All Souls Book Review Essay - 987 Words

All Souls: A Family Story From Southie By Micheal Patrick MacDonald. (Ballentine Books under The Random House Publishing Corporation, 1999, 266pp. $14.00) Michael Patrick MacDonald saw hatred animated on a Friday in the early days of October. Some people were reading the newspaper in brightly lit kitchens. Some children were coloring with brightly hued crayons. Some fathers were getting into cars in front of their beautiful homes. But there were no crayons, bright kitchens, or fathers in nice cars on Dorchester Street in Southie that day. Only the cruelest manifestation of blind hatred. Michael Patrick MacDonald was an innocent child when he stood only feet away from a black man who was having the life literally beaten from his†¦show more content†¦In a ‘He was a good man underneath all of that rage sort of fashion, he exposes Southies grave and serious problems, all the while maintaining that it was the best place in the whole world. We tend to marginalize the poor, the destitute, the food stamp and welfare recipients among us. We like to pretend that they are not there, much like the residents of Southie liked to pretend that the violence and anger and tragedy in Southie werent there. We like to try to compartmentalize this part of our own society, this very real set of people who still live in our towns. Who mourn their dead at our churches, who lower them into the ground in our cemeteries, who hand food stamps to the cashier at our grocery stores. We have all been guilty of it. How could we not be? How could we really grasp, realize, come to terms with, comprehend such an alien life? Michael Patrick MacDonald is our translator. He relays the past as Southie has written it on his heart. He hands it to us in a language we might better understand. MacDonald opens the door and invites us to sit down at his Southie dinner table. To lie on a mattress on the floor next to him and his brothers. To come to the hospita l and watch Ma MacDonald beat the daylights out of a man who didnt value her family as much as she did. To stand inside the sterile green walls at Mass Mental. To trade stories with all the Southie kids about who had a connection to Whitey Bulger. ToShow MoreRelatedA Controversial Issue Of Pi1093 Words   |  5 PagesA controversial issue for this book would definitely be the religion. Pi’s mother and father found it totally absurd to have more than one religion, and contradicting ones at that. As did the pandit, the priest, and the imam. In the book, there is a three-page long argument between the priest, the imam, the pandit, and Pi’s parents all claiming the other is mistaken and that Pi is a Muslim or a Hindu or a Christian. Pi blurts out, â€Å"Bapu Gandhi said, ‘All religions are true.’ I just want to love GodRead MoreAnalysis Of What Dreams May Come739 Words   |  3 Pagesbreathed brilliant life into the tragic story of a family pulled apart by death and the journey one man makes through heaven and even hell to save his soul mate, based from the book, What Dreams May Come by Richard Matheson. This movie is boldly beautiful and a rollercoaster of feelings that brings you to the emotional edge but sadly doesn’t quite get us all the way over. In the beginning of the movies, events occur rather quickly. Chris and Annie, unbelievably effective and heartbreakingly performedRead MoreCompare And Contrast Augustine And Virtue Ethics872 Words   |  4 PagesAugustine says â€Å"Virtue gives perfection to the soul; the soul obtains virtue by following God,† Augustine makes a very strong connection between being virtuous and following God, and how the soul plays an important role for one to become virtuous. 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Financial Analysis of Starbucks - 1131 Words

The company that I am writing about is Starbucks, the international coffee shop chain. The companys financial statements for this analysis are from the FY2011 Annual Report and 10-K. The company has 10787 stores in the United States, of which 38% are franchised and the remainder are company-owned. The franchise model is more common when the company operates internationally. There are 6216 Starbucks stores internationally and of these 63% are franchises, with just 37% company-owned. The franchise model for international expansion has been utilized to help Starbucks expand quickly in foreign countries and to mitigate foreign political risk and to ensure that the product/service offering is tailored to local tastes (Thompson, 2012). The company is now in the process of buying back some overseas franchise stores in order to retain more profits for itself (Franchise Press, 2011). This paper will take a look at the companys most recent annual report to analyze the financial statements. Debt Starbucks does not have a lot of long-term debt. There was a point in the mid-2000s where Starbucks was struggling, closing stores and seeing reduced profitability. In August of 2007 the company made its first (and to this point only) debt issue. The issue was for $550 million at 6.25% on a 10-year issue (Trent, 2007). This debt remains on the companys books today, as $549.5 million on the balance sheet in long-term debt. The total liabilities that Starbucks has on its balance sheetShow MoreRelatedStarbucks : Starbucks Financial Analysis1185 Words   |  5 PagesStarbucks Financial Analysis It’s hard to drive the street these days and not see a Starbuck’s coffee house sitting on a corner with cars lined up in the drive-thru or consumers gathering in their cafà © to socialize. This has been the scene since the first Starbucks was opened in 1971. Since then, Howard Schultz, chairman and CEO, has embarked on a quest to bring Italian bistro traditions to the United States. 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Starbuck’s coffee employees or the people in charge to get the coffee, travel to coffee farms in differentRead MoreStarbucks Financial Analysis 03-072727 Words   |  11 PagesThe American University in Cairo Acct 501 Spring 08 Starbucks Financial Analysis Years 2003-2007 Presented to: Dr. Adel Ibrahim Presented by: Ahmed El-Shorbagy 800-07-0477 Ahmed Tawfik 900-98-5749 Mahmoud El Gindy 800-07-0417 Mohammed Abo Solyman 900-02-1301 Mohammed Hassan 800-07-1982 Table of Contents Executive Summary 3 Introduction 4 Financial Statement Analysis 5 Consolidated Balance Sheet 5 Consolidated Income Statement 5 Consolidated Cash Flow

Digitization for Economic Growth and Job Creation MyAssignmenthelp

Question: Discuss about the Digitization for Economic Growth and Job Creation. Answer: Introduction The mass adoption of the digital technology by different sectors of the society, governments, enterprises, consumers has materialized in the recent time. This acts a major economic driver which facilitates creating the jobs and speeds the development factors up. In the present scenario of the lethargic international economy, the digitization can play a significant role in encouraging the financial development and growth (Katz, Koutroumpis and Martin 2014). The analysts indicate that, even if the environment of international economy is quite unfavorable, digitization has provided a huge economic boost to the global financial output and created around six million global jobs in 2011 (Quaadgras, Weill and Ross 2014). However, the impact of digitization may have been different in different sectors. In addition to that, where the developed economies have higher financial developmental benefits of around twenty five per cent, the developing economies do not have the scope of having higher benefits (Turber and Smiela 2014). The primary reason behind this may be the conflicting impacts of digitization on the different economic structures. In this literature review, the specific economic impacts of the digitization on the targeted sectors are discussed. To define the digitization To investigate the impact of digitization on different sectors within any organization To evaluate the impact of digitization on employment To analyze the gap in the literature Defining Digitization According to Gooding, Terras and Warwick (2013) the level of digitization of a country can be determined through six major traits, such as, ubiquity, reliability, affordability, usability, speed and skill. The factor, ubiquity is the degree to which the organizations and consumers would have the global access to the digital applications and services; affordability is the degree to which the digital services are valued so that it is available to as much as people in the country; reliability is the quality of the affordable digital service; the speed is the degree which can determine the access of the digital service; usability is the easiness of using the digital services and the capability of the domestic services in boosting the service applications; the skill is the capability of the users in integrating the digital services as a part of their business and life. If the definition of digitization is concerned, according to Goldfarb, Greenstein and Tucker (2015) Digitization is the process of transforming analog material into binary electronic (digital) form, especially for storage and use in a computer. With the help of digitization, the materials can be converted to the analog formats which are read by people in a digital format that can also be read by machines. There are numerous devices such as the cameras, scanners which can be used in the digitization of the knowledge contents. These technologies enhance the process of digitization of almost all the materials including the photographs, rare paper documents, videos and sound recordings (Greenstein and Tucker 2015). Digitization helps in improving the access of the data resources. The projects with digital access allow the clients in searching for the rapid and comprehensive approach at any time anywhere. However, it is an expensive and time consuming venture, yet it is an influential met hod to deal with the issues with the continuous shortage of resources in the developing countries. The digitization comes with a lot of opportunities that ease the entire procedure of working. Especially the technologies like smart machines such as machine learning, robots; smart devices such as laptops, personal computers, smart phones, mobile networks and other smart digital techniques like big data, cloud computing, have shown some major advancements in the past decades. These improvements have huge social and economic impacts on the global scenario. In addition to that, these changes have important implications on employment. Several industries have been created due to digitization. Moreover, numerous industries have created millions of jobs for them who are involved with the technological sectors and for the advanced clients who may have the opportunity of using advanced tools and software as a primary component of their work across different industries. However, using the digital tools and technologies, the people have the ability of connecting anyone at any time. From using a simple mobile phone to the online platforms, the connectivity amongst people has increased in a larger way. According to Heeks (2013) the amount of potential beneficiaries has also increased who use the digital technologies as a part of their work or regular life. The approximate numbers of people who use mobile services on a daily basis have already crossed 3.6 billion. In the developing countries, the employment in the digital sector has increased in a remarkable way. According to Borowiecki and Navarrete (2017) in most of the OECD countries, the employment in the information and communication industry has generated around 5.74 per cent of the entire employment in the business sector. The countries of G 20 generated membership around 4.66 to 6.45 per cent. The countries with emerging economy have also benefitted as Bachi et al. (2014) shown that the IT industry of Brazil have generated around sixteen per cent of jobs between 2010 and 2013. The IT BPO industries of developing countries are flourishing and it has generated around 3.5 million workers all over the world. Sectored Impact of Digitization In order to understand the impact of digitization on the economic sectors, one should discuss the job creation opportunities and productivity across the developed and emerging economies. The application of digitization can affect various functions of any organization. The functions of any organization can be divided in four areas such as production, business, operation and market. Digitalization has a reflective effect on these sectors. The idea of digitization has an influencing effect on the management of production assets of the organization. The enables the company to shift the labor intensive jobs to the promising economies while it develops the client interfaces. This creates a huge amount of jobs in the market as it leads to the emergence of fresh and new technologies for manufacturing (Reed 2014). For instance, it can be said that Samsung works with Apple for the iPhone products but they also compete in the consumer market in an aggressive way. With the advancements of the 3D technologies, there are new ways to manufacture the complicated products; therefore it leads to the importation of jobs back to the emerging economies. Digitization has a huge impact on reshaping the business models. This helps in lowering the obstacles in expanding the business market and entering a new market. Therefore it helps the markets to expand its reach. For example with the emergence of the video calling facilities such as Skype or WhatsApp calls, it is possible for the companies to deal with their employees all over the world (Reed 2014). These digital facilities offer telephonic facilities to around five hundred million customers who can use the voice over Internet protocol technology and connect with anyone in the world who also uses the same. Therefore, these disrupts the existing business models for the operators all around the world, therefore numerous companies avail this facility for connecting to their employees. This enhances the opportunities of the companies to enter in a new market, therefore leading to generate new job opportunities. Digitization has changed the notion of building the products, brands and products and communicates with the customers. The organizations are now depending the social media and other new communication services to build their brands. Moreover the users are now finding more buying options online, even if they opt for buying new products offline. According to Coreynen, Matthyssens and Van Bockhave (2017) around forty per cent of the allover buyers use the online services to research about the items they are going to buy in the physical outlets. The digitization therefore enables the organizations in creating more products online that can align with the tastes of the consumers. The function of online technologies as a retail channel often tends to create a significant expansion in the market reach that leads to generate more job opportunities. The emergence of online technologies has created a new market online that has emerged more job opportunities in the market. The digitization also has a great impact on the companies in operating so that they can generate more competitive advantages. Due to digitization, more global entities have been created and that had ensures to be in touch across countries. Reed (2014) show that one of the four American employee telecommunicate on a daily basis showing the outsourcing of resources. Therefore, it makes them more efficient and it enables to create more job opportunities. Impact of Digitization on employment The degree and types of the impact that digitization has on the employment sector is mostly derived through the economic factors. As the digitization enhances the market access in a significant way, the growth of jobs tends to increase at the same time. However, for understanding the dynamic relation of employment and digitization, the scholars have examined the major economic activities in the market. Coreynen, Matthyssens and Van Bockhave (2017) have identified that there are five key areas that can divide the entire economy in three significant sectors: primary, secondary and tertiary. The primary sector includes farming, agriculture, mining and the processing of the natural products; the secondary sector includes the manufacturing such as building, making and assembling the primarily finished products; the tertiary sector includes the provided services to the businesses and the consumers that includes transportation, retailers, entertainment organizations, healthcare providers, b anks etc. Most of the literatures have focused on the analysis of the subsectors of the tertiary and secondary sectors where most of the activities are affected by digitization. However, in most of the literature, it is found that it tends to cluster on the manufacturing, financial services, retail and the hospitality sectors. Digitization has shown the least impact on the primary sectors. According to Coreynen, Matthyssens and Van Bockhave (2017) the nature of employment is changing in a broad way. These changes have influences not only in the quality of jobs and earnings; it also increases the individual risk that an employee bears. The links between the employers and the employees are shifting rapidly. The short term works now involve more micro jobs and online works. This review has mostly focused on the developed countries and the economy. Digitization has a huge impact primarily on three variables: growth per capita or GDP, creation of jobs and the innovation. Classifying the production functions models of assessing the economic impact has a huge impact on the economy of any country. If there is a continuous increase of the digitization by ten percentages, it triggers around 0.50 to 0.62 percent gain in the per capita GDP. However, most of the studies have focused on the penetration of broadband services that have established that there is a continuous gain of ar ound 0.16 to 0.25 percent. In addition to that, the below table shows that how the industry productivity, output and the employment with the development of digitization in different sectors. However, most of the literature on this issue has insufficient information in creating the job opportunities in certain sectors in the rising markets. It illustrates that the financial services and the manufacturing business in the world creates more job opportunities as they are able to transform their support activities to other countries where they have to spend lower cost for the labors. The companies have taken opportunities for off shoring their legal, financial, logistics and the communication services. The productivity gains in the financial fields are mostly the result of abilities in decreasing the labor costs while it tends to increase the output. Conclusion After conducting the literature review, it can be said that, there are not much sufficient data in the impact of digitization in the creation of job opportunities in the secondary sector. As the tertiary sector has been influenced mostly by the innovation and emergence of the digitization, most of the literatures have focused on that sector itself. The secondary sector includes the building, making and assembling the products. Therefore, from this literature review, a gap has been identified in the researches in the job opportunities in the secondary sector. Therefore, the further researches will be conducted on this issue. Reference list Agrawal, A., Horton, J., Lacetera, N. and Lyons, E., 2015. Digitization and the contract labor market: A research agenda. InEconomic analysis of the digital economy(pp. 219-250). University of Chicago Press. Bachi, V., Fresa, A., Pierotti, C. and Prandoni, C., 2014, November. The Digitization Age: Mass Culture Is Quality Culture. Challenges for Cultural Heritage and Society. InEuro-Mediterranean Conference(pp. 786-801). Springer International Publishing. Blbaum, B. ed., 2016.Trust and Communication in a Digitized World: Models and Concepts of Trust Research. Springer. Borowiecki, K.J. and Navarrete, T., 2017. Digitization of heritage collections as indicator of innovation.Economics of Innovation and New Technology,26(3), pp.227-246. Bourreau, M., Gensollen, M., Moreau, F. and Waelbroeck, P., 2013. Selling less of more? The impact of digitization on record companies.Journal of cultural economics,37(3), pp.327-346. Coreynen, W., Matthyssens, P. and Van Bockhaven, W., 2017. Boosting servitization through digitization: Pathways and dynamic resource configurations for manufacturers.Industrial Marketing Management,60, pp.42-53. Goldfarb, A., Greenstein, S.M. and Tucker, C.E., 2015. Introduction to" Economic Analysis of the Digital Economy". InEconomic Analysis of the Digital Economy(pp. 1-17). University of Chicago Press. Gooding, P., Terras, M. and Warwick, C., 2013. The myth of the new: Mass digitization, distant reading, and the future of the book.Literary and Linguistic Computing, p.fqt051. Greenstein, S.M. and Tucker, C.E., 2015.Economic analysis of the digital economy. University of Chicago Press. Heeks, R., 2013. Information technology impact sourcing.Communications of the ACM,56(12), pp.22-25. Kagermann, H., 2015. Change through digitizationValue creation in the age of Industry 4.0. InManagement of permanent change(pp. 23-45). Springer Fachmedien Wiesbaden. Katz, R., Koutroumpis, P. and Martin Callorda, F., 2014. Using a digitization index to measure the economic and social impact of digital agendas.info,16(1), pp.32-44. Klein-Avraham, I. and Reich, Z., 2016. Out of the frame: A longitudinal perspective on digitization and professional photojournalism.new media society,18(3), pp.429-446. Loebbecke, C. and Picot, A., 2015. Reflections on societal and business model transformation arising from digitization and big data analytics: A research agenda.The Journal of Strategic Information Systems,24(3), pp.149-157. Quaadgras, A., Weill, P. and Ross, J.W., 2014. Management commitments that maximize business impact from IT.Journal of Information Technology,29(2), pp.114-127. Reed, T.V., 2014.Digitized lives: culture, power, and social change in the internet era. Routledge. Sabbagh, K., Friedrich, R.O.M.A.N., El-Darwiche, B.A.H.J.A.T., Singh, M.I.L.I.N.D. and Koster, A.L.E.X., 2013. Digitization for economic growth and job creation: Regional and industry perspective.The global information technology report, pp.35-42. Tarut?, A. and Gatautis, R., 2014. ICT impact on SMEs performance.Procedia-Social and Behavioral Sciences,110, pp.1218-1225. Turber, S. and Smiela, C., 2014. A business model type for the internet of things.

The aim of this research is, eventually, to Essay Example

The aim of this research is, eventually, to Essay Context of the intended research CRIT is a receptor that was foremost encountered on the surface of aSchistosomaspecies ; in theSchistosoma,it acts as a decoy C2-binding receptor in order to protect this parasite from complement onslaught by viing with C4 for the binding of C2 ( Inal and Schifferli, 2002 ) . Complement is, basically, an enzyme system that is triggered upon immune system onslaught: most of the enzymes in this system are identified through standardised labeling: they are labelled C followed by a figure and so a codification based on the cleavage merchandises when proteolysed, for illustration, C5b-9. Complement onslaught ( Carroll, 1998 ) plays a major function in supporting hosts from immune onslaught, in footings of extinguishing foreign encroachers, and involves a complex tract of interactions, in order that the procedure does non take to self devastation: so, unregulated complement action can take to autoimmune diseases ( Ohet al. ,2003 ) , and other conditions/diseases such as bosom onslaught ( K ilgoreet al. ,1994 ) , Alzheimer’s disease ( Bradtet al. ,1998 ) . We will write a custom essay sample on The aim of this research is, eventually, to specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on The aim of this research is, eventually, to specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on The aim of this research is, eventually, to specifically for you FOR ONLY $16.38 $13.9/page Hire Writer CRIT ( or Sh-TOR as it was antecedently known ) was found inSchistosoma,as a complement C2 protein, that could barricade complement activation, therefore bring oning bilharzia in worlds ; it was hypothesized that the CRIT blocked complement activation through its C2 binding site ; CRIT look in the parasite therefore acts as a steerer C2 binding receptor, protecting the parasite against complement onslaught by viing with C4 for the binding of C2, at the ed1 sphere ( Hui, 2005 ) . CRIT has later been found that other animate beings, that are suited as theoretical account systems for analyzing CRIT action besides express CRIT, for illustration, the rat andTrypanosoma.Recent work has besides shown that worlds have a CRIT factor, labeled ( Hu ) -CRIT which is expressed in a broad scope of human cells, particularly in hematopoietic cells ( Inalet al. ,2005 ) . Further elaborate surveies of CRIT have shown that it is a transmembrane receptor with two extracellular and two in intracellular spheres with an active 11 amino-acid peptide subdivision ( called CRIT-H17 ) which is hypothesized to be involved in the complement suppression activity of CRIT ( Hui, 2005 ) . Much work has been undertaken on clarifying the mechanism of action of CRIT, in footings of it being a potentially utile molecule in handling immunological diseases and other diseases, such as malignant neoplastic disease. For illustration, Inalet Al.( 2005 ) have shown that CRIT barricading can take to deprotection in CRIT-expressing human myeloid cell lines and in monocytes, ensuing in a greater susceptibleness to complement-mediated lysisin vitro. Other research, such as that by Mollet Al.( 2006 ) has shown that CRIT look is different in patients with kidney upsets, through assorted alterations in up- or down-regulation of CRIT look, taking to the suggestion that the upregulation of CRIT in activated podocytes might stand for a self-defense mechanism, stand foring a ‘last line’ of defense mechanism in membranous kidney disease of the kidney. Other surveies have looked at the existent mechanism of operation of the CRIT tract, for illustration Huiet Al.( 2005 ) looked at the look of a functional recombinant von Willebrand factor-A sphere from human complement C2, in footings of this being a possible binding site for C4 and CRIT. As we have seen, CRIT competes with C4b for the binding of C2, with the major adhering site on C2 being located on a short peptide sequence that was antecedently of unknown beginning ; Huiet al. ,( 2005 ) , nevertheless, looked at a part on C2 that was known to hold binding capacity, the von Willebrand Factor-A, and found that, so, this peptide sequence inhibits complement activity ; utilizing a cloned von Willebrand Factor-A sequence, Huiet Al.( 2005 ) were able to look in item at the interactions between C2 and CRIT and C4b. This pilot survey that is intended to be undertaken as portion of this reappraisal of CRIT is intended to take this work of Huiet Al.( 2005 ) farther. As will be seen, on adh ering the serum complement protein, C2, the CRIT peptide, H17 can cut down complement-mediated redness in vivo [ 7 ] and it is intended that CRIT-ed1 and H17 will be tested as possible distinction therapeutics peculiarly aiming monocytic leukemia. To better the efficaciousness of these peptides, structural information on the manner they interact with C2, such that this can be ‘tweaked’ to increase efficiency of binding. The CRIT-H17 peptide will be synthesized full length as an 11-mer, but besides as a 10-mer, 9-mer and 8-mer. We will besides mutate to alanine the amino acids believed to interact with the vWFA sphere of C2. CRIT-H17 will farther be synthesized as a head-to-toe cyclised version of H17 ( to mime the native CRIT molecule ) . Prior to the structural surveies, nevertheless, these peptides will be tested for their efficaciousness at cut downing complement activationin vitro. In add-on, interactions of these peptides with C2 vWFA sphere will be monitored for by a novel technique utilizing electrospray ionization mass spectroscopy ( developed within the Institute for Health Research A ; Policy at LMU by Dr. A. Bligh ) [ 8 ] . This technique can besides observe the presence of two adhering sites and if there are two ligands whether they bind competitively and with what affinity. To supervise conformational alterations on interaction, in add-on to working out dynamicss of interaction, we will utilize Double Polarisation Interferometry ( AnaLight Quantum ) through coaction with Dr. R.B. Sim ( MRC Immunochemistry Unit, Univ. of Oxford ) . Prof. Peter Gros ( Centre for Biomolecular Research, Utrecht ) has approached the applier for CRIT peptides for co-crystallisation with an available C2a ( von Willebrand Factor A [ vWFA ] and serine peptidase ) concept and we expect this coaction to continue and to finally demo the points of contact between CRIT-ed1 and C2 ( via the vWFA sphere ) . It is hoped that this methodological analysis will let a deeper apprehension of how CRIT binds with other molecules in the complement tract, and how this tract is regulated in footings of supplying a intervention option for some of the diseases/conditions that are known to develop following perturbation, or irregular operation of, this complement tract. Introduction The purpose of this research is, finally, to transport out a pilot survey to back up preliminary grounds that the complement receptor CRIT ( Complement C2 Receptor Inhibitor Trispanning ) plays a function in monocyte/macrophage terminal distinction. We aim to demo that by triping distinction through CRIT, it is possible to suppress the proliferation of myeloid leukemia cells. This could hold of import deductions for an alternate intervention agenda for monocytic leukemia. By the terminal of this survey we expect to demo the undermentioned: I ) that monocytes which can adhere C2 through CRIT maintain monocytic phenotypein vitroorin vivo ;II ) that monocytes can be induced to terminally distinguish by barricading the interaction of CRIT with its blood relation ligand, complement C2 or as monocytes move into an extravascular environment devoid of C2 ; that a knockdown of CRIT look in monocyte carcinoma cell lines or physical blocking of CRIT-C2 interaction induces them to terminally dis tinguish, and that, likewise, a blocking of CRIT-C2 interaction on leukaemic monocytes will halt proliferation and bring on distinction ; and, in conclusion, that, conversely, monocytes that are C2-/- , can non be induced to terminally distinguish by barricading the interaction of CRIT with its ligand, C2, nevertheless on traveling into an extravascular environment, other excess mechanisms, such as interaction of monocyte integrins with VCAM molecules on endothelial cells, may still bring on distinction. In consequence, basically, either barricading ligand interaction with CRIT or cut downing CRIT look should excite cell rhythm apprehension ( irreversible block at G1 ) and terminal distinction into cells with a macrophage phenotype. These conditions represent a fresh tract for monocyte/macrophage terminal distinction, based on the theoretical account proposed, and affecting the complement receptor, CRIT. In footings of monocyte leukemia, besides advancing cell rhythm apprehension, barricading CRIT with anti-CRIT-ed1 has the added benefit of rendering the cell more susceptible to complement-mediated cytolysis, as described antecedently for monocyte carcinoma cell lines ( U937 and THP-1 ) and primary monocytes showing CRIT [ 1 ] . It is intended that this research will lend to a deeper apprehension of how the complement tract works in worlds, in peculiar with respect to how abnormalities in the operation of the complement tract can do disease, and how CRIT look modulates the operation of the complement tract in human systems. The informations obtained from this pilot survey will be used to look into five chief issues: I ) The function of CRIT in myeloid distinction The function of CRIT in myeloid distinction has been studied with an antagonist CRIT-based peptide termed H17 ( NH2-HEVKIKHFSPY-CO2H ) consisting the 11aa C-terminus of CRIT-ed1. Preliminary work suggests that in adhering to C2 and therefore barricading the interaction of C2 with CRIT [ 1 ] , H17 may bring on the distinction of monocytes/promonocytic cell lines along the tract of macrophage distinction, and significantly, inhibit cell proliferation. The different curative attacks that are presently used in handling acute leukemia include cytotoxicity, programmed cell death and distinction. Differentiation therapy was developed over a decennary ago and Acts of the Apostless by bring oning cell rhythm apprehension and hence distinction in leukaemic monocytes [ 2 ] , therefore elegantly avoiding cytotoxicity effects. Retinoids, such as all-trans-retinoic acid ( ATRA ) are used to handle promyelocytic leukemia by specifically aiming neoplastic cells whilst non impacting normal mature ce lls. Many successes in the intervention of monocytic leukaemias have been reported since [ 3-5 ] . We suggest that a CRIT-based peptide ( H17 or an H17 derived function ) could finally offer an of import alternate intervention for monocytic leukemia by bring oning distinction of monocytic cells. The peptide will be tested entirely and in combination with ATRA in a mouse theoretical account of acute promyelocytic leukemia [ 6 ] . two ) The construction of CRIT peptides ( ed1 and H17 ) and of CRIT peptides interacting with the von Willebrand Factor A ( vWFA ) sphere of complement C2 On adhering the serum complement protein, C2, the CRIT peptide, H17 can cut down complement-mediated redness in vivo [ 7 ] and we will prove CRIT-ed1 and H17 as possible distinction therapeutics peculiarly aiming monocytic leukemia. To better the efficaciousness of these peptides, we aim to utilize structural information on the manner they interact with C2. The CRIT-H17 peptide will be synthesized full length as an 11-mer, but besides as a 10-mer, 9-mer and 8-mer. We will besides mutate to alanine the amino acids believed to interact with the vWFA sphere of C2. CRIT-H17 will farther be synthesized as a head-to-toe cyclised version of H17 ( to mime the native CRIT molecule ) . Prior to structural surveies, these peptides will be tested for their efficaciousness at cut downing complement activation in vitro. Interactions of these peptides with C2 vWFA sphere will be monitored for by a novel technique utilizing electrospray ionization mass spectroscopy ( developed within the Institute for Health Research A ; Policy at LMU by Dr. A. Bligh ) [ 8 ] . This technique can besides observe the presence of two adhering sites and if there are two ligands whether they bind competitively and with what affinity. To supervise conformational alterations on interaction, in add-on to working out dynamicss of interaction, we will utilize Double Polarisation Interferometry ( AnaLight Quantum ) through coaction with Dr. R.B. Sim ( MRC Immunochemistry Unit, Univ. of Oxford ) . Prof. Peter Gros ( Centre for Biomolecular Research, Utrecht ) has approached the applier for CRIT peptides for co-crystallisation with an available C2a ( von Willebrand Factor A [ vWFA ] and serine peptidase ) concept and we expect this coaction to continue and to finally demo the points of contact between CRIT-ed1 and C2 ( via the vWFA sphere ) . three ) Expression profile of CRIT in autoimmune disease and malignant neoplastic disease With a position to understanding the function of CRIT in autoimmune disease and malignant neoplastic disease, the applier is join forcesing on a Swiss National Foundation funded undertaking with Prof. J. Schifferli ( Univ. Hospital Basel ) to do a CRIT smasher mouse. To happen an association between CRIT look degrees and the disease procedure, a comparing of CRIT look ( messenger RNA and protein ) in normal tissue with that in autoimmune disease and malignant neoplastic disease will be made. In situ hybridization surveies every bit good as immunohistochemistry, utilizing dual staining and/or staining of consecutive subdivisions with anti-CRIT and cell specific markers, will be conducted to corroborate look in sertoli cells, podocyte cells, keratinocytes, encephalon [ 1 ] . The distribution of CRIT in normal and morbid tissue will be studied, peculiarly tissues injured by inflammatory or necrotic procedures: joints-synovium in arthritis, myocardial infarction etc. Previously, we carri ed out a survey along these lines, which looked at CRIT look in assorted kidney diseases [ 9 ] . This survey revealed CRIT upregulation in membranous kidney diseases on glomerular podocyte cells. Unlike CR1, hitherto the lone other complement regulator described on podocytes, and which is non upregulated in membranous nephropathy, we believe that CRIT on podocytes represents a last line of defense mechanism against onslaught by complement. Functional information back uping this was later obtained ( manuscript in Complement regulators are frequently upregulated in malignant neoplastic disease [ 10 ] and so expression degrees of CRIT in assorted human malignances will be assessed excessively. Critically, CRIT is upregulated in liver malignant neoplastic disease ( Fig. 4 ) and thyroid malignant neoplastic disease ( non shown ) . As obstruction of CRIT with antibody sensitises cells to complement lysis [ 1 ] , such findings may hold applications in malignant neoplastic disease. Already schemes to barricade complement regulators with specific antibodies have been used successfully with a position to developing fresh malignant neoplastic disease immunotherapies [ 11,12 ] . In a recent development, membrane-bound complement regulative proteins ( mCRP ) have been downregulated by siRNA to render tumour cells sensitive to complement [ 13 ] . Therefore we will bring forth vector-based shRNAs ( utilizing psiRNA vector [ In vivo Gen ] ) to stably strike hard down CRIT look and see the consequence on tumor cells. four ) CRIT extracellular peptide ( H17 ) and its usage in modulating complement-mediated redness in in vivo theoretical accounts of autoimmune disease With a position to therapeutically suppress redness due to classical tract activation in theoretical accounts of complement-mediated autoimmune disease, CRIT has been targeted to suppress the Reversed Passive Arthus Reaction in mice [ 7 ] . By disposal of an counter peptide, H17, which binds complement C2 and prevents its activation it was possible to significantly cut down complement-mediated redness. To prove this peptide as a curative against autoimmune diseases in which the classical tract is peculiarly of import we are join forcesing with labs that have the appropriate animate being theoretical accounts. Experimental autoimmune myasthenia gravis ( EAMG ) is an antibody-mediated autoimmune disease impacting the neuromuscular junction. The disease, which is besides T cell-dependent, is an accurate theoretical account in footings of its pathology and clinical result of human myasthenia gravis ( MG ) . We have been approached by Prof. P. Christadoss and Dr. E. Tuzun of the Universit y of Texas, Galveston to prove H17 in their mouse theoretical account of MG [ 14,15 ] and will continue with this coaction. 1.2.5 Does CRIT adhere other serum proteins through its extracellular spheres? In a collaborative survey with Prof. Marina Botto ( Imperial College ) we will look into whether CRIT is a receptor for any other proteins beside complement C2 and FB, with which it binds with high and low affinity, severally. To prove whether the extracellular spheres of CRIT have other adhering spouses, receptor affinity chromatography [ 16 ] will be used to see whether ed1 binds other proteins from the serum of a C2 deficient ( C2D ) patient or of a combined C2/FB smasher mouse [ 17,18 ] . As the function of the 2nd extracellular sphere, ed2 has non been established, normal serum will be used ab initio to place ed2-binding proteins adhering to ed2 affinity columns by standard mass-spec designation protocols. Further experiments will be conducted to see if CRIT binds integrins. The principle for this is that CRIT-ed1 binds the vWFA1 sphere of complement C2 [ 19 ] and vWFA spheres are typically found in integrins, such as Very Late Antigen 4 ( VLA-4 ) on monocytes. The interaction w ith vascular cell adhesion molecule-1 ( VCAM-1 ) molecules on the endothelium is believed to non merely intercede attachment [ 20 ] and transendothelial migration [ 21 ] but besides to excite distinction [ 22 ] . Methodology to be utilized in the survey of the purposes of the undertaking: I ) The function of CRIT in myeloid distinction As we have seen, the function of CRIT in myeloid distinction has been studied with an antagonist CRIT-based peptide termed H17 ( NH2-HEVKIKHFSPY-CO2H ) consisting the 11aa C-terminus of CRIT-ed1. Preliminary work suggests that in adhering to C2 and therefore barricading the interaction of C2 with CRIT [ 1 ] , H17 may bring on the distinction of monocytes/promonocytic cell lines along the tract of macrophage distinction, and significantly, inhibit cell proliferation. It is intended that this pilot survey will go on the work that has been started in this respect, and will lend original research findings to the intervention of diseases that are caused by failures in the proper operation of the complement tract in worlds. The different curative attacks that are presently used in handling acute leukemia include cytotoxicity, programmed cell death and distinction. Differentiation therapy was developed over a decennary ago and Acts of the Apostless by bring oning cell rhythm apprehension and hence distinction in leukaemic monocytes [ 2 ] , therefore elegantly avoiding cytotoxicity effects. Retinoids, such as all-trans-retinoic acid ( ATRA ) are used to handle promyelocytic leukemia by specifically aiming neoplastic cells whilst non impacting normal mature cells. Many successes in the intervention of monocytic leukaemias have been reported since [ 3-5 ] . We suggest that a CRIT-based peptide ( H17 or an H17 derived function ) could finally offer an of import alternate intervention for monocytic leukemia by bring oning distinction of monocytic cells. The peptide will be tested entirely and in combination with ATRA in a mouse theoretical account of acute promyelocytic leukemia [ 6 ] . This will take to cons equences which could be of great usage in developing alternate therapies for handling conditions that arise as a consequence of failure of the right operation of the complement tract in worlds. two ) The construction of CRIT peptides ( ed1 and H17 ) and of CRIT peptides interacting with the von Willebrand Factor A ( vWFA ) sphere of complement C2 As has been seen, Huiet Al.( 2005 ) looked at the look of a functional recombinant von Willebrand factor-A sphere from human complement C2, in footings of this being a possible binding site for C4 and CRIT. As we have seen, CRIT competes with C4b for the binding of C2, with the major adhering site on C2 being located on a short peptide sequence that was antecedently of unknown beginning ; Huiet al. ,( 2005 ) , nevertheless, looked at a part on C2 that was known to hold binding capacity, the von Willebrand Factor-A, and found that, so, this peptide sequence inhibits complement activity ; utilizing a cloned von Willebrand Factor-A sequence, Huiet Al.( 2005 ) were able to look in item at the interactions between C2 and CRIT and C4b. The current survey will take the work of Huiet Al.( 2005 ) further, by looking in item at the CRIT tract, in footings of adhering the serum complement protein, C2, the CRIT peptide, H17 can cut down complement-mediated rednessin vivo[ 7 ] and we will prove CRIT-ed1 and H17 as possible distinction therapeutics peculiarly aiming monocytic leukemia. To better the efficaciousness of these peptides, we aim to utilize structural information on the manner they interact with C2. The CRIT-H17 peptide will be synthesized full length as an 11-mer, but besides as a 10-mer, 9-mer and 8-mer. We will besides mutate to alanine the amino acids believed to interact with the vWFA sphere of C2. CRIT-H17 will farther be synthesized as a head-to-toe cyclised version of H17 ( to mime the native CRIT molecule ) . Prior to structural surveies, these peptides will be tested for their efficaciousness at cut downing complement activation in vitro. Interactions of these peptides with C2 vWFA sphere will be moni tored for by a novel technique utilizing electrospray ionization mass spectroscopy ( developed within the Institute for Health Research A ; Policy at LMU by Dr. A. Bligh ) [ 8 ] . This technique can besides observe the presence of two adhering sites and if there are two ligands whether they bind competitively and with what affinity. To supervise conformational alterations on interaction, in add-on to working out dynamicss of interaction, we will utilize Double Polarisation Interferometry ( AnaLight Quantum ) through coaction with Dr. R.B. Sim ( MRC Immunochemistry Unit, Univ. of Oxford ) . Prof. Peter Gros ( Centre for Biomolecular Research, Utrecht ) has approached the applier for CRIT peptides for co-crystallisation with an available C2a ( von Willebrand Factor A [ vWFA ] and serine peptidase ) concept and we expect this coaction to continue and to finally demo the points of contact between CRIT-ed1 and C2 ( via the vWFA sphere ) . three ) Expression profile of CRIT in autoimmune disease and malignant neoplastic disease With a position to understanding the function of CRIT in autoimmune disease and malignant neoplastic disease, the applier is join forcesing on a Swiss National Foundation funded undertaking with Prof. J. Schifferli ( Univ. Hospital Basel ) to do a CRIT smasher mouse. To happen an association between CRIT look degrees and the disease procedure, a comparing of CRIT look ( messenger RNA and protein ) in normal tissue with that in autoimmune disease and malignant neoplastic disease will be made. In situ hybridization surveies every bit good as immunohistochemistry, utilizing dual staining and/or staining of consecutive subdivisions with anti-CRIT and cell specific markers, will be conducted to corroborate look in sertoli cells, podocyte cells, keratinocytes, encephalon [ 1 ] . The distribution of CRIT in normal and morbid tissue will be studied, peculiarly tissues injured by inflammatory or necrotic procedures: joints-synovium in arthritis, myocardial infarction etc. Previously, we carri ed out a survey along these lines, which looked at CRIT look in assorted kidney diseases [ 9 ] . This survey revealed CRIT upregulation in membranous kidney diseases on glomerular podocyte cells. Unlike CR1, hitherto the lone other complement regulator described on podocytes, and which is non upregulated in membranous nephropathy, we believe that CRIT on podocytes represents a last line of defense mechanism against onslaught by complement. Functional information back uping this was later obtained ( manuscript in Complement regulators are frequently upregulated in malignant neoplastic disease [ 10 ] and so expression degrees of CRIT in assorted human malignances will be assessed excessively. Critically, CRIT is upregulated in liver malignant neoplastic disease ( Fig. 4 ) and thyroid malignant neoplastic disease ( non shown ) . As obstruction of CRIT with antibody sensitises cells to complement lysis [ 1 ] , such findings may hold applications in malignant neoplastic disease. Already schemes to barricade complement regulators with specific antibodies have been used successfully with a position to developing fresh malignant neoplastic disease immunotherapies [ 11,12 ] . In a recent development, membrane-bound complement regulative proteins ( mCRP ) have been downregulated by siRNA to render tumour cells sensitive to complement [ 13 ] . Therefore we will bring forth vector-based shRNAs ( utilizing psiRNA vector [ In vivo Gen ] ) to stably strike hard down CRIT look and see the consequence on tumor cells. four ) CRIT extracellular peptide ( H17 ) and its usage in modulating complement-mediated redness in in vivo theoretical accounts of autoimmune disease With a position to therapeutically suppress redness due to classical tract activation in theoretical accounts of complement-mediated autoimmune disease, CRIT has been targeted to suppress the Reversed Passive Arthus Reaction in mice [ 7 ] . By disposal of an counter peptide, H17, which binds complement C2 and prevents its activation it was possible to significantly cut down complement-mediated redness. To prove this peptide as a curative against autoimmune diseases in which the classical tract is peculiarly of import we are join forcesing with labs that have the appropriate animate being theoretical accounts. Experimental autoimmune myasthenia gravis ( EAMG ) is an antibody-mediated autoimmune disease impacting the neuromuscular junction. The disease, which is besides T cell-dependent, is an accurate theoretical account in footings of its pathology and clinical result of human myasthenia gravis ( MG ) . We have been approached by Prof. P. Christadoss and Dr. E. Tuzun of the Universit y of Texas, Galveston to prove H17 in their mouse theoretical account of MG [ 14,15 ] and will continue with this coaction. 1.2.5 Does CRIT adhere other serum proteins through its extracellular spheres? In a collaborative survey with Prof. Marina Botto ( Imperial College ) we will look into whether CRIT is a receptor for any other proteins beside complement C2 and FB, with which it binds with high and low affinity, severally. To prove whether the extracellular spheres of CRIT have other adhering spouses, receptor affinity chromatography [ 16 ] will be used to see whether ed1 binds other proteins from the serum of a C2 deficient ( C2D ) patient or of a combined C2/FB smasher mouse [ 17,18 ] . As the function of the 2nd extracellular sphere, ed2 has non been established, normal serum will be used ab initio to place ed2-binding proteins adhering to ed2 affinity columns by standard mass-spec designation protocols. Further experiments will be conducted to see if CRIT binds integrins. The principle for this is that CRIT-ed1 binds the vWFA1 sphere of complement C2 [ 19 ] and vWFA spheres are typically found in integrins, such as Very Late Antigen 4 ( VLA-4 ) on monocytes. The interaction w ith vascular cell adhesion molecule-1 ( VCAM-1 ) molecules on the endothelium is believed to non merely intercede attachment [ 20 ] and transendothelial migration [ 21 ] but besides to excite distinction [ 22 ] . CRIT is a receptor that was foremost encountered on the surface of aSchistosomaspecies ; in theSchistosoma,it acts as a decoy C2-binding receptor in order to protect this parasite from complement onslaught by viing with C4 for the binding of C2 ( Inal and Schifferli, 2002 ) . Complement is, basically, an enzyme system that is triggered upon immune system onslaught: most of the enzymes in this system are identified through standardised labeling: they are labelled C followed by a figure and so a codification based on the cleavage merchandises when proteolysed, for illustration, C5b-9. Complement onslaught ( Carroll, 1998 ) plays a major function in supporting hosts from immune onslaught, in footings of extinguishing foreign encroachers, and involves a complex tract of interactions, in order that the procedure does non take to self devastation: so, unregulated complement action can take to autoimmune diseases ( Ohet al. ,2003 ) , and other conditions/diseases such as bosom onslaught ( K ilgoreet al. ,1994 ) , Alzheimer’s disease ( Bradtet al. ,1998 ) . CRIT ( or Sh-TOR as it was antecedently known ) was found inSchistosoma,as a complement C2 protein, that could barricade complement activation, therefore bring oning bilharzia in worlds ; it was hypothesized that the CRIT blocked complement activation through its C2 binding site ; CRIT look in the parasite therefore acts as a steerer C2 binding receptor, protecting the parasite against complement onslaught by viing with C4 for the binding of C2, at the ed1 sphere ( Hui, 2005 ) . CRIT has later been found that other animate beings, that are suited as theoretical account systems for analyzing CRIT action besides express CRIT, for illustration, the rat andTrypanosoma.Recent work has besides shown that worlds have a CRIT factor, labeled ( Hu ) -CRIT which is expressed in a broad scope of human cells, particularly in hematopoietic cells ( Inalet al. ,2005 ) . Further elaborate surveies of CRIT have shown that it is a transmembrane receptor with two extracellular and two in intracellular spheres with an active 11 amino-acid peptide subdivision ( called CRIT-H17 ) which is hypothesized to be involved in the complement suppression activity of CRIT ( Hui, 2005 ) . Much work has been undertaken on clarifying the mechanism of action of CRIT, in footings of it being a potentially utile molecule in handling immunological diseases and other diseases, such as malignant neoplastic disease. For illustration, Inalet Al.( 2005 ) have shown that CRIT barricading can take to deprotection in CRIT-expressing human myeloid cell lines and in monocytes, ensuing in a greater susceptibleness to complement-mediated lysisin vitro. Other research, such as that by Mollet Al.( 2006 ) has shown that CRIT look is different in patients with kidney upsets, through assorted alterations in up- or down-regulation of CRIT look, taking to the suggestion that the upregulation of CRIT in activated podocytes might stand for a self-defense mechanism, stand foring a ‘last line’ of defense mechanism in membranous kidney disease of the kidney. Introduction The purpose of this research is, finally, to transport out a pilot survey to back up preliminary grounds that the complement receptor CRIT ( Complement C2 Receptor Inhibitor Trispanning ) plays a function in monocyte/macrophage terminal distinction. We aim to demo that by triping distinction through CRIT, it is possible to suppress the proliferation of myeloid leukemia cells. This could hold of import deductions for an alternate intervention agenda for monocytic leukemia. By the terminal of this survey we expect to demo the undermentioned: I ) that monocytes which can adhere C2 through CRIT maintain monocytic phenotypein vitroorin vivo ;II ) that monocytes can be induced to terminally distinguish by barricading the interaction of CRIT with its blood relation ligand, complement C2 or as monocytes move into an extravascular environment devoid of C2 ; that a knockdown of CRIT look in monocyte carcinoma cell lines or physical blocking of CRIT-C2 interaction induces them to terminally dis tinguish, and that, likewise, a blocking of CRIT-C2 interaction on leukaemic monocytes will halt proliferation and bring on distinction ; and, in conclusion, that, conversely, monocytes that are C2-/- , can non be induced to terminally distinguish by barricading the interaction of CRIT with its ligand, C2, nevertheless on traveling into an extravascular environment, other excess mechanisms, such as interaction of monocyte integrins with VCAM molecules on endothelial cells, may still bring on distinction. In consequence, basically, either barricading ligand interaction with CRIT or cut downing CRIT look should excite cell rhythm apprehension ( irreversible block at G1 ) and terminal distinction into cells with a macrophage phenotype. These conditions represent a fresh tract for monocyte/macrophage terminal distinction, based on the theoretical account proposed, and affecting the complement receptor, CRIT. In footings of monocyte leukemia, besides advancing cell rhythm apprehension, barricading CRIT with anti-CRIT-ed1 has the added benefit of rendering the cell more susceptible to complement-mediated cytolysis, as described antecedently for monocyte carcinoma cell lines ( U937 and THP-1 ) and primary monocytes showing CRIT [ 1 ] . Bradt, B.M.et al. ,1998. Complement-dependent proinflammatory belongingss of the Alzheimer’s disease B-peptide.J. Exp. Med.188, pp.431. Carroll, M.C. , 1998. The function of complement and complement receptors in initiation and ordinance of unsusceptibility.Ann Rev Immun16,pp.545-568. Hui, K-M. , 2005. Biochemical and functional surveies of a fresh complement inhibitor, CRIT, with its interaction spouses. Dissertation submitted to the University of Basel, 2005. Hui, K-M.et al. ,2005. Expression of functional recombinant von Willebrand factor-A sphere from human complement C2: a possible binding site for C4 and CRIT.Biochem J.389, pp.863-868. Inal, J.M. , 2005. Complement C2 receptor inhibitor trispanning: from adult male to schistosome.Springer Seminars in Immunology27 ( 3 ), pp.320-331. Inal, J.M.et al. ,2005. Complement C2 receptor inhibitor trispanning: a fresh human complement inhibitory receptor.Journal of Immunology74, pp.356-366. Inal, J.M. and Schifferli, J.A. , 2002. Complement C2 receptor inhibitor trispanning and the B-chain of C4 portion a binding site for complement C2.Journal of Immunology168, pp.5213-5221. Kilgore, K.S.et al. ,1994. The complement system in myocardial ischaemia/reperfusion hurt.Cardiovasc Research28, pp.437. Makrides, S.C.et al. ,1992. Cell surface look of the C3b/C4b receptor ( CR1 ) protects the hamster ovary cells from lysis by human complement.J.Biol.Chem.34, pp.24754-24761. Moll, S.et al. ,2006. CRIT is expressed on podocytes in normal human kidney and upregulated in membranous kidney disease.Kidney International69,pp.1961-1968. Oh, K-S.et al. ,2003. Inhibition of complement activation by recombinant Sh-CRIT-ed1 parallels.Immunology110, pp.73-79.