Search results for: beta cells
1143 A Comparative Study of the Maximum Power Point Tracking Methods for PV Systems Using Boost Converter
Authors: M. Doumi, A. Miloudi, A.G. Aissaoui, K. Tahir, C. Belfedal, S. Tahir
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The studies on the photovoltaic system are extensively increasing because of a large, secure, essentially exhaustible and broadly available resource as a future energy supply. However, the output power induced in the photovoltaic modules is influenced by an intensity of solar cell radiation, temperature of the solar cells and so on. Therefore, to maximize the efficiency of the photovoltaic system, it is necessary to track the maximum power point of the PV array, for this Maximum Power Point Tracking (MPPT) technique is used. These algorithms are based on the Perturb-Observe, Conductance-Increment and the Fuzzy Logic methods. These techniques vary in many aspects as: simplicity, convergence speed, digital or analogical implementation, sensors required, cost, range of effectiveness, and in other aspects. This paper presents a comparative study of three widely-adopted MPPT algorithms; their performance is evaluated on the energy point of view, by using the simulation tool Simulink®, considering different solar irradiance variations. MPPT using fuzzy logic shows superior performance and more reliable control to the other methods for this application.Keywords: photovoltaic system, MPPT, perturb and observe (P&O), incremental conductance (INC), Fuzzy Logic (FLC)
Procedia PDF Downloads 4111142 Passive Heat Exchanger for Proton Exchange Membrane Fuel Cell Cooling
Authors: Ivan Tolj
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Water produced during electrochemical reaction in Proton Exchange Membrane (PEM) fuel cell can be used for internal humidification of reactant gases; hydrogen and air. On such a way it is possible to eliminate expensive external humidifiers and simplify fuel cell balance-of-plant (BoP). When fuel cell operates at constant temperature (usually between 60 °C and 80 °C) relatively cold and dry ambient air heats up quickly upon entering channels which cause further drop in relative humidity (below 20%). Low relative humidity of reactant gases dries up polymer membrane and decrease its proton conductivity which results in fuel cell performance drop. It is possible to maintain such temperature profile throughout fuel cell cathode channel which will result in close to 100 % RH. In order to achieve this, passive heat exchanger was designed using commercial CFD software (ANSYS Fluent). Such passive heat exchanger (with variable surface area) is suitable for small scale PEM fuel cells. In this study, passive heat exchanger for single PEM fuel cell segment (with 20 x 1 cm active area) was developed. Results show close to 100 % RH of air throughout cathode channel with increased fuel cell performance (mainly improved polarization curve) and improved durability.Keywords: PEM fuel cell, passive heat exchange, relative humidity, thermal management
Procedia PDF Downloads 2771141 Autophagy Suppresses Tumorigenesis through Upregulation of MiR-449a in Colorectal Cancer
Authors: Sheng-Hui Lan, Shan-Ying Wu, Shu-Ching Lin, Wei-Chen Wang, Hsiao-Sheng Liu
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Autophagy is an essential mechanism to maintain cellular homeostasis through its degradation function, and the autophagy deficiency is related various diseases including tumorigenesis in several cancers. MicroRNAs (miRNAs) are small none coding RNAs, which regulate gene expression through degradation of mRNA or inhibition of translation. However, the relationship between autophagy deficiency and dysregulated miRNAs is still unclear. We revealed a mechanism that autophagy up-regulates miR-449a expression at the transcriptional level through activation of forkhead transcription factor family member FoxO1 and then suppresses tumorigenesis in CRC. Our data showed that the autophagic activity and miR-449a expression were lower in colorectal cancer (CRC) and has a positive correlation. We further reveal that autophagy degrades p300 expression and then suppresses acetylation of FoxO1. Under autophagic induction conditions, FoxO1 is transported from the cytoplasm to the nucleus and binds to the miR-449a promoter and then promotes miR-449a expression. In addition, either miR-449a overexpression or amiodarone-induced autophagy inhibits cell cycle progression, proliferation, colony formation migration, invasion, and tumor formation of SW480 cells. Our findings indicate that autophagy inducers may have the potential to be used for prevention and treatment of CRC through upregulation of miR-449a expression.Keywords: autophagy, MiR-449a, FoxO1, colorectal cancer
Procedia PDF Downloads 3201140 Eradication of Gram-Positive Bacteria by Photosensitizers Immobilized in Polymers
Authors: Marina Nisnevitch, Anton Valkov, Faina Nakonechny, Kate Adar Raik, Yamit Mualem
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Photosensitizers are dye compounds belonging to various chemical groups that in all the cases have a developed structure of conjugated double bonds. Under illumination with visible light, the photosensitizers are excited and transfer the absorbed energy to the oxygen dissolved in an aqueous phase, leading to production of a reactive oxygen species which cause irreversible damage to bacterial cells. When immobilized onto a solid phase, photosensitizers preserve their antibacterial properties. In the present study, photosensitizers were immobilized in polyethylene or propylene and tested for antimicrobial activity against Gram-positive S. aureus, S. epidermidis and Streptococcus sp. For this purpose, water-soluble photosensitizers, Rose Bengal sodium salt, and methylene blue as well as water-insoluble hematoporphyrin and Rose Bengal lactone, were immobilized by dissolution in melted polymers to yield 3 mm diameter rods and 3-5 mm beads. All four photosensitizers were found to be effective in the eradication of Gram-positive bacteria under illumination by a white luminescent lamp or sunlight. The immobilized photosensitizers can be applied for continuous water disinfection; they can be easily removed at the end of the treatment and reused.Keywords: antimicrobial polymers, gram-positive bacteria, immobilization of photosensitizers, photodynamic antibacterial activity
Procedia PDF Downloads 2421139 Inflammatory Cytokine (Interleukin-8): A Diagnostic Marker in Leukemia
Authors: Sandeep Pandey, Nimra Habib, Ranjana Singh, Abbas Ali Mahdi
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Leukemia is a malignancy of blood that mainly affects children and young adults; while advancement in the early diagnosis will have the potential to improve the outcome of diseases. A wide range of disease including leukemia shows inflammatory signals in their pathogenesis. In a pilot study conducted in our laboratory, 52 people were screened, of which 26 had leukemia and 26 were free from any kind of malignancy. We performed the estimation of the inflammatory cytokine Interleukin-8 and it was found significantly raised in all the leukemia patients concerning healthy volunteers who participated in the study. Flow cytometry had been performed for the confirmation of leukemia and further genomic, and proteomic, analyses of the sample revealed that IL-8 levels showed a positive correlation in patients with leukemia. The results had shown constitutive secretion of interleukin-8 by leukemia cells. So, our finding demonstrated that IL-8 is considered to have a role in the pathogenesis of leukemia, and quantification of IL-8 levels in leukemia conditions might be more useful and feasible in the clinical setting for the prediction of drug responses where it may represent a putative target for innovative diagnostic toward effective therapeutic approaches. However, further research explorations in this area are needed that include a greater number of patients with all different forms of leukemia, and estimating their IL-8 levels may hold the key for the additional predictive values on the recurrence of leukemia and its prognosis.Keywords: T-ALL, IL-8, leukemia pathogenesis, cancer therapeutics
Procedia PDF Downloads 721138 Optimization of Operational Parameters and Design of an Electrochlorination System to Produce Naclo
Authors: Pablo Ignacio Hernández Arango, Niels Lindemeyer
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Chlorine, as Sodium Hypochlorite (NaClO) solution in water, is an effective, worldwide spread, and economical substance to eliminate germs in the water. The disinfection potential of chlorine lies in its ability to degrade the outer surfaces of bacterial cells and viruses. This contribution reports the main parameters of the brine electrolysis for the production of NaClO, which is afterward used for the disinfection of water either for drinking or recreative uses. Herein, the system design was simulated, optimized, build, and tested based on titanium electrodes. The process optimization considers the whole process, from the salt (NaCl) dilution tank in order to maximize its operation time util the electrolysis itself in order to maximize the chlorine production reducing the energy and raw material (salt and water) consumption. One novel idea behind this optimization process is the modification of the flow pattern inside the electrochemical reactors. The increasing turbulence and residence time impact positively the operations figures. The operational parameters, which are defined in this study were compared and benchmarked with the parameters of actual commercial systems in order to validate the pertinency of those results.Keywords: electrolysis, water disinfection, sodium hypochlorite, process optimization
Procedia PDF Downloads 1281137 The Mitigation of Quercetin on Lead-Induced Neuroinflammation in a Rat Model: Changes in Neuroinflammatory Markers and Memory
Authors: Iliyasu Musa Omoyine, Musa Sunday Abraham, Oladele Sunday Blessing, Iliya Ibrahim Abdullahi, Ibegbu Augustine Oseloka, Nuhu Nana-Hawau, Animoku Abdulrazaq Amoto, Yusuf Abdullateef Onoruoiza, Sambo Sohnap James, Akpulu Steven Peter, Ajayi Abayomi
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The neuroprotective role of inflammation from detrimental intrinsic and extrinsic factors has been reported. However, the overactivation of astrocytes and microglia due to lead toxicity produce excessive pro-inflammatory cytokines, mediating neurodegenerative diseases. The present study investigated the mitigatory effects of quercetin on neuroinflammation, correlating with memory function in lead-exposed rats. In this study, Wistar rats were administered orally with Quercetin (Q: 60 mg/kg) and Succimer as a standard drug (S: 10 mg/kg) for 21 days after lead exposure (Pb: 125 mg/kg) of 21 days or in combination with Pb, once daily for 42 days. Working and reference memory was assessed using an Eight-arm radial water maze (8-ARWM). The changes in brain lead level, the neuronal nitric oxide synthase (nNOS) activity, and the level of neuroinflammatory markers such as tumour necrosis factor-alpha (TNF-α) and Interleukin 1 Beta (IL-1β) were determined. Immunohistochemically, astrocyte expression was evaluated. The results showed that the brain level of lead was increased significantly in lead-exposed rats. The expression of astrocytes increased in the CA3 and CA1 regions of the hippocampus, and the levels of brain TNF-α and IL-1β increased in lead-exposed rats. Lead impaired reference and working memory by increasing reference memory errors and working memory incorrect errors in lead-exposed rats. However, quercetin treatment effectively improved memory and inhibited neuroinflammation by reducing astrocytes’ expression and the levels of TNF-α and IL-1β. The expression of astrocytes and the levels of TNF-α and IL-1β correlated with memory function. The possible explanation for quercetin’s anti-neuroinflammatory effect is that it modulates the activity of cellular proteins involved in the inflammatory response; inhibits the transcription factor of nuclear factor-kappa B (NF-κB), which regulates the expression of proinflammatory molecules; inhibits kinases required for the synthesis of Glial fibrillary acidic protein (GFAP) and modifies the phosphorylation of some proteins, which affect the structure and function of intermediate filament proteins; and, lastly, induces Cyclic-AMP Response Element Binding (CREB) activation and neurogenesis as a compensatory mechanism for memory deficits and neuronal cell death. In conclusion, the levels of neuroinflammatory markers negatively correlated with memory function. Thus, quercetin may be a promising therapy in neuroinflammation and memory dysfunction in populations prone to lead exposure.Keywords: lead, quercetin, neuroinflammation, memory
Procedia PDF Downloads 541136 Salt Stress Affects Growth, Nutrition and Anatomy of Stipa lagascae: A Psammophile Grass in Southern Tunisia
Authors: Raoudha Abdellaoui, Faycal Boughalleb, Zohra Chebil
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In arid and semi-arid regions, salinity represents a major constraint towards plants’ growth. Stipa lagascae, a psammophile grass, is a promised species since its economic and ecological interests. Our study aims to explore the effects of different salt concentrations (0; 100; 200; 300 and 400 mM) on physiological, biochemical and anatomic parameters. Salt stress was applied on S. lagascae plants cultivated under controlled conditions. Results show that salinity reduces biomass production especially when plants are subjected to severe stress (>200 mM NaCl). Concerning the nutritional level, the fact of enriching soil with NaCl, leads to an accumulation of Na+ against other nutritional elements (K+, Ca2+). To maintain tissues hydration, S. lagascae established osmotic adaptation by accumulation of proline and soluble sugars. Salt stress affected significantly root and foliar anatomy. Indeed, plants increased their vessels’ diameter and mesophyll surface. S. lagascae plants reduced also the surface of the belluforme cells to defeat dehydration. According to our results, S. lagascae seems to be a tolerant plant at acceptable concentrations that do not exceed 6g/l.Keywords: anatomical adaptations, mineral nutrition, plant growth, salt stress, stipa lagascae
Procedia PDF Downloads 2651135 Antioxidant and Anti-Inflammatory Activities of Bioactive Compounds Derived from Thunbergia laurifolia Aqueous Leave Extract
Authors: Marasri Junsi, Sunisa Siripongvutikorn, Chutha Takahashi Yupanqui, Worrapong Usawakesmanee
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Thunbergia laurifolia has been used for folklore medicine purposes and consumed in the form of herbal tea in Thailand since ancient times. To evaluate the bioactive compounds of aqueous leave extract possessed antioxidant and anti-inflammatory activities. The antioxidant activities were examined by total extractable phenolic content (TPC), total extractable flavonoid content (TFC), ABTS radical scavenging, DPPH radical scavenging, FRAP reducing antioxidant power expressed as mg of gallic acid trolox and caffeic acid for the equivalents. Results indicated that the extract had high TPC and antioxidant activities. In addition, the HPLC-DAD analysis of phenolics and flavonoids indicated the presence of caffeic acid and rutin as bioactive compounds. Exposure of cells with the extract using nitric oxide (NO) production in RAW 264.7 murine macrophage cell line induced by lipopolysaccharide (LPS) was significantly reduced NO production and increased cell proliferation. The obtained results demonstrated that the extract contains a high potential to be used as anti-inflammatory and antioxidant substances.Keywords: Thunbergia laurifolia, anti-inflammatory, antioxidant activities, RAW264.7
Procedia PDF Downloads 3111134 Fixed-Frequency Pulse Width Modulation-Based Sliding Mode Controller for Switching Multicellular Converter
Authors: Rihab Hamdi, Amel Hadri Hamida, Ouafae Bennis, Fatima Babaa, Sakina Zerouali
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This paper features a sliding mode controller (SMC) for closed-loop voltage control of DC-DC three-cells buck converter connected in parallel, operating in continuous conduction mode (CCM), based on pulse-width modulation (PWM). To maintain the switching frequency, the approach is to incorporate a pulse-width modulation that utilizes an equivalent control, inferred by applying the SM control method, to produce a control sign to be contrasted and the fixed-frequency within the modulator. Detailed stability and transient performance analysis have been conducted using Lyapunov stability criteria to restrict the switching frequency variation facing wide variations in output load, input changes, and set-point changes. The results obtained confirm the effectiveness of the proposed control scheme in achieving an enhanced output transient performance while faithfully realizing its control objective in the event of abrupt and uncertain parameter variations. Simulations studies in MATLAB/Simulink environment are performed to confirm the idea.Keywords: DC-DC converter, pulse width modulation, power electronics, sliding mode control
Procedia PDF Downloads 1471133 Surfactant Free Synthesis of Magnetite/Hydroxyapatite Composites for Hyperthermia Treatment
Authors: M. Sneha, N. Meenakshi Sundaram
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In recent times, magnetic hyperthermia is used for cancer treatment as a tool for active targeting of delivering drugs to the targeted site. It has a potential advantage over other heat treatment because there is no systemic buildup in organs and large doses are possible. The aim of this study is to develop a suitable magnetic biomaterial that can destroy the cancer cells as well as induce bone regeneration. In this work, the composite material was synthesized in two-steps. First, porous iron oxide nano needles were synthesized by hydrothermal process. Second, the hydroxyapatite, were synthesized from natural calcium (i.e., egg shell) and inorganic phosphorous source using wet chemical method. The crystalline nature is confirmed by powder X-ray diffraction analysis (XRD). Thermal analysis and the surface area of the material is studied by Thermo Gravimetric Analysis (TGA), Brunauer-Emmett and Teller (BET) technique. Scanning electron microscope (SEM) images show that the particles have nanoneedle-like morphology. The magnetic property is studied by vibrating sample magnetometer (VSM) technique which confirms the superparamagnetic behavior. This paper presents a simple and easy method for synthesis of magnetite/hydroxyapatite composites materials.Keywords: iron oxide nano needles, hydroxyapatite, superparamagnetic, hyperthermia
Procedia PDF Downloads 6411132 The Effects of Separating Inferior Alveolar Neurovascular Bundles on Osteogenesis of Tissue-Engineered Bone and Vascularization
Authors: Lin Feng, E. Lingling, Hongchen Liu
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In order to evaluate the effects of autologous blood vessels and nerves on vascularization. A dog model of tissue-engineered bone vascularization was established by constructing inferior alveolar neurovascular bundles through the mandibular canal. Sixteen 12-month-old healthy beagles were randomly divided into two groups (n=8). Group A retained inferior alveolar neurovascular bundles, and Group B retained inferior alveolar nerves. Bone marrow mesenchymal stem cells were injected into β-tricalcium phosphate to prepare internal tissue-engineered bone scaffold. A personalized titanium mesh was then prepared by rapid prototyping and fixed by external titanium scaffold. Two dogs in each group were sacrificed on the 30th, 45th, 60th, and 90th postoperative days respectively. The bone was visually examined, scanned by CT, and subjected to HE staining, immunohistochemical staining, vascular casting and PCR to detect the changes in osteogenesis and vascularization.The two groups had similar outcomes in regard to osteogenesis and vascularization (P>0.05) both showed remarkable regenerative capacities. The model of tissue-engineered bone vascularization is potentially applicable in clinical practice to allow satisfactory osteogenesis and vascularization.Keywords: inferior alveolar neurovascular bundle, osteogenesis, tissue-engineered bone, vascularization
Procedia PDF Downloads 3901131 Effects of Voltage Pulse Characteristics on Some Performance Parameters of LiₓCoO₂-based Resistive Switching Memory Devices
Authors: Van Son Nguyen, Van Huy Mai, Alec Moradpour, Pascale Auban Senzier, Claude Pasquier, Kang Wang, Pierre-Antoine Albouy, Marcelo J. Rozenberg, John Giapintzakis, Christian N. Mihailescu, Charis M. Orfanidou, Thomas Maroutian, Philippe Lecoeur, Guillaume Agnus, Pascal Aubert, Sylvain Franger, Raphaël Salot, Nathalie Brun, Katia March, David Alamarguy, Pascal ChréTien, Olivier Schneegans
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In the field of Nanoelectronics, a major research activity is being developed towards non-volatile memories. To face the limitations of existing Flash memory cells (endurance, downscaling, rapidity…), new approaches are emerging, among them resistive switching memories (Re-RAM). In this work, we analysed the behaviour of LixCoO2 oxide thin films in electrode/film/electrode devices. Preliminary results have been obtained concerning the influence of bias pulses characteristics (duration, value) on some performance parameters, such as endurance and resistance ratio (ROFF/RON). Besides, Conducting Probe Atomic Force Microscopy (CP-AFM) characterizations of the devices have been carried out to better understand some causes of performance failure, and thus help optimizing the switching performance of such devices.Keywords: non volatile resistive memories, resistive switching, thin films, endurance
Procedia PDF Downloads 6111130 Cloning and Expression a Gene of β-Glucosidase from Penicillium echinulatum in Pichia pastoris
Authors: Amanda Gregorim Fernandes, Lorena Cardoso Cintra, Rosalia Santos Amorim Jesuino, Fabricia Paula De Faria, Marcio José Poças Fonseca
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Bioethanol is one of the most promising biofuels and able to replace fossil fuels and reduce its different environmental impacts and can be generated from various agroindustrial waste. The Brazil is in first place in bioethanol production to be the largest producer of sugarcane. The bagasse sugarcane (SCB) has lignocellulose which is composed of three major components: cellulose, hemicellulose and lignin. Cellulose is a homopolymer of glucose units connected by glycosidic linkages. Among all species of Penicillium, Penicillium echinulatum has been the focus of attention because they produce high quantities of cellulase and the mutant strain 9A02S1 produces higher enzyme levels compared to the wild. Among the cellulases, the cellobiohydrolases enzymes are the main components of the cellulolytic system of fungi, and are also responsible for most of the potential hydrolytic in enzyme cocktails for the industrial processing of plant biomass and several cellobiohydrolases Penicillium had higher specific activity against cellulose compared to CBH I from Trichoderma reesei. This fact makes it an interesting pattern for higher yields in the enzymatic hydrolysis, and also they are important enzymes in the hydrolysis of crystalline regions of cellulose. Therefore, finding new and more active enzymes become necessary. Meanwhile, β-glycosidases act on soluble substrates and are highly dependent on cellobiohydrolases and endoglucanases action to provide the substrate in the hydrolysis of the biomass, but the cellobiohydrolases and endoglucanases are highly dependent β-glucosidases to maintain efficient hydrolysis. Thus, there is a need to understand the structure-function relationships that govern the catalytic activity of cellulolytic enzymes to elucidate its mechanism of action and optimize its potential as industrial biocatalysts. To evaluate the enzyme β-glucosidase of Penicillium echinulatum (PeBGL1) the gene was synthesized from the assembly sequence from a library in induction conditions and then the PeBGL1 gene was cloned in the vector pPICZαA and transformed into P. pastoris GS115. After processing, the producers of PeBGL1 were analyzed for enzyme activity and protein profile where a band of approximately 100 kDa was viewed. It was also carried out the zymogram. In partial characterization it was determined optimum temperature of 50°C and optimum pH of 6,5. In addition, to increase the secreted recombinant PeBGL1 production by Pichia pastoris, three parameters of P. pastoris culture medium were analysed: methanol, nitrogen source concentrations and the inoculum size. A 23 factorial design was effective in achieving the optimum condition. Altogether, these results point to the potential application of this P. echinulatum β-glucosidase in hydrolysis of cellulose for the production of bioethanol.Keywords: bioethanol, biotechnology, beta-glucosidase, penicillium echinulatum
Procedia PDF Downloads 2421129 Modeling of Carbon Monoxide Distribution under the Sky-Train Stations
Authors: Suranath Chomcheon, Nathnarong Khajohnsaksumeth, Benchawan Wiwatanapataphee
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Carbon monoxide is one of the harmful gases which have colorless, odorless, and tasteless. Too much carbon monoxide taken into the human body causes the reduction of oxygen transportation within human body cells leading to many symptoms including headache, nausea, vomiting, loss of consciousness, and death. Carbon monoxide is considered as one of the air pollution indicators. It is mainly released as soot from the exhaust pipe of the incomplete combustion of the vehicle engine. Nowadays, the increase in vehicle usage and the slowly moving of the vehicle struck by the traffic jam has created a large amount of carbon monoxide, which accumulated in the street canyon area. In this research, we study the effect of parameters such as wind speed and aspect ratio of the height building affecting the ventilation. We consider the model of the pollutant under the Bangkok Transit System (BTS) stations in a two-dimensional geometrical domain. The convention-diffusion equation and Reynolds-averaged Navier-stokes equation is used to describe the concentration and the turbulent flow of carbon monoxide. The finite element method is applied to obtain the numerical result. The result shows that our model can describe the dispersion patterns of carbon monoxide for different wind speeds.Keywords: air pollution, carbon monoxide, finite element, street canyon
Procedia PDF Downloads 1261128 Simulation, Design, and 3D Print of Novel Highly Integrated TEG Device with Improved Thermal Energy Harvest Efficiency
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Despite the remarkable advancement of solar cell technology, the challenge of optimizing total solar energy harvest efficiency persists, primarily due to significant heat loss. This excess heat not only diminishes solar panel output efficiency but also curtails its operational lifespan. A promising approach to address this issue is the conversion of surplus heat into electricity. In recent years, there is growing interest in the use of thermoelectric generators (TEG) as a potential solution. The integration of efficient TEG devices holds the promise of augmenting overall energy harvest efficiency while prolonging the longevity of solar panels. While certain research groups have proposed the integration of solar cells and TEG devices, a substantial gap between conceptualization and practical implementation remains, largely attributed to low thermal energy conversion efficiency of TEG devices. To bridge this gap and meet the requisites of practical application, a feasible strategy involves the incorporation of a substantial number of p-n junctions within a confined unit volume. However, the manufacturing of high-density TEG p-n junctions presents a formidable challenge. The prevalent solution often leads to large device sizes to accommodate enough p-n junctions, consequently complicating integration with solar cells. Recently, the adoption of 3D printing technology has emerged as a promising solution to address this challenge by fabricating high-density p-n arrays. Despite this, further developmental efforts are necessary. Presently, the primary focus is on the 3D printing of vertically layered TEG devices, wherein p-n junction density remains constrained by spatial limitations and the constraints of 3D printing techniques. This study proposes a novel device configuration featuring horizontally arrayed p-n junctions of Bi2Te3. The structural design of the device is subjected to simulation through the Finite Element Method (FEM) within COMSOL Multiphysics software. Various device configurations are simulated to identify optimal device structure. Based on the simulation results, a new TEG device is fabricated utilizing 3D Selective laser melting (SLM) printing technology. Fusion 360 facilitates the translation of the COMSOL device structure into a 3D print file. The horizontal design offers a unique advantage, enabling the fabrication of densely packed, three-dimensional p-n junction arrays. The fabrication process entails printing a singular row of horizontal p-n junctions using the 3D SLM printing technique in a single layer. Subsequently, successive rows of p-n junction arrays are printed within the same layer, interconnected by thermally conductive copper. This sequence is replicated across multiple layers, separated by thermal insulating glass. This integration created in a highly compact three-dimensional TEG device with high density p-n junctions. The fabricated TEG device is then attached to the bottom of the solar cell using thermal glue. The whole device is characterized, with output data closely matching with COMSOL simulation results. Future research endeavors will encompass the refinement of thermoelectric materials. This includes the advancement of high-resolution 3D printing techniques tailored to diverse thermoelectric materials, along with the optimization of material microstructures such as porosity and doping. The objective is to achieve an optimal and highly integrated PV-TEG device that can substantially increase the solar energy harvest efficiency.Keywords: thermoelectric, finite element method, 3d print, energy conversion
Procedia PDF Downloads 621127 Mechanistic Structural Insights into the UV Induced Apoptosis via Bcl-2 proteins
Authors: Akash Bera, Suraj Singh, Jacinta Dsouza, Ramakrishna V. Hosur, Pushpa Mishra
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Ultraviolet C (UVC) radiation induces apoptosis in mammalian cells and it is suggested that the mechanism by which this occurs is the mitochondrial pathway of apoptosis through the release of cytochrome c from the mitochondria into the cytosol. The Bcl-2 family of proteins pro-and anti-apoptotic is the regulators of the mitochondrial pathway of apoptosis. Upon UVC irradiation, the proliferation of apoptosis is enhanced through the downregulation of the anti-apoptotic protein Bcl-xl and up-regulation of Bax. Although the participation of the Bcl-2 family of proteins in apoptosis appears responsive to UVC radiation, to the author's best knowledge, it is unknown how the structure and, effectively, the function of these proteins are directly impacted by UVC exposure. In this background, we present here a structural rationale for the effect of UVC irradiation in restoring apoptosis using two of the relevant proteins, namely, Bid-FL and Bcl-xl ΔC, whose solution structures have been reported previously. Using a variety of biophysical tools such as circular dichroism, fluorescence and NMR spectroscopy, we show that following UVC irradiation, the structures of Bcl-xlΔC and Bid-FL are irreversibly altered. Bcl-xLΔC is found to be more sensitive to UV exposure than Bid-FL. From the NMR data, dramatic structural perturbations (α-helix to β-sheet) are seen to occur in the BH3 binding region, a crucial segment of Bcl-xlΔC which impacts the efficacy of its interactions with pro-apoptotic tBid. These results explain the regulation of apoptosis by UVC irradiation. Our results on irradiation dosage dependence of the structural changes have therapeutic potential for the treatment of cancer.Keywords: Bid, Bcl-xl, UVC, apoptosis
Procedia PDF Downloads 1271126 Mechanical Response of Aluminum Foam Under Biaxial Combined Quasi-Static Compression-Torsional Loads
Authors: Solomon Huluka, Akrum Abdul-Latif, Rachid Baleh
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Metal foams have been developed intensively as a new class of materials for the last two decades due to their unique structural and multifunctional properties. The aim of this experimental work was to characterize the effect of biaxial loading complexity (combined compression-torsion) on the plastic response of highly uniform architecture open-cell aluminum foams of spherical porous with a density of 80%. For foam manufacturing, the Kelvin cells model was used to generate the generally spherical shape with a cell diameter of 11 mm. A patented rig called ACTP (Absorption par Compression-Torsion Plastique), was used to investigate the foam response under quasi-static complex loading paths having different torsional components (i.e. 0°, 45° and 60°). The key mechanical responses to be examined are yield stress, stress plateau, and energy absorption capacity. The collapse mode was also investigated. It was concluded that the higher the loading complexity, the greater the yield strength and the greater energy absorption capacity of the foam. Experimentally, it was also noticed that there were large softening effects that occurred after the first pick stress for both biaxial-45° and biaxial-60° loading.Keywords: aluminum foam, loading complexity, characterization, biaxial loading
Procedia PDF Downloads 1421125 The Methods of Immobilization of Laccase for Direct Transfer in an Enzymatic Fuel Cell
Authors: Afshin Farahbakhsh, Hoda Khodadadi
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In this paper, we compare five methods of biological fuel cell fabrication by combining a Shewanella oneidensis microbial anode and a laccase-modified air-breathing cathode. As a result of biofuel cell laccase with graphite nanofibers, carbon surface (PAMAN) on the pt/hpg electrode, graphite sheets MWCNT and with (PG) and (MWCNT) showed, respectively. Describes methods for creating controllable and reproducible bio-anodes and demonstrates the versatility of hybrid biological fuel cells. The laccase-based biocathodes prepared either with the crude extract or with the purified enzyme can provide electrochemically active and stable biomaterials. The laccase-based biocathodes prepared either with the crude extract or with the purified enzyme can provide electrochemically active and stable biomaterials. When the device was fed with transdermal extracts, containing only 30μM of glucose, the average peak power was proportionally lower (0.004mW). The result of biofuel cell with graphite nanofibers showed the enzymatic fuel cell reaches 0.5 V at open circuit voltage with both, ethanol and methanol and the maximum current density observed for E2electrode was 228.94mAcm.Keywords: enzymatic electrode, fuel cell, immobilization, laccase
Procedia PDF Downloads 2611124 Liquid Crystal Based Reconfigurable Reflectarray Antenna Design
Authors: M. Y. Ismail, M. Inam
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This paper presents the design and analysis of Liquid Crystal (LC) based tunable reflectarray antenna with slot embedded patch element configurations within X-band frequency range. The slots are shown to modify the surface current distribution on the patch element of reflectarray which causes the resonant patch element to provide different resonant frequencies depending on the slot dimensions. The simulated results are supported and verified by waveguide scattering parameter measurements of different reflectarray unit cells. Different rectangular slots on patch element have been fabricated and a change in resonant frequency from 10.46GHz to 8.78GHz has been demonstrated as the width of the rectangular slot is varied from 0.2W to 0.6W. The rectangular slot in the center of the patch element has also been utilized for the frequency tunable reflectarray antenna design based on K-15 Nematic LC. For the active reflectarray antenna design, a frequency tunability of 1.2% from 10GHz to 9.88GHz has been demonstrated with a dynamic phase range of 103° provided by the measured scattering parameter results. Time consumed by liquid crystals for reconfiguration, which is one of the drawback of LC based design, has also been disused in this paper.Keywords: liquid crystal, tunable reflectarray, frequency tunability, dynamic phase range
Procedia PDF Downloads 3321123 Optimal Design of InGaP/GaAs Heterojonction Solar Cell
Authors: Djaafar F., Hadri B., Bachir G.
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We studied mainly the influence of temperature, thickness, molar fraction and the doping of the various layers (emitter, base, BSF and window) on the performances of a photovoltaic solar cell. In a first stage, we optimized the performances of the InGaP/GaAs dual-junction solar cell while varying its operation temperature from 275°K to 375 °K with an increment of 25°C using a virtual wafer fabrication TCAD Silvaco. The optimization at 300°K led to the following result Icc =14.22 mA/cm2, Voc =2.42V, FF =91.32 %, η = 22.76 % which is close with those found in the literature. In a second stage ,we have varied the molar fraction of different layers as well their thickness and the doping of both emitters and bases and we have registered the result of each variation until obtaining an optimal efficiency of the proposed solar cell at 300°K which was of Icc=14.35mA/cm2,Voc=2.47V,FF=91.34,and η =23.33% for In(1-x)Ga(x)P molar fraction( x=0.5).The elimination of a layer BSF on the back face of our cell, enabled us to make a remarkable improvement of the short-circuit current (Icc=14.70 mA/cm2) and a decrease in open circuit voltage Voc and output η which reached 1.46V and 11.97% respectively. Therefore, we could determine the critical parameters of the cell and optimize its various technological parameters to obtain the best performance for a dual junction solar cell. This work opens the way with new prospects in the field of the photovoltaic one. Such structures will thus simplify the manufacturing processes of the cells; will thus reduce the costs while producing high outputs of photovoltaic conversion.Keywords: modeling, simulation, multijunction, optimization, silvaco ATLAS
Procedia PDF Downloads 6211122 Study of Sub-Surface Flow in an Unconfined Carbonate Aquifer in a Tropical Karst Area in Indonesia: A Modeling Approach Using Finite Difference Groundwater Model
Authors: Dua K. S. Y. Klaas, Monzur A. Imteaz, Ika Sudiayem, Elkan M. E. Klaas, Eldav C. M. Klaas
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Due to its porous nature, karst terrains – geomorphologically developed from dissolved formations, is vulnerable to water shortage and deteriorated water quality. Therefore, a solid comprehension on sub-surface flow of karst landscape is essential to assess the long-term availability of groundwater resources. In this paper, a single-continuum model using a finite difference model, MODLFOW, was constructed to represent an unconfined carbonate aquifer in a tropical karst island of Rote in Indonesia. The model, spatially discretized in 20 x 20 m grid cells, was calibrated and validated using available groundwater level and atmospheric variables. In the calibration and validation steps, Parameter Estimation (PEST) and geostatistical pilot point methods were employed to estimate hydraulic conductivity and specific yield values. The results show that the model is able to represent the sub-surface flow indicated by good model performances both in calibration and validation steps. The final model can be used as a robust representation of the system for future study on climate and land use scenarios.Keywords: carbonate aquifer, karst, sub-surface flow, groundwater model
Procedia PDF Downloads 1481121 Impact of Simulated Brain Interstitial Fluid Flow on the Chemokine CXC-Chemokine-Ligand-12 Release From an Alginate-Based Hydrogel
Authors: Wiam El Kheir, Anais Dumais, Maude Beaudoin, Bernard Marcos, Nick Virgilio, Benoit Paquette, Nathalie Faucheux, Marc-Antoine Lauzon
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The high infiltrative pattern of glioblastoma multiforme cells (GBM) is the main cause responsible for the actual standard treatments failure. The tumor high heterogeneity, the interstitial fluid flow (IFF) and chemokines guides GBM cells migration in the brain parenchyma resulting in tumor recurrence. Drug delivery systems emerged as an alternative approach to develop effective treatments for the disease. Some recent studies have proposed to harness the effect CXC-lchemokine-ligand-12 to direct and control the cancer cell migration through delivery system. However, the dynamics of the brain environment on the delivery system remains poorly understood. Nanoparticles (NPs) and hydrogels are known as good carriers for the encapsulation of different agents and control their release. We studied the release of CXCL12 (free or loaded into NPs) from an alginate-based hydrogel under static and indirect perfusion (IP) conditions. Under static conditions, the main phenomena driving CXCL12 release from the hydrogel was diffusion with the presence of strong interactions between the positively charged CXCL12 and the negatively charge alginate. CXCL12 release profiles were independent from the initial mass loadings. Afterwards, we demonstrated that the release could tuned by loading CXCL12 into Alginate/Chitosan-Nanoparticles (Alg/Chit-NPs) and embedded them into alginate-hydrogel. The initial burst release was substantially attenuated and the overall cumulative release percentages of 21%, 16% and 7% were observed for initial mass loadings of 0.07, 0.13 and 0.26 µg, respectively, suggesting stronger electrostatic interactions. Results were mathematically modeled based on Fick’s second law of diffusion framework developed previously to estimate the effective diffusion coefficient (Deff) and the mass transfer coefficient. Embedding the CXCL12 into NPs decreased the Deff an order of magnitude, which was coherent with experimental data. Thereafter, we developed an in-vitro 3D model that takes into consideration the convective contribution of the brain IFF to study CXCL12 release in an in-vitro microenvironment that mimics as faithfully as possible the human brain. From is unique design, the model also allowed us to understand the effect of IP on CXCL12 release in respect to time and space. Four flow rates (0.5, 3, 6.5 and 10 µL/min) which may increase CXCL12 release in-vivo depending on the tumor location were assessed. Under IP, cumulative percentages varying between 4.5-7.3%, 23-58.5%, 77.8-92.5% and 89.2-95.9% were released for the three initial mass loadings of 0.08, 0.16 and 0.33 µg, respectively. As the flow rate increase, IP culture conditions resulted in a higher release of CXCL12 compared to static conditions as the convection contribution became the main driving mass transport phenomena. Further, depending on the flow rate, IP had a direct impact on CXCL12 distribution within the simulated brain tissue, which illustrates the importance of developing such 3D in-vitro models to assess the efficiency of a delivery system targeting the brain. In future work, using this very model, we aim to understand the impact of the different phenomenon occurring on GBM cell behaviors in response to the resulting chemokine gradient subjected to various flow while allowing them to express their invasive characteristics in an in-vitro microenvironment that mimics the in-vivo brain parenchyma.Keywords: 3D culture system, chemokines gradient, glioblastoma multiforme, kinetic release, mathematical modeling
Procedia PDF Downloads 841120 TiO2 Formation after Nanotubes Growth on Ti-15Mo Alloy Surface for Different Annealing Temperatures
Authors: A. L. R. Rangel, J. A. M. Chaves, A. P. R. Alves Claro
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Surface modification of titanium and its alloys using TiO2 nanotube growth has been widely studied for biomedical field due to excellent interaction between implant and biological environment. The success of this treatment is directly related to anatase phase formation (TiO2 phase) which affects the cells growth. The aim of this study was to evaluate the phases formed in the nanotubes growth on the Ti-15Mo surface. Nanotubes were grown by electrochemical anodization of the alloy in ammonium fluoride based glycerol electrolyte for 24 hours at 20V. Then, the samples were annealed at 200°,400°, 450°, 500°, 600°, and 800° C for 1 hour. Contact angles measurements, scanning electron microscopy images and X rays diffraction analysis (XRD) were carried out for all samples. Raman Spectroscopy was used to evaluate TiO2 phases transformation in nanotubes samples as well. The results of XRD showed anatase formation for lower temperatures, while at 800 ° C the rutile phase was observed all over the surface. Raman spectra indicate that this phase transition occurs between 500 and 600 °C. The different phases formed have influenced the nanotubes morphologies, since higher annealing temperatures induced agglutination of the TiO2 layer, disrupting the tubular structure. On the other hand, the nanotubes drastically reduced the contact angle, regardless the annealing temperature.Keywords: nanotubes, TiO2, titanium alloys, Ti-15Mo
Procedia PDF Downloads 3831119 Leakage Current Analysis of FinFET Based 7T SRAM at 32nm Technology
Authors: Chhavi Saxena
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FinFETs can be a replacement for bulk-CMOS transistors in many different designs. Its low leakage/standby power property makes FinFETs a desirable option for memory sub-systems. Memory modules are widely used in most digital and computer systems. Leakage power is very important in memory cells since most memory applications access only one or very few memory rows at a given time. As technology scales down, the importance of leakage current and power analysis for memory design is increasing. In this paper, we discover an option for low power interconnect synthesis at the 32nm node and beyond, using Fin-type Field-Effect Transistors (FinFETs) which are a promising substitute for bulk CMOS at the considered gate lengths. We consider a mechanism for improving FinFETs efficiency, called variable supply voltage schemes. In this paper, we’ve illustrated the design and implementation of FinFET based 4x4 SRAM cell array by means of one bit 7T SRAM. FinFET based 7T SRAM has been designed and analysis have been carried out for leakage current, dynamic power and delay. For the validation of our design approach, the output of FinFET SRAM array have been compared with standard CMOS SRAM and significant improvements are obtained in proposed model.Keywords: FinFET, 7T SRAM cell, leakage current, delay
Procedia PDF Downloads 4551118 Basics of Gamma Ray Burst and Its Afterglow
Authors: Swapnil Kumar Singh
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Gamma-ray bursts (GRB's), short and intense pulses of low-energy γ rays, have fascinated astronomers and astrophysicists since their unexpected discovery in the late sixties. GRB'sare accompanied by long-lasting afterglows, and they are associated with core-collapse supernovae. The detection of delayed emission in X-ray, optical, and radio wavelength, or "afterglow," following a γ-ray burst can be described as the emission of a relativistic shell decelerating upon collision with the interstellar medium. While it is fair to say that there is strong diversity amongst the afterglow population, probably reflecting diversity in the energy, luminosity, shock efficiency, baryon loading, progenitor properties, circumstellar medium, and more, the afterglows of GRBs do appear more similar than the bursts themselves, and it is possible to identify common features within afterglows that lead to some canonical expectations. After an initial flash of gamma rays, a longer-lived "afterglow" is usually emitted at longer wavelengths (X-ray, ultraviolet, optical, infrared, microwave, and radio). It is a slowly fading emission at longer wavelengths created by collisions between the burst ejecta and interstellar gas. In X-ray wavelengths, the GRB afterglow fades quickly at first, then transitions to a less-steep drop-off (it does other stuff after that, but we'll ignore that for now). During these early phases, the X-ray afterglow has a spectrum that looks like a power law: flux F∝ E^β, where E is energy and beta is some number called the spectral index. This kind of spectrum is characteristic of synchrotron emission, which is produced when charged particles spiral around magnetic field lines at close to the speed of light. In addition to the outgoing forward shock that ploughs into the interstellar medium, there is also a so-called reverse shock, which propagates backward through the ejecta. In many ways," reverse" shock can be misleading; this shock is still moving outward from the restframe of the star at relativistic velocity but is ploughing backward through the ejecta in their frame and is slowing the expansion. This reverse shock can be dynamically important, as it can carry comparable energy to the forward shock. The early phases of the GRB afterglow still provide a good description even if the GRB is highly collimated since the individual emitting regions of the outflow are not in causal contact at large angles and so behave as though they are expanding isotropically. The majority of afterglows, at times typically observed, fall in the slow cooling regime, and the cooling break lies between the optical and the X-ray. Numerous observations support this broad picture for afterglows in the spectral energy distribution of the afterglow of the very bright GRB. The bluer light (optical and X-ray) appears to follow a typical synchrotron forward shock expectation (note that the apparent features in the X-ray and optical spectrum are due to the presence of dust within the host galaxy). We need more research in GRB and Particle Physics in order to unfold the mysteries of afterglow.Keywords: GRB, synchrotron, X-ray, isotropic energy
Procedia PDF Downloads 881117 Biodegradation of Chlorophenol Derivatives Using Macroporous Material
Authors: Dmitriy Berillo, Areej K. A. Al-Jwaid, Jonathan L. Caplin, Andrew Cundy, Irina Savina
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Chlorophenols (CPs) are used as a precursor in the production of higher CPs and dyestuffs, and as a preservative. Contamination by CPs of the ground water is located in the range from 0.15-100mg/L. The EU has set maximum concentration limits for pesticides and their degradation products of 0.1μg/L and 0.5μg/L, respectively. People working in industries which produce textiles, leather products, domestic preservatives, and petrochemicals are most heavily exposed to CPs. The International Agency for Research on Cancers categorized CPs as potential human carcinogens. Existing multistep water purification processes for CPs such as hydrogenation, ion exchange, liquid-liquid extraction, adsorption by activated carbon, forward and inverse osmosis, electrolysis, sonochemistry, UV irradiation, and chemical oxidation are not always cost effective and can cause the formation of even more toxic or mutagenic derivatives. Bioremediation of CPs derivatives utilizing microorganisms results in 60 to 100% decontamination efficiency and the process is more environmentally-friendly compared with existing physico-chemical methods. Microorganisms immobilized onto a substrate show many advantages over free bacteria systems, such as higher biomass density, higher metabolic activity, and resistance to toxic chemicals. They also enable continuous operation, avoiding the requirement for biomass-liquid separation. The immobilized bacteria can be reused several times, which opens the opportunity for developing cost-effective processes for wastewater treatment. In this study, we develop a bioremediation system for CPs based on macroporous materials, which can be efficiently used for wastewater treatment. Conditions for the preparation of the macroporous material from specific bacterial strains (Pseudomonas mendocina and Rhodococus koreensis) were optimized. The concentration of bacterial cells was kept constant; the difference was only the type of cross-linking agents used e.g. glutaraldehyde, novel polymers, which were utilized at concentrations of 0.5 to 1.5%. SEM images and rheology analysis of the material indicated a monolithic macroporous structure. Phenol was chosen as a model system to optimize the function of the cryogel material and to estimate its enzymatic activity, since it is relatively less toxic and harmful compared to CPs. Several types of macroporous systems comprising live bacteria were prepared. The viability of the cross-linked bacteria was checked using Live/Dead BacLight kit and Laser Scanning Confocal Microscopy, which revealed the presence of viable bacteria with the novel cross-linkers, whereas the control material cross-linked with glutaraldehyde(GA), contained mostly dead cells. The bioreactors based on bacteria were used for phenol degradation in batch mode at an initial concentration of 50mg/L, pH 7.5 and a temperature of 30°C. Bacterial strains cross-linked with GA showed insignificant ability to degrade phenol and for one week only, but a combination of cross-linking agents illustrated higher stability, viability and the possibility to be reused for at least five weeks. Furthermore, conditions for CPs degradation will be optimized, and the chlorophenol degradation rates will be compared to those for phenol. This is a cutting-edge bioremediation approach, which allows the purification of waste water from sustainable compounds without a separation step to remove free planktonic bacteria. Acknowledgments: Dr. Berillo D. A. is very grateful to Individual Fellowship Marie Curie Program for funding of the research.Keywords: bioremediation, cross-linking agents, cross-linked microbial cell, chlorophenol degradation
Procedia PDF Downloads 2131116 pH and Thermo-Sensitive Nanogels for Anti-Cancer Therapy
Authors: V. Naga Sravan Kumar Varma, H. G. Shivakumar
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The aim of the study was to develop dual sensitive poly (N-isopropylacrylamide-co-acrylic acid) (PNA) nanogels(NGs) and studying its applications for Anti-Cancer therapy. NGs were fabricated by free radical polymerization using different amount of N-isopropylacrylamide and acrylic acid. A study for polymer composition over the effect on LCST in different pH was evaluated by measuring the absorbance at 500nm using UV spectrophotometer. Further selected NG’s were evaluated for change in hydrodynamic diameters in response to pH and temperature. NGs which could sharply respond to low pH value of cancer cells at body temperature were loaded with Fluorouracil (5-FU) using equilibrium swelling method and studied for drug release behaviour in different pH. A significant influence of NGs polymer composition over pH dependent LCST was observed. NGs which were spherical with an average particle size of 268nm at room temperature, shrinked forming an irregular shape when heated above to their respective LCST. 5FU loaded NGs did not intervene any difference in pH depended LCST behaviour of NGs. The in vitro drug release of NGs exhibited a pH and thermo-dependent control release. The cytoxicity study of blank carrier to MCF7 cell line showed no cytotoxicity. The results indicated that PNA NGs could be used as a potential drug carrier for anti-cancer therapy.Keywords: pH and thermo-sensitive, nanogels, P(NIPAM-co-AAc), anti-cancer, 5-FU
Procedia PDF Downloads 3501115 Identification of Anaplasma Species in Cattle of Khouzestan Province from Iran by PCR
Authors: Ali Bagherpour
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The aim of this study was to determinate the variety of Anaplasma species among cattle of Khuzestan province, Iran. From April 2013 to June 2013, a total of 200 blood samples were collected via the jugular vein from healthy cattle (100), randomly. The extracted DNA from blood cells were amplified by Anaplasma-all primers, which amplify an approximately 1468bp DNA fragment from region of 16S rRNA gene from various members of the genus Anaplasma. For raising the test sensivity, the PCR products were amplified with the primers, which were designed from the region flanked by the first primers. The amplified nested PCR product had an expected PCR product with 345 nucleotides in length. 44 out of 100 cattle blood samples were Anaplasma spp. positive by first PCR and nested PCR. All cattle positive samples were further analyzed for the presence of A. centrale, A. bovis and A. phagocytophilum by specific nested PCR. A.phagocytophilum was identified by specific nested PCR in 3% of cattle blood samples. The extracted DNA from positive Anaplasma spp. samples were amplified by Anaplasma marginale/ovis specific primers, which amplify an approximately 866bp DNA fragment from region of msp4 gene. 41 out of 100 cattle blood samples (41%) were positive for Anaplasma marginale and Anaplasma ovis, respectively.Keywords: Iran, Khuzestan, Anaplasma species, Cattle, A. marginale, A. ovis, A. phagocytophilum, PCR
Procedia PDF Downloads 5011114 Rationally Designed Dual PARP-HDAC Inhibitor Elicits Striking Anti-leukemic Effects
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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