Molecular Mechanisms of Sepsis

Molecular Mechanisms of Sepsis Title: Protein-protein interaction network and functional module analysis to reveal the mechanism of sepsis in polytrauma patients Highlights: We explored the molecular basis of sepsis induced by polytrauma using PPI network. A total of 342 DEGs including 110 up- and 232 down-regulated genes were obtained. TRAF3 was related with the innate immune responses in sepsis. ITGB3 was the key gene involved in coagulation dysregulation in sepsis. CASP6 and RASA1 played key roles in the cell apoptosis mechanism of sepsis. Abstract Objective Sepsis represents the systemic inflammatory response to microbial infection. The pathogenesis of sepsis remains unclear. In this study, we aimed to explore the molecular mechanism of sepsis inpolytrauma patients. Methods The differentially expressed genes (DEGs) between the polytrauma patients with and without sepsis were identified by analyzing the GSE12624 microarray data using the limma package of R. The protein-protein interaction (PPI) network was extracted from the human PPI datasets by using MATLAB. The functional modules in the PPI network were identified by the MCODE network clustering algorithm. The KEGG pathway analysis was performed in each module. The phylogenetic tree was constructed using phylogeny inference package (PHYLIP). Result Total of 342 DEGs including 110 up- and 232 down-regulated genes were obtained. The PPI network identified several hub genes which had more interactions with others, such as TRAF3, ITGB3, CASP6 and RASA1. Further phylogenetic analysis indicated the high conservation of these hub genes. In the module analysis, four significant modules were identified. All the genes (COL1A2, FN1, ITGA2B, ITGB3 and CD36) in module 2 were enriched in extracellular matrix (ECM)-receptor interaction pathway. In module 4, CASP6 and CASP3 were enriched in apoptosis pathway. Conclusion We predicted genes such as TRAF3, ITGB3, CASP6 and RASA1 which were closely associated with sepsis induced by polytrauma. Among them, ITGB3 may play key role in the coagulation dysregulation of polytrauma patients with sepsis, and CASP6 and RASA1 may be the key genes in the cell apoptosis mechanism of sepsis. Keywords Sepsis, DEGs, GO, PPI network, phylogenetic tree Introduction Polytrauma is a syndrome of multiple injuries exceeding a defined severity with sequential systemic reactions that can lead to dysfunction or failure of remote organs and vital systems, which have not themselves been directly injured [1]. Sepsis, as one of the complications of polytrauma [2], is the systemic inflammatory response to microbial infection that often leads to increasing susceptibility to secondary infections, multiorgan failure, and death [3]. A sixteen years clinical study indicated that 10.2% of polytrauma patients infected sepsis during their hospital course [4]. Polytrauma is a major cause of morbidity and mortality in global and sepsis (3.1-17%) is one of the predominant causes of late death in polytrauma patients [5]. The disease severity is increasing according to the order of sepsis, severe sepsis and septic shock in the systemic inflammatory response syndrome (SIRS) [6]. Mortality has been reported to be as high as 45.6% for patients with severe sepsis or septic shock [7]. Based on the pathogenesis of sepsis, many therapies have been applied in the clinical practice such as antimicrobial therapy [8, 9] and hemodynamic support and adjunctive therapy [10, 11]. Currently, the Surviving Sepsis Campaign (SSC) has attempted to increase the awareness and establish the practice guidelines to improve the recognition and treatment for the patients with sepsis [12, 13]. At present, there are four approved mechanisms in the pathogenesis of sepsis [14]. The first one is dysregulated coagulation. Sepsis patients frequently manifest disseminated intravascular coagulation (DIC) with consumption of platelets and prolongation of clotting times [15]. The second one is inflammatory response. The inflammatory response is an important and central component of sepsis because the elements of response drive the physiological alterations that manifest as the SIRS [16]. Third, many cellular aspects become dysfunctional in sepsis which behave either excessive activation or depressed function [17]. The last one is metabolic alterations. It was reported that endogenous glucose production was markedly increased in the patients [18]. However, the specific molecular mechanisms of them remain entirely unclear. In this study, the differentially expressed genes (DEGs) between the polytrauma patients with sepsis and without sepsis were identified. Gene ontology (GO) analysis , protein-protein interaction (PPI) network and phylogenetic tree construction were performed to explore the molecular basis of sepsis induced by polytrauma. Materials and methods Microarray data The gene expression profile of GSE12624 based on the CodeLink UniSet Human I Bioarray platform (GE Healthcare/Amersham Biosciences) was downloaded from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). The dataset available in this analysis contained 70 samples including 34 polytrauma patients with sepsis and 36 polytrauma patients without sepsis. Data preprocessing and DEGs screening For the microarray data, Robust Multichip Average (RMA) in the Affy package of R was used to compute normalized expression measures from the raw expression values. Probe annotation was obtained by using the Bioconductor package. The limma package was used to identify the DEGs with p-value 1 [19]. GO enrichment analysis of DEGs GO analysis was performed using the DAVID online tool (http://david.abcc.ncifcrf.gov/) [20]. For GO enrichment of DEGs, we selected GOTERM_BP_FAT, GOTERM_CC_FAT and GOTERM_MF_FAT as the gene set categories. A p-value of less than 0.05 was set as the cut-off criterion. PPI network construction The human PPI datasets with 108477 interacting protein pairs were downloaded from PINA2 (http://cbg.garvan.unsw.edu.au/pina/interactome.stat.do) at December 26, 2013. The PPI networks of the DEGs in sepsis were extracted from the human PPI datasets by usingMATLAB [21]. The proteins in the network served as nodes and the degree of a node corresponded to the number of interactions with other proteins [22]. The protein with high degree was considered as the hub node. Identification of functional modules in PPI network PPI network visualization and network parameters evaluation were performed by using Cytoscape software. The modules were identified by the MCODE (a cytoscape plug-in) network clustering algorithm with the default parameters [23]. The module with score larger than 2 was considered as significant. KEGG pathway analysis of each module was performed by applying the DAVID annotation tool. Phylogenetic tree construction In this study, we constructed the phylogenetic tree based on the nucleotide sequences to investigate the sequence conservation of the DEGs whosedegree were large than 30. The BLAST program is used to search for homologous sequences of these DEGs. The DNA sequence of these DEGs and their homologous genes in FASTA format were obtained from the nucleic acid database in NCBI (http://www.ncbi.nlm.nih.gov/nuccore). The phylogenetic tree was constructed by using phylogeny inference package (PHYLIP) with the default parameters [24]. The gene conservation was estimated by the distance from gene to the phylogenetic tree root. Result DEGs between the patients with and without sepsis After statistical analysis of the microarray data, a total of 342 DEGs were screened out. Among them, 110 were down-regulated and 232 were up-regulated in sepsis. The top 20 significantly up- and down-regulated DEGs are shown in Table 1. GO enrichment analysis The 342 DEGs were significantly enriched into 95GOterms including 81 biological processes terms, 10 cellular component terms and 4 molecular function terms. The top 10 GO biological processes termswere mainly related to the purine base (purine base biosynthetic process, purine base metabolic process, purine nucleoside monophosphate biosynthetic process and purine ribonucleoside monophosphate biosynthetic process), nucleobase (nucleobase metabolic process and nucleobase biosynthetic process) and regulation of protein modification (regulation of protein modification process and positive regulation of protein modification process). The 10 significantly enriched GO terms of cellular component included four lumen related terms (organelle lumen, membrane-enclosed lumen, intracellular organelle lumen and nuclear lumen), two membrane related terms (extrinsic to membrane and plasma membrane part) and four other cellular component terms (peroxisome, microbody, nuclear body and Golgi apparatus) . For molecular function, four significant GO terms were enriched finally. They were acyl-CoA binding, sons of mothers against decapentaplegic homologue (SMAD) binding, aryl hydrocarbon receptor binding and potassium channel inhibitor activity (Table 2). PPI network of DEGs A PPI network consisting of 225 DEGs and 1048 non-DEGs is shown in Fig. 1. This network included 1145 gene nodes and 1273 interactions. The connectivity degree of each node in this PPI network was calculated and the results of top 20 nodes are listed in Table 3. Among them, the genes CRK (encoding CDC2 related protein kina), RASA1 (encoding RAS p21 protein activator 1), TRAF3 (encoding tumour-necrosis-factor receptor associated factor 3), ZHX1 (encode zinc-fingers and homeoboxes), ITGB3 (encoding integrin ÃŽ ²3), RPA1 (encoding replication protein A1), JAK3 (encoding Janus kinases 3), and CASP6 (encoding caspase-6) with the degree over 30 were selected as the hub genes. Module analysis of PPI network A total of 7 modules were constructed by using MCODE plug-in. After excluding the modules with the score less than 2, 4 significant modules were considered as functional ones associated with sepsis (Table 4). According to the Fig. 2, the numbers of nodes and edges were similar in each model. The detailed results of KEGG pathway analysis for each module are provided in Table 5. For module 1, no pathway was enriched in the KEGG pathway analysis. For module 2, a total of 14 significant enriched pathways were identified. Among them, all the genes in this module were enriched in the pathway of extracellular matrix (ECM)-receptor interaction. In addition, except CD36 (encoding glycoprotein IV), the other four genes (ITGB3 and ITGA2B encoding integrin ÃŽ ±IIbÃŽ ²3, COL1A2 encoding the ÃŽ ± 2 chain of type 1 collagen and FN1 encoding fibrinogen 1) were enriched in the focal adhesion and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. There were three significant enriched pathways in module 3. HIF1A (encoding hypoxia inducible factor-1), ARNT (encoding arylhydrocarbon receptor nuclear translocator) and ARNT2 (encoding arylhydrocarbon receptor nuclear translocator 2) were enriched in the pathway of renal cell carcinoma and pathways in cancer. HIF1A and ARNT were enriched in the pathway of Hypoxia-inducible factor 1 (HIF-1) signaling. For the module 4, five significant pathways were found. Among them, CASP3 (encoding caspase 3) and BIRC5 (encoding baculoviral IAP repeat–containing 5 and also called survivin) were enriched in the pathway of colorectal cancer, hepatitis B and pathways in cancer. CASP6 and CASP3 were enriched in apoptosis pathway. CASP3 and RASA1 were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway (Table 5). Phylogenetic tree analysis Based on the result of PPI network analysis, the selected hub genes were chosen to construct the phylogenetic tree. The phylogenetic tree of ZHX1 was unable to be constructed, as only three homologous sequences were searched out. The phylogenetic trees of the other seven hub genes were constructed by the DEGs and their top nine significant homologous genes. The results showed that CRK, RASA1, TRAF3, ITGB3, RPA1 and CASP6 were the genes that were closer to tree roots indicating that the conservation of these genes was high during evolution. However, the conservation of JAK3 was low because of appearing in the late period of evolution (Fig. 3). Discussion Currently, sepsis remains a serious clinical problem. The four approved mechanisms of sepsis were dysregulated coagulation, inflammatory response, and cellular dysfunctional and metabolic alterations. However, the specific molecular mechanisms are still incompletely understood. For better understanding the pathogenesis, we identified and analyzed the DEGs between the patients with and without sepsis. As a result, a total of 342 DEGs including 110 up-regulated genes and 232 down-regulated genes were found. These genes were significantly enriched in GO terms including purine base biosynthetic process, regulation of protein modification process and peroxisome. Among them, the process of purine base biosynthesis is the most significantly enriched process. It was reported that de novo purine biosynthesis was essential for infectivity, growth and virulence of many bacteria in mammals [25]. The pathogenesis of sepsis was related with the bacterial infection [26]. Therefore, the purine base biosynthesis process may associate with sepsis based on the tissue response to bacterial infection. For the regulation of protein modification, Wu et al. reported that the alterations in the phosphorylation of myofibrillar proteins and the Ca2+ sensitivity of myofibrillar ATPase might contribute to alter cardiac function during the progression of sepsis [27]. The cardiac dysfunction was the clinical characteristic in severe sepsis and septic shock [28]. Thus, the phosphorylation of myofibrillar proteins may be related with the sepsis-induced cardiac dysfunction. Furthermore, we mapped the DEGs to the PPI network and identified high conserved hub genes. Among them, the high conservation of CRK, RASA1, TRAF3, ITGB3, RPA1 and CASP6 were proved by the phylogenetic tree analysis. They may be the crucial genes in the pathogenesis of sepsis. For TRAF3, it is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family [29]. This protein participates in the activation of the innate immune response [30]. In the PPI network, TBK1 (encoding TANK-binding kinase 1) was a non-DEG interacted with TRAF3. It was reported that TIR domain-containing adaptor-inducing IFN-ÃŽ ² (TRIF) could interact with noncanonical IKKs (IKKà Ã‚ µ and TBK-1) and IKKÃŽ ¹ (also called IKKà Ã‚ µ) through TRAF3 in the Toll-like receptors (TLR) signaling pathway [31]. The innate immune system constitutes the first line of defense by rapidly detecting invading pathogens through the TLR [32] and is a danger signal in systemic inflammatory response syndrome and sepsi s [33]. Thus, TRAF3 may be the mediator of innate immune responses in sepsis induced by polytrauma. We also performed the modular analysis of the PPI network and four functional modules were identified. Based on the result of the KEGG pathway analysis of each module, we found that the pathways in module 2 and 4 were more related with sepsis. The ECM-receptor interaction pathway was the most significant pathway in module 2 and all the genes of this module were enriched in this pathway. Fibronectin and collagen are the components of ECM [34]. Integrin family are the receptors transducing signals from the ECM [35]. Among them, integrin ÃŽ ±IIbÃŽ ²3 is the platelet integrin promoting theaggregation of platelets [36-38]. Moreover, it was reported that collagen type I could induce the aggregation of platelet [39]. Integrin ÃŽ ±IIbÃŽ ²3 is one of the platelet collagen receptors in platelets [40]. It was reported that platelet-specific elements initiated at the cytoplasmic domains of integrin ÃŽ ±IIbÃŽ ²3, which was a signal that leaded to conformational changes within the extracellular do mains of integrin and expression of the fibrinogen receptor, then the simultaneous occupancy on adjacent platelets of receptors with dimeric fibrinogen molecules leaded to platelet aggregation [41]. In addition, CD36 is spatially associated with the ÃŽ ±IIbÃŽ ²3 integrin on the surface of platelets [42]. Thus, we speculated that the binding of collagen type I and ÃŽ ±IIbÃŽ ²3 might need the participation of CD36, and then conformational changes within the extracellular domains of integrin and the binding between fibrinogen and fibrinogen receptor could lead to platelet aggregation. Disseminated platelet aggregation is one of the characteristics of the DIC in sepsis [43, 44]. The up-regulated expression of ITGB3 in sepsis may lead to the disseminated platelet aggregation. Hence, we concluded that the coagulation dysregulation in the polytrauma patients with sepsis may be associated with the increase of disseminated platelet aggregation caused by the up-regulated expression of ITGB3. Thus, ITGB3 may play key roles in the coagulation dysregulation of the polytrauma patients with sepsis. Hub nodes CASP6 and RASA1 were predicted to be closely interacted with each other in module 4. Besides, CASP3, TOP1, BIRC5 and AURKB (Aurora B kinase) were also included in module 4. Among them, CASP6 and CASP3 were enriched in apoptosis pathway. It was reported that CASP6 may be associated with the cell apoptosis in sepsis [45] and blocking caspases might have some beneficial effects in decreasing cell apoptosis in sepsis [46]. Thus, we further confirmed that the up-regulated expression of CASP6 may promote cell apoptosis in sepsis. Besides, TOP1 is cleaved late during cell apoptosis by CASP6 and CASP3 [47]. The TOP1 cleavage complexes contribute to cell apoptosis [48]. Therefore, the increase of these complexes induced by the up-regulated CASP6 can promote the cell apoptosis in sepsis. Moreover, full-length TOP1 could induce DNA cleavage by single-strand breaks which is the signal of cell apoptosis [49, 50]. Therefore, the exaggerated gene expression of TOP1 in our study might cont ribute to cell apoptosis in sepsis. In addition, it was reported that CASP3 could modulate a given set of proteins to generate, depending on the intensity of the input signals, opposite outcomes (survival vs death) through differential processing of RASA1 [51]. Some articles reported that low CASP3 activity leaded to the cleavage of the RASA1 protein into an amino-terminal fragment [52, 53]. RASA1 bound BIRC5 is a bifunctional protein complex that can suppress cell apoptosis and regulated cell division, so as to generate anti-apoptotic signals [54]. AURKB exists in a complex with BIRC5 [55]. Considering the up-regulated expression of RASA1 and AURKB, we speculated that there may be a switch mechanism of CASP3-RASA1 in cell apoptosis and BIRC5 and AURKB might play roles in the anti-apoptosis mechanism of RASA1. In summary, CASP6 and RASA1 are the key genes in the pathogenesis of sepsis induced by polytrauma. Conclusion In this study, we obtained four key genes related with pathogenesis of sepsisinduced by polytrauma. Among them, TRAF3 was related with the innate immune responses in sepsis,ITGB3 may play key role in the coagulation dysregulation of the polytrauma patients with sepsis and CASP6 and RASA1 were associated with the mechanism of cell apoptosisin sepsis. For further investigating the association of these hub nodes with sepsis and verifying the role of the interactions among the genes in the pathogenesis of sepsis, more studies are required in the future.

Ethical Issues in Globalization and International Marketing.

Ethical Issues in Globalization and International Marketing. ABSTRACT: The globalization of markets and increase in the productivity made several marketers and business persons to concentrate more on the ethical issues in cross-cultural settings. This article is mainly intended for ethical analysis and making decisions over the international marketing scenario. This paper provides few guidelines which may serve marketers in the area of marketing ethics. It is also used to assist out the marketers to behave in an ethical fashionable way. The local marketing conditions may differ out along from place to place, but some global marketing ethical principles should be applicable to all markets along the world. This Paper suggests creating a standard uniform code of ethics that will provide a solution to the problem of diversification in different cultures by implementing strategies in international marketing. Keywords: Globalization, International Marketing, Ethical principles. INTRODUCTION: Globalization and international marketing ethical issues are allied with one another. Steady increase in globalization lead to few problems which include ethics. From 1950 to 2000, world trade expanded almost 20-fold, far outstripping world output, which grew by six and a half times (WTO, 2001). Globalization refers to the process in which different cultures, societies and economies throughout the world will be connected and integrated through by a global network of transportation, communication, trade and business. This term is sometimes referred to as a economic globalization where several economies of the nations are combined through by a foreign investments, trade, capitalization, migration and many other factors. And it may be referred through by various other related terms. Increase in the globalization may result in many problems including ethical ones as both are related through in one way or the other. From past four decades the global trade increased by seven times where im ports, exports, trade and foreign investments played a major role in its increasing extent and surveillance. Even the cross border investments of small and medium ranging businesses are also increased almost five to six times in its productivity, yearly outflow and development along from the past 25 years and this meant that different persons are working along different geographical, social and marketing boundaries along worldwide. This shows out alternatively the related problems along with the change of different environments including ethical problems, financial and marketing personnel problems along locally and globally. If this trend continues the prophesies about globalization by Levitt will become reality in 2020. (Recep YÃ ¼cel, 2009) To manage out this trend fairly and situational there is a need to create universal ethical principles and norms. Theoretical Framework: Globalization: 2.1.1 History: According to Friedman (1999), globalization is:The inexorable integration of markets, nation States and technologies to a degree never witnessed before. Globalization is a term which was proposed and under veining its extent and development from thousands of years. But it significantly accelerated from 1980Â ´s after the demolishment of USSR. The word globalization is first employed in oxford dictionary in 1930. In considering the history of globalization, some authors focus on events since the discovery of the America in 1492, but most scholars and theorists concentrate on the much more recent past (www.globalpolicy.org).It was not until 1960Â ´s the term is widely used by economists and other social scientists. Since from its evolution the term is inspired to numerous and conceptive wordings and definitions dating back across the movements of different trading and cultural perceptive. United Nations termed the word globalization has many meanings and ways to define. According to it when using the term globalization in economical context it may refers to the one which cuts out the boundaries or barriers in between different nation s and establish out the smooth and efficient way for their trading and exchange which may include capitals, services, labor etc. Tom.J.Palmer described globalization as The diminution or elimination of state- enforced restrictions on exchanges across the borders and the increasingly integrated and complex global system of production and exchange that has emerged as a result. Roughly economic globalization is world trade and financial marketing integrated together. Globalization in other terms may refer as the process of forming global institutions. The global institutions are those which may be operated as that considering the entire world as single place. They may be distinguished from others in various terms such as in functioning at regional, national and international where each level may represent a different scope and set of social relationships. 2.1.2 Dimensions of Globalization: Globalization is the term which may be represented in various dimensions and it related to almost every fields of daily life. It differs from profession to profession i.e. for example it differs from some marketing staff to an engineer. Dimensions for globalization are as follows: (www.globalpolicy.org) Economics-Related to globalization in trading, finance, money, corporations and banking. Political-Related to science, governance, wars, peace, IGOS, NGOS, regimes. Sociology-Related to communities, conflicts, classes, nations, agreements. Psychology-Related to individuals as subjects and objects to global action. Anthropology-Related to overlapping of cultures, adapting, clashing, merging. Communications- Related by considering information as knowledge and tools-internet. Geography- Everything provided it can be anchored to as space. We do not consider globalization as some purely economical, industrial or some financial term which may relate or revolve through problems like free trade or some expanding role of financial and industrial markets. We consider globalization as a multi dimensional term and in fact it is a spectrum of four processes. Building the global economy Formation of world opinion Democratization, or the creation of a global economy The emergence of global political institutions. Building the global economy is the process where when once got up in the longer run its evolution related to international and interregional trade is primarily a function not of actual and growing gnp but will potential for structural change. The rapid emergence of global financial markets over the past two decades and they particularly effect the foreign exchange field and other forms of international investment will lead to reduce the influence of even major governments on their economy and in global economies and might loosen out the links between economic and political power has been broken out. According to Kongar, globalization has three dimensions. These are political, economic, and cultural aspects of globalism (www.kongar.org). Formation of the world opinion is the process where the working of the world system and all its conditions and actions of the participants are oriented to a common set of problems coming out from responsive to common aspirations and emerging out from world-wide problems. It is a process of social construction which contains both the reality and the values. Reality helps us to make sense of the world and values help us to keep priorities which we can accept some and to reject parallel. Democratization is the process in which one can define in narrow and the broadest terms. In broader term one may be defined it as a learning process in which humans can try to learn itself in the condition of `equality under law`. Similarly in narrower context we can define it more precisely as accumulation of conditions necessary for possible emergence of a global community, community of democracies and a global level association of a democratic character. Global Institutions: The emergence of global institutions is the process which shows up to what extent the global institutions will sort out the effect of globalization. When comes to globalization in international business it splits out to two faces one in markets and the other in production. The globalization of marketing side is the one in which merging of historically distinct markets in order to convert it into a huge global market and globalization of production refers to the merging of goods and services from although the world to take advantages in several national conditions like the difference in cost and quality factors etc. As markets globalize and increasing in cost factor and productivity, several globalized institutions are formed to manage out the matters related to this such as to manage, regulate the policies and to form several multinational treaties to govern the globalized business system. From past 55 years more number of global institutions has evolved to perform these tasks they are, General Agreement on Tariffs and Trade(GATT) and its successor, the World Trade Organization (WTO); the International Monetary Fund (IMF) and its twin sister, the World Bank and the United Nations (UN). All these institutions were created by voluntary agreement between individual nation-states, and their functions are enshrined in international treaties. (Hill, ibid: 9) All the above institutions play a major role in developing international business ethical rules and regulations. World Trade Organization is mainly responsible to guide and focus on all the countries who signed the treaty. Till date W.T.O has mo re than 145 nations and its purpose is to develop multinational agreements between the country member states. (www.imf.org). Global Business Strategies: Theodore Levitt (1983: 92-102) has argued that, due to the advent of modern communications and transport technologies, consumer tastes and preferences are becoming global, which is creating global markets for standardized consumer products. Local companies deal with overseas business investment and trade, managers must identify that managing international business vary from managing local business. We can observe that each country is unique, in culture, laws, legal systems, political factors and economy of country. Despite widespread globalization, still there are many big and enduring differences between the countries (Hill, ibid:. 19-37). Marketing strategies change from country to country as there is difference in culture and other factors. If we assume marketing strategy used in India may not be applied in Sweden and the strategy implemented in Sweden is not implemented in USA because of difference in various factors among countries for instance if we consider advertising in Germany it is illegal to use comparative advertising (Cateora Graham,2005: 483). Kuwait government controlled TV network to allows only 32 minutes of advertising per day in the evening (Sunil Erevelles and his colleagues,2002). According to Barlett and Ghoshal (1989), firms can use four strategies an international strategy, a multi-domestic strategy, a global strategy and a transnational strategy. Company use international strategy focus on transferring skills and its products transformed from different overseas market and give less importance to local markets. Organizations implements multi domestic strategy alters their marketing and business strategy to local or domestic conditions. Companies implement global strategy focus on acquire cost reductions produced from experience curve effects and local economy. Company implement transnational strategy involves a parallel focus on declining of costs, transferring skills and products. Ethical Problems in International Marketing: Research in Marketing Ethics is defined as the systematic study of how moralstandards are applied to marketing decisions, behaviors and institutions (Laczniak andMurphy 1993). 2.2.1 History of Ethics: Ethics is related to the field of philosophy concerned with morals and values. Ethics is divided into five branches: Meta ethics, Political ethics, normative ethics, virtue ethics and practical philosophy. Meta-Ethics: It focuses more on the grounds used to justify moral judgment than moral creating moral judgment. This ethics is just descriptive. Political-Ethics: It is concerned more on testing good society and the origins of political power such as government. Normative-Ethics: It is related to the developing theories which decide the actions done by human are right or wrong. Deontological ethics, utilitarian ethics and virtue ethics are all normative. Practical-Ethics: This ethics uses ethical principles and theories in practical environment such as, medical ethics, business ethics etc.

To what extent did comprehensive schools enable working class :: Economics

To what extent did comprehensive schools enable working class pupils to succeed? Comprehensive schools enabled working class students to succeed because when there was the Tripartite System the majority of working class pupils would go to secondary modern schools as the 11+ test was favoured towards middle class experiences and language. Pupils attending secondary modern schools were seen as a student failing, this then affected the attention the students got at school, the opportunities open to the students and they also gained a low self-esteem. It also creates a â€Å"self believing prophecy† from low self esteem. In addition to that secondary modern schools only had a third of the funding with 80% of the population attending them. This meant that there were fewer qualifications to gain and less good qualified teachers, which in essences was preparing them for unskilled manual work. The tripartite system legitimated inequality through the ideology that ability is inborn rather than the products of the child’s upbringing and environment, and thus can be identified early on in life Because the 11+ test favoured middle class, it was mostly middle class students that went to grammar schools. This created a social class division when one of the reasons for having Free State education was more ‘equal’ opportunities. When comprehensive schools were introduced in 1965, it was designed to overcome the unfairness of the tripartite system by abolishing the 11+ exam and sending all pupils to the same type of secondary school (with the exception of private school students who continued to go to private schools). Since the schools joined, there were more qualifications on offer to students. Middle class and working class worked together. But never the less, the system continued to reproduce class inequality. Some secondary modern schools were placed where the majority of working class students lived, so in some schools it was still mainly working class. Whilst in others, mostly middle class. In addition to that, many comprehensives were streamed into ability groups, where middle-class pupils tend to dominate the higher streams. Even where ability groups were not present, Ball argued that teachers continued to label working class pupils negatively and to restrict their opportunities. More recently, both Ball and Whitty have examined how the policy of marketisation also reproduces and legitimates inequality. Marketisation is largely the result of the 1988 Education Reform Act, which reduced direct state control and introduced market forces into education so as to create competition between schools and increase parental choice. They state that marketisation reproduces inequality through exam league tables and the funding formula. Publishing each schools exam results in a league table ensures that schools that achieve good results are more in demand, because parents

Usage of Plague as a Biological Weapon Essay -- Biology Terrorism Terr

Usage of Plague as a Biological Weapon Bioterrorism is defined as the intentional use of dangerous microorganisms or viruses to kill a large population of people. Common examples of biological agents include anthrax, botulism, smallpox, and the plague. The most common form is the bubonic plague that caused the deaths of a large percentage of the population in Europe during the Middle Ages. The bacterium, Yersinia pestis, causes three forms of the plague; however the pneumonic plague is used in bioterrorism because of its advantages in transmission and production. To be infected with the pneumonic plague, a person simply needs to breathe in enough of the aerosolized bacteria to allow them to incubate inside the body. Symptoms usually appear two to four days afterward and treatment consists of antibiotics and hospitalization. Death occurs if an infected person does not receive medical aid within 48 hours of symptom appearance. Its advantages as a pathogen make the plague an impending biological weapon. The halls are empty and dark. The clock on the lounge wall reads 2:34 AM and a few nurses finish their routine patient checks at the General Hospital in Boston, Massachusetts. The slight humming and beeps from the machines are the only sounds heard in the hospital as the last nurse quietly returns to her office. Unknown to the staff and patients, a terrorist attack has been launched within the building. There are no alarms, warnings, or signs that signal that anything has happened. From the outside, it would seem as if it was simply another night at the hospital. Yet, millions of aerosolized bacteria have been released into the air through the air conditioning system, causing every room with an air conditioning vent to explode wit... ...Bibliography Brannon, Heather. (2005) Plague as a Bioterrorism Threat. About Inc. July 20, 2005: http://dermatology.about.com/cs/bioterrorism/a/plague.htm Emedicine. (2003-2005). Biological Warfare. Emedicine Consumer Health. July 20, 2005: http://www.emedicinehealth.com/articles/15704-3.asp Inglesby, T.V. et al. (2000). Plague as a Biological Weapon. Journal of American Medicine, (Vol. 283), p. 2281-2290. International Medical Corps. (1984-2004). Biological Threats. International Medical Corps. July 31, 2005: http://www.imcworldwide.org/cbr/L1C-m2.html Michigan Homeland Security. (2001-2005). Bioterrorism Agent Information. Michigan Homeland Security. July 20, 2005: http://www.michigan.gov/homeland/0,1607,7-173-23607-57902--,00.html Perry, R., Fetherson, J. D., (1997) Yersinia pestis- Etiologic Agent of Plague. Clinical Microbiology Reviews, (Vol. 10), p. 35-66

Harry Potter and the Philosiphers Stone imaginary writing

I have missed you ever so much. Things are wonderful; I actually made some friends today. Namely Ron Weasley, he a funny, ginger hair boy, a bit obnoxious I must say but lovely all the same. Oh, and guess who the other one is? The famous HARRY POTTER! He's such a lovely boy, handsome and heroic. They saved me from a troll! How weird? I know. What is a troll doing in a school? I bet that's what you're probably asking? It was enormous and vile! It was a dreadful ordeal and I would not wish such a thing upon no one. After charms class we were on our way to dinner and I overheard Ron talking about me and making harsh remarks that I think I'm better than everybody else, that I am snob and a ‘know it all'. I then ran off as I was hurt by those words and spent the rest of the evening crying in the girl's toilet. Meanwhile Professor Quirell ran into the dinner hall screaming, ‘TROLL in the dungeon, TROLL in the dungeon, I thought you ought to know' and then he fainted. After the Professor's traumatic display, the teachers ran off to get rid of the troll while Harry and Ron came in the toilets to warn me of that a troll was on the school premises. But believe it or not immediately after they entered the toilets, the troll came in and that was when everything got very chaotic. The troll tried to attack us; Ron then used a spell that we learnt earlier in charms class to control the troll's club and used it to clobber it on the head until it fainted and Harry then dragged me to safety. It was one of the most horrific and terrifying experience I have ever encountered in my life. I really do appreciate Harry's bravery and Ron's quick thinking, so all in all it was a joint effort that saved your precious daughters life. But let's not dwell on the negative events that took place at Hogwarts. On a positive aspect we won the gold cop for Gryffindor house. At first I did not think that we would stand a chance because the end-of-year feast was decked out with Slytherin colours of green and silver to celebrate Slytherin's winning the house cup for the seventh year in a row. There was a huge banner showing the Slytherin serpent covered the wall behind the high table. Dumbledore began awarding the houses with their points; â€Å"in fourth place, Gryffindor, with three hundred and twelve points,† I really did not know what to say, and I felt so disappointed. Not to my surprise in first place was Slytherin with four hundred and seventy-two. A storm of cheering and stamping broke out from the Slytherin table. Dumbledore then said â€Å"yes, yes, well done, Slytherin.† â€Å"However, recent events must be taken into account†, and the room went silent. Then he says he has a few last-minute points to dish out. â€Å"First to Mr Ronald Weasley, for the best-played chess Hogwarts has seen in years, I award Gryffindor house fifty points†. â€Å"Second to Miss Hermione Granger†¦ for the cool use of logic in the face of fire, I award Gryffindor house fifty points†. I then buried my face in my arms from disbelief. Dumbledore then said â€Å"third to Mr Harry Potter†¦for pure nerve and outstanding courage, I award Gryffindor house sixty points.† Everyone knew that Gryffindor now had four hundred and seventy points – exactly the same as Slytherin. We had drawn for the House Cup – if only Dumbledore had given Harry just one more point. Dumbledore raised his hand and the room gradually went silent. â€Å"There are all kinds of courage,† he said smiling. It takes a great deal of bravery to stand up to our enemies, but just as much to stand up to our friends. I therefore award ten points to Mr Neville Longbottom.† A loud noise erupted from Gryffindor table and Harry, Ron and I stood up and cheered with exhilaration, we were so overwhelmed with excitement, we just could not keep still. In an instant the green became scarlet and the silver became gold; the vast Slytherin serpent vanished and a soaring Gryffindor lion took its place. It really felt great and I am looking forward to next year. My first year has almost ended but it was a remarkable and an awe-inspiring experience, surely one I will never forget. It seemed that thing would be back to normal next year, well as normal as it ever was at Hogwarts. I can't wait to see you Mum and Dad. I love you loads. Tell every one high and I will be home soon.

What Is the Difference Between Being Educated and Being Trained?

This Month’s Q&A Technology Tips What is the difference between being educated and being trained? What is so important about education? The difference is huge, and education is hugely important. TRiO is all about setting the foundation to get the best education you can get. Let us look at just a couple of points. One obvious point is that education is the door to opportunity. It is said that success happens at the inter section of education and opportunity. A person who has credentials (i. e. a college degree) is able to seize the moment whenever an opportunity presents itself.This actually allows additional opportunities to flourish. Furthermore, with a degree, all sorts of opportunities somehow become available. The world perceives an educated person as being complete; therefore, he or she is seen as much more likely to be a good employee or partner in any given endeavor. Two: Education informs everything else a person does in life. The quality of the work of an educated per son always gets noticed. That person is thus much more likely to get ahead in all aspects of life and career.Take for example a painter or a poet, two professions normally not thought of as being tied to college degrees. Many people can draw or paint, and many like to express deep thoughts through poetry. Without an education, an artist will not be able to achieve the credibility of any piece proclaiming to represent certain political, or historical, or philosophical truths. Such an artist will likely not achieve much respect or success even if his work shows talent. America is the land of opportunity, but you have to seize that opportunity.TRiO, too, is a program of educational opportunity in education, but you have to embrace the TRiO mission and your dreams. You can be trained at any number of skills like doing hair, and that will earn you a living, but you should want more. Make it your everyday resolution that you will be an educated person no matter what it takes, and then sei ze every opportunity to be that student. The best way to win is to finish what you start. Winners start a project and then keep working until the task is completed, even if the task becomes difficult.They start, they work, they acknowledge mistakes and celebrate small victories, and they finish. When you think about it, getting to the finish line is the only thing that really counts. It is not possible to get anywhere if we consistently allow every obstacle that presents itself to allow us to fail to finish what we start. A half-hearted effort rarely paves the way to the winner’s circle. When a winner starts a project, he or she sees it through to completion. Hello students! I am Rubina Khan, and I am delighted to be your new College Success Coordinator.I shall be reaching out to all students to offer my best support and encouragement so each one of you are able to stay in school and earn your degrees. TRIO is a simple and direct road map for enduring success. Houston Communi ty College, plays an essential role in transforming the lives of its students and making our community work. It is a fact that with TRIO programs, students are given the resources, preparation, and support to succeed both professionally and personally in their academic goals. Earning a college degree is a challenge, but it doesn’t have to be a struggle.I am here to equip all of you to overcome any challenges and obstacles of an academic or social-that may pull you off the path to graduation. As the famous saying of Benjamin Franklin goes â€Å"An investment in knowledge always pays the best interest†. When students pursue and experience a post- secondary education, they have the opportunity to read books and listen to the lectures of top experts in their fields. College graduates definitely have an edge in the job market over those who have not experienced a higher education. Without doubt, a higher education serves as the gateway for better options in life.I congratul ate all students who are pursuing their goals to become graduates and anticipate them being rewarded for all their dedication and hard work. My best wishes to all students. Rumi, the Sufi Poet of love and the great Persian Philosopher and Mystic, said, â€Å"Let the beauty you love be what you do, [so when] you do things from your soul, you feel a river moving in you, a joy. † I believe everyone has a purpose in life and finding out what that purpose is one of the greatest achievements because only then can you truly start living your own life and achieve the inner peace.As a member of the TRiO Program who’s enjoy working as a science tutor, I have some tips for my TRiO students to stay motivated in college, school, life, etc. I have studied and enjoyed various cultures and schools of thought, and I have always appreciated the cultured and intelligent ones. Many years ago, it became evident to me that not only did I find what was important in my life, but also what pur pose my life holds. Then, I became mastered the mind over matter philosophy and decided to explore more of the world. It’s a breath of fresh air to see people like myself achieving the dream â€Å"In the Land Of Free,† and it is a great comforting.I believe that remaining motivated and focused are two of the most powerful assets to have, especially for one in school such as me. It would be naive to say that dental school is a complete breeze and that every step along the way poses no difficulty. As a student I would like to share what I feel keeps me most focused, determined, and motivated. I am a firm believer that if you have something to live for, such as purpose, desire, or a lifetime dream, your motivation and determination will invariably open new doors for you.So if there is one thing I want to share with all my TRiO students today, it is find your purpose, your desire, your dream and move forward. Don’t look back. Don’t lose your focus. You can an d will achieve what you set your mind on. Believe in yourself, and stand firmly for your beliefs. And remember that â€Å"there are two great days in our life first the day we are born and the day we discover why. † We chose the Phoenix as the name of this Newsletter because of legendary bird is said to have had the power to rise out of ashes and live again.Symbolically student support service wants to be that force that makes you thrive even when you feel like a fallen Phoenix Houston Community College seeks to provide equal educational opportunities without regard to race, color, religion, national origin, sex, sexual orientation, age, veteran status or disability. This policy extends to employment, admissions, and all programs and activities supported by the College. The information in this publication will be made available in large print, taped or computer-based format upon request

The Hunters: Moonsong Chapter Thirty-Five

Initiation night for the newest members of the Vitale Society had arrived at last. The cavernous room was lit only by golden candlelight from long tapers placed around the space and by the fire of high-flaming torches against the wal s. In the flickering light, the animals carved in the wood of the pil ars and arches almost seemed to be moving. Matt, dressed in a dark hooded robe like the other initiates, gazed around proudly. They'd worked hard, and the room looked amazing. At the front of the room, beneath the highest arch, a long table had been placed, draped in a heavy red satin cloth and looking like some kind of altar. In the center of the table sat a huge deep stone bowl, almost like a baptismal font, and around it roses and orchids were set. More flowers had been scattered on the floor, and the scent of the crushed blossoms underfoot was so strong that it was dizzying. The pledges were lined up, evenly spaced, before the altar. As if she'd picked up on his pride at how everything had turned out, Chloe pushed her dark hood back a bit and leaned toward him to mutter, â€Å"Pretty fabulous, huh?† Matt smiled at her. So what if she was dating someone else? He stil liked her. He wanted to stay friends, even if that was al there could be between them. He tugged at his robe self-consciously; the fabric was heavy, and he didn't like the way it blocked his peripheral vision. The current masked members of the Vitale Society wove silently among the pledges, handing out goblets ful of some kind of liquid. Matt sniffed his and smel ed ginger and chamomile as Wellas less familiar scents: so this was where the herbs had been used. He smiled at the girl who gave it to him, but got no response. Her eyes behind the mask slid over him neutral y, and she moved on. Once he was a ful member of the Vitale Society, he would know who these current members were, would see them without their masks. He sipped from his goblet and grimaced: it tasted strange and bitter. The soft rustlings of cloaked figures moving across the floor were silenced as the last of the goblets was handed out and the masked Vitales quietly retreated under the arch behind the altar to watch. Ethan stepped forward, up to the altar, and pushed back his hood. â€Å"Welcome,† he said, holding out his hands to the assembled pledges. â€Å"Welcome to true power at last.† The candlelight flickered over his face, twisting it into something unfamiliar and almost sinister. Matt twitched nervously and took another swal ow of the bitter herbal mixture. â€Å"A toast!† Ethan cal ed. He raised his own goblet, and before him, the pledges raised theirs. He hesitated for a moment, then said, â€Å"To moving beyond the veil and discovering the truth.† Matt raised his goblet and drained it with the other pledges. The mixture left a gritty feeling on his tongue, and he scraped it absently against his teeth. Ethan looked around at the pledges and smiled, locking gazes with one after another. â€Å"You've al worked so hard,† he said affectionately. â€Å"Each of you has reached his or her personal peak of intel igence, strength, and leadership ability now. Together, you are a force to be reckoned with. You have been perfected.† Matt managed to politely restrain himself from rol ing his eyes. It was nice to be praised, of course, but sometimes Ethan was a little too over the top: perfected? Matt doubted it was even possible. It seemed to him that you could always strive to be a little more, or a little less, something. You could always wish to be better. But even if he could, after al , be perfected, he suspected that it would take more than a few obstacle courses and group problem-solving exercises to do it. â€Å"And now it is time to at last discover your purpose,† Ethan continued. â€Å"Time to complete the final stage in your transformation from ordinary students into true avatars of power.† He took a clean and shining silver cup from the altar and dipped it into the deep stone bowl in front of him. â€Å"With every step forward in evolution, there must be some sacrifice. I regret any pain this wil cause you. Be comforted by the knowledge that al suffering is temporary. Anna, step forward.† There was a slight uneasy stirring among the pledges. This talk of suffering and sacrifice was different than Ethan's usual emphasis on honor and power. Matt frowned. Something was wrong here. But Anna, looking tiny in her long robe, walked without hesitation up to the altar and pushed back her hood. â€Å"Drink of me,† Ethan said, handing her the silver cup. Anna blinked uncertainly and then, her eyes on Ethan, tipped back her head and drained the cup. As she handed it back to Ethan, she licked her lips automatical y, and Matt tried to peer more closely at her. In the flickering candlelight, her lips looked unnatural y red and slick. Then Ethan led her around the side of the altar and into his arms. He smiled, and his face twisted, his eyes dilating and his lips pul ing back in a snarl. His teeth looked so long, so sharp. Matt tried to shout a warning but realized with horror that he couldn't move his lips, couldn't draw the breath to cal out. He knew, suddenly, that he had been a fool. Ethan sank his fangs deep into Anna's neck. Matt strained, trying to run toward them, to attack Ethan and throw him away from Anna. But he couldn't move at al . He must be under some kind of compulsion. Or perhaps something in the drink, some magic ingredient, had made them al docile and stil . He watched helplessly as Anna struggled for a few moments, then went limp, her eyes rol ing back in her head. Unceremoniously, Ethan let her body drop to the ground. â€Å"Don't be afraid,† he said kindly, gazing around at the horrified, frozen pledges. â€Å"Al of us† – he gestured toward the silent, masked Vitale behind him – â€Å"went through this initiation recently. You must brace yourself to suffer what is only a smal , temporary death, and then you wil be one of us, a true Vitale. Never growing old, never dying. Powerful forever.† Sharp white teeth and golden eyes shining in the candlelight, Ethan reached out toward the next pledge as Matt struggled again to shout, to fight. Ethan continued, â€Å"Stuart, step forward.† Elena smel ed so good, rich and sweet like an exotic ripe fruit. Damon wanted to simply bury his head in the soft skin at the crook of her neck and just inhale her for a decade or two. Snaking his arm through hers, he pul ed her closer. â€Å"You can't come in with me,† she told him for the second time. â€Å"I might be able to get James to talk to me because it's a question about my parents, but I don't think he'l tel me anything if someone else is there. Whatever the truth is about the Vitale Society and my parents, I think he's embarrassed about it. Or afraid, or †¦ something.† Without paying attention to what she was doing, Elena shifted her grip and held on to Damon's arm more firmly. â€Å"Fine,† Damon said stubbornly. â€Å"I'l wait outside. I won't let him see me. But you're not to walk across campus at night by yourself. It's not safe.† â€Å"Yes, Damon,† Elena said in a convincing imitation of meekness, and rested her head on his shoulder. The lemony scent of her shampoo mixed with the more essential Elena smel of her. Damon sighed with contentment. She cared for him, he knew that, and Stefan had taken himself out of the picture. She was stil young, his princess, and a human heart could heal. Maybe, with Stefan gone, she would final y see how much closer she was, mind and soul, to Damon, how perfectly they fit together. In any case, she was his for now. He lifted his free hand and stroked her head, her silky hair pliant beneath his fingers, and smiled. The professor's house was barely off campus, just across the street from the gilded entrance gates. They'd almost reached the edge of campus when a familiar presence that had been lurking nearby at last came very close. Damon wheeled to scan the shadows, pul ing Elena with him. â€Å"What is it?† Elena said, alarmed. Come out, Damon thought with exasperation, sending his silent message toward the thickest shadows at the base of a crowd of oak trees. You know you can't hide from me. One dark shadow detached itself from the rest, stepping forward on the path. Stefan simply gazed at the ground, shoulders slumped, his hands loose and open by his sides. Elena gasped, a smal hurt sound. Stefan looked terrible, Damon thought, not without sympathy. His face seemed hol ow and strained, his cheekbones more prominent than usual, and Damon would have bet that he wasn't feeding properly. Damon felt a twinge of disquiet. He didn't take pleasure in causing his brother pain. Not anymore. â€Å"Well?† Damon said, raising his eyebrows. Stefan glanced up at him. I don't want to fight with you, Damon, he said silently. So don't, Damon shot back at him, and Stefan's mouth twitched in a half smile of acknowledgment. â€Å"Stefan,† Elena said suddenly, sounding like the word had been jerked out of her. â€Å"Please, Stefan.† Stefan stared down at the path under his feet, not meeting her eyes. â€Å"I sensed you were nearby, Elena, and I felt your anxiety,† he said wearily. â€Å"I thought you might have been in trouble. I'm sorry, I was mistaken. I shouldn't have come.† Elena stiffened, and her long dark lashes fel over her eyes, hiding, Damon was almost sure, the beginnings of tears. A long silence stretched between them. Final y, irritated by the tension, Damon made an effort to ease it. â€Å"So,† he said casual y, â€Å"we broke into the campus security office last night.† Stefan looked up with a flicker of interest. â€Å"Oh? Did you find anything useful?† â€Å"Crime scene photos, but they weren't very helpful,† Damon said, shrugging. â€Å"The folders were marked with black Vs, so we're trying to figure out what that means. Elena's going to talk to her professor about the Vitale Society, see if it could have anything to do with them.† â€Å"The†¦ Vitale Society?† Stefan said hesitantly. Damon waved a hand dismissively. â€Å"A secret society from back in the day when Elena's parents were here,† he said. â€Å"Who knows? It may be nothing.† Drawing a hand across his face, Stefan seemed to be thinking hard. â€Å"Oh, no,† he muttered. Then, looking at Elena for the first time, he asked, â€Å"Where's Matt?† â€Å"Matt?† Elena echoed, startled out of her wistful contemplation of Stefan. â€Å"Um, I think he had some kind of meeting tonight. Footbal stuff, maybe?† â€Å"I have to go,† Stefan said tightly, and was immediately gone. With his enhanced abilities, Damon could hear Stefan's light footsteps racing away. But to Elena, he knew, Stefan had been nothing but a silently vanishing blur. Elena turned to Damon, her face crumpling in what he recognized as a prelude to more tears. â€Å"Why would he fol ow me if he doesn't want to talk to me?† she said, her voice hoarse with sorrow. Damon gritted his teeth. He was trying hard to be patient, to wait for Elena to give him her heart, but she kept thinking of Stefan. â€Å"He told you,† he said, keeping his voice even. â€Å"He wants to make sure you're safe, but he doesn't want to be with you. But I do.† Firmly recapturing her arm with his, he tugged her lightly forward. â€Å"Shal we?†