Introduction

Introduction:?
The composite insulators for overhead ?transmission lines have been used in ?worldwide and have been replaced the ?traditional strings of glass and ceramic ?insulators due to their several advantages ?such as more resistance to pollution and ?vandalism, light weight. However, some of ?these new insulators have been failed by ?the catastrophic and not well understood ?mechanical brittle fracture. Many studies ?have attributed the cause of brittle fracture ?as the sum of several factors such as ?pollution, humidity, UV radiation, intense ?electric field, corona discharges, which ?could cause the formation of acids (nitric, ?sulphuric acids) that would attack the ?composite rod of insulators due to the ?stress corrosion crack. Nowadays, there are ?several types of composite insulators but, ?basically, they are made of three parts: (i) ?composite rod of glass fiber reinforced ?polymer, (ii) housing and sheds of silicone ?rubber to protect the composite rod and ?increase the electrical breakdown voltage; ?respectively and (iii) metallic end-fittings.?

Composite insulator components:?
A composite insulator is made of at least ?two insulating parts – a core and housing. ?It is equipped with end fittings.?
?? Core: The core is the internal insulating ?part of a composite insulator. It is intended ?to carry the mechanical load. It consists ?mainly of glass fibers positioned in a resin ?matrix so as to achieve maximum tensile ?strength.?

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?? Housing: The housing is external to the ?core and protects it from the weather. It ?may be equipped with watersheds. Some ?designs of composite insulators employ a ?sheath made of insulating material between ?the weathersheds and the core. This sheath ?is part of housing.?
? ? End fittings: End fittings transmit the ?mechanical load to the core. They are ?usually made of metal.?
Advantage of composite insulator:?
Polymeric composite insulators offer ?significant advantages over porcelain and ?glass insulators, especially for ultra HV ?transmission lines.?
• Light weight, and lower construction ?and transportation costs.?
• Vandalism resistance, less gunshot damage.?
• Better contamination performance.?
• Improved transmission line aesthetics.?
• Hydrophobicity of insulator surfaces.?

Disadvantage of composite insulator:?
Composite insulators also have weaknesses
• They are subjected to chemical changes ?on the surface due to weathering and ?from dry band arcing or flashover.?
• Long reliability is unknown.?
• Faulty insulators are hard to find, for it ?is difficult to check for inconsistencies ?or damages.?
• Less experience in the field, still ?changing as more polymer products ?come out.?

China has hundreds of composite insulator ?manufacturers, and these manufacturers ?supply all Chinese power system and also ?export most of the countries in the world. ?
Insulator manufacturer types according to ?voltage: ?
• Manufacturers only make 11kv – 33kv. ?
• Manufacturers make 10kv – 110kv.?
• Manufacturers make 10kv – 500kv.?
• ? Manufacturers make 10kv – 1000kv.?
• ? Manufacturers make AC and DC voltage.?

Introduction

Introduction :
Marpol is international convention for the prevention of pollution from ships. This agreement was signed in 1973 and some amendments were made to this convention in 1978. Also, this convention includes many measures to reduce the dumping of waste, oil spill and combustion waste in the marine environment. Its main objective is to preserve the marine environment through the complete elimination of pollution with oil and other harmful substances and to reduce the accidental discharge of these substances. This agreement was implemented in 1983, and in 2005 it was signed by 136 countries. In addition, the convention currently consists of six technical annexes, including provisions aimed at preventing and reducing pollution from ships (incidental pollution or routine operation), and most annexes have designated special areas for discharge with strict controls on discharges. Here is the list of the marpol 73/78 annexes. convention.

Annex I:
The prevention of pollution by oil & oily water. Annex I is the first application made by marpol and one of the most important international marine environmental agreement. This convention was applied to reduce the pollution seas and oceans from ships. Annex I was began to be enforced on 2 October 1983 to achieved their aim which is to keep the marine environment in safe by the complete elimination of pollution by oil and other harmful substance and minimize the accidental discharge of such substance. Marpol Annex I include the discharge requirements for the prevention of pollution by oil and oily materials. It began enforce the oil discharge criteria described in the 1969 amendments to the 1954 Oil Pollution Convention.It also include the idea of “special areas” which are considered to be at risk to oil pollution. Discharge of oil within them have been completely outlawed. The first half of Marpol Annex I deals with engine room waste. They deal with new technologies and equipment such as: Oily water separators (OWS) and Oil Content meters (OCM) and The second half of the Marpol Annex I deal with cleaning the cargo areas and tanks. Oil Discharge Monitoring Equipment (ODME) is a technology that has greatly helped improve efficiency.

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Annex II:
The Control of pollution by noxious liquid substances in bulk. It began enforced in 6 April 1987 and it tells us that the discharge criteria for the elimination of pollution by noxious liquid substances carried in large quantities. It divides substances into and introduces detailed operational standards and measures. The discharge of pollutants is allowed only to reception facilities with certain concentrations and conditions. No matter what, no discharge of residues containing pollutants is permitted within 12 miles of the nearest land. Stricter restrictions apply to “special areas”.
Annex II covers the International Bulk Chemical Code (IBC Code) in conjunction with Chapter 7 of the SOLAS Convention. Previously, chemical tankers constructed before 1 July 1986 must comply with the requirements of the Code for the Construction and Equipment of Ships Carrying Dangerous Chemicals in Bulk (BCH Code).

Annex III:
Prevention of pollution by harmful substances carried by sea in packaged form and it entry to force in 1 July 1992. Annex III include the general requirements for the standards on packing, marking, labeling, documentation, stowage, quantity subtraction, division and notifications for preventing pollution by harmful substances. The Annex is in line with the procedures detailed in the International Maritime Dangerous Goods (IMDG) Code, which has been expanded to include marine pollutants. The amendments entered into force on 1 January 1991.

Annex IV:
The Pollution by sewage from ships and it entry to force in 27 September 2003. Include the requirements to control pollution of the sea by sewage from ships.

Annex V:
The Pollution by garbage from ships and it entry to force in 31 December 1988. It specifies the distances from land in which materials may be disposed of and subdivides different types of garbage and marine debris. The requirements are much stricter in a number of “special areas” but perhaps the most prominent part of the Annex is the complete ban of dumping plastic into the ocean.

Annex VI:
The Prevention of air pollution from ships and it entry to force in 19 May 2005. It include the requirements to regulate the air pollution being emitted by ships, including the emission of ozone-depleting substances, Nitrogen Oxides (NOx), Sulphur Oxides (SOx), Volatile Organic Compounds (VOCs) and shipboard incineration. It also establishes requirements for reception facilities for wastes from exhaust gas cleaning systems, incinerators, fuel oil quality, for off-shore platforms and drilling rigs and for the establishment of SOx Emission Control Areas (SECAs).

Conclusion:
Marpol is international convention for the prevention of pollution from ships and it contain six annex which are; Prevention of pollution by oil & oily water, Control of pollution by noxious liquid substances in bulk, Prevention of pollution by harmful substances carried by sea in packaged form, Pollution by sewage from ships, Pollution by garbage from ships and The Prevention of air pollution from ships. All these annexes to achieve the objective which is to preserve the marine environment through the complete elimination of pollution with oil and other harmful substances and to reduce the accidental discharge of these substances.

Reference:
International maritime organization. (2017).MARPOL Consolidated Edition, 2017. picture. Retrieved on 30 May 2018 from https://www.amnautical.com/products/marpol-consolidated-edition-2017#.Ww_wYCJRWEc

wikipedia. Marpol 73/78. Retrieved on 30 May 2018 from https://en.m.wikipedia.org/wiki/MARPOL_73/78

Introduction

Introduction:
Receptor tyrosine-protein kinase ERCB-2, also known as the CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human). Erythroblastic oncogene B is a gene isolated from avian genome, which is commonly called Human Epidermal Growth Factor Receptor 2 (HER2). Over-expression of this oncogene has been shown to play a key role in the enlargement and progression of certain destructive types of breast cancer.
HER2 and cancer
The over-expression of the ERBB2 gene, occurs in about 15-30% of breast cancers (Burstein, 2005). 1 Breast cancer is the most common cancer diagnosed in women, accounting for approximately 23% of all cancer diagnoses and 14% of cancer-related deaths in women universal. Over expression is also known to occur in ovarian, stomach, adenocarcinoma of the lung and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma (Santin, 2005) 2,3. HER2 is coamplified with the gene GRB7, which is a proto-oncogene connected with breast, testicular embryo cell, gastric, and esophageal lumps. HER2 proteins have been shown to form bunches in cell membranes that may play a role in tumor genesis (Kaufmann, 2011) 4
Current therapy for the breast cancer:
Trastuzumab has become the typical of repair in the dealing with patients with HER2 optimistic breast cancer. The addition of Trastuzumab to chemotherapy schedules in the adjuvant setting progresses concern in women with early stage breast cancer (Madarnas, 2008) 5-8 Pertuzumab is a monoclonal antibody used in the concoction with Trastuzumab and Docetaxel for the dealing of metastatic HER2-positive breast cancer. It’s also used in the same assortment as a neoadjuvant in early HER2-optimistic breast cancer.

HER2 and EGFR, was approved in 2007 in combination with Capecitabine or Letrozole in patients with metastatic breast cancer that overexpress the HER2 receptor. In addition to breast cancer, these HER2/EGFR dual kinase inhibitors are being inspected in a number of solid tumors, like lung, gastric, and prostate cancers. All of these small molecule inhibitors contains a mutual structure categorized by a pyrimidine or pyrimidine analogue at its core. 9 Mechanism of action of Trastuzumab and Pertuzumab is mentioned in Fig.1.

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Tomoyasu Ishikawa at. al. has reported substituted Pyrrolo 3,2-d pyrimidine scaffold as Novel HER2 and EGFR dual inhibitors (Tomoyasu, 2011) 9 Jianzong Li et. al has reported the discovery of a potential HER2 inhibitor from ordinary products for the controlling of HER2-positive breast cancer (Jianzong, 2016). 10 From the detailed study of literature review (Tomoyasu, 2011). 9 and 10 we have decided to design novel 6,7-dihydropyrano 2,3-d pyrimidin-5-one derivatives as HER2 inhibitors with the help of molecular modeling. Design of Dihydropyrano 2,3-d pyrimidin-5-one scaffold of innovative HER2/EGFR inhibitor are described in Fig. 2. Design and pharmacokinetic profile of Dihydropyrano 2,3-d pyrimidin-5-one scaffold is mentioned in Fig. 3.
Molecular target prediction:
Bioactive small molecules such as drugs, proteins or other macro-molecular marks to modulate their undertaking, which in turn results in the pragmatic phenotype properties. Drawing the letters of bioactive small molecules is a key step in the direction of unraveling the molecular mechanisms underlying their bioactivity and predicting potential side effects. Recently, large datasets of protein and small molecule interactions have become persisting, providing a unique source of information for the development of knowledge-based tactics to computationally identify new targets for uncharacterized molecules, which are the secondary targets for the molecules. Swiss target prediction, a web server to correctly predict the targets of bioactive molecules based on a combination of 2D and 3D likeness dealings with known ligands. Molecular target of novel derivatives was forecast by Swiss Target Predictor (Gfeller D, 2013) 11 Molecular target prediction of novel selected dihydropyrano 2,3-d pyrimidin-5-one scaffold of HER2/EGFR inhibitors are described in Table 1 for 8.

Molecular docking studies:
Preparation of Protein:
Crystallographic structures of the targets (3RCD) were obtained from the Protein Data Bank and saved in typical 3D coordinate format (Deepthy, 2016). 12 Preparation of active site was done by the explicit hydrogen atoms missing in the PDB structure were added using AutoDock-4 docking software. Additionally, the atom list of the molecules were set, which indicates numbers of all the atoms of the active site residues elaborate.

Molecular Docking:
Docking is a technique which predicts the preferred alignment of one molecule to a second when bound to each other to form a stable composite. The docking was done by using Autodock 2. In Autodock, the proteins were sophisticated by removing water molecules and polar hydrogen’s and kollmann charges were added. Gridbox for docking replications were constructed with 40 points in x, y, and z direction to be highlighted on the active site by AutoGrid utility of the Autodock program.
Bioactivity Prediction:
Bioactivity score is another computational tactic used to determine whether a particular molecule is similar to the known drugs or not in their molecular belongings and operational geographies. Bioactivity prediction of all selected compounds was done using Molinspiration online software tool. According to the bioactivity score, if >0 is active; if (?5. 0 to – 0.0) is moderately active and if <?5 is inactive. Bioactivity scores of designing compounds are mentioned in Table 10.

ADME/T Studies:
In silico toxicity profile of designing compounds was performed using the SWISSADME program (Ishan, 2018) 13 To be effective as a drug, a potent molecule must reach its target in the body in necessary concentration, and stay there in a bioactive form long sufficient for the expected biologic events to happen. Drug development embraces assessment of absorption, distribution, metabolism and excretion (ADME). Earlier in the discovery process, at a stage when measured compounds are numerous, but access to the physical samples is limited. In that context, computer models constitute valid replacements to pilot.

Result and discussion:
Protein kinases play important roles in signal transduction ways that control several cellular drives, including proliferation, differentiation, immigration, apoptosis, and angiogenesis. Signal transduction pathways are upregulated in many tumor cells, protein kinase inhibitors that board these unregulated pathways are attractive candidates for the spite therapy. The directing of HER) or EGFR by tyrosine kinase inhibitors (TKIs) symbolizes such therapeutic methodology. With the help of molecular docking studies of novel dihydropyrano 2,3-d pyrimidin-5-one scaffold show that dihydropyrano 2,3-d pyrimidin-5-one has a momentous effect on HER2/EGFR.
Among all the compounds H11 (-8.8 kcal/mol), H2 (-8.7 kcal/mol), H15 (-8.6 Kcal/mol), and H17 (-8.7 Kcal/mol) has a maximum binding affinity as associated to Cipecitabine (-6.0 kcal/mol), STD1 (-7.2 Kcal/mol) and STD2 (-7.9 Kcal/mol) and other derivatives. It has been observed that 1-(2-Chlorophenoxy) -3-(trifluoromethyl) benzene pocket play important role in kinase selectivity and pharmacokinetics profile. Methyl group at 6,7-dihydropyrano 2,3-d pyrimidin-5-one scaffold has a key role in the ATP binding site of HER2. Replacement of a ketone with hydroxyl group in 6,7-dihydro-5H-pyrano 2,3-d pyrimidin pocket also gives good binding affinity with Epidermal growth factor receptor. 2,6-dimethylocta-2,6-den side chain has potent effects on cell activity.

Molinspiration software showed predication of biological activity of novel derivatives. Out of the 18 design compounds H16 and H18 showed the better biological activity of G-protein coupled receptor, Ion channel Modulator, Kinase inhibitor, Nuclease receptor, Protease inhibitor, Enzyme inhibitory activity. H16 and H18 are active and remaining all compounds are moderately active.
The SWISSADME predictions indicated that the ability to penetrate the BBB was described by all compounds. All the compounds did not cross the BBB. In addition, all the compounds were revealed as non-inhibitors of the P-gp inhibitor. CYP enzymes, including several CYP450 substrates and inhibitors, play a vital role in drug metabolism. The outcomes showed that most compounds were non-inhibitors of CYP450 enzymes. The SWISS molecular target prediction it has observed that most of the compounds have significant activity against tyrosine kinase, epidermal growth factor receptor, Receptor tyrosine-protein kinase ERBB-2, Receptor tyrosine-protein kinase ERBB-3, and ERBB4 intracellular domain.
Conclusion:
HER2/EGFR are potential targets for design and development of novel anticancer agents. Molecular modeling and virtual screening play significant role in drug discovery and development. Most of the compounds giving significance activity on tyrosine kinase. 3-Chloro-4-(3-(trifluoromethyl)phenoxy)phenylamino scaffold is important for kinase selectivity and pharmacokinetic profiles. 6,7-Dihydropyrano 2,3-d pyrimidin-5-one scaffold is vital for inhibition of ligand dependent HER2 dimerization and signaling. All the compounds did not cross the BBB and non-inhibitors of the P-gp inhibitor. CYP enzymes, including several CYP450 substrates and inhibitors, play a vital role in drug metabolism. Further synthesis and in vivo as well as invitro biological activity will potential for novel therapeutic approach of breast cancer episode.

Author information:
Corresponding Author: Dr. Ishan I Panchal
[email protected] of Interest
Authors have no Conflict of Interest.

References:
1 Burstein, HJ. “The distinctive nature of HER2-positive breast cancers”. The New Eng. J of Medi. 2005,353(16),1652–42 Santin, AD; Bellone, S; Roman, JJ; McKenney, JK; Pecorelli, S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu”. Int J of Gynaeco and Obst. 2008,102 (2),128–31.

3 Buza, N; Roque, DM; Santin, AD. HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges. Arch of Patho & Labo Med. 2014,138 (3), 343–50.

4 Kaufmann, R; Müller, P; Hildenbrand, G; Hausmann, M; Cremer, C. Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy. J of Micro 2011, 242 (1), 46–54.

5 Y, Madarnas.; M, Trudeau.; JA Franek.; D, McCready, KI Pritchard.; H, Messersmith, Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. Can. Treat. Revi. 2008, 34 (6), 539–557.
6 G, Mariani.; A, Fasolo.; E, De Benedictis.; L, Gianni.; Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nat. Cli. Prac. Oncol. 2009,6 (2), 93–104.
7 MJ, Piccart-Gebhart; M, Procter.; B, Leyland-Jones. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. The New. Eng. J. of Med. 2005, 353 (16),1659–1672.
8 EH, Romond.; EA, Perez.; J, Bryant. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. The New Eng. J of Med. 2005, 353 (16), 1673–1684.

9 Tomoyasu I.; Masaki S.;Hiroshi B.;Youichi K.;Mami O.;Takahiko T.; Yoshikazu O.;Toshiya T. Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2) /Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo 3,2-d pyrimidine Scaffold. J. Med. Chem. 2011, 54, 8030?8050.

10 Jianzong Li.; Haiyang W.; Junjie Li.; Jinku Bao.; Chuanfang Wu. Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer. Int. J. Mol. Sci. 2016, 17, 1055.

11 Gfeller D.; Michielin O.; Zoete V. Shaping the interaction landscape of bioactive molecules, Bioinformatics 2013, 29, 3073-3079
12 Deepthy C.; Leena KP.; Manju P.; Jinsha MJ.; Jilsha G. Insilico drug design and molecular docking studies of some novel benzothiazole derivatives as anti-cancer and anti-inflammatory agents. Int. J. Pharm. Pharm Sci, 2014, 6 (2), 203-208.

13 Ishan IP.; Dhrubo JS.; Ashish S.; Ashish P.; Vashisth B. Molecular Docking and Synthesis of Some Substituted Sulphonylurea/Pyrrolidine -Based Derivatives as Hypoglycemic Agents. J. of Chem. and Pharma. Res., 2017, 9 (8), 164-172.

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