Search results for: adipose mesenchymal stem cells
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 3772

Search results for: adipose mesenchymal stem cells

1672 The Antagonistic/Synergistic Effect of Probiotic Yeast Saccharomyces boulardii on Candida glabrata Adhesion

Authors: Zorica Tomičić, Ružica Tomičić, Peter Raspor

Abstract:

Growing resistance of pathogenic yeast Candida glabrata to many classes of antifungal drugs has stimulated efforts to discover new agents to combat a rising number of invasive C. glabrata infections, which deserves a great deal of concern due to the high mortality rate in immunocompromised populations. One promising strategy is the use of probiotic microorganisms, which, when administered in adequate amounts, confers a health benefit. A selected number of probiotic organisms, Saccharomyces boulardii among them, have been tested as potential biotherapeutic agents. The aim of this study was to investigate the effect of the probiotic yeast S. boulardii on the adhesion of clinical isolates of C. glabrata at different temperatures, pH values, and in the presence of three clinically important antifungal drugs, such as fluconazole, itraconazole and amphotericin B. The method used to assess adhesion was crystal violet staining. The selection of antimycotics concentrations used in the adhesion assay was based on minimum inhibitory concentrations (MICs) obtained by the preliminarily performed microdilution modification of the Reference method for broth dilution antifungal susceptibility testing of yeast (Clinical and Laboratory Standards Institute (CLSI), standard M27-A2). the results showed that despite the nonadhesiveness of S. boulardii cells, probiotic yeast significantly suppressed the adhesion of C. glabrata strains. Besides, at specific strain ratios, a slight stimulatory effect was observed in some C. glabrata strains, which highlights the importance of strain specificity and opens up further research interests. When environmental conditions are considered, temperature and pH significantly influenced co-culture adhesion of C. glabrata and S. boulardii. The adhesion of C. glabrata strains was relatively equally reduced over all tested temperature range (28°C, 37°C, 39°C and 42°C) in the presence of S. boulardii cells, while the adhesion of a few C. glabrata strains were significantly stimulated at 28°C and suppressed at 42°C. Further, the adhesion was highly dependent on pH, with the highest adherence at pH 4 and lowest at pH 8.5. It was observed that S. boulardii did not manage to suppress the adhesion of C. glabrata strains at high pH. Antimycotics on the other hand showed a greater impact, since S. boulardii failed to affect co-culture adhesion at higher antimycotics concentrations. As expected, exposure to various concentrations of amphotericin B significantly reduced the adherence ability of C.glabrata strains both in a single culture and co-culture with S. boulardii. Therefore, it can be speculated that S. boulardii could substitute the effect of antimycotics in a range concentrations and with specific type of strains. This would certainly change the view on the treatment of yeast infections in the future.

Keywords: adhesion, antimycotics, candida glabrata, saccharomyces boulardii

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1671 Robust Single/Multi bit Memristor Based Memory

Authors: Ahmed Emara, Maged Ghoneima, Mohamed Dessouky

Abstract:

Demand for low power fast memories is increasing with the increase in IC’s complexity, in this paper we introduce a proposal for a compact SRAM based on memristor devices. The compact size of the proposed cell (1T2M compared to 6T of traditional SRAMs) allows denser memories on the same area. In this paper, we will discuss the proposed memristor memory cell for single/multi bit data storing configurations along with the writing and reading operations. Stored data stability across successive read operation will be illustrated, operational simulation results and a comparison of our proposed design with previously conventional SRAM and previously proposed memristor cells will be provided.

Keywords: memristor, multi-bit, single-bit, circuits, systems

Procedia PDF Downloads 374
1670 Identification, Synthesis, and Biological Evaluation of the Major Human Metabolite of NLRP3 Inflammasome Inhibitor MCC950

Authors: Manohar Salla, Mark S. Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E. Croker, Janet C. Reid, Jong Min Baek, Paul V. Bernhardt, Elizabeth M. J. Gillam, Matthew A. Cooper, Avril A. B. Robertson

Abstract:

MCC950 is a potent and selective inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that shows early promise for treatment of inflammatory diseases. The identification of major metabolites of lead molecule is an important step during drug development process. It provides an information about the metabolically labile sites in the molecule and thereby helping medicinal chemists to design metabolically stable molecules. To identify major metabolites of MCC950, the compound was incubated with human liver microsomes and subsequent analysis by (+)- and (−)-QTOF-ESI-MS/MS revealed a major metabolite formed due to hydroxylation on 1,2,3,5,6,7-hexahydro-s-indacene moiety of MCC950. This major metabolite can lose two water molecules and three possible regioisomers were synthesized. Co-elution of major metabolite with each of the synthesized compounds using HPLC-ESI-SRM-MS/MS revealed the structure of the metabolite (±) N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. Subsequent synthesis of individual enantiomers and coelution in HPLC-ESI-SRM-MS/MS using a chiral column revealed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. To study the possible cytochrome P450 enzyme(s) responsible for the formation of major metabolite, MCC950 was incubated with a panel of cytochrome P450 enzymes. The result indicated that CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2J2 and CYP3A4 are most likely responsible for the formation of the major metabolite. The biological activity of the major metabolite and the other synthesized regioisomers was also investigated by screening for for NLRP3 inflammasome inhibitory activity and cytotoxicity. The major metabolite had 170-fold less inhibitory activity (IC50-1238 nM) than MCC950 (IC50-7.5 nM). Interestingly, one regioisomer had shown nanomolar inhibitory activity (IC50-232 nM). However, no evidence of cytotoxicity was observed with any of these synthesized compounds when tested in human embryonic kidney 293 cells (HEK293) and human liver hepatocellular carcinoma G2 cells (HepG2). These key findings give an insight into the SAR of the hexahydroindacene moiety of MCC950 and reveal a metabolic soft spot which could be blocked by chemical modification.

Keywords: Cytochrome P450, inflammasome, MCC950, metabolite, microsome, NLRP3

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1669 Bio-Functional Polymeric Protein Based Materials Utilized for Soft Tissue Engineering Application

Authors: Er-Yuan Chuang

Abstract:

Bio-mimetic matters have biological functionalities. This might be valuable in the development of versatile biomaterials. At biological fields, protein-based materials might be components to form a 3D network of extracellular biomolecules, containing growth factors. Also, the protein-based biomaterial provides biochemical and structural assistance of adjacent cells. In this study, we try to prepare protein based biomaterial, which was harvested from living animal. We analyzed it’s chemical, physical and biological property in vitro. Besides, in vivo bio-interaction of the prepared biomimetic matrix was tested in an animal model. The protein-based biomaterial has degradability and biocompatibility. This development could be used for tissue regenerations and be served as platform technologies.

Keywords: protein based, in vitro study, in vivo study, biomaterials

Procedia PDF Downloads 189
1668 Dental Ethics versus Malpractice, as Phenomenon with a Growing Trend

Authors: Saimir Heta, Kers Kapaj, Rialda Xhizdari, Ilma Robo

Abstract:

Dealing with emerging cases of dental malpractice with justifications that stem from the clear rules of dental ethics is a phenomenon with an increasing trend in today's dental practice. Dentists should clearly understand how far the limit of malpractice goes, with or without minimal or major consequences, for the affected patient, which can be justified as a complication of dental treatment, in support of the rules of dental ethics in the dental office. Indeed, malpractice can occur in cases of lack of professionalism, but it can also come as a consequence of anatomical and physiological limitations in the implementation of the dental protocols, predetermined and indicated by the patient in the paragraph of the treatment plan in his personal card. This study is of the review type with the aim of the latest findings published in the literature about the problem of dealing with these phenomena. The combination of keywords is done in such a way with the aim to give the necessary space for collecting the right information in the networks of publications about this field, always first from the point of view of the dentist and not from that of the lawyer or jurist. From the findings included in this article, it was noticed the diversity of approaches towards the phenomenon depends on the different countries based on the legal basis that these countries have. There is a lack of or a small number of articles that touch on this topic, and these articles are presented with a limited number of data on the same topic. Conclusions: Dental malpractice should not be hidden under the guise of various dental complications that we justify with the strict rules of ethics for patients treated in the dental chair. The individual experience of dental malpractice must be published with the aim of serving as a source of experience for future generations of dentists.

Keywords: dental ethics, malpractice, professional protocol, random deviation

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1667 Functionalization of Carboxylated Single-Walled Carbon Nanotubes with 2-En 4-Hydroxy Cyclo 1-Octanon and Toxicity Investigation

Authors: D. ChobfroushKhoei, S. K. Heidari , Sh. Dariadel

Abstract:

Carbon nanotubes were used in medical sciences especially in drug delivery system and cancer therapy. In this study, we functionalized carboxylated single-wall carbon nanotubes (SWNT-COOH) with 2-en 4-hydroxy cyclo 1-octanon. Synthesized sample was characterized by FT-IR, Raman spectroscopy, SEM, TGA and cellular investigations. The results showed well formation of SWNT-Ester. Cell viability assay results and microscopic observations demonstrated that cancerous cells were killed in the sample. The synthesized sample can be used as a toxic material for cancer therapy.

Keywords: MWNT-COOH, functionalization, phenylisocyanate, phenylisothiocyanate, 1, 4-phenylendiamine, toxicity investigation

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1666 The Use of Medical Biotechnology to Treat Genetic Disease

Authors: Rachel Matar, Maxime Merheb

Abstract:

Chemical drugs have been used for many centuries as the only way to cure diseases until the novel gene therapy has been created in 1960. Gene therapy is based on the insertion, correction, or inactivation of genes to treat people with genetic illness (1). Gene therapy has made wonders in Parkison’s, Alzheimer and multiple sclerosis. In addition to great promises in the healing of deadly diseases like many types of cancer and autoimmune diseases (2). This method implies the use of recombinant DNA technology with the help of different viral and non-viral vectors (3). It is nowadays used in somatic cells as well as embryos and gametes. Beside all the benefits of gene therapy, this technique is deemed by some opponents as an ethically unacceptable treatment as it implies playing with the genes of living organisms.

Keywords: gene therapy, genetic disease, cancer, multiple sclerosis

Procedia PDF Downloads 541
1665 Regulation of Water Balance of the Plant from the Different Geo-Environmental Locations

Authors: Astghik R. Sukiasyan

Abstract:

Under the drought stress condition, the plants would grow slower. Temperature is one of the most important abiotic factors which suppress the germination processes. However, the processes of transpiration are regulated directly by the cell water, which followed to an increase in volume of vacuoles. During stretching under the influence of water pressure, the cell goes into the state of turgor. In our experiments, lines of the semi-dental sweet maize of Armenian population from various zones of growth under mild and severe drought stress were tested. According to results, the value of the water balance of the plant cells may reflect the ability of plants to adapt to drought stress. It can be assumed that the turgor allows evaluating the number of received dissolved substance in cell.

Keywords: turgor, drought stress, plant growth, Armenian Zea Maize Semidentata

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1664 Development of Electromyography (EMG) Signal Acquisition System by Simple Electronic Circuits

Authors: Divya Pradip Roy, Md. Zahirul Alam Chowdhury

Abstract:

Electromyography (EMG) sensors are generally used to record the electrical activity produced by skeletal muscles. The conventional EMG sensors available in the market are expensive. This research suggests a low cost EMG sensor design which can be built with simple devices within our reach. In this research, one instrumentation amplifier, two high pass filters, two low pass filters and an inverting amplifier is connected sequentially. The output from the circuit exhibits electrical potential generated by the muscle cells when they are neurologically activated. This electromyography signal is used to control prosthetic devices, identifying neuromuscular diseases and for various other purposes.

Keywords: EMG, high pass filter, instrumentation amplifier, inverting amplifier, low pass filter, neuromuscular

Procedia PDF Downloads 175
1663 Social Discourses on Lone Motherhood in South Korea: Social Prejudice and Process of Resistance, Adaptation and Negotiation

Authors: Thi Thu Van Nguyen

Abstract:

In South Korea, Confucianism has not only played a crucial position in Korean traditional culture but also deeply rooted in people’s mind. Confucianism bears a special emphasis on the traditional family pattern characterized by paternalism. Therefore, non-paternity families are barely recognized and unwed mothers are faced with numerous prejudices in their life. Prejudice to unwed mothers in Korea is believed to stem from social discourses against lone motherhood which is the way how people look and talk about unwed mothers and from the early time these social discourses have big impacts on their daily lives. However, after the 1990s, along with the rapid transformation of family pattern and support from social welfare organizations, unwed mothers have gradually got to escape from the social prejudice then established themselves as a new family form. This study is aimed at researching social discourses on lone motherhood in Korea and the process of resistance, adaptation and negotiation of unwed mothers in three different stages: the antenatal, postnatal stages and social inclusion. The anthropological method is employed. Twenty single young mothers of the Korean Unwed Mothers Families' Association were engaged in the author’s detailed interviews. The study’s frame analysis is based on the theoretical framework on social discourses on lone motherhood by Simon Duncan and Rosalind Edwards (1999). This study is an effort to comprehend and investigate the difficulties experienced by unwed mothers living in negative social discourses and the way they overcome the difficulties.

Keywords: unwed mothers, gender, social discourses, social prejudice, Confucianism

Procedia PDF Downloads 270
1662 On the Causes of Boko Haram Terrorism: Socio-Economic versus Religious Injunctions

Authors: Sogo Angel Olofinbiyi

Abstract:

There have been widespread assumptions across the globe that the root cause of Boko Haram terrorism in Nigeria is religious rather than socio-economic. An investigation into this dichotomy allowed this study to fully demonstrate that the root cause of Boko Haram’s terrorist actions emanates from the non-fulfillment of socio-economic goals that are prompted by the violation of fundamental human rights, corruption, poverty, unconstitutional and undemocratic practices in the northern part of the Nigerian state. To achieve its aim of establishing the root cause of the terrorism crisis in the latter country, the study critically appraised the socio-economic context of the insurgency by adopting one-on-one in-depth interviews involving forty (40) participants to interrogate the phenomenon. Empirical evidence from the study demonstrated that the evolution of Boko Haram terrorism was a response to socio-economic phlebotomy, political and moral putrescence, and the dehumanization of people that stem from a combination of decades of mismanagement and pervasive corruption by various Nigerian leaders. The study concludes that, as long as the endemic socio-economic problems caused by global capitalism vis-a-vis unequal hegemonic power exchange as expressed in socio-political, ethno-religious and cultural forms persist in the Nigerian society, the terrorism insurgency will recur and remain an inevitable enterprise and indeed a normal social reaction to every undesirable state of affairs. Based on the findings, the study urges the need for the amelioration of the conditions of the vast majority of the Nigerian populace by making socio-economic facilities available to them through the political state.

Keywords: Boko Haram Terrorism, insurgency, socio-economic, religious injunctions

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1661 Effect of Degree of Phosphorylation on Electrospinning and In vitro Cell Behavior of Phosphorylated Polymers as Biomimetic Materials for Tissue Engineering Applications

Authors: Pallab Datta, Jyotirmoy Chatterjee, Santanu Dhara

Abstract:

Over the past few years, phosphorous containing polymers have received widespread attention for applications such as high performance optical fibers, flame retardant materials, drug delivery and tissue engineering. Being pentavalent, phosphorous can exist in different chemical environments in these polymers which increase their versatility. In human biochemistry, phosphorous based compounds exert their functions both in soluble and insoluble form occurring as inorganic or as organophosphorous compounds. Specifically in case of biomacromolecules, phosphates are critical for functions of DNA, ATP, phosphoproteins, phospholipids, phosphoglycans and several coenzymes. Inspired by the role of phosphorous in functional biomacromolecules, design and synthesis of biomimetic materials are thus carried out by several authors to study macromolecular function or as substitutes in clinical tissue regeneration conditions. In addition, many regulatory signals of the body are controlled by phoshphorylation of key proteins present either in form of growth factors or matrix-bound scaffold proteins. This inspires works on synthesis of phospho-peptidomimetic amino acids for understanding key signaling pathways and this is extended to obtain molecules with potentially useful biological properties. Apart from above applications, phosphate groups bound to polymer backbones have also been demonstrated to improve function of osteoblast cells and augment performance of bone grafts. Despite the advantages of phosphate grafting, however, there is limited understanding on effect of degree of phosphorylation on macromolecular physicochemical and/or biological properties. Such investigations are necessary to effectively translate knowledge of macromolecular biochemistry into relevant clinical products since they directly influence processability of these polymers into suitable scaffold structures and control subsequent biological response. Amongst various techniques for fabrication of biomimetic scaffolds, nanofibrous scaffolds fabricated by electrospinning technique offer some special advantages in resembling the attributes of natural extracellular matrix. Understanding changes in physico-chemical properties of polymers as function of phosphorylation is therefore going to be crucial in development of nanofiber scaffolds based on phosphorylated polymers. The aim of the present work is to investigate the effect of phosphorous grafting on the electrospinning behavior of polymers with aim to obtain biomaterials for bone regeneration applications. For this purpose, phosphorylated derivatives of two polymers of widely different electrospinning behaviors were selected as starting materials. Poly(vinyl alcohol) is a conveniently electrospinnable polymer at different conditions and concentrations. On the other hand, electrospinning of chitosan backbone based polymers have been viewed as a critical challenge. The phosphorylated derivatives of these polymers were synthesized, characterized and electrospinning behavior of various solutions containing these derivatives was compared with electrospinning of pure poly (vinyl alcohol). In PVA, phosphorylation adversely impacted electrospinnability while in NMPC, higher phosphate content widened concentration range for nanofiber formation. Culture of MG-63 cells on electrospun nanofibers, revealed that degree of phosphate modification of a polymer significantly improves cell adhesion or osteoblast function of cultured cells. It is concluded that improvement of cell response parameters of nanofiber scaffolds can be attained as a function of controlled degree of phosphate grafting in polymeric biomaterials with implications for bone tissue engineering applications.

Keywords: bone regeneration, chitosan, electrospinning, phosphorylation

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1660 Efficacy and Safety of COVID-19 Vaccination in Patients with Multiple Sclerosis: Looking Forward to Post-COVID-19

Authors: Achiron Anat, Mathilda Mandel, Mayust Sue, Achiron Reuven, Gurevich Michael

Abstract:

Introduction: As coronavirus disease 2019 (COVID-19) vaccination is currently spreading around the world, it is of importance to assess the ability of multiple sclerosis (MS) patients to mount an appropriate immune response to the vaccine in the context of disease-modifying treatments (DMT’s). Objectives: Evaluate immunity generated following COVID-19 vaccination in MS patients, and assess factors contributing to protective humoral and cellular immune responses in MS patients vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) virus infection. Methods: Review our recent data related to (1) the safety of PfizerBNT162b2 COVID-19 mRNA vaccine in adult MS patients; (2) the humoral post-vaccination SARS-CoV2 IgG response in MS vaccinees using anti-spike protein-based serology; and (3) the cellular immune response of memory B-cells specific for SARS-CoV-2 receptor-binding domain (RBD) and memory T-cells secreting IFN-g and/or IL-2 in response to SARS-CoV2 peptides using ELISpot/Fluorospot assays in MS patients either untreated or under treatment with fingolimod, cladribine, or ocrelizumab; (4) covariate parameters related to mounting protective immune responses. Results: COVID-19 vaccine proved safe in MS patients, and the adverse event profile was mainly characterised by pain at the injection site, fatigue, and headache. Not any increased risk of relapse activity was noted and the rate of patients with acute relapse was comparable to the relapse rate in non-vaccinated patients during the corresponding follow-up period. A mild increase in the rate of adverse events was noted in younger MS patients, among patients with lower disability, and in patients treated with DMTs. Following COVID-19 vaccination protective humoral immune response was significantly decreased in fingolimod- and ocrelizumab- treated MS patients. SARS-CoV2 specific B-cell and T-cell cellular responses were respectively decreased. Untreated MS patients and patients treated with cladribine demonstrated protective humoral and cellular immune responses, similar to healthy vaccinated subjects. Conclusions: COVID-19 BNT162b2 vaccine proved as safe for MS patients. No increased risk of relapse activity was noted post-vaccination. Although COVID-19 vaccination is new, accumulated data demonstrate differences in immune responses under various DMT’s. This knowledge can help to construct appropriate COVID-19 vaccine guidelines to ensure proper immune responses for MS patients.

Keywords: covid-19, vaccination, multiple sclerosis, IgG

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1659 Biosensor for Determination of Immunoglobulin A, E, G and M

Authors: Umut Kokbas, Mustafa Nisari

Abstract:

Immunoglobulins, also known as antibodies, are glycoprotein molecules produced by activated B cells that transform into plasma cells and result in them. Antibodies are critical molecules of the immune response to fight, which help the immune system specifically recognize and destroy antigens such as bacteria, viruses, and toxins. Immunoglobulin classes differ in their biological properties, structures, targets, functions, and distributions. Five major classes of antibodies have been identified in mammals: IgA, IgD, IgE, IgG, and IgM. Evaluation of the immunoglobulin isotype can provide a useful insight into the complex humoral immune response. Evaluation and knowledge of immunoglobulin structure and classes are also important for the selection and preparation of antibodies for immunoassays and other detection applications. The immunoglobulin test measures the level of certain immunoglobulins in the blood. IgA, IgG, and IgM are usually measured together. In this way, they can provide doctors with important information, especially regarding immune deficiency diseases. Hypogammaglobulinemia (HGG) is one of the main groups of primary immunodeficiency disorders. HGG is caused by various defects in B cell lineage or function that result in low levels of immunoglobulins in the bloodstream. This affects the body's immune response, causing a wide range of clinical features, from asymptomatic diseases to severe and recurrent infections, chronic inflammation and autoimmunity Transient infant hypogammaglobulinemia (THGI), IgM deficiency (IgMD), Bruton agammaglobulinemia, IgA deficiency (SIgAD) HGG samples are a few. Most patients can continue their normal lives by taking prophylactic antibiotics. However, patients with severe infections require intravenous immune serum globulin (IVIG) therapy. The IgE level may rise to fight off parasitic infections, as well as a sign that the body is overreacting to allergens. Also, since the immune response can vary with different antigens, measuring specific antibody levels also aids in the interpretation of the immune response after immunization or vaccination. Immune deficiencies usually occur in childhood. In Immunology and Allergy clinics, apart from the classical methods, it will be more useful in terms of diagnosis and follow-up of diseases, if it is fast, reliable and especially in childhood hypogammaglobulinemia, sampling from children with a method that is more convenient and uncomplicated. The antibodies were attached to the electrode surface via the poly hydroxyethyl methacrylamide cysteine nanopolymer. It was used to evaluate the anodic peak results obtained in the electrochemical study. According to the data obtained, immunoglobulin determination can be made with a biosensor. However, in further studies, it will be useful to develop a medical diagnostic kit with biomedical engineering and to increase its sensitivity.

Keywords: biosensor, immunosensor, immunoglobulin, infection

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1658 Do Immune Organ Weights Indicate Immunomodulation of Polyunsaturated Fatty Acids?

Authors: H. Al-Khalifa, A. Al-Nasser

Abstract:

The main immune organs in poultry are the thymus, spleen and bursa of Fabricius. During an immune response, mature lymphocytes and other immune cells interact with antigens in these tissues. Consequently, the mass of these organs can in some cases indicate immune status. The objective of the current study was to investigate the effect of feeding flaxseed on immune tissue weights. Cobb 500 broiler chickens were fed flaxseed at 15%, the control diet did not contain any flaxseed. Results showed that dietary supplementation with flaxseed did not affect the weights of the spleens of broiler chickens. However, it significantly lowered bursa weights (p<0.01), compared to the control diet. In addition, the bursae were thinner in appearance compared with bursii from chickens fed the control diets.

Keywords: bursa of fabricius, flaxseed, spleen, thymus

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1657 Interval Functional Electrical Stimulation Cycling and Nutritional Counseling Improves Lean Mass to Fat Mass Ratio and Decreases Cardiometabolic Disease Risk in Individuals with Spinal Cord Injury

Authors: David Dolbow, Daniel Credeur, Mujtaba Rahimi, Dobrivoje Stokic, Jennifer Lemacks, Andrew Courtner

Abstract:

Introduction: Obesity is at epidemic proportions in the spinal cord injury (SCI) population (66-75%), as individuals who suffer from paralysis undergo a dramatic decrease in muscle mass and a dramatic increase in adipose deposition. Obesity is a major public health concern which includes a doubling of the risk of heart disease, stroke and type II diabetes mellitus. It has been demonstrated that physical activity, and especially HIIT, can promote a healthy body composition and decrease the risk cardiometabolic disease in the able-bodied population. However, SCI typically limits voluntary exercise to the arms, but a high prevalence of shoulder pain in persons with chronic SCI (60-90%) can cause increased arm exercise to be problematic. Functional electrical stimulation (FES) cycling has proven to be a safe and effective way to exercise paralyzed leg muscles in clinical and home settings, saving the often overworked arms. Yet, HIIT-FES cycling had not been investigated prior to the current study. The purpose of this study was to investigate the body composition changes with combined HIIT-FES cycling and nutritional counseling on individuals with SCI. Design: A matched (level of injury, time since injury, body mass index) and controlled trail. Setting: University exercise performance laboratory. Subjects: Ten individuals with chronic SCI (C5-T9) ASIA impairment classification (A & B) were divided into the treatment group (n=5) for 30 minutes of HIIT-FES cycling 3 times per week for 8 weeks and nutritional counseling over the phone for 30 minutes once per week for 8 weeks and the control group (n=5) who received nutritional counseling only. Results: There was a statistically significant difference between the HIIT-FES group and the control group in mean body fat percentage change (-1.14 to +0.24) respectively, p = .030). There was also a statistically significant difference between the HIIT-FES and control groups in mean change in legs lean mass (+0.78 kg to -1.5 kg) respectively, p = 0.004. There was a nominal decrease in weight, BMI, total fat mass and a nominal increase in total lean mass for the HIIT-FES group over the control group. However, these changes were not found to be statistically significant. Additionally, there was a nominal decrease in the mean blood glucose levels for both groups 101.8 to 97.8 mg/dl for the HIIT-FES group and 94.6 to 93 mg/dl for the Nutrition only group, however, neither were found to be statistically significant. Conclusion: HIIT-FES cycling combined with nutritional counseling can provide healthful body composition changes including decreased body fat percentage in just 8 weeks. Future study recommendations include a greater number of participants, a primer electrical stimulation exercise program to better ready participants for HIIT-FES cycling and a greater volume of training above 30 minutes, 3 times per week for 8 weeks.

Keywords: body composition, functional electrical stimulation cycling, high-intensity interval training, spinal cord injury

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1656 Effect of Boric Acid Content on the Structural and Optical Properties of In2O3 Films Prepared by Spray Pyrolysis Technique

Authors: Mustafa Öztas, Metin Bedir, Yahya Özdemir

Abstract:

Boron doped of In2O3 films were prepared by spray pyrolysis technique at 350 °C substrate temperature, which is a low cost and large area technique to be well-suited for the manufacture of solar cells, using boric acid (H3BO3) as dopant source, and their properties were investigated as a function of doping concentration. X-ray analysis showed that the films were polycrystalline fitting well with a hexagonal structure and have preferred orientation in (220) direction. The changes observed in the energy band gap and structural properties of the films related to the boric acid concentration are discussed in detail.

Keywords: spray pyrolysis, In2O3, boron, optical properties, boric acid

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1655 Antiulcer Potential of Heme Oxygenase-1 Inducers

Authors: Gaweł Magdalena, Lipkowska Anna, Olbert Magdalena, Frąckiewicz Ewelina, Librowski Tadeusz, Nowak Gabriel, Pilc Andrzej

Abstract:

Heme oxygenase-1 (HO-1), also known as heat shock protein 32 (HSP32), has been shown to be implicated in cytoprotection in various organs. Its activation plays a significant role in acute and chronic inflammation, protecting cells from oxidative injury and apoptosis. This inducible isoform of HO catalyzes the first and rate-limiting step in heme degradation to produce equimolar quantities of biologically active products: carbon monoxide (CO), free iron and biliverdin. CO has been reported to possess anti-apoptotic properties. Moreover, it inhibits the production of proinflammatory cytokines and stimulates the synthesis of the anti-inflammatory interleukin-10 (IL-10), as well as promotes vasodilatation at sites of inflammation. The second product of catalytic HO-1 activity, free cytotoxic iron, is promptly sequestered into the iron storage protein ferritin, which lowers the pro-oxidant state of the cell. The third product, biliverdin, is subsequently converted by biliverdin reductase into the bile pigment bilirubin, the most potent endogenous antioxidant among the constituents of human serum, which modulates immune effector functions and suppresses inflammatory response. Furthermore, being one of the so-called stress proteins, HO-1 adaptively responds to different stressors, such as reactive oxygen species (ROS), inflammatory cytokines and heavy metals and thus protects cells against such conditions as ischemia, hemorrhagic shock, heat shock or hypoxia. It is suggested that pharmacologic modulation of HO-1 may represent an effective strategy for prevention of stress and drug-induced gastrointestinal toxicity. HO-1 is constitutively expressed in normal gastric, intestinal and colonic mucosa and up-regulated during inflammation. It has been proven that HO-1 up-regulated by hemin, heme and cobalt-protoporphyrin ameliorates experimental colitis. In addition, the up-regulation of HO-1 partially explains the mechanism of action of 5-aminosalicylic acid (5-ASA), which is used clinically as an anti-colitis agent. In 2009 Ueda et al. has reported for the first time that mucosal protection by Polaprezinc, a chelate compound of zinc and L-carnosine used as an anti-ulcer drug in Japan, is also attributed to induction of HO-1 in the stomach. Since then, inducers of HO-1 are desired subject of research, as they may constitute therapeutically effective anti-ulcer drugs.

Keywords: heme oxygenase-1, gastric lesions, gastroprotection, Polaprezinc

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1654 Solar Cell Using Chemical Bath Deposited PbS:Bi3+ Films as Electron Collecting Layer

Authors: Melissa Chavez Portillo, Mauricio Pacio Castillo, Hector Juarez Santiesteban, Oscar Portillo Moreno

Abstract:

Chemical bath deposited PbS:Bi3+ as an electron collection layer is introduced between the silicon wafer and the Ag electrode the performance of the PbS heterojunction thin film solar thin film solar cells with 1 cm2 active area. We employed Bi-doping to transform it into an n-type semiconductor. The experimental results reveal that the cell response parameters depend critically on the deposition procedures in terms of bath temperature, deposition time. The device achieves an open-circuit voltage of 0.4 V. The simple and low-cost deposition method of PbS:Bi3+ films is promising for the fabrication.

Keywords: Bi doping, PbS, thin films, solar cell

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1653 Effects of the Ambient Temperature and the Defect Density on the Performance the Solar Cell (HIT)

Authors: Bouzaki Mohammed Moustafa, Benyoucef Boumediene, Benouaz Tayeb, Benhamou Amina

Abstract:

The ambient temperature and the defects density in the Hetero-junction with Intrinsic Thin layers solar cells (HIT) strongly influence their performances. In first part, we presented the bands diagram on the front/back simulated solar cell based on a-Si: H / c-Si (p)/a-Si:h. In another part, we modeled the following layers structure: ZnO/a-Si:H(n)/a-Si:H(i)/c-Si(p)/a-Si:H(p)/Ag where we studied the effect of the ambient temperature and the defects density in the gap of the crystalline silicon layer on the performance of the heterojunction solar cell with intrinsic layer (HIT).

Keywords: heterojunction solar cell, solar cell performance, bands diagram, ambient temperature, defect density

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1652 Growing Sorghum Varieties with Potential of Fodder and Biofuel Crops, with Potential of Two Harvest in One Year

Authors: Farah Jafarpisheh, John Hutson, Howard Fallowfield

Abstract:

Growing Sorghum varieties, with the potential of the animal food source, by using the treated wastewater from High Rate Algae Ponds (HRAPs) is an attractive subject. For the first time, in South Australia, Sorghum Earthnote variety one (SE1) has been grown using the wastewater from HRAPs. In this study, after the first harvest, the roots left in the soil. After a short period of time, sorghum started to regrow again, which can increase the value of planting sorghum by using the wastewater. This study demonstrates the higher amount of green biomass with the potential of animal food source after the second harvest. Different parameters, including height(mm), number of leaves and tiller, Brix percentage, fresh and dry leaf weight(g), total top fresh weight(g), stem and seed dry and fresh weight(g) have been measured in the field after first and second harvest. The results demonstrated the higher height, number of tiller, and diameter after the second harvest. Number of leaves and leaves fresh weight and total top weight increased by 6 and 10 times, respectively. Brix percentage increased by 2 times. In the first harvest, no seeds harvested, while in the second harvest, 134 g seeds harvested. This sorghum variety (SE1) showed the acceptable green biomass, especially after the second harvest. This property will add to the value of sorghum in this condition, as it will not need extra fertilizer and labor work for seed planting.

Keywords: energy, high rate algae ponds, HRAPs, Sorghum, waste water

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1651 Immuno-Protective Role of Mucosal Delivery of Lactococcus lactis Expressing Functionally Active JlpA Protein on Campylobacter jejuni Colonization in Chickens

Authors: Ankita Singh, Chandan Gorain, Amirul I. Mallick

Abstract:

Successful adherence of the mucosal epithelial cells is the key early step for Campylobacter jejuni pathogenesis (C. jejuni). A set of Surface Exposed Colonization Proteins (SECPs) are among the major factors involved in host cell adherence and invasion of C. jejuni. Among them, constitutively expressed surface-exposed lipoprotein adhesin of C. jejuni, JlpA, interacts with intestinal heat shock protein 90 (hsp90α) and contributes in disease progression by triggering pro-inflammatory response via activation of NF-κB and p38 MAP kinase pathway. Together with its ability to express in the bacterial surface, higher sequence conservation and predicted predominance of several B cells epitopes, JlpA protein reserves its potential to become an effective vaccine candidate against wide range of Campylobacter sps including C. jejuni. Given that chickens are the primary sources for C. jejuni and persistent gut colonization remain as major cause for foodborne pathogenesis to humans, present study explicitly used chickens as model to test the immune-protective efficacy of JlpA protein. Taking into account that gastrointestinal tract is the focal site for C. jejuni colonization, to extrapolate the benefit of mucosal (intragastric) delivery of JlpA protein, a food grade Nisin inducible Lactic acid producing bacteria, Lactococcus lactis (L. lactis) was engineered to express recombinant JlpA protein (rJlpA) in the surface of the bacteria. Following evaluation of optimal surface expression and functionality of recombinant JlpA protein expressed by recombinant L. lactis (rL. lactis), the immune-protective role of intragastric administration of live rL. lactis was assessed in commercial broiler chickens. In addition to the significant elevation of antigen specific mucosal immune responses in the intestine of chickens that received three doses of rL. lactis, marked upregulation of Toll-like receptor 2 (TLR2) gene expression in association with mixed pro-inflammatory responses (both Th1 and Th17 type) was observed. Furthermore, intragastric delivery of rJlpA expressed by rL. lactis, but not the injectable form, resulted in a significant reduction in C. jejuni colonization in chickens suggesting that mucosal delivery of live rL. lactis expressing JlpA serves as a promising vaccine platform to induce strong immune-protective responses against C. jejuni in chickens.

Keywords: chickens, lipoprotein adhesion of Campylobacter jejuni, immuno-protection, Lactococcus lactis, mucosal delivery

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1650 EU Policies in Determining Refugee Status

Authors: Adriano Mortada

Abstract:

Human history is rife with conflict, and the question of refugee status determination and their rehabilitation has been up for debate since. Refugee Status Determination is the administrative or legal process by which UNHCR or governments determine whether a person seeking international protection or asylum can be identified as a refugee under international, regional, or national law. Refugee Status Determination is considered to be a vital process in aiding refugees’ realization of their rights under international law. One of the major reasons why the refugee status determination is considered an “issue”, and is one that is much debated upon annually, is the fact that the national bureaucratic systems are rigid and unbending. This is particularly concerning in the 21st century despite human advancement in policy and diplomacy, working in tandem with the United Nations and their charters and resolutions on human rights and dignity. The paper seeks to criticize the European member states' response to the refugee crisis and their inflexible and prejudiced bureaucratic systems when it comes to refugee status determination. The paper looks at multiple case studies as primary evidence and the alternate case studies where the system helped refugees, like those in Jordan, Pakistan, Turkey, and Lebanon. The main concern of the paper is to highlight the bias in the selected European systems, which do not stem from the Human Rights Charter but rather on the basis of geographical backgrounds, cultural and religious affiliations of those seeking refugee status or asylum in their respective countries. The paper hopes to not only create awareness about this issue but also provide a research background to advocacy programs to bring a change in the systems.

Keywords: refugee status determination, human rights, bureaucracy, United Nations, European Union

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1649 DNA Methylation Changes Caused by Lawsone

Authors: Zuzana Poborilova, Anna B. Ohlsson, Torkel Berglund, Anna Vildova, Petr Babula

Abstract:

Lawsone is a pigment that occurs naturally in plants. It has been used as a skin and hair dye for a long time. Moreover, its different biological activities have been reported. The present study focused on the effect of lawsone on a plant cell model represented by tobacco BY-2 cell suspension culture, which is used as a model comparable with the HeLa cells. It has been shown that lawsone inhibits the cell growth in the concentration-dependent manner. In addition, changes in DNA methylation level have been determined. We observed decreasing level of DNA methylation in the presence of increasing concentrations of lawsone. These results were accompanied with overproduction of reactive oxygen species (ROS). Since epigenetic modifications can be caused by different stress factors, there could be a connection between the changes in the level of DNA methylation and ROS production caused by lawsone.

Keywords: DNA methylation, lawsone, naphthoquinone, reactive oxygen species

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1648 Assessment of the Efficacy of Routine Medical Tests in Screening Medical Radiation Staff in Shiraz University of Medical Sciences Educational Centers

Authors: Z. Razi, S. M. J. Mortazavi, N. Shokrpour, Z. Shayan, F. Amiri

Abstract:

Long-term exposure to low doses of ionizing radiation occurs in radiation health care workplaces. Although doses in health professions are generally very low, there are still matters of concern. The radiation safety program promotes occupational radiation safety through accurate and reliable monitoring of radiation workers in order to effectively manage radiation protection. To achieve this goal, it has become mandatory to implement health examination periodically. As a result, based on the hematological alterations, working populations with a common occupational radiation history are screened. This paper calls into question the effectiveness of blood component analysis as a screening program which is mandatory for medical radiation workers in some countries. This study details the distribution and trends of changes in blood components, including white blood cells (WBCs), red blood cells (RBCs) and platelets as well as received cumulative doses from occupational radiation exposure. This study was conducted among 199 participants and 100 control subjects at the medical imaging departments at the central hospital of Shiraz University of Medical Sciences during the years 2006–2010. Descriptive and analytical statistics, considering the P-value<0.05 as statistically significance was used for data analysis. The results of this study show that there is no significant difference between the radiation workers and controls regarding WBCs and platelet count during 4 years. Also, we have found no statistically significant difference between the two groups with respect to RBCs. Besides, no statistically significant difference was observed with respect to RBCs with regards to gender, which has been analyzed separately because of the lower reference range for normal RBCs levels in women compared to men and. Moreover, the findings confirm that in a separate evaluation between WBCs count and the personnel’s working experience and their annual exposure dose, results showed no linear correlation between the three variables. Since the hematological findings were within the range of control levels, it can be concluded that the radiation dosage (which was not more than 7.58 mSv in this study) had been too small to stimulate any quantifiable change in medical radiation worker’s blood count. Thus, use of more accurate method for screening program based on the working profile of the radiation workers and their accumulated dose is suggested. In addition, complexity of radiation-induced functions and the influence of various factors on blood count alteration should be taken into account.

Keywords: blood cell count, mandatory testing, occupational exposure, radiation

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1647 Case Report of Intramural Pregnancy

Authors: S. Woźniak, J. Rybka, T. Paszkowski, P. Milart

Abstract:

A 30-year-old patient, who was pregnant for her second 9 weeks, was admitted to the hospital due to a suspected incomplete miscarriage. A fetal egg was found in the uterine cavity near the mouth of the fallopian tube. The patient was qualified for dilatation and curettage. The histopathological examination revealed fragments of the trophoblast. Two months later, the patient was re-admitted to the hospital due to vaginal bleeding and elevated levels of beta-hCG. Additional tests were performed. An intramural pregnancy was suspected. The patient was qualified for embolization of the uterine arteries and then treatment with methotrexate. Three weeks later, during a routine gynecological examination, a detached tumor 4 cm in diameter was found in the vagina. The material was sent for histopathological examination, which showed the presence of trophoblastic cells.

Keywords: ectopic pregnancy, intramural pregnancy, uterine artery embolization, methotrexate

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1646 Fixed Point Iteration of a Damped and Unforced Duffing's Equation

Authors: Paschal A. Ochang, Emmanuel C. Oji

Abstract:

The Duffing’s Equation is a second order system that is very important because they are fundamental to the behaviour of higher order systems and they have applications in almost all fields of science and engineering. In the biological area, it is useful in plant stem dependence and natural frequency and model of the Brain Crash Analysis (BCA). In Engineering, it is useful in the study of Damping indoor construction and Traffic lights and to the meteorologist it is used in the prediction of weather conditions. However, most Problems in real life that occur are non-linear in nature and may not have analytical solutions except approximations or simulations, so trying to find an exact explicit solution may in general be complicated and sometimes impossible. Therefore we aim to find out if it is possible to obtain one analytical fixed point to the non-linear ordinary equation using fixed point analytical method. We started by exposing the scope of the Duffing’s equation and other related works on it. With a major focus on the fixed point and fixed point iterative scheme, we tried different iterative schemes on the Duffing’s Equation. We were able to identify that one can only see the fixed points to a Damped Duffing’s Equation and not to the Undamped Duffing’s Equation. This is because the cubic nonlinearity term is the determining factor to the Duffing’s Equation. We finally came to the results where we identified the stability of an equation that is damped, forced and second order in nature. Generally, in this research, we approximate the solution of Duffing’s Equation by converting it to a system of First and Second Order Ordinary Differential Equation and using Fixed Point Iterative approach. This approach shows that for different versions of Duffing’s Equations (damped), we find fixed points, therefore the order of computations and running time of applied software in all fields using the Duffing’s equation will be reduced.

Keywords: damping, Duffing's equation, fixed point analysis, second order differential, stability analysis

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1645 Resveratrol Ameliorates Benzo(a)Pyrene Induced Testicular Dysfunction and Apoptosis: Involvement of p38 MAPK/ATF2/iNOS Signaling

Authors: Kuladip Jana, Bhaswati Banerjee, Parimal C. Sen

Abstract:

Benzo(a)pyrene [B(a)P] is an environmental toxicant present mostly in cigarette smoke and car exhaust, is an aryl hydrocarbon receptor (AhR) ligand that exerts its toxic effects on both male and female reproductive systems along with carcinogenesis in skin, prostate, ovary, lung and mammary glands. Our study was focused on elucidating the molecular mechanism of B(a)P induced male reproductive toxicity and its prevention with phytochemical like resveratrol. In this study, the effect of B(a)P at different doses (0.1, 0.25, 0.5, 1 and 5 mg /kg body weight) was studied on male reproductive system of Wistar rat. A significant decrease in cauda epididymal sperm count and motility along with the presence of sperm head abnormalities and altered epididymal and testicular histology were documented following B(a)P treatment. B(a)P treatment resulted apoptotic sperm cells as observed by TUNEL and Annexin V-PI assay with increased Reactive Oxygen Species (ROS), altered sperm mitochondrial membrane potential (ΔΨm) with a simultaneous decrease in the activity of antioxidant enzymes and GSH status. TUNEL positive apoptotic cells also observed in testis as well as isolated germ and Leydig cells following B(a)P exposure. Western Blot analysis revealed the activation of p38 mitogen activated protein kinase (p38MAPK), cytosolic translocation of cytochrome-c, upregulation of Bax and inducible nitric oxide synthase (iNOS) with cleavage of poly ADP ribose polymerase (PARP) and down regulation of BCl2 in testis upon B(a)P treatment. The protein and mRNA levels of testicular key steroidogenesis regulatory proteins like steroidogenic acute regulatory protein (StAR), cytochrome P450 IIA1 (CYPIIA1), 3β hydroxy steroid dehydrogenase (3β HSD), 17β hydroxy steroid dehydrogenase (17β HSD) showed a significant decrease in a dose dependent manner while an increase in the expression of cytochrome P450 1A1 (CYP1A1), Aryl hydrocarbon Receptor (AhR), active caspase- 9 and caspase- 3 following B(a)P exposure. We conclude that exposure of benzo(a)pyrene caused testicular gamatogenic and steroidogenic disorders by induction of oxidative stress, inhibition of StAR and other steroidogenic enzymes along with activation of p38MAPK and initiated caspase-3 mediated germ and Leydig cell apoptosis. Next we investigated the role of resveratrol on B(a)P induced male reproductive toxicity. Our study highlighted that resveratrol co-treatment with B(a)P maintained testicular redox potential, increased serum testosterone level and prevented steroidogenic dysfunction with enhanced expression of major testicular steroidogenic proteins (CYPIIA1, StAR, 3β HSD,17β HSD) relative to treatment with B(a)P only. Resveratrol suppressed B(a)P-induced testicular activation of p38 MAPK, ATF2, iNOS and ROS production; cytosolic translocation of Cytochome c and Caspase 3 activation thereby prevented oxidative stress of testis and inhibited apoptosis. Resveratrol co-treatment also decreased B(a)P-induced AhR protein level, its nuclear translocation and subsequent CYP1A1 promoter activation, thereby decreased protein and mRNA levels of testicular cytochrome P4501A1 (CYP1A1) and prevented BPDE-DNA adduct formation. Our findings cumulatively suggest that resveratrol prevents activation of B(a)P by modulating the transcriptional regulation of CYP1A1 and acting as an antioxidant thus prevents B(a)P-induced oxidative stress and testicular apoptosis.

Keywords: benzo(a)pyrene, resveratrol, testis, apoptosis, cytochrome P450 1A1 (CYP1A1), aryl hydrocarbon receptor (AhR), p38 MAPK/ATF2/iNOS

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1644 Modeling of Anode Catalyst against CO in Fuel Cell Using Material Informatics

Authors: M. Khorshed Alam, H. Takaba

Abstract:

The catalytic properties of metal usually change by intermixturing with another metal in polymer electrolyte fuel cells. Pt-Ru alloy is one of the much-talked used alloy to enhance the CO oxidation. In this work, we have investigated the CO coverage on the Pt2Ru3 nanoparticle with different atomic conformation of Pt and Ru using a combination of material informatics with computational chemistry. Density functional theory (DFT) calculations used to describe the adsorption strength of CO and H with different conformation of Pt Ru ratio in the Pt2Ru3 slab surface. Then through the Monte Carlo (MC) simulations we examined the segregation behaviour of Pt as a function of surface atom ratio, subsurface atom ratio, particle size of the Pt2Ru3 nanoparticle. We have constructed a regression equation so as to reproduce the results of DFT only from the structural descriptors. Descriptors were selected for the regression equation; xa-b indicates the number of bonds between targeted atom a and neighboring atom b in the same layer (a,b = Pt or Ru). Terms of xa-H2 and xa-CO represent the number of atoms a binding H2 and CO molecules, respectively. xa-S is the number of atom a on the surface. xa-b- is the number of bonds between atom a and neighboring atom b located outside the layer. The surface segregation in the alloying nanoparticles is influenced by their component elements, composition, crystal lattice, shape, size, nature of the adsorbents and its pressure, temperature etc. Simulations were performed on different size (2.0 nm, 3.0 nm) of nanoparticle that were mixing of Pt and Ru atoms in different conformation considering of temperature range 333K. In addition to the Pt2Ru3 alloy we also considered pure Pt and Ru nanoparticle to make comparison of surface coverage by adsorbates (H2, CO). Hence, we assumed the pure and Pt-Ru alloy nanoparticles have an fcc crystal structures as well as a cubo-octahedron shape, which is bounded by (111) and (100) facets. Simulations were performed up to 50 million MC steps. From the results of MC, in the presence of gases (H2, CO), the surfaces are occupied by the gas molecules. In the equilibrium structure the coverage of H and CO as a function of the nature of surface atoms. In the initial structure, the Pt/Ru ratios on the surfaces for different cluster sizes were in range of 0.50 - 0.95. MC simulation was employed when the partial pressure of H2 (PH2) and CO (PCO) were 70 kPa and 100-500 ppm, respectively. The Pt/Ru ratios decrease as the increase in the CO concentration, without little exception only for small nanoparticle. The adsorption strength of CO on the Ru site is higher than the Pt site that would be one of the reason for decreasing the Pt/Ru ratio on the surface. Therefore, our study identifies that controlling the nanoparticle size, composition, conformation of alloying atoms, concentration and chemical potential of adsorbates have impact on the steadiness of nanoparticle alloys which ultimately and also overall catalytic performance during the operations.

Keywords: anode catalysts, fuel cells, material informatics, Monte Carlo

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1643 Computational Insights Into Allosteric Regulation of Lyn Protein Kinase: Structural Dynamics and Impacts of Cancer-Related Mutations

Authors: Mina Rabipour, Elena Pallaske, Floyd Hassenrück, Rocio Rebollido-Rios

Abstract:

Protein tyrosine kinases, including Lyn kinase of the Src family kinases (SFK), regulate cell proliferation, survival, and differentiation. Lyn kinase has been implicated in various cancers, positioning it as a promising therapeutic target. However, the conserved ATP-binding pocket across SFKs makes developing selective inhibitors challenging. This study aims to address this limitation by exploring the potential for allosteric modulation of Lyn kinase, focusing on how its structural dynamics and specific oncogenic mutations impact its conformation and function. To achieve this, we combined homology modeling, molecular dynamics simulations, and data science techniques to conduct microsecond-length simulations. Our approach allowed a detailed investigation into the interplay between Lyn’s catalytic and regulatory domains, identifying key conformational states involved in allosteric regulation. Additionally, we evaluated the structural effects of Dasatinib, a competitive inhibitor, and ATP binding on Lyn active conformation. Notably, our simulations show that cancer-related mutations, specifically I364L/N and E290D/K, shift Lyn toward an inactive conformation, contrasting with the active state of the wild-type protein. This may suggest how these mutations contribute to aberrant signaling in cancer cells. We conducted a dynamical network analysis to assess residue-residue interactions and the impact of mutations on the Lyn intramolecular network. This revealed significant disruptions due to mutations, especially in regions distant from the ATP-binding site. These disruptions suggest potential allosteric sites as therapeutic targets, offering an alternative strategy for Lyn inhibition with higher specificity and fewer off-target effects compared to ATP-competitive inhibitors. Our findings provide insights into Lyn kinase regulation and highlight allosteric sites as avenues for selective drug development. Targeting these sites may modulate Lyn activity in cancer cells, reducing toxicity and improving outcomes. Furthermore, our computational strategy offers a scalable approach for analyzing other SFK members or kinases with similar properties, facilitating the discovery of selective allosteric modulators and contributing to precise cancer therapies.

Keywords: lyn tyrosine kinase, mutation analysis, conformational changes, dynamic network analysis, allosteric modulation, targeted inhibition

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