Search results for: alloy target
2677 Predicting and Obtaining New Solvates of Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin Based on the Ccdc Statistical Tools and Hansen Solubility Parameters
Authors: J. Ticona Chambi, E. A. De Almeida, C. A. Andrade Raymundo Gaiotto, A. M. Do Espírito Santo, L. Infantes, S. L. Cuffini
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The solubility of active pharmaceutical ingredients (APIs) is challenging for the pharmaceutical industry. The new multicomponent crystalline forms as cocrystal and solvates present an opportunity to improve the solubility of APIs. Commonly, the procedure to obtain multicomponent crystalline forms of a drug starts by screening the drug molecule with the different coformers/solvents. However, it is necessary to develop methods to obtain multicomponent forms in an efficient way and with the least possible environmental impact. The Hansen Solubility Parameters (HSPs) is considered a tool to obtain theoretical knowledge of the solubility of the target compound in the chosen solvent. H-Bond Propensity (HBP), Molecular Complementarity (MC), Coordination Values (CV) are tools used for statistical prediction of cocrystals developed by the Cambridge Crystallographic Data Center (CCDC). The HSPs and the CCDC tools are based on inter- and intra-molecular interactions. The curcumin (Cur), target molecule, is commonly used as an anti‐inflammatory. The demethoxycurcumin (Demcur) and bisdemethoxycurcumin (Bisdcur) are natural analogues of Cur from turmeric. Those target molecules have differences in their solubilities. In this way, the work aimed to analyze and compare different tools for multicomponent forms prediction (solvates) of Cur, Demcur and Biscur. The HSP values were calculated for Cur, Demcur, and Biscur using the chemical group contribution methods and the statistical optimization from experimental data. The HSPmol software was used. From the HSPs of the target molecules and fifty solvents (listed in the HSP books), the relative energy difference (RED) was determined. The probability of the target molecules would be interacting with the solvent molecule was determined using the CCDC tools. A dataset of fifty molecules of different organic solvents was ranked for each prediction method and by a consensus ranking of different combinations: HSP, CV, HBP and MC values. Based on the prediction, 15 solvents were selected as Dimethyl Sulfoxide (DMSO), Tetrahydrofuran (THF), Acetonitrile (ACN), 1,4-Dioxane (DOX) and others. In a starting analysis, the slow evaporation technique from 50°C at room temperature and 4°C was used to obtain solvates. The single crystals were collected by using a Bruker D8 Venture diffractometer, detector Photon100. The data processing and crystal structure determination were performed using APEX3 and Olex2-1.5 software. According to the results, the HSPs (theoretical and optimized) and the Hansen solubility sphere for Cur, Demcur and Biscur were obtained. With respect to prediction analyses, a way to evaluate the predicting method was through the ranking and the consensus ranking position of solvates already reported in the literature. It was observed that the combination of HSP-CV obtained the best results when compared to the other methods. Furthermore, as a result of solvent selected, six new solvates, Cur-DOX, Cur-DMSO, Bicur-DOX, Bircur-THF, Demcur-DOX, Demcur-ACN and a new Biscur hydrate, were obtained. Crystal structures were determined for Cur-DOX, Biscur-DOX, Demcur-DOX and Bicur-Water. Moreover, the unit-cell parameter information for Cur-DMSO, Biscur-THF and Demcur-ACN were obtained. The preliminary results showed that the prediction method is showing a promising strategy to evaluate the possibility of forming multicomponent. It is currently working on obtaining multicomponent single crystals.Keywords: curcumin, HSPs, prediction, solvates, solubility
Procedia PDF Downloads 632676 Modeling of CREB Pathway Induced Gene Induction: From Stimulation to Repression
Authors: K. Julia Rose Mary, Victor Arokia Doss
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Electrical and chemical stimulations up-regulate phosphorylaion of CREB, a transcriptional factor that induces its target gene production for memory consolidation and Late Long-Term Potentiation (L-LTP) in CA1 region of the hippocampus. L-LTP requires complex interactions among second-messenger signaling cascade molecules such as cAMP, CAMKII, CAMKIV, MAPK, RSK, PKA, all of which converge to phosphorylate CREB which along with CBP induces the transcription of target genes involved in memory consolidation. A differential equation based model for L-LTP representing stimulus-mediated activation of downstream mediators which confirms the steep, supralinear stimulus-response effects of activation and inhibition was used. The same was extended to accommodate the inhibitory effect of the Inducible cAMP Early Repressor (ICER). ICER is the natural inducible CREB antagonist represses CRE-Mediated gene transcription involved in long-term plasticity for learning and memory. After verifying the sensitivity and robustness of the model, we had simulated it with various empirical levels of repressor concentration to analyse their effect on the gene induction. The model appears to predict the regulatory dynamics of repression on the L-LTP and agrees with the experimental values. The flux data obtained in the simulations demonstrate various aspects of equilibrium between the gene induction and repression.Keywords: CREB, L-LTP, mathematical modeling, simulation
Procedia PDF Downloads 2952675 Understanding the Motivations behind the Assassination of Turkish Armenian Journalist, Hrant Dink
Authors: Nusret Mesut Sahin
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Hrant Dink, a prominent Turkish-Armenian journalist, and editor-in-chief of the bilingual Turkish-Armenian newspaper Agos was assassinated in Istanbul on January 19th, 2007 by a nationalist extremist, Ogun Samast. Dink had been voicing the atrocities against the Armenians between 1915 and 1922 during the Ottoman rule, and his comments on the issue appeared in the Turkish media many times before his assassination. It has been argued that the suffocating atmosphere created by the Turkish news media targeting Mr. Dink made him a target of an extremist Turkish juvenile. This study analyzes the media news to understand and explain why Hrant Dink became the target of a nationalist extremist. In this research, content analysis of news articles (N= 170) is conducted to identify whether there is a link between hate speech against Hrant Dink in the Turkish media and his assassination. The content of the newspaper articles is categorized and coded according to the hate language being used. The analysis suggested that Turkish media paved the way for Dink’s assassination. Hate speech against Hrant Dink on the media had risen gradually before the assassination. The study also found that the number of news stories covering hate speech and racist discourse against non-Muslim citizens of Turkey also increased dramatically before the assassination. Therefore, hate speech against minorities in media narratives and news reports should be monitored, and political figures or leaders of social groups who are targeted by some media outlets should be protected.Keywords: Hrant Dink, assassination, Turkish Armenian journalist, media
Procedia PDF Downloads 1612674 Clustering of Natural and Nature Derived Compounds for Cardiovascular Disease: Pharmacophore Modeling
Authors: S. Roy, R. Rekha, K. Sriram, G. Subhadra, R. Johana
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Cardiovascular disease remains a leading cause of death in most industrialized countries. Many chemical drugs are available in the market which targets different receptor proteins related to cardiovascular diseases. Of late the traditional herbal drugs are safer when compared to chemical drugs because of its side effects. However, many herbal remedies used in treating cardiovascular diseases have not undergone scientific assessment to prove its pharmacological activities. There are many natural compounds, nature derived and Natural product mimic compounds are available which are in the market as approved drug. In the most of the cases drug activity at the molecular level are not known. Here we have categorized those compounds with our experimental compounds in different classes based on the structural similarity and physicochemical properties, using a tool, Chemmine and has attempted to understand the mechanism of the action of a experimental compound, which are clustered with Simvastatin, Lovastatin, Mevastatin and Pravastatin. Target protein molecule for Simvastatin, Lovastatin, Mevastatin and Pravastatin is HMG-CoA reductase, so we concluded that the experimental compound may be able to bind to the same target. Molecular docking and atomic interaction studies with simvastatin and our experimental compound were compared. A pharmacophore modeling was done based on the experimental compound and HMG-CoA reductase inhibitor.Keywords: molecular docking, physicochemical properties, pharmacophore modeling structural similarity, pravastatin
Procedia PDF Downloads 3222673 Two Layer Photo-Thermal Deflection Model to Investigate the Electronic Properties in BGaAs/GaAs Alloys
Authors: S. Ilahi, M. Baira, F. Saidi, N. Yacoubi, L. Auvray, H. Maaref
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Photo-thermal deflection technique (PTD) is used to study the nonradiative recombination process in BGaAs/GaAs alloy with boron composition of 3% and 8% grown by metal organic chemical vapor deposition (MOCVD). A two layer theoretical model has been developed taking into account both thermal and electronic contribution in the photothermal signal allowing to extract the electronic parameters namely electronic diffusivity, surface and interface recombination. It is found that the increase of boron composition alters the BGaAs epilayers transport properties.Keywords: photothermal defelction technique, two layer model, BGaAs/GaAs alloys, boron composition
Procedia PDF Downloads 3012672 Progress Towards Optimizing and Standardizing Fiducial Placement Geometry in Prostate, Renal, and Pancreatic Cancer
Authors: Shiva Naidoo, Kristena Yossef, Grimm Jimm, Mirza Wasique, Eric Kemmerer, Joshua Obuch, Anand Mahadevan
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Background: Fiducial markers effectively enhance tumor target visibility prior to Stereotactic Body Radiation Therapy or Proton therapy. To streamline clinical practice, fiducial placement guidelines from a robotic radiosurgery vendor were examined with the goals of optimizing and standardizing feasible geometries for each treatment indication. Clinical examples of prostate, renal, and pancreatic cases are presented. Methods: Vendor guidelines (Accuray, Sunnyvale, Ca) suggest implantation of 4–6 fiducials at least 20 mm apart, with at least a 15-degree angular difference between fiducials, within 50 mm or less from the target centroid, to ensure that any potential fiducial motion (e.g., from respiration or abdominal/pelvic pressures) will mimic target motion. Also recommended is that all fiducials can be seen in 45-degree oblique views with no overlap to coincide with the robotic radiosurgery imaging planes. For the prostate, a standardized geometry that meets all these objectives is a 2 cm-by-2 cm square in the coronal plane. The transperineal implant of two pairs of preloaded tandem fiducials makes the 2 cm-by-2 cm square geometry clinically feasible. This technique may be applied for renal cancer, except repositioned in a sagittal plane, with the retroperitoneal placement of the fiducials into the tumor. Pancreatic fiducial placement via endoscopic ultrasound (EUS) is technically more challenging, as fiducial placement is operator-dependent, and lesion access may be limited by adjacent vasculature, tumor location, or restricted mobility of the EUS probe in the duodenum. Fluoroscopically assisted fiducial placement during EUS can help ensure fiducial markers are deployed with optimal geometry and visualization. Results: Among the first 22 fiducial cases on a newly installed robotic radiosurgery system, live x-ray images for all nine prostatic cases had excellent fiducial visualization at the treatment console. Renal and pancreatic fiducials were not as clearly visible due to difficult target access and smaller caliber insertion needle/fiducial usage. The geometry of the first prostate case was used to ensure accurate geometric marker placement for the remaining 8 cases. Initially, some of the renal and pancreatic fiducials were closer than the 20 mm recommendation, and interactive feedback with the proceduralists led to subsequent fiducials being too far to the edge of the tumor. Further feedback and discussion of all cases are being used to help guide standardized geometries and achieve ideal fiducial placement. Conclusion: The ideal tradeoffs of fiducial visibility versus the thinnest possible gauge needle to avoid complications needs to be systematically optimized among all patients, particularly in regards to body habitus. Multidisciplinary collaboration among proceduralists and radiation oncologists can lead to improved outcomes.Keywords: fiducial, prostate cancer, renal cancer, pancreatic cancer, radiotherapy
Procedia PDF Downloads 932671 Functional Surfaces and Edges for Cutting and Forming Tools Created Using Directed Energy Deposition
Authors: Michal Brazda, Miroslav Urbanek, Martina Koukolikova
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This work focuses on the development of functional surfaces and edges for cutting and forming tools created through the Directed Energy Deposition (DED) technology. In the context of growing challenges in modern engineering, additive technologies, especially DED, present an innovative approach to manufacturing tools for forming and cutting. One of the key features of DED is its ability to precisely and efficiently deposit Fully dense metals from powder feedstock, enabling the creation of complex geometries and optimized designs. Gradually, it becomes an increasingly attractive choice for tool production due to its ability to achieve high precision while simultaneously minimizing waste and material costs. Tools created using DED technology gain significant durability through the utilization of high-performance materials such as nickel alloys and tool steels. For high-temperature applications, Nimonic 80A alloy is applied, while for cold applications, M2 tool steel is used. The addition of ceramic materials, such as tungsten carbide, can significantly increase the tool's resistance. The introduction of functionally graded materials is a significant contribution, opening up new possibilities for gradual changes in the mechanical properties of the tool and optimizing its performance in different sections according to specific requirements. In this work, you will find an overview of individual applications and their utilization in the industry. Microstructural analyses have been conducted, providing detailed insights into the structure of individual components alongside examinations of the mechanical properties and tool life. These analyses offer a deeper understanding of the efficiency and reliability of the created tools, which is a key element for successful development in the field of cutting and forming tools. The production of functional surfaces and edges using DED technology can result in financial savings, as the entire tool doesn't have to be manufactured from expensive special alloys. The tool can be made from common steel, onto which a functional surface from special materials can be applied. Additionally, it allows for tool repairs after wear and tear, eliminating the need for producing a new part and contributing to an overall cost while reducing the environmental footprint. Overall, the combination of DED technology, functionally graded materials, and verified technologies collectively set a new standard for innovative and efficient development of cutting and forming tools in the modern industrial environment.Keywords: additive manufacturing, directed energy deposition, DED, laser, cutting tools, forming tools, steel, nickel alloy
Procedia PDF Downloads 512670 The Use of Water Resources Yield Model at Kleinfontein Dam
Authors: Lungile Maliba, O. I. Nkwonta, E Onyari
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Water resources development and management are regarded as crucial for poverty reduction in many developing countries and sustainable economic growth such as South Africa. The contribution of large hydraulic infrastructure and management of it, particularly reservoirs, to development remains controversial. This controversy stems from the fact that from a historical point of view construction of reservoirs has brought fewer benefits than envisaged and has resulted in significant environmental and social costs. A further complexity in reservoir management is the variety of stakeholders involved, all with different objectives, including domestic and industrial water use, flood control, irrigation and hydropower generation. The objective was to evaluate technical adaptation options for kleinfontein Dam’s current operating rule curves. To achieve this objective, the current operating rules curves being used in the sub-basin were analysed. An objective methodology was implemented in other to get the operating rules with regards to the target storage curves. These were derived using the Water Resources Yield/Planning Model (WRY/PM), with the aim of maximising of releases to demand zones. The result showed that the system is over allocated and in addition the demands exceed the long-term yield that is available for the system. It was concluded that the current operating rules in the system do not produce the optimum operation such as target storage curves to avoid supply failures in the system.Keywords: infrastructure, Kleinfontein dam, operating rule curve, water resources yield and planning model
Procedia PDF Downloads 1402669 Biocompatibility of Calcium Phosphate Coatings With Different Crystallinity Deposited by Sputtering
Authors: Ekaterina S. Marchenko, Gulsharat A. Baigonakova, Kirill M. Dubovikov, Igor A. Khlusov
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NiTi alloys combine biomechanical and biochemical properties. This makes them a perfect candidate for medical applications. However, there is a serious problem with these alloys, such as the release of Ni from the matrix. Ni ions are known to be toxic to living tissues and leach from the matrix into the surrounding implant tissues due to corrosion after prolonged use. To prevent the release of Ni ions, corrosive strong coatings are usually used. Titanium nitride-based coatings are perfect corrosion inhibitors and also have good bioactive properties. However, there is an opportunity to improve the biochemical compatibility of the surface by depositing another layer. This layer can consist of elements such as calcium and phosphorus. The Ca and P ions form different calcium phosphate phases, which are present in the mineral part of human bones. We therefore believe that these elements must promote osteogenesis and osteointegration. In view of the above, the aim of this study is to investigate the effect of crystallinity on the biocompatibility of a two-layer coating deposited on NiTi substrate by sputtering. The first step of the research, apart from the NiTi polishing, is the layer-by-layer deposition of Ti-Ni-Ti by magnetron sputtering and the subsequent synthesis of this composite in an N atmosphere at 900 °C. The total thickness of the corrosion resistant layer is 150 nm. Plasma assisted RF sputtering was then used to deposit a bioactive film on the titanium nitride layer. A Ca-P powder target was used to obtain such a film. We deposited three types of Ca-P layers with different crystallinity and compared them in terms of cytotoxicity. One group of samples had no Ca-P coating and was used as a control. We obtained different crystallinity by varying the sputtering parameters such as bias voltage, plasma source current and pressure. XRD analysis showed that all coatings are calcium phosphate, but the sample obtained at maximum bias and plasma source current and minimum pressure has the most intense peaks from the coating phase. SEM and EDS showed that all three coatings have a homogeneous and dense structure without cracks and consist of calcium, phosphorus and oxygen. Cytotoxic tests carried out on three types of samples with Ca-P coatings and a control group showed that the control sample and the sample with Ca-P coating obtained at maximum bias voltage and plasma source current and minimum pressure had the lowest number of dead cells on the surface, around 11 ± 4%. Two other types of samples with Ca-P coating have 40 ± 9% and 21 ± 7% dead cells on the surface. It can therefore be concluded that these two sputtering modes have a negative effect on the corrosion resistance of the whole samples. The third sputtering mode does not affect the corrosion resistance and has the same level of cytotoxicity as the control. It can be concluded that the most suitable sputtering mode is the third with maximum bias voltage and plasma source current and minimum pressure.Keywords: calcium phosphate coating, cytotoxicity, NiTi alloy, two-layer coating
Procedia PDF Downloads 672668 Bionaut™: A Breakthrough Robotic Microdevice to Treat Non-Communicating Hydrocephalus in Both Adult and Pediatric Patients
Authors: Suehyun Cho, Darrell Harrington, Florent Cros, Olin Palmer, John Caputo, Michael Kardosh, Eran Oren, William Loudon, Alex Kiselyov, Michael Shpigelmacher
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Bionaut Labs, LLC is developing a minimally invasive robotic microdevice designed to treat non-communicating hydrocephalus in both adult and pediatric patients. The device utilizes biocompatible microsurgical particles (Bionaut™) that are specifically designed to safely and reliably perform accurate fenestration(s) in the 3rd ventricle, aqueduct of Sylvius, and/or trapped intraventricular cysts of the brain in order to re-establish normal cerebrospinal fluid flow dynamics and thereby balance and/or normalize intra/intercompartmental pressure. The Bionaut™ is navigated to the target via CSF or brain tissue in a minimally invasive fashion with precise control using real-time imaging. Upon reaching the pre-defined anatomical target, the external driver allows for directing the specific microsurgical action defined to achieve the surgical goal. Notable features of the proposed protocol are i) Bionaut™ access to the intraventricular target follows a clinically validated endoscopy trajectory which may not be feasible via ‘traditional’ rigid endoscopy: ii) the treatment is microsurgical, there are no foreign materials left behind post-procedure; iii) Bionaut™ is an untethered device that is navigated through the subarachnoid and intraventricular compartments of the brain, following pre-designated non-linear trajectories as determined by the safest anatomical and physiological path; iv) Overall protocol involves minimally invasive delivery and post-operational retrieval of the surgical Bionaut™. The approach is expected to be suitable to treat pediatric patients 0-12 months old as well as adult patients with obstructive hydrocephalus who fail traditional shunts or are eligible for endoscopy. Current progress, including platform optimization, Bionaut™ control, and real-time imaging and in vivo safety studies of the Bionauts™ in large animals, specifically the spine and the brain of ovine models, will be discussed.Keywords: Bionaut™, cerebrospinal fluid, CSF, fenestration, hydrocephalus, micro-robot, microsurgery
Procedia PDF Downloads 1722667 Exo-III Assisted Amplification Strategy through Target Recycling of Hg²⁺ Detection in Water: A GNP Based Label-Free Colorimetry Employing T-Rich Hairpin-Loop Metallobase
Authors: Abdul Ghaffar Memon, Xiao Hong Zhou, Yunpeng Xing, Ruoyu Wang, Miao He
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Due to deleterious environmental and health effects of the Hg²⁺ ions, various online, detection methods apart from the traditional analytical tools have been developed by researchers. Biosensors especially, label, label-free, colorimetric and optical sensors have advanced with sensitive detection. However, there remains a gap of ultrasensitive quantification as noise interact significantly especially in the AuNP based label-free colorimetry. This study reported an amplification strategy using Exo-III enzyme for target recycling of Hg²⁺ ions in a T-rich hairpin loop metallobase label-free colorimetric nanosensor with an improved sensitivity using unmodified gold nanoparticles (uGNPs) as an indicator. The two T-rich metallobase hairpin loop structures as 5’- CTT TCA TAC ATA GAA AAT GTA TGT TTG -3 (HgS1), and 5’- GGC TTT GAG CGC TAA GAA A TA GCG CTC TTT G -3’ (HgS2) were tested in the study. The thermodynamic properties of HgS1 and HgS2 were calculated using online tools (http://biophysics.idtdna.com/cgi-bin/meltCalculator.cgi). The lab scale synthesized uGNPs were utilized in the analysis. The DNA sequence had T-rich bases on both tails end, which in the presence of Hg²⁺ forms a T-Hg²⁺-T mismatch, promoting the formation of dsDNA. Later, the Exo-III incubation enable the enzyme to cleave stepwise mononucleotides from the 3’ end until the structure become single-stranded. These ssDNA fragments then adsorb on the surface of AuNPs in their presence and protect AuNPs from the induced salt aggregation. The visible change in color from blue (aggregation stage in the absence of Hg²⁺) and pink (dispersion state in the presence of Hg²⁺ and adsorption of ssDNA fragments) can be observed and analyzed through UV spectrometry. An ultrasensitive quantitative nanosensor employing Exo-III assisted target recycling of mercury ions through label-free colorimetry with nanomolar detection using uGNPs have been achieved and is further under the optimization to achieve picomolar range by avoiding the influence of the environmental matrix. The proposed strategy will supplement in the direction of uGNP based ultrasensitive, rapid, onsite, label-free colorimetric detection.Keywords: colorimetric, Exo-III, gold nanoparticles, Hg²⁺ detection, label-free, signal amplification
Procedia PDF Downloads 3122666 Non-Linear Transformation of Bulk Acoustic Waves at Oblique Incidence on Plane Solid Boundary
Authors: Aleksandr I. Korobov, Natalia V. Shirgina, Aleksey I. Kokshaiskiy
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The transformation of two types of acoustic waves can occur on a flat interface between two solids at oblique incidence of longitudinal and shear bulk acoustic waves (BAW). This paper presents the results of experimental studies of the properties of reflection and propagation of longitudinal wave and generation of second and third longitudinal and shear harmonics of BAW at oblique incidence of longitudinal BAW on a flat rough boundary between two solids. The experimental sample was a rectangular isosceles pyramid made of D16 aluminum alloy with the plane parallel bases cylinder made of D16 aluminum alloy pressed to the base. The piezoelectric lithium niobate transducer with a resonance frequency of 5 MHz was secured to one face of the pyramid to generate a longitudinal wave. Longitudinal waves emitted by this transducer felt at an angle of 45° to the interface between two solids and reflected at the same angle. On the opposite face of the pyramid, and on the flat side of the cylinder was attached longitudinal transducer with resonance frequency of 10 MHz or the shear transducer with resonance frequency of 15 MHz. These transducers also effectively received signal at a frequency of 5 MHz. In the spectrum of the transmitted and reflected BAW was observed shear and longitudinal waves at a frequency of 5 MHz, as well as longitudinal harmonic at a frequency harmonic of 10 MHz and a shear harmonic at frequency of 15 MHz. The effect of reversing changing of external pressure applied to the rough interface between two solids on the value of the first and higher harmonics of the BAW at oblique incidence on the interface of the longitudinal BAW was experimentally investigated. In the spectrum of the reflected signal from the interface, there was a decrease of amplitudes of the first harmonics of the signal, and non-monotonic dependence of the second and third harmonics of shear wave with an increase of the static pressure applied to the interface. In the spectrum of the transmitted signal growth of the first longitudinal and shear harmonic amplitude and non-monotonic dependence - first increase and then decrease in the amplitude of the second and third longitudinal shear harmonic with increasing external static pressure was observed. These dependencies were hysteresis at reversing changing of external pressure. When pressure applied to the border increased, acoustic contact between the surfaces improves. This increases the energy of the transmitted elastic wave and decreases the energy of the reflected wave. The second longitudinal acoustic harmonics generation was associated with the Hertz nonlinearity on the interface of two pressed rough surfaces, the generation of the third harmonic was caused by shear hysteresis nonlinearity due to dry friction on a rough interface. This study was supported by the Russian Science Foundation (project №14-22-00042).Keywords: generation of acoustic harmonics, hysteresis nonlinearity, Hertz nonlinearity, transformation of acoustic waves
Procedia PDF Downloads 3782665 In Silico Analysis of Salivary miRNAs to Identify the Diagnostic Biomarkers for Oral Cancer
Authors: Andleeb Zahra, Itrat Rubab, Sumaira Malik, Amina Khan, Muhammad Jawad Khan, M. Qaiser Fatmi
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Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. Recent studies have highlighted the role of miRNA in disease pathology, indicating its potential use in an early diagnostic tool. miRNAs are small, double stranded, non-coding RNAs that regulate gene expression by deregulating mRNAs. miRNAs play important roles in modifying various cellular processes such as cell growth, differentiation, apoptosis, and immune response. Dis-regulated expression of miRNAs is known to affect the cell growth, and this may function as tumor suppressors or oncogenes in various cancers. Objectives: The main objectives of this study were to characterize the extracellular miRNAs involved in oral cancer (OC) to assist early detection of cancer as well as to propose a list of genes that can potentially be used as biomarkers of OC. We used gene expression data by microarrays already available in literature. Materials and Methods: In the first step, a total of 318 miRNAs involved in oral carcinoma were shortlisted followed by the prediction of their target genes. Simultaneously, the differentially expressed genes (DEGs) of oral carcinoma from all experiments were identified. The common genes between lists of DEGs of OC based on experimentally proven data and target genes of each miRNA were identified. These common genes are the targets of specific miRNA, which is involved in OC. Finally, a list of genes was generated which may be used as biomarker of OC. Results and Conclusion: In results, we included some of pathways in cancer to show the change in gene expression under the control of specific miRNA. Ingenuity pathway analysis (IPA) provided a list of major biomarkers like CDH2, CDK7 and functional enrichment analysis identified the role of miRNA in major pathways like cell adhesion molecules pathway affected by cancer. We observed that at least 25 genes are regulated by maximum number of miRNAs, and thereby, they can be used as biomarkers of OC. To better understand the role of miRNA with respect to their target genes further experiments are required, and our study provides a platform to better understand the miRNA-OC relationship at genomics level.Keywords: biomarkers, gene expression, miRNA, oral carcinoma
Procedia PDF Downloads 3762664 Design, Simulation and Fabrication of Electro-Magnetic Pulse Welding Coil and Initial Experimentation
Authors: Bharatkumar Doshi
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Electro-Magnetic Pulse Welding (EMPW) is a solid state welding process carried out at almost room temperature, in which joining is enabled by high impact velocity deformation. In this process, high voltage capacitor’s stored energy is discharged in an EM coil resulting in a damped, sinusoidal current with an amplitude of several hundred kiloamperes. Due to these transient magnetic fields of few tens of Tesla near the coil is generated. As the conductive (tube) part is positioned in this area, an opposing eddy current is induced in this part. Consequently, high Lorentz forces act on the part, leading to acceleration away from the coil. In case of a tube, it gets compressed under forming velocities of more than 300 meters per second. After passing the joining gap it collides with the second metallic joining rod, leading to the formation of a jet under appropriate collision conditions. Due to the prevailing high pressure, metallurgical bonding takes place. A characteristic feature is the wavy interface resulting from the heavy plastic deformations. In the process, the formation of intermetallic compounds which might deteriorate the weld strength can be avoided, even for metals with dissimilar thermal properties. In order to optimize the process parameters like current, voltage, inductance, coil dimensions, workpiece dimensions, air gap, impact velocity, effective plastic strain, shear stress acting in the welding zone/impact zone etc. are very critical and important to establish. These process parameters could be determined by simulation using Finite Element Methods (FEM) in which electromagnetic –structural couple field analysis is performed. The feasibility of welding could thus be investigated by varying the parameters in the simulation using COMSOL. Simulation results shall be applied in performing the preliminary experiments of welding the different alloy steel tubes and/or alloy steel to other materials. The single turn coil (S.S.304) with field shaper (copper) has been designed and manufactured. The preliminary experiments are performed using existing EMPW facility available Institute for Plasma Research, Gandhinagar, India. The experiments are performed at 22kV charged into 64µF capacitor bank and the energy is discharged into single turn EM coil. Welding of axi-symetric components such as aluminum tube and rod has been proven experimentally using EMPW techniques. In this paper EM coil design, manufacturing, Electromagnetic-structural FEM simulation of Magnetic Pulse Welding and preliminary experiment results is reported.Keywords: COMSOL, EMPW, FEM, Lorentz force
Procedia PDF Downloads 1852663 Audio-Visual Co-Data Processing Pipeline
Authors: Rita Chattopadhyay, Vivek Anand Thoutam
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Speech is the most acceptable means of communication where we can quickly exchange our feelings and thoughts. Quite often, people can communicate orally but cannot interact or work with computers or devices. It’s easy and quick to give speech commands than typing commands to computers. In the same way, it’s easy listening to audio played from a device than extract output from computers or devices. Especially with Robotics being an emerging market with applications in warehouses, the hospitality industry, consumer electronics, assistive technology, etc., speech-based human-machine interaction is emerging as a lucrative feature for robot manufacturers. Considering this factor, the objective of this paper is to design the “Audio-Visual Co-Data Processing Pipeline.” This pipeline is an integrated version of Automatic speech recognition, a Natural language model for text understanding, object detection, and text-to-speech modules. There are many Deep Learning models for each type of the modules mentioned above, but OpenVINO Model Zoo models are used because the OpenVINO toolkit covers both computer vision and non-computer vision workloads across Intel hardware and maximizes performance, and accelerates application development. A speech command is given as input that has information about target objects to be detected and start and end times to extract the required interval from the video. Speech is converted to text using the Automatic speech recognition QuartzNet model. The summary is extracted from text using a natural language model Generative Pre-Trained Transformer-3 (GPT-3). Based on the summary, essential frames from the video are extracted, and the You Only Look Once (YOLO) object detection model detects You Only Look Once (YOLO) objects on these extracted frames. Frame numbers that have target objects (specified objects in the speech command) are saved as text. Finally, this text (frame numbers) is converted to speech using text to speech model and will be played from the device. This project is developed for 80 You Only Look Once (YOLO) labels, and the user can extract frames based on only one or two target labels. This pipeline can be extended for more than two target labels easily by making appropriate changes in the object detection module. This project is developed for four different speech command formats by including sample examples in the prompt used by Generative Pre-Trained Transformer-3 (GPT-3) model. Based on user preference, one can come up with a new speech command format by including some examples of the respective format in the prompt used by the Generative Pre-Trained Transformer-3 (GPT-3) model. This pipeline can be used in many projects like human-machine interface, human-robot interaction, and surveillance through speech commands. All object detection projects can be upgraded using this pipeline so that one can give speech commands and output is played from the device.Keywords: OpenVINO, automatic speech recognition, natural language processing, object detection, text to speech
Procedia PDF Downloads 802662 High Motivational Salient Face Distractors Slowed Target Detection: Evidence from Behavioral Studies
Authors: Rashmi Gupta
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Rewarding stimuli capture attention involuntarily as a result of an association process that develops quickly during value learning, referred to as the reward or value-driven attentional capture. It is essential to compare reward with punishment processing to get a full picture of value-based modulation in visual attention processing. Hence, the present study manipulated both valence/value (reward as well as punishment) and motivational salience (probability of an outcome: high vs. low) together. Series of experiments were conducted, and there were two phases in each experiment. In phase 1, participants were required to learn to associate specific face stimuli with a high or low probability of winning or losing points. In the second phase, these conditioned stimuli then served as a distractor or prime in a speeded letter search task. Faces with high versus low outcome probability, regardless of valence, slowed the search for targets (specifically the left visual field target) and suggesting that the costs to performance on non-emotional cognitive tasks were only driven by motivational salience (high vs. loss) associated with the stimuli rather than the valence (gain vs. loss). It also suggests that the processing of motivationally salient stimuli is right-hemisphere biased. Together, results of these studies strengthen the notion that our visual attention system is more sensitive to affected by motivational saliency rather than valence, which termed here as motivational-driven attentional capture.Keywords: attention, distractors, motivational salience, valence
Procedia PDF Downloads 2212661 Quantifying the Protein-Protein Interaction between the Ion-Channel-Forming Colicin A and the Tol Proteins by Potassium Efflux in E. coli Cells
Authors: Fadilah Aleanizy
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Colicins are a family of bacterial toxins that kill Escherichia coli and other closely related species. The mode of action of colicins involves binding to an outer membrane receptor and translocation across the cell envelope, leading to cytotoxicity through specific targets. The mechanism of colicin cytotoxicity includes a non-specific endonuclease activity or depolarization of the cytoplasmic membrane by pore-forming activity. For Group A colicins, translocation requires an interaction between the N-terminal domain of the colicin and a series of membrane- bound and periplasmic proteins known as the Tol system (TolB, TolR, TolA, TolQ, and Pal and the active domain must be translocated through the outer membranes. Protein-protein interactions are intrinsic to virtually every cellular process. The transient protein-protein interactions of the colicin include the interaction with much more complicated assemblies during colicin translocation across the cellular membrane to its target. The potassium release assay detects variation in the K+ content of bacterial cells (K+in). This assays is used to measure the effect of pore-forming colicins such as ColA on an indicator organism by measuring the changes of the K+ concentration in the external medium (K+out ) that are caused by cell killing with a K+ selective electrode. One of the goals of this work is to employ a quantifiable in-vivo method to spot which Tol protein are more implicated in the interaction with colicin A as it is translocated to its target.Keywords: K+ efflux, Colicin A, Tol-proteins, E. coli
Procedia PDF Downloads 4102660 Electrochemical Study of Copper–Tin Alloy Nucleation Mechanisms onto Different Substrates
Authors: Meriem Hamla, Mohamed Benaicha, Sabrine Derbal
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In the present work, several materials such as M/glass (M = Pt, Mo) were investigated to test their suitability for studying the early nucleation stages and growth of copper-tin clusters. It was found that most of these materials stand as good substrates to be used in the study of the nucleation and growth of electrodeposited Cu-Sn alloys from aqueous solution containing CuCl2, SnCl2 as electroactive species and Na3C6H5O7 as complexing agent. Among these substrates, Pt shows instantaneous models followed by 3D diffusion-limited growth. On the other hand, the electrodeposited copper-tin thin films onto Mo substrate followed progressive nucleation. The deposition mechanism of the Cu-Sn films has been studied using stationary electrochemical techniques (cyclic voltammetery (CV) and chronoamperometry (CA). The structural, morphological and compositional of characterization have been studied using X-ray diffraction (XRD), scanning electron microscopy (SEM) and EDAX techniques respectively.Keywords: electrodeposition, CuSn, nucleation, mechanism
Procedia PDF Downloads 3982659 Microstructure and SEM Analysis of Joints Fabricated by FSW of Aluminum Alloys 5083 and 6063
Authors: Jaskirat Singh, Roshan Lal Virdi, Khushdeep Goyal
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The purpose of this paper is to perform a microstructural analysis of Friction Stir Welded joints of aluminum alloys 6063 and 5083, also to check the properties of the weld zone by SEM analysis. FSW experiments were carried on CNC Vertical milling machine. The tools used for welding were the round cylindrical pin shape and square pin shape. It is found that Microstructure shows the uniformly distributed material with minimum heat affected zone and dense welded zone without any defect. Microstructures indicate that the weld material is defect free. The SEM shows the diffusion of material with base metal with proper bonding without any defect.Keywords: friction stir welding, aluminum alloy, microstructure, SEM analysis
Procedia PDF Downloads 3082658 Electro-Winning of Dilute Solution of Copper Metal from Sepon Mine, Lao PDR
Authors: S. Vasailor, C. Rattanakawin
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Electro-winning of copper metal from dilute sulfate solution (13.7 g/L) was performed in a lab electrolytic cell with stainless-steel cathode and lead-alloy anode. The effects of various parameters including cell voltage, electro-winning temperature and time were studied in order to acquire an appropriate current efficiency of copper deposition. The highest efficiency is about 95% obtaining from electro-winning condition of 3V, 55°C and 3,600 s correspondingly. The cathode copper with 95.5% Cu analyzed using atomic absorption spectrometry can be obtained from this single-winning condition. In order to increase the copper grade, solvent extraction should be used to increase the sulfate concentration, say 50 g/L, prior to winning the cathode copper effectively.Keywords: copper metal, current efficiency, dilute sulfate solution, electro-winning
Procedia PDF Downloads 1382657 The Processing of Context-Dependent and Context-Independent Scalar Implicatures
Authors: Liu Jia’nan
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The default accounts hold the view that there exists a kind of scalar implicature which can be processed without context and own a psychological privilege over other scalar implicatures which depend on context. In contrast, the Relevance Theorist regards context as a must because all the scalar implicatures have to meet the need of relevance in discourse. However, in Katsos, the experimental results showed: Although quantitatively the adults rejected under-informative utterance with lexical scales (context-independent) and the ad hoc scales (context-dependent) at almost the same rate, adults still regarded the violation of utterance with lexical scales much more severe than with ad hoc scales. Neither default account nor Relevance Theory can fully explain this result. Thus, there are two questionable points to this result: (1) Is it possible that the strange discrepancy is due to other factors instead of the generation of scalar implicature? (2) Are the ad hoc scales truly formed under the possible influence from mental context? Do the participants generate scalar implicatures with ad hoc scales instead of just comparing semantic difference among target objects in the under- informative utterance? In my Experiment 1, the question (1) will be answered by repetition of Experiment 1 by Katsos. Test materials will be showed by PowerPoint in the form of pictures, and each procedure will be done under the guidance of a tester in a quiet room. Our Experiment 2 is intended to answer question (2). The test material of picture will be transformed into the literal words in DMDX and the target sentence will be showed word-by-word to participants in the soundproof room in our lab. Reading time of target parts, i.e. words containing scalar implicatures, will be recorded. We presume that in the group with lexical scale, standardized pragmatically mental context would help generate scalar implicature once the scalar word occurs, which will make the participants hope the upcoming words to be informative. Thus if the new input after scalar word is under-informative, more time will be cost for the extra semantic processing. However, in the group with ad hoc scale, scalar implicature may hardly be generated without the support from fixed mental context of scale. Thus, whether the new input is informative or not does not matter at all, and the reading time of target parts will be the same in informative and under-informative utterances. People’s mind may be a dynamic system, in which lots of factors would co-occur. If Katsos’ experimental result is reliable, will it shed light on the interplay of default accounts and context factors in scalar implicature processing? We might be able to assume, based on our experiments, that one single dominant processing paradigm may not be plausible. Furthermore, in the processing of scalar implicature, the semantic interpretation and the pragmatic interpretation may be made in a dynamic interplay in the mind. As to the lexical scale, the pragmatic reading may prevail over the semantic reading because of its greater exposure in daily language use, which may also lead the possible default or standardized paradigm override the role of context. However, those objects in ad hoc scale are not usually treated as scalar membership in mental context, and thus lexical-semantic association of the objects may prevent their pragmatic reading from generating scalar implicature. Only when the sufficient contextual factors are highlighted, can the pragmatic reading get privilege and generate scalar implicature.Keywords: scalar implicature, ad hoc scale, dynamic interplay, default account, Mandarin Chinese processing
Procedia PDF Downloads 3242656 Readability Facing the Irreducible Otherness: Translation as a Third Dimension toward a Multilingual Higher Education
Authors: Noury Bakrim
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From the point of view of language morphodynamics, interpretative Readability of the text-result (the stasis) is not the external hermeneutics of its various potential reading events but the paradigmatic, semantic immanence of its dynamics. In other words, interpretative Readability articulates the potential tension between projection (intentionality of the discursive event) and the result (Readability within the syntagmatic stasis). We then consider that translation represents much more a metalinguistic conversion of neurocognitive bilingual sub-routines and modular relations than a semantic equivalence. Furthermore, the actualizing Readability (the process of rewriting a target text within a target language/genre) builds upon the descriptive level between the generative syntax/semantic from and its paradigmatic potential translatability. Translation corpora reveal the evidence of a certain focusing on the positivist stasis of the source text at the expense of its interpretative Readability. For instance, Fluchere's brilliant translation of Miller's Tropic of cancer into French realizes unconsciously an inversion of the hierarchical relations between Life Thought and Fable: From Life Thought (fable) into Fable (Life Thought). We could regard the translation of Bernard Kreiss basing on Canetti's work die englischen Jahre (les annees anglaises) as another inversion of the historical scale from individual history into Hegelian history. In order to describe and test both translation process and result, we focus on the pedagogical practice which enables various principles grounding in interpretative/actualizing Readability. Henceforth, establishing the analytical uttering dynamics of the source text could be widened by other practices. The reversibility test (target - source text) or the comparison with a second translation in a third language (tertium comparationis A/B and A/C) point out the evidence of an impossible event. Therefore, it doesn't imply an uttering idealistic/absolute source but the irreducible/non-reproducible intentionality of its production event within the experience of world/discourse. The aim of this paper is to conceptualize translation as the tension between interpretative and actualizing Readability in a new approach grounding in morphodynamics of language and Translatability (mainly into French) within literary and non-literary texts articulating theoretical and described pedagogical corpora.Keywords: readability, translation as deverbalization, translation as conversion, Tertium Comparationis, uttering actualization, translation pedagogy
Procedia PDF Downloads 1662655 Using Authentic and Instructional Materials to Support Intercultural Communicative Competence in ELT
Authors: Jana Beresova
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The paper presents a study carried out in 2015-2016 within the national scheme of research - VEGA 1/0106/15 based on theoretical research and empirical verification of the concept of intercultural communicative competence. It focuses on the current conception concerning target languages teaching compatible with the Common European Framework of Reference for Languages: Learning, teaching, assessment. Our research had revealed how the concept of intercultural communicative competence had been perceived by secondary-school teachers of English in Slovakia before they were intensively trained. Intensive workshops were based on the use of both authentic and instructional materials with the goal to support interculturally oriented language teaching aimed at challenging thinking. The former concept that supported the development of the students´ linguistic knowledge and the use of a target language to obtain information about the culture of the country whose language learners were learning was expanded by the meaning-making framework which views language as a typical means by which culture is mediated. The goal of the workshop was to influence English teachers to better understand the concept of intercultural communicative competence, combining theory and practice optimally. The results of the study will be presented and analysed, providing particular recommendations for language teachers and suggesting some changes in the National Educational Programme from which English learners should benefit in their future studies or professional careers.Keywords: authentic materials, English language teaching, instructional materials, intercultural communicative competence
Procedia PDF Downloads 2712654 Triple Modulation on Wound Healing in Glaucoma Surgery Using Mitomycin C and Ologen Augmented with Anti-Vascular Endothelial Growth Factor
Authors: Reetika Sharma, Lalit Tejwani, Himanshu Shekhar, Arun Singhvi
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Purpose: To describe a novel technique of trabeculectomy targeting triple modulation on wound healing to increase the overall success rate. Method: Ten eyes of 10 patients underwent trabeculectomy with subconjunctival mitomycin C (0.4mg/ml for 4 minutes) application combined with Ologen implantation subconjunctivally and subsclerally. Five of these patients underwent additional phacoemulsification with intraocular lens implantation. The Ologen implant was wet with 0.1 ml Bevacizumab. Result: All the eyes achieved target intraocular pressure (IOP), which was maintained until one year of follow-up. Two patients needed anterior chamber reformation at day two post surgery. One patient needed cataract surgery after four months of surgery and achieved target intraocular pressure on two topical antiglaucoma medicines. Conclusion: Vascular endothelial growth factor (VEGF) concentration has been seen to increase in the aqueous humor after filtration surgery. Ologen implantation helps in collagen remodelling, antifibroblastic response, and acts as a spacer. Bevacizumab augmented Ologen, in addition, targets the increased VEGF and helps in decreasing scarring. Anti-VEGF augmented Ologen in trabeculectomy with mitomycin C (MMC) hence appears to have encouraging short-term intraocular pressure control.Keywords: ologen, anti-VEGF, trabeculectomy, scarring
Procedia PDF Downloads 1892653 Effect of Copper Addition at a Rate of 4% Weight on the Microstructure, Mechanical Characteristics, and Surface Roughness on the Hot Extrusion of Aluminum
Authors: S. M. A. Al Qawabah, A. I. O. Zaid
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Al-4%Cu alloys are now widely used in many engineering applications especially in robotic, aerospace and vibration control area. The main problem arises from the weakness of their mechanical characteristics. Therefore, this study is directed towards enhancing the mechanical properties through severe plastic deformation. In this work, the hot direct extrusion process was chosen to provide the required hot work for this purpose. A direct extrusion die was designed and manufactured to be used in this investigation. The general microstructure, microhardness, surface roughness, and compression tests were performed on specimens from the produced Al-4%Cu alloy both in the as cast and after extrusion conditions. It was found that a pronounced enhancement in the mechanical characteristics of the produced Al-4%Cu after extrusion was achieved. The microhardness increased by 89.3%, the flow stress was decreased by 10% at 0.2 strain and finally the surface roughness was reduced by 81.6%.Keywords: aluminum, copper, surface roughness, hot extrusion
Procedia PDF Downloads 5712652 A pH-Activatable Nanoparticle Self-Assembly Triggered by 7-Amino Actinomycin D Demonstrating Superior Tumor Fluorescence Imaging and Anticancer Performance
Authors: Han Xiao
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The development of nanomedicines has recently achieved several breakthroughs in the field of cancer treatment; however, the biocompatibility and targeted burst release of these medications remain a limitation, which leads to serious side effects and significantly narrows the scope of their applications. The self-assembly of intermediate filament protein (IFP) peptides was triggered by a hydrophobic cation drug 7-amino actinomycin D (7-AAD) to synthesize pH-activatable nanoparticles (NPs) that could simultaneously locate tumors and produce antitumor effects. The designed IFP peptide included a target peptide (arginine–glycine–aspartate), a negatively charged region, and an α-helix sequence. It also possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step method. 7-AAD molecules with excellent near-infrared fluorescence properties could be target delivered into tumor cells by NPs and released immediately in the acidic environments of tumors and endosome/lysosomes, ultimately inducing cytotoxicity by arresting the tumor cell cycle with inserted DNA. It is noteworthy that the IFP/7-AAD NPs tail vein injection approach demonstrated not only high tumor-targeted imaging potential, but also strong antitumor therapeutic effects in vivo. The proposed strategy may be used in the delivery of cationic antitumor drugs for precise imaging and cancer therapy.Keywords: 7-amino actinomycin D, intermediate filament protein, nanoparticle, tumor image
Procedia PDF Downloads 1382651 A Large Language Model-Driven Method for Automated Building Energy Model Generation
Authors: Yake Zhang, Peng Xu
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The development of building energy models (BEM) required for architectural design and analysis is a time-consuming and complex process, demanding a deep understanding and proficient use of simulation software. To streamline the generation of complex building energy models, this study proposes an automated method for generating building energy models using a large language model and the BEM library aimed at improving the efficiency of model generation. This method leverages a large language model to parse user-specified requirements for target building models, extracting key features such as building location, window-to-wall ratio, and thermal performance of the building envelope. The BEM library is utilized to retrieve energy models that match the target building’s characteristics, serving as reference information for the large language model to enhance the accuracy and relevance of the generated model, allowing for the creation of a building energy model that adapts to the user’s modeling requirements. This study enables the automatic creation of building energy models based on natural language inputs, reducing the professional expertise required for model development while significantly decreasing the time and complexity of manual configuration. In summary, this study provides an efficient and intelligent solution for building energy analysis and simulation, demonstrating the potential of a large language model in the field of building simulation and performance modeling.Keywords: artificial intelligence, building energy modelling, building simulation, large language model
Procedia PDF Downloads 282650 Life Stage Customer Segmentation by Fine-Tuning Large Language Models
Authors: Nikita Katyal, Shaurya Uppal
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This paper tackles the significant challenge of accurately classifying customers within a retailer’s customer base. Accurate classification is essential for developing targeted marketing strategies that effectively engage this important demographic. To address this issue, we propose a method that utilizes Large Language Models (LLMs). By employing LLMs, we analyze the metadata associated with product purchases derived from historical data to identify key product categories that act as distinguishing factors. These categories, such as baby food, eldercare products, or family-sized packages, offer valuable insights into the likely household composition of customers, including families with babies, families with kids/teenagers, families with pets, households caring for elders, or mixed households. We segment high-confidence customers into distinct categories by integrating historical purchase behavior with LLM-powered product classification. This paper asserts that life stage segmentation can significantly enhance e-commerce businesses’ ability to target the appropriate customers with tailored products and campaigns, thereby augmenting sales and improving customer retention. Additionally, the paper details the data sources, model architecture, and evaluation metrics employed for the segmentation task.Keywords: LLMs, segmentation, product tags, fine-tuning, target segments, marketing communication
Procedia PDF Downloads 272649 A Computational Investigation of Potential Drugs for Cholesterol Regulation to Treat Alzheimer’s Disease
Authors: Marina Passero, Tianhua Zhai, Zuyi (Jacky) Huang
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Alzheimer’s disease has become a major public health issue, as indicated by the increasing populations of Americans living with Alzheimer’s disease. After decades of extensive research in Alzheimer’s disease, only seven drugs have been approved by Food and Drug Administration (FDA) to treat Alzheimer’s disease. Five of these drugs were designed to treat the dementia symptoms, and only two drugs (i.e., Aducanumab and Lecanemab) target the progression of Alzheimer’s disease, especially the accumulation of amyloid-b plaques. However, controversial comments were raised for the accelerated approvals of either Aducanumab or Lecanemab, especially with concerns on safety and side effects of these two drugs. There is still an urgent need for further drug discovery to target the biological processes involved in the progression of Alzheimer’s disease. Excessive cholesterol has been found to accumulate in the brain of those with Alzheimer’s disease. Cholesterol can be synthesized in both the blood and the brain, but the majority of biosynthesis in the adult brain takes place in astrocytes and is then transported to the neurons via ApoE. The blood brain barrier separates cholesterol metabolism in the brain from the rest of the body. Various proteins contribute to the metabolism of cholesterol in the brain, which offer potential targets for Alzheimer’s treatment. In the astrocytes, SREBP cleavage-activating protein (SCAP) binds to Sterol Regulatory Element-binding Protein 2 (SREBP2) in order to transport the complex from the endoplasmic reticulum to the Golgi apparatus. Cholesterol is secreted out of the astrocytes by ATP-Binding Cassette A1 (ABCA1) transporter. Lipoprotein receptors such as triggering receptor expressed on myeloid cells 2 (TREM2) internalize cholesterol into the microglia, while lipoprotein receptors such as Low-density lipoprotein receptor-related protein 1 (LRP1) internalize cholesterol into the neuron. Cytochrome P450 Family 46 Subfamily A Member 1 (CYP46A1) converts excess cholesterol to 24S-hydroxycholesterol (24S-OHC). Cholesterol has been approved for its direct effect on the production of amyloid-beta and tau proteins. The addition of cholesterol to the brain promotes the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), secretase, and amyloid precursor protein (APP), which all aid in amyloid-beta production. The reduction of cholesterol esters in the brain have been found to reduce phosphorylated tau levels in mice. In this work, a computational pipeline was developed to identify the protein targets involved in cholesterol regulation in brain and further to identify chemical compounds as the inhibitors of a selected protein target. Since extensive evidence shows the strong correlation between brain cholesterol regulation and Alzheimer’s disease, a detailed literature review on genes or pathways related to the brain cholesterol synthesis and regulation was first conducted in this work. An interaction network was then built for those genes so that the top gene targets were identified. The involvement of these genes in Alzheimer’s disease progression was discussed, which was followed by the investigation of existing clinical trials for those targets. A ligand-protein docking program was finally developed to screen 1.5 million chemical compounds for the selected protein target. A machine learning program was developed to evaluate and predict the binding interaction between chemical compounds and the protein target. The results from this work pave the way for further drug discovery to regulate brain cholesterol to combat Alzheimer’s disease.Keywords: Alzheimer’s disease, drug discovery, ligand-protein docking, gene-network analysis, cholesterol regulation
Procedia PDF Downloads 762648 The Molecule Preserve Environment: Effects of Inhibitor of the Angiotensin Converting Enzyme on Reproductive Potential and Composition Contents of the Mediterranean Flour Moth, Ephestia kuehniella Zeller
Authors: Yezli-Touiker Samira, Amrani-Kirane Leila, Soltani Mazouni Nadia
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Due to secondary effects of conventional insecticides on the environment, the agrochemical research has resulted in the discovery of novel molecules. That research work will help in the development of a new group of pesticides that may be cheaper and less hazardous to the environment and non-target organisms which is the main desired outcome of the present work. Angiotensin-converting enzyme as a target for the development of novel insect growth regulators. Captopril is an inhibitor of angiotensin converting enzyme (ACE) it was tested in vivo by topical application on reproduction of Ephestia kuehniella Zeller (Lepidoptera: Pyralidae). The compound is diluted in acetone and applied topically to newly emerged pupae (10µg/ 2µl). The effects of this molecule was studied,on the biochemistry of ovary (on amounts nucleic acid, proteins, the qualitative analysis of the ovarian proteins and the reproductive potential (duration of the pre-oviposition, duration of the oviposition, number of eggs laid and hatching percentage). Captopril reduces significantly quantity of ovarian proteins and nucleic acid. The electrophoresis profile reveals the absence of tree bands at the treated series. This molecule reduced the duration of the oviposition period, the fecundity and the eggviability.Keywords: environment, ephestia kuehniella, captopril, reproduction, the agrochemical research
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