-term RTX therapy, which correlated with a decrease in the disease activity index. RTX is an effective treatment option for SSc with an elevation of acute-phase reactants.

Keywords: C-reactive protein, interstitial lung disease, systemic sclerosis, rituximab

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Authors: Seyed Davar Siadat, Samira Tarashi, Abolfazl Fateh, Arfa Moshiri

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Background: The global health issue of tuberculosis (TB) still affects patients in every country. TB control may not be as effective as it should be, especially when resistant strains are involved. In this regard, mycobacterial MTases play a major role in tuberculosis, but the mechanisms underlying their function have yet to be fully deciphered. Methods: Five resistant isolates of M.tb were accumulated. As a reference strain, M.tb H37Rv (ATCC 27249) was used. For this analysis, seven putative mycobacterial MTase genes (Rv0645c, Rv1694, Rv2966c, Rv3919c, Rv2756c, Rv1988, and Rv3263), as well as Rv1392 as SAM synthase, were selected. Comparing mutations and expression levels of MTases in different strains was accomplished by PCR-sequencing and qRT-PCR. The relative expression levels of these genes were calculated using the 2 -ΔΔCt method. Results: The Rv3919c gene (T to G in codon 341) and Rv1392 gene (G to A in codon 97) were the only mutations found in the INHR strain. In all sensitive and resistant isolates, Rv0645c, Rv3263, Rv2756c, and Rv2966c were overexpressed. However, the expression of Rv1988 and Rv3919c decreased in the sensitive strains, whereas the expression of Rv1694 increased. There was also a decreased expression of Rv1392 in the INHR isolate. Conclusion: The presence of mycobacterial MTases as well as resistance to antibiotics were found to be correlated in M.tb strains. Undoubtedly, there are some MTases that are associated with the virulence process. It is necessary to conduct additional studies to fully explore the impact of mycobacterial MTases within specific strains of M.tb to develop novel diagnostic and treatment strategies.

Keywords: mycobacterium tuberculosis, drug resistance, methyltransferases, s-adenosylmethionine

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Authors: Mohammed Althobiti, Patrick Booms, Dorota Fiszer, Philip Hopkins

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Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. MH results from anaesthetics induced breakdown of calcium homeostasis. RYR1 and CACN1AS mutations represent the aetiology in ~70% of the MH population. Previous studies indicate that up to 25% of MH patients carry no variants in these genes. Therefore, the aim of this study is to investigate the relationships between MH susceptibility and genes encoding skeletal muscle Ca2+ channels as well as accessory proteins. The JSRP, encoding JP-45, was previously sequenced and novel genetic variants were identified. The variant p.P108L (c.323C > T) was identified in exon 4 and encodes a change from a proline at amino acid 108 to leucine residue. The variant P108L was detected in two patients out of 50 with 4% frequency in the sample population. The alignment of DNA sequences in different species indicates highly conserved proline sequences involved in the substitution of the P108L variant. In this study, the variant P108L co-segregates with the SNP p.V92A (c.275T > C) at the same exon, both variants being inherited in the same two patients only. This indicates that the two variants may represent a haplotype. Therefore, a set of single nucleotide polymorphisms and statistical analysis will be used to investigate the effects of haplotypes on MH susceptibility. Furthermore, investigating the effect of the P108L variant in combination with RYR1 mutations or other genetic variants in other genes as a combination of two or more genetic variants, haplotypes may then provide stronger genetic evidence indicating that JSRP1 is associated with MH susceptibility. In conclusion, these preliminary results lend a potential modifier role of the variant P108L in JSRP1 in MH susceptibility and further investigations are suggested to confirm these results.

Keywords: JSRP1, malignant hyperthermia, RyR1, skeletal muscle

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Authors: Filipe Cardoso de Oliveira, Lino Marcos da Silva, Ademar Nogueira do Nascimento, Cristiano Hora de Oliveira Fontes

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This article presents a mathematical formulation for the production Break-Even Point problem in a non-homogeneous system. The optimization problem aims to obtain the composition of the best product mix in a non-homogeneous industrial plant, with the lowest cost until the breakeven point is reached. The problem constraints represent real limitations of a generic non-homogeneous industrial plant for n different products. The proposed model is able to solve the equilibrium point problem simultaneously for all products, unlike the existing approaches that propose a resolution in a sequential way, considering each product in isolation and providing a sub-optimal solution to the problem. The results indicate that the product mix found through the proposed model has economical advantages over the traditional approach used.

Keywords: branch and bound, break-even point, non-homogeneous production system, integer linear programming, management accounting

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Authors: Mohamed Houas, Maamar Benbachir

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In this paper, under weak assumptions, we study the existence and uniqueness of solutions for a nonlinear fractional boundary value problem. New existence and uniqueness results are established using Banach contraction principle. Other existence results are obtained using scheafer and krasnoselskii's fixed point theorem. At the end, some illustrative examples are presented.

Keywords: caputo derivative, boundary value problem, fixed point theorem, local conditions

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Authors: Mayank, Navneet Kaur, Narinder Singh

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The V599 mutations in the BRAF protein are extremely oncogenic, responsible for countless of malignant conditions. Along with wild type, V599E, V599D, and V599R are the important mutated variants of the BRAF proteins. The BRAF inhibitory anticancer agents are continuously developing, and sorafenib is a BRAF inhibitor that is under clinical use. The crystal structure of sorafenib bounded to wild type, and V599 is known, showing a similar interaction pattern in both the case. The mutated 599th residue, in both the case, is also found not interacting directly with the co-crystallized sorafenib molecule. However, the IC50 value of sorafenib was found extremely different in both the case, i.e., 22 nmol/L for wild and 38 nmol/L for V599E protein. Molecular docking study and MMGBSA binding energy results also revealed a significant difference in the binding pattern of sorafenib in both the case. Therefore, to explore the role of distinctively situated 599th residue, we have further conducted comprehensive computational studies. The molecular dynamics simulation, residue interaction network (RIN) analysis, and residue correlation study results revealed the importance of the 599th residue on the therapeutic outcome and overall dynamic of the BRAF protein. Therefore, although the position of 599th residue is very much distinctive from the ligand-binding cavity of BRAF, still it has exceptional control over the overall functional outcome of the protein. The insight obtained here may seem extremely important and guide us while designing ideal BRAF inhibitory anticancer molecules.

Keywords: BRAF, oncogenic, sorafenib, computational studies

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Authors: Zeynep Aytaç, Nuri Yücel

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Today, as the need for high efficiency and fuel-efficient engines have increased, centrifugal compressor designs are expected to be high-efficient and have high-pressure ratios than ever. The present study represents a design methodology of centrifugal compressor placed in a mini jet engine for the design and off-design points with the utilization of computational fluid dynamics (CFD) and compares the performance characteristics at the mentioned two points. Although the compressor is expected to provide the required specifications at the design point, it is known that it is important for the design to deliver the required parameters at the off-design point also as it will not operate at the design point always. It was observed that the obtained mass flow rate, pressure ratio, and efficiency values are within the limits of the design specifications for the design and off-design points. Despite having different design inputs for the mentioned two points, they reveal similar flow characteristics in the general frame.

Keywords: centrifugal compressor, computational fluid dynamics, design point, off-design point

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Authors: G. V. Novikov, V. S. Sivozhelezov, S. S. Kolesnikov, K. V. Shaitan

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The study reports about the influence of binding of orthosteric ligands as well as point mutations on the conformational dynamics of β-2-adrenoreceptor. Using molecular dynamics simulation we found that there was a little fraction of active states of the receptor in its apo (ligand free) ensemble corresponded to its constitutive activity. Analysis of MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion in intracellular part of its alpha-helices. Thus receptor’s constitutive activity directly results from its conformational dynamics. On the other hand the binding of a full agonist resulted in a significant shift of the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized the receptor in its inactive state. It is likely that the binding of inverse agonists might be a universal way of constitutive activity inhibition in vivo. Our results indicate that ligand binding redistribute pre-existing conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) of the receptor rather than cause induced fit in it. Therefore, the ensemble of biologically relevant receptor conformations is encoded in its spatial structure, and individual conformations from that ensemble might be used by the cell in conformity with the physiological behaviour.

Keywords: seven-transmembrane receptors, constitutive activity, activation, x-ray crystallography, principal component analysis, molecular dynamics simulation

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Authors: Nurin Amalina Widityani, Adinda Syifa Azhari, Twin Aji Kusumagiani, Eleonora Agustine

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Fertilizer industry activities contribute to environmental changes. Changes to the environment became one of a few problems in this era of globalization. Parameters that can be seen as criteria to identify changes in the environment can be seen from the aspects of physics, chemistry, and biology. One aspect that can be assessed quickly and efficiently to describe environmental change is the aspect of physics, one of which is the value of magnetic susceptibility (χ). The rock magnetism method can be used as a proxy indicator of environmental changes, seen from the value of magnetic susceptibility. The rock magnetism method is based on magnetic susceptibility studies to measure and classify the degree of pollutant elements that cause changes in the environment. This research was conducted in the area around the fertilizer plant, with five coring points on each track, each coring point a depth of 15 cm. Magnetic susceptibility measurements were performed by in-situ and ex-situ. In-situ measurements were carried out directly by using the SM30 tool by putting the tools on the soil surface at each measurement point and by that obtaining the value of the magnetic susceptibility. Meanwhile, ex-situ measurements are performed in the laboratory by using the Bartington MS2B tool’s susceptibility, which is done on a coring sample which is taken every 5 cm. In-situ measurement shows results that the value of magnetic susceptibility at the surface varies, with the lowest score on the second and fifth points with the -0.81 value and the highest value at the third point, with the score of 0,345. Ex-situ measurements can find out the variations of magnetic susceptibility values at each depth point of coring. At a depth of 0-5 cm, the value of the highest XLF = 494.8 (x10-8m³/kg) is at the third point, while the value of the lowest XLF = 187.1 (x10-8m³/kg) at first. At a depth of 6-10 cm, the highest value of the XLF was at the second point, which was 832.7 (x10-8m³/kg) while the lowest XLF is at the first point, at 211 (x10-8m³/kg). At a depth of 11-15 cm, the XLF’s highest value = 857.7 (x10-8m³/kg) is at the second point, whereas the value of the lowest XLF = 83.3 (x10-8m³/kg) is at the fifth point. Based on the in situ and exsit measurements, it can be seen that the highest magnetic susceptibility values from the surface samples are at the third point.

Keywords: magnetic susceptibility, fertilizer plant, Bartington MS2B, SM30

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Authors: Wei-Na Li, Mei-Lan Piao, Nam Kim

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We proposed a novel computer-generated hologram (CGH) achieved scheme, wherein the CGH is generated from a point cloud which is transformed by a mapping relationship of a series of elemental images captured from a real three-dimensional (3D) object by using a lens array. This scheme is composed of three procedures: mapping from elemental images to point cloud, hologram generation, and hologram display. A mapping method is figured out to achieve a virtual volume date (point cloud) from a series of elemental images. This mapping method consists of two steps. Firstly, the coordinate (x, y) pairs and its appearing number are calculated from the series of sub-images, which are generated from the elemental images. Secondly, a series of corresponding coordinates (x, y, z) are calculated from the elemental images. Then a hologram is generated from the volume data that is calculated by the previous two steps. Eventually, a spatial light modulator (SLM) and a green laser beam are utilized to display this hologram and reconstruct the original 3D object. In this paper, in order to show a more auto stereoscopic display of a real 3D object, we successfully obtained the actual depth data of every discrete point of the real 3D object, and overcame the inherent drawbacks of the depth camera by obtaining point cloud from the elemental images.

Keywords: elemental image, point cloud, computer-generated hologram (CGH), autostereoscopic display

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Authors: Betsy Ng, Seng Chee Tan, Choon Lang Quek, Peter Looker, Jaime Koh

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The purpose of the present study was to determine the particular scale rating that stands out for an instrument. The instrument was designed to assess student perceptions of various learning environments, namely face-to-face, online and blended. The original instrument had a 5-point Likert items (1 = strongly disagree and 5 = strongly agree). Alternate versions were modified with a 6-point Likert scale and a bar scale rating. Participants consisted of undergraduates in a local university were involved in the usability testing of the instrument in an electronic setting. They were presented with the 5-point, 6-point and percentage-bar (100-point) scale ratings, in response to their perceptions of learning environments. The 5-point and 6-point Likert scales were presented in the form of radio button controls for each number, while the percentage-bar scale was presented with a sliding selection. Among these responses, 6-point Likert scale emerged to be the best overall. When participants were confronted with the 5-point items, they either chose 3 or 4, suggesting that data loss could occur due to the insensitivity of instrument. The insensitivity of instrument could be due to the discreet options, as evidenced by response interpolation. To avoid the constraint of discreet options, the percentage-bar scale rating was tested, but the participant responses were not well-interpolated. The bar scale might have provided a variety of responses without a constraint of a set of categorical options, but it seemed to reflect a lack of perceived and objective accuracy. The 6-point Likert scale was more likely to reflect a respondent’s perceived and objective accuracy as well as higher sensitivity. This finding supported the conclusion that 6-point Likert items provided a more accurate measure of the participant’s evaluation. The 5-point and bar scale ratings might not be accurately measuring the participants’ responses. This study highlighted the importance of the respondent’s perception of accuracy, respondent’s true evaluation, and the scale’s ease of use. Implications and limitations of this study were also discussed.

Keywords: usability, interpolation, sensitivity, Likert scales, accuracy

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Authors: Ahmed El-Banbi, Ahmed El-Maraghi

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PVT properties are needed as input data in all reservoir, production, and surface facilities engineering calculations. In the absence of PVT reports on valid reservoir fluid samples, engineers rely on PVT correlations to generate the required PVT data. The accuracy of PVT correlations varies, and no correlation group has been found to provide accurate results for all oil types. The effect of inaccurate PVT data can be significant in engineering calculations and is well documented in the literature. Bubble point pressure can sometimes be obtained from external sources. In this paper, we show how to utilize the known bubble point pressure to improve the accuracy of calculated PVT properties from correlations. We conducted a systematic study using around 250 reservoir oil samples to quantify the effect of pre-knowledge of bubble point pressure. The samples spanned a wide range of oils, from very volatile oils to black oils and all the way to low-GOR oils. A method for shifting both undersaturated and saturated sections of the PVT properties curves to the correct bubble point is explained. Seven PVT correlation families were used in this study. All PVT properties (e.g., solution gas-oil ratio, formation volume factor, density, viscosity, and compressibility) were calculated using the correct bubble point pressure and the correlation estimated bubble point pressure. Comparisons between the calculated PVT properties and actual laboratory-measured values were made. It was found that pre-knowledge of bubble point pressure and using the shifting technique presented in the paper improved the correlation-estimated values by 10% to more than 30%. The most improvement was seen in the solution gas-oil ratio and formation volume factor.

Keywords: PVT data, PVT properties, PVT correlations, bubble point pressure

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Authors: Mohamed Amine Haraoubia, Abdelaziz Hamzaoui, Najib Essounbouli

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The pursuit of the MPPT has led to the development of many kinds of controllers, one of which is the Fuzzy Logic Controller, which has proven its worth. To further tune this controller this paper will discuss and analyze the use of Genetic Algorithms to tune the Fuzzy Logic Controller. It will provide an introduction to both systems, and test their compatibility and performance.

Keywords: fuzzy logic controller, fuzzy logic, genetic algorithm, maximum power point, maximum power point tracking

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Authors: Chengming Li, Yong Yin, Peipei Guo, Xiaoli Liu

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Without taking account of the attribute richness of POI (point of interest) data and spatial distribution limited by roads, a POI generalization method considering both attribute information and spatial distribution has been proposed against the existing point generalization algorithm merely focusing on overall information of point groups. Hierarchical characteristic of urban POI information expression has been firstly analyzed to point out the measurement feature of the corresponding hierarchy. On this basis, an urban POI generalizing strategy has been put forward: POIs urban road network have been divided into three distribution pattern; corresponding generalization methods have been proposed according to the characteristic of POI data in different distribution patterns. Experimental results showed that the method taking into account both attribute information and spatial distribution characteristics of POI can better implement urban POI generalization in the mapping presentation.

Keywords: POI, road network, selection method, spatial information expression, distribution pattern

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Authors: Dua K. S. Y. Klaas, Monzur A. Imteaz, Ika Sudiayem, Elkan M. E. Klaas, Eldav C. M. Klaas

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Properly selecting the most suitable and effective geostatistics method in the parameterization step of groundwater modeling is critical to attain a satisfactory model. In this paper, two geostatistics methods, i.e., Grid-Based Pilot Point (GB-PP) and Head-Zonation Based Pilot Point (HZB-PP) methods, were applied in an eogenetic karst catchment and compared using as model performances and computation time the criteria. Overall, the results show that appropriate selection of method is substantial in the parameterization of physically-based groundwater models, as it influences both the accuracy and simulation times. It was found that GB-PP method performed comparably superior to HZB-PP method. However, reflecting its model performances, HZB-PP method is promising for further application in groundwater modeling.

Keywords: groundwater model, geostatistics, pilot point, parameterization step

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Authors: Byeong-Uk Lim, Young-Ran Song, Sang-Ho Baik

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This study aimed to develop yeast starters for scientific alcohol production and systematic quality control of whisky. A total of 389 yeast strains were isolated from traditional Korean fermentation starter (nuruk) and rice wine (makgeolli), and ten strains were finally selected for their high alcohol productivities, in which their alcohol productions were above 17.3% (v/v) during 10 days under two steps of glucose feeding condition (30% and then 15%, w/v). By 18s rDNA sequence analysis, all strains were identified as Saccharomyces cerevisiae (SC), and they can grow well under 50% (w/v) glucose and 10% (v/v) ethanol conditions. Furthermore, the capability of ten different SC strains to ferment rice wine for whisky was studied. Rice wine was fermented with only steamed rice, water, and two types of enzymes (glucoamylase and α-amylase) during 14 days at 25 °C, and then their oenological properties have been determined. As the results, the fermented rice wines indicated the final pH range of 4.24-4.38 and acidity range of 0.12-0.18. The highest ethanol production of 20.2% (v/v) was found in the fermentation with a SC-156 strain, whereas SC-92 (16.8%) and SC-119 (16.4%) showed significantly lowest ethanol productions. In addition, the residual sugar contents showed negative correlation with alcohol contents. Moreover, this study focused on nucleotide polymorphisms in the MSN2 and MSN4 genes to investigate the cause of the defective stress responses in yeast. Consequently, it was also confirmed that the deletion of the N termini of Msn4p from identified point mutations in SC-63, SC-95, SC-156, SC-158, and SC-160 strains.

Keywords: yeast, high-alcohol, whisky, rice wine

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Authors: Mona Vijayaran, Gurleen Oberoi, Sanjay Mishra

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Introduction: p190 BCR‐ABL1 in CML is often associated with monocytosis. In the case described here, monocytosis is associated with coexisting p210 BCR‐ABL and CMML clones. Mutation analysis using next‐generation sequence (NGS) in our case showed TET2 and SRSF2 mutations. Aims & Objectives: A 75-year male was evaluated for monocytosis and thrombocytopenia. CBC showed Hb-11.8g/dl, TLC-12,060/cmm, Monocytes-35%, Platelets-39,000/cmm. Materials & Methods: Bone marrow examination showed a hypercellular marrow with myeloid series showing sequential maturation up to neutrophils with 30% monocytes. Immunophenotyping by flow cytometry from bone marrow had 3% blasts. Making chronic myelomonocytic leukemia as the likely diagnosis. NGS for myeloid mutation panel had TET2 (48.9%) and SRSF2 (32.5%) mutations. This report further supported the diagnosis of CMML. To fulfil the WHO diagnostic criteria for CMML, a BCR ABL1 by RQ-PCR was sent. The report came positive for p210 (B3A2, B2A2) Major Transcript (M-BCR) % IS of 38.418. Result: The patient was counselled regarding the unique presentation of the presence of 2 clones- P210 CML and CMML. After discussion with an international faculty with vast experience in CMML. It was decided to start this elderly gentleman on Imatinib 200mg and not on azacytidine, as ASXL1 was not present; hence, his chances of progressing to AML would be less and on the other end, if CML is left untreated then chances of progression to blast phase would always be a possibility. After 3 months on Imatinib his platelet count improved to 80,000 to 90,000/cmm, but his monocytosis persists. His 3rd month BCR-ABL1 IS% is 0.004%. Conclusion: After searching the literature, there were no case reports of a coexisting CML p210 with CMML. This case might be the first case report. p190 BCR ABL1 is often associated with monocytosis. There are few case reports of p210 BCR ABL1 positivity in patients with monocytosis but none with coexisting CMML. This case highlights the need for extensively evaluating patients with monocytosis with next-generation sequencing for myeloid mutation panel and BCR-ABL1 by RT-PCR to correctly diagnose and treat them.

Keywords: CMML, NGS, p190 CML, Imatinib

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Authors: Sanaa Bardaweel

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Inorganic polyphosphate (poly P) is present in all living forms tested to date, from each of the three kingdoms of life. Studied mainly in prokaryotes, poly P and its associated enzymes are vital in diverse basic metabolism, in at least some structural functions and, notably, in stress responses. These plentiful and unrelated roles for poly P are probably the consequence of its presence in life-forms early in evolution. The genomes of many bacterial species, including pathogens, encode a homologue of a major poly P synthetic enzyme, poly P kinase 1 (PPK1). Genetic deletion of ppk1 results in reduced poly P levels and loss of pathogens virulence towards protozoa and animals. Thus far, no PPK1 homologue has been identified in higher-order eukaryotes and, therefore, PPK1 represents a novel target for chemotherapy. The idea of the current study is to purify the PPK1 from Escherichia coli to homogeneity in order to study the effect of active site point mutations on PPK1 catalysis via the application of site-directed mutagenesis strategy. The knowledge obtained about the active site of PPK1 will be utilized to characterize the catalytic and kinetic mechanism of PPK1 with model substrates. Comprehensive understanding of the enzyme kinetic mechanism and catalysis will be used to design and screen a library of synthetic compounds for potential discovery of selective PPK1-inhibitors.

Keywords: antimicobial, Escherichia coli, inorganic polyphosphate, PPK1-inhibitors

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Authors: Muhammad Younis

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A ternary 4-point approximating non-stationary subdivision scheme has been introduced that generates the family of $C^2$ limiting curves. The theory of asymptotic equivalence is being used to analyze the convergence and smoothness of the scheme. The comparison of the proposed scheme has been demonstrated using different examples with the existing 4-point ternary approximating schemes, which shows that the limit curves of the proposed scheme behave more pleasantly and can generate conic sections as well.

Keywords: ternary, non-stationary, approximation subdivision scheme, convergence and smoothness

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Authors: Shruti Govindarajan

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In-utero gene editing with CRISPR-Cas9 opens up new possibilities for treating genetic disorders during pregnancy while still in mother’s womb. By targeting genetic mutations in the early stages of fetal development, this approach could potentially prevent severe conditions—like cystic fibrosis, sickle cell anemia, and muscular dystrophy—from causing harm. CRISPR-Cas9, which allows precise DNA edits, could be delivered into fetal cells through vectors such as adeno-associated viruses (AAVs) or nanoparticles, correcting disease-causing mutations and possibly offering lifelong relief from these disorders. For families facing severe genetic diagnoses, in-utero gene editing could provide a transformative option. However, technical challenges remain, including ensuring that gene editing only targets the intended cells and verifying long-term safety. Ethical considerations are also at the forefront of this technology. The editing of a fetus's genes brings up difficult questions about consent, especially since these genetic changes will affect the child’s entire life without their input. There's also concern over possible unintended side effects, or changes passed down to future generations. Moreover, if used beyond therapeutic purposes, this technology could be misused for ‘enhancements,’ like selecting for certain physical or cognitive traits, raising concerns about inequality and social pressures. In this way, in-utero gene editing brings both exciting potential and complex moral questions. As research progresses, addressing these scientific and ethical concerns will be key to ensuring that this technology is used responsibly, prioritizing safety, fairness, and a focus on alleviating genetic disease. A cautious and inclusive approach, along with clear regulations, will be essential to realizing the benefits of in-utero gene editing while protecting against unintended consequences.

Keywords: in-utero gene editing, CRISPR, bioethics, genetic disorder

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Authors: Amjad Abdullah, Amjad Yahya, Bushra Aljohani, Amani Alghamdi

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Change point detection is an important part of data analysis. The presence of a change point refers to a significant change in the behavior of a time series. In this article, we examine the detection of multiple change points of parameters of the exponential Lomax distribution, which is broad and flexible compared with other distributions while fitting data. We used the Schwarz information criterion and binary segmentation to detect multiple change points in publicly available data on the average temperature in the ozone layer. The change points were successfully located.

Keywords: binary segmentation, change point, exponentialLomax distribution, information criterion

Procedia PDF Downloads 174

Authors: Amal M. Nassar, Nehal S. Ahmed, Rasha S. Kamal

Abstract:

Some lube oil additives improve the base oil performance such as viscosity index improvers and pour point depressants which are the most important type of additives. In the present work, some homopolymeric additives were prepared by esterification of acrylic acid with different alcohols (1-dodecyl, 1-hexadecyl, and 1-octadecyl )and then homopolymerization of the prepared esters with different ratio of benzoyl peroxide catalyst (0.25%& 0.5 % and 1%). Structure of the prepared esters was confirmed by Infra-Red Spectroscopy. The molecular weights of the prepared homopolymers were determined by using Gel Permeation Chromatograph. The efficiency of the prepared homopolymers as viscosity index improvers and pour point depressants for lube oil was the investigation. It was found that all the prepared homopolymers are effective as viscosity index improvers and pour point depressants.

Keywords: lube oil additives, homopolymerization, viscosity index improver, pour point depressant

Procedia PDF Downloads 231

Authors: S. Fahiminiya, J. Nadaf, F. Rauch, L. Jerome-Majewska, J. Majewski

Abstract:

Background: Sequencing of protein coding regions of human genome (Whole Exome Sequencing; WES), has demonstrated a great success in the identification of causal mutations for several rare genetic disorders in human. Generally, most of WES studies have focused on rare variants in coding exons and splicing-sites where missense substitutions lead to the alternation of protein product. Although focusing on this category of variants has revealed the mystery behind many inherited genetic diseases in recent years, a subset of them remained still inconclusive. Here, we present the result of our WES studies where analyzing only rare variants in coding regions was not conclusive but further investigation revealed the involvement of non-coding variants and copy number variations (CNV) in etiology of the diseases. Methods: Whole exome sequencing was performed using our standard protocols at Genome Quebec Innovation Center, Montreal, Canada. All bioinformatics analyses were done using in-house WES pipeline. Results: To date, we successfully identified several disease causing mutations within gene coding regions (e.g. SCARF2: Van den Ende-Gupta syndrome and SNAP29: 22q11.2 deletion syndrome) by using WES. In addition, we showed that variants in non-coding regions and CNV have also important value and should not be ignored and/or filtered out along the way of bioinformatics analysis on WES data. For instance, in patients with osteogenesis imperfecta type V and in patients with glucocorticoid deficiency, we identified variants in 5'UTR, resulting in the production of longer or truncating non-functional proteins. Furthermore, CNVs were identified as the main cause of the diseases in patients with metaphyseal dysplasia with maxillary hypoplasia and brachydactyly and in patients with osteogenesis imperfecta type VII. Conclusions: Our study highlights the importance of considering non-coding variants and CNVs during interpretation of WES data, as they can be the only cause of disease under investigation.

Keywords: whole exome sequencing data, non-coding variants, copy number variations, rare diseases

Procedia PDF Downloads 419

Authors: Osamede Asowata

Abstract:

Optimized gain in respect to output power of stand-alone photovoltaic (PV) systems is one of the major focus of PV in recent times. This is evident in its low carbon emission and efficiency. Power failure or outage from commercial providers, in general, does not promote development to public and private sector; these basically limit the development of industries. The need for a well-structured PV system is of importance for an efficient and cost effective monitoring system. The purpose of this paper is to validate the maximum power point of an off-grid PV system taking into consideration the most effective tilt and orientation angles for PV's in the southern hemisphere. This paper is based on analyzing the system using a solar charger with maximum power point tracking (MPPT) from a pulse width modulation (PWM) perspective. The power conditioning device chosen is a solar charger with MPPT. The practical setup consists of a PV panel that is set to an orientation angle of 0°N, with a corresponding tilt angle of 36°, 26°, and 16°. Preliminary results include regression analysis (normal probability plot) showing the maximum power point in the system as well the best tilt angle for maximum power point tracking.

Keywords: poly-crystalline PV panels, solar chargers, tilt and orientation angles, maximum power point tracking, MPPT, Pulse Width Modulation (PWM).

Procedia PDF Downloads 176

Authors: Donghwan Lee, Gichun Cha, Jooyoung Park, Junkyeong Kim, Seunghee Park

Abstract:

3D shape models of the existing structure are required for many purposes such as safety and operation management. The traditional 3D modeling methods are based on manual or semi-automatic reconstruction from close-range images. It occasions great expense and time consuming. The Terrestrial Laser Scanner (TLS) is a common survey technique to measure quickly and accurately a 3D shape model. This TLS is used to a construction site and cultural heritage management. However there are many limits to process a TLS point cloud, because the raw point cloud is massive volume data. So the capability of carrying out useful analyses is also limited with unstructured 3-D point. Thus, segmentation becomes an essential step whenever grouping of points with common attributes is required. In this paper, members segmentation algorithm was presented to separate a raw point cloud which includes only 3D coordinates. This paper presents a clustering approach based on a fuzzy method for this objective. The Fuzzy C-Means (FCM) is reviewed and used in combination with a similarity-driven cluster merging method. It is applied to the point cloud acquired with Lecia Scan Station C10/C5 at the test bed. The test-bed was a bridge which connects between 1st and 2nd engineering building in Sungkyunkwan University in Korea. It is about 32m long and 2m wide. This bridge was used as pedestrian between two buildings. The 3D point cloud of the test-bed was constructed by a measurement of the TLS. This data was divided by segmentation algorithm for each member. Experimental analyses of the results from the proposed unsupervised segmentation process are shown to be promising. It can be processed to manage configuration each member, because of the segmentation process of point cloud.

Keywords: fuzzy c-means (FCM), point cloud, segmentation, terrestrial laser scanner (TLS)

Procedia PDF Downloads 234

Authors: Bui Phuong Linh, Yuki Sakakibara, Ryuto Tanaka, Elizabeth H. Pigney, Taishi Hashiguchi

Abstract:

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease, often associated with type II diabetes, which sometimes progresses to more serious conditions such as liver fibrosis and hepatocellular carcinoma (HCC). NASH has become an important health problem worldwide, buttherapeutic agents for NASH have not yet been approved, and animal models with high clinical correlation are required. TheSTAM™ mouse shows the same pathological progression as human NASH patients and has been widely used for both drug efficacy and basic research, such as lipid profiling and gut microbiota research. In this study, we analyzed the RNA-seq data of STAM™mice at each pathological stage (steatosis, steatohepatitis, liver fibrosis, and HCC) and examined the clinical correlation at the genetic level. NASH was induced in male mice by a single subcutaneous injection of 200 µg streptozotocin solution 2 days after birth and feeding with high fat dietafter 4 weeks of age. The mice were sacrificed and livers collected at 6, 8, 10, 12, 16, and 20 weeks of age. For liver samples, the left lateral lobe was snap frozen in liquid nitrogen and stored at -80˚C for RNA-seq analysis. Total RNA of the cells was isolated using RNeasy mini kit. The gene expression of the canonical pathways in NASH progression from steatosis to hepatocellular carcinoma were analyzed, such as immune system process, oxidation-reduction process, lipid metabolic process. Moreover, since it has been reported that genetic traits are involved in the development of NASH-HCC, we next analyzed the genetic mutations in the STAM™mice. The number of individuals showing mutations in Mtorinvolved in Insulin signaling increases as the disease progresses, especially in the liver cancer phase. These results indicated a clinical correlation of gene profiles in the STAM™mouse.

Keywords: steatosis, non-alcoholic steatohepatitis, fibrosis, hepatocellular carcinoma, RNA-seq

Procedia PDF Downloads 153

Authors: Faisal Anwar, Dawar Zaidi, Shubham Dixit, Nafees Ahmedii

Abstract:

This paper analyzes the various properties of biodiesel such as pour point, cloud point, viscosity, calorific value, etc produced from different feedstocks. The aim of the work is to analyze change in these properties after converting feedstocks to biodiesel and then comparring it with ASTM 6751-02 standards to check whether they are suitable for diesel engines or not. The conversion of feedstocks is carried out by a process called transesterification. This conversion is carried out to reduce viscosity, pour point, etc. It has been observed that there is some remarkable change in the properties of oil after conversion.

Keywords: biodiesel, ethyl ester, free fatty acid, production

Procedia PDF Downloads 366

Authors: Kishor J. shinde

Abstract:

We determine the values of k and p such that the Sturm-Liouville differential operator τu=-(d^2 u)/(dx^2) + kx^p u is in limit point case or limit circle case at infinity. In particular it is shown that τ is in the limit point case when (i) for p=2 and ∀k, (ii) for ∀p and k=0, (iii) for all p and k>0, (iv) for 0≤p≤2 and k<0, (v) for p<0 and k<0. τ is in the limit circle case when (i) for p>2 and k<0.

Keywords: limit point case, limit circle case, Sturm-Liouville, infinity

Procedia PDF Downloads 367