Isotope Coded Affinity Tag: Applications and Benefits

Isotope Coded Affinity Tag: Applications and Benefits Proteomics is a vital and necessary branch of science targeted at the in-depth study of proteins and their structure to understand their function; as an important pharmacological tool in drug discovery and drug development. The most widely used analytical approach to protein separation and quantification, usually involves integrating protein separation by 2D polyacrylamide gel electrophoresis with micro capillary reverse phase-liquid chromatography protein identification; and finally, detection by mass spectrometry. However, the presence of limitations such as the lack of automation and high costs associated within the combination technique led to the research and introduction of a better and more reliable technique involving the use of isotope coded affinity tags (ICAT). This report looks at the history of isotope coded affinity tags, its advantages over 2D electrophoretic techniques, the principles associated with the technique, its development over the years and finally its application and contribution to the growth and development of analytical science. It also aims to comment on future developmental routes for the technology. TABLE OF CONTENTS (Jump to) A. Background B. Introduction to protein quantification B.1. 2D Polyacrylamide Gel Electrophoresis B.2. Reverse Phase High Liquid Chromatography B.3. Mass Spectrometry B.4. Problems associated with 2DLC-MS combination technique C. Introduction to Isotope Coded Affinity Tags (ICATs)   C.1. Major advancements in isotope coded affinity tag approach D. Principles of Isotope Coded Affinity Tags (ICATs) D.1. Protein Sampling D.2. ICAT reagent Tagging D.3. Peptide Isolation D.4. Protein quantification D.5. Peptide identification E. Applications of Isotope Coded Affinity Tags (ICATs) E.1. Applications in the quantitative identification of cancer  biomarkers E.2. Applications in the quantification of antimalarial drugs  and their metabolites in biological fluids E.3. Quantification of protein expression in oxidative-stressed liver  cells as a therapeutic target for the treatment of liver disease E.4. Quantitative analysis of defaulted proteins present in the brain as  a therapeutic target for the treatment of brain diseases E.5. Applications in the proteomic analysis of recombinant proteins F. Future Development of Isotope Coded Affinity Tags (ICATs) BACKGROUND Proteins are very important components of biologically active systems and some of their functions include structural foundation (connective tissue), transportation (carrier proteins) or immunity (antibodies). Specific and selective protein-protein interactions within the body are the basis for key metabolic and kinetic pathways within living organisms. A disruption in a specific proteins interaction and function, leading to a small or large interference in the subsequent metabolic pathway within the body due to any number of reasons; is the major cause of disease which if not dealt with, can lead to fatality. For this reason, Proteomics is a vital and necessary branch of science targeted at the in-depth study of proteins and their structures; to understand their function as an important pharmacological tool in drug discovery and drug development. Developments in proteomics and genomics over the years through quantitative-structure activity relationship (QSAR) studies and computer aid ed drug design (CADD), has helped to identify novel drugs and their targets for action. INTRODUCTION TO PROTEIN QUANTIFICATION The use of Isotope coded affinity tags as a protein quantification method in proteomics was first developed in 1999 by Aebersold et al. to aid the detection and purification of recombinant proteins[1]. Before the research done in 1999, most widely used approaches to protein quantification were done by 2D Polyacrylamide Gel Electrophoresis (2D PAGE) combined with micro-capillary Liquid reversed phase liquid chromatography (2DLC) and novel electrospray ionization (ESI-MS) or tandem mass spectrometry (MS-MS) technique for detection [2]. B.1. 2D POLYACRYLAMIDE GEL ELECTROPHORESIS This is because 2D Polyacrylamide Gel Electrophoresis (2D PAGE) is very well known for its sensitivity and high resolving separation power. It is also a highly adaptable technique, and its resourcefulness makes it highly sort after for the separation of biological molecules including proteins, based on both physiochemical properties and other chemical-specific interactions. The limit of detection is well documented to a resolution of more than 7000 macromolecules in a singular separation. A large variety and combination of solvents and additives can be used with 2D-PAGE electrophoretic technique to ensure analytes solubility within complex protein mixtures. B.2. REVERSE PHASE LIQUID CHROMATOGRAPHY The inclusion of liquid chromatography as a second separation step also allows for the further separation of the protein mixtures based on difference in retention properties of the components. Recent breakthrough in the analytical approach to liquid chromatography involves the used of two HPLC pumps connected through a detailed 6-port valve system; which results in a more comprehensive separation by gradient elution of complex protein mixtures at high speed and quick run times. B.3. MASS SPECTROMETRY Finally, a mass spectrometric technique (Electrospray ionization (EIMS) or tandem mass spectrometry (MSMS)) which provides a UV detection of protein and measures the mass to charge ratios of the eluted peptides is employed. The detector produces a comprehensive chromatogram by plotting UV signals against their corresponding reverse phase retention times, and then the ESI-MS/MS-MS provides mass information for the eluted peptides. Figure 2: The construction of a 2DLC column and its interface with mass spectrometry. (A) A pressure bomb is used for column packing and sample loading. (B) The flow rate of in the 2-D column is controlled at 100-300 nL/min, and ESI is achieved by applying 2 kV to the gold wire.[4 5] B.4. PROBLEMS ASSOCIATED WITH THE 2DLC-MS COMBINATION TECHNIQUE However, in spite of the popularity of the combination technique, a number of limitations exist that makes the technique far from perfect. It has been documented that complex proteins and peptides with very high alkalinity or basicity and some trans-membrane proteins cannot be separated by this combination method. Also during total cell analysis, the combinatorial technique was found to readily accommodate highly abundant protein separation with the lower abundant proteins being scarcely detected. The over process also requires several sequential stages including difficult techniques such as in-gel digestion; making the combination technique highly labour intensive, difficult to automate and hence non-cost effective. This called for a further development in proteomic research to overcome these problems by possibly avoiding the separation step by electrophoresis and hence the introduction of the use of novel Isotope coded affinity tags (ICAT). INTRODUCTION TO ISOTOPE CODED AFFINITY TAGS The approach of isotope coded affinity tagging mainly combined with a form of high performance liquid chromatography and tandem mass spectrometry (LC-MS/MS) is a relatively new and improved method used in proteomics for the precise quantification and identification of protein sequences within simple or complex protein mixtures. It has been documented to be simpler as it is capable of directly quantifying the proteins from complex mixtures, eliminating the electrophoretic stage. This makes isotope coded affinity tagging more efficient, easily-automated and hence a lot less labour and cost intensive than the electrophoretic process. The use of ICAT is the new and preferred analytical method for protein quantification. Isotope coded affinity tagging is based on a class of chemical reagents called Isotope coded affinity tags (ICAT). The ICAT reagent occurs in two forms depending on the number of deuteriums; light containing none or heavy containing eight. ICAT reagents are made up of three major functional units: A distinct chemically reactive group responsible for the selective labelling of the SH groups of thiol (cysteine) residues, An isotope coded linker responsible for the soluble properties of the reagent and it also provides a site for the addition of the isotopic label, And a biotin affinity tag used to achieve protein isolation and identification. It depends on the principle of strong binding interaction of biotin and avidin. C 1. MAJOR ADVANCEMENTS IN ISOTOPE CODED AFFINITY TAG LABELLING Since the technique was initially introduced in 1999 for the labelling of protein mixtures at low levels, there have been valuable technological advancements in the approach using isotope coded affinity tags (ICATs) within the pharmaceutical industry. These include: The design and modification of affinity tags to improve on the chromatographic separation process. [25] The use of variable peptide specific affinity tags to maximise large-scale quantification on individual processes. [25] An introduction to the combination of different tags to achieve maximum proteome industry [21] The use of exopeptidases to efficiently remove the affinity tags from the peptides in the purification stage [22, 23] D. PRINCIPLES OF ISOTOPE CODED AFFINITY TAG (ICAT) APPROACH Isotope coded affinity tags are used for identifying and quantifying the protein content of two different cell states or population within a mixture. The technique is based largely on two concepts: The peptide sequence of the protein to be quantified (between 5-25 Amino acids long) contains sufficient information to identify that unique protein. And those peptides tagged with the light and heavy reagents respectively are chemically identical and hence serve as very ideal internal standards for quantification. Figure 4. A schematic diagram for the ICAT approach to protein quantification. The principles of Isotope coded affinity tags as documented by Aebersold et al. are divided into four stages: Sampling, Tagging, Isolation and Quantification. D.1. PROTEIN SAMPLING Firstly, two different protein samples containing reduced cysteine (thiol) side chains are individually derived; by breaking down the cell structure, and isolating and extracting the proteins required from the cell. D.2. ICAT REAGENT TAGGING For one of the protein samples, the light form of the ICAT reagent (containing zero deuterium) is introduced to covalently bind to the SH cysteine residues; whilst for the other, the heavy form of ICAT reagent (containing eight deuterium) is used. The individual labelled mixtures represent different cell states or populations. The two samples are then combined into one complex protein mixture and a protease enzyme is added to cut-up or cleave the larger protein molecules into tagged smaller peptides fragments. D.3. PEPTIDE ISOLATION Avidin is then introduced to the mixture to act as a magnet and due to the strong and highly specific binding interaction of biotin and avidin, the ICAT-tagged peptides are isolated from the mixture through affinity chromatography. The isolated peptides are then analysed and separated by micro-capillary high performance liquid chromatography- mass spectrometry (HPLC-MS/MS). D.4. PROTEIN QUANTIFICATION This is the most important step of the analytical process as the quantity and sequence identity of the proteins from which the tagged peptides originated, are automatically determined. Quantification is achieved by comparing the integrated peak intensities for simultaneously eluted pairs of identical, doubly charged peptide ions. The pair corresponds to the two different forms of the ICAT reagent with the mass spectrometer running successively in two modes. One mode measures the comparative fragmenting of peptides eluting from the micro-capillary column whilst the other records the sequence information of the tagged peptides in the same molar ratios as the corresponding proteins. This also means that the chemically identical ICAT-labelled peptide ions are readily identified because as they co-elute, they differ in mass-to-charge (m/z) ratio because of an 8 deuterium difference in the mass of the ICAT-reagents. D.5. PEPTIDE IDENTIFICATION The final stage of isotope coded affinity tagging involves an automated correlation with protein sequence data banks using algorithms and permutations, to identify the protein from which the sequenced peptide originated and hence identify the protein. A combination of all results generated on the chromatogram by the mass spectrometer; and analysis of the ICAT reagent-labelled peptides therefore determines the relative quantities as well as the sequence identities of the components of protein mixtures in a single automated operation. In mass spectrometry, the ratios between the intensities of the lower and upper mass components of these pairs of peaks provide an accurate measure of the relative abundance of the peptides (and hence the proteins) in the original cell pools because the MS intensity response to a given peptide is independent of the isotopic composition of the ICAT reagents. E. APPLICATIONS OF ISOTOPE CODED AFFINITY TAGS The use of ICAT reagent -labelled internal standards, has now become a common and fundamental practice in quantitative mass spectrometry. It has been researched to great advantage in a number of different fields of biochemistry. E.1. Quantitative identification of Cancer biomarkers [9,10] Analytical methods that employ isotope coded affinity tags are very useful and hence popular in the development of high throughput approach to early cancer detection in humans. [9]The significant quantification and identification of cancer biomarkers using ICAT reagents is a therapeutic target for cancer treatment. In this case, protein samples containing cancerous and non-cancerous cells are denatured and reduced to expose the cysteine -SH peptide residues contained. They can then subsequently labelled with the light or heavy forms of isotope coded affinity tags in vivo using stable isotopic labelling (SILAC; (e.g., 2H, 13C, 15N, and 18O)) or in vitro using isobaric tags (iTRAQ). This approach allows expressed proteins and peptides in malignant, cancer-derived cells to be compared with non-cancerous cells.[8] The use of labelled peptides as internal standards allows for relative and/or absolute estimation and quantification of the abundance of the differential proteins present. Emer ging technologies such as the use of protein microarrays are opportunities presently being researched and developed for future improvements in cancer biomarker identification. [10] E.2. Quantification of antimalarial drugs and their metabolites in biological fluids [7] Malaria is a deadly disease responsible for millions of deaths every year, in many tropical and developing countries. Antimalarial drugs such as chloroquine, mefloquine and pyrimethamine and their metabolites; interact with specific dihydrofolate enzymatic sites in plasmodium falciparum malaria. Since enzymes are largely made up of proteins, many enzymatic functions are made up of peptide peptide interactions. Isotope coded affinity tagging combined with high performance liquid chromatography has been documented by Kalpesh N. P. et al, 2010 [7] to be a reliable method for the selective determination and quantification of these potent antimalarial drugs in biological fluids. ICAT reagents are very useful in the extraction stage of the antimalarial drug from a biological matrix as they provide high peptide selectivity and specificity, to avoid interference from multiple antimalarial combination, or endogenous peptides that exist within the matrix. The use of the ICAT approach has grea tly aided research and development into the pharmacokinetics of different antimalarial drugs especially Chloroquine.[7,8] E.3. Quantification of protein expression in oxidative-stressed liver cells as a therapeutic target for the treatment of liver disease [12] A major pathogenic event recurrent in several variations of liver diseases in humans, involves oxidative stress of the liver caused by the formation of reactive oxygen species. Hepatocytes normally have mechanisms responsible for the regulation of oxidative and anti-oxidative molecules within the cell. However, the presence of reactive oxygen species in the liver affects major cellular components including cell proteins, and eventually, the cells regulatory ability. This leads to metabolic or proliferative liver disease and eventual cell fatality.[13] Reactive oxygen species (ROS) are largely represented by mitochondria and cytochrome P450 enzymes in liver cells. The expression of certain protein molecules termed as biomarkers within oxidative-stressed liver cells, and their subsequent quantification using ICAT reagents, can enable an early detection of liver disease. It can also allow for the progressive monitoring of liver damage as a therapeutic target to the treatment of liver disease.[15] E.4. Quantitative analysis of defaulted proteins present in the brain as a therapeutic target for the treatment of brain diseases. The brain is a very complex structure, vital to the existence of mankind. However, a lot of the underlying mechanisms responsible for the normal function and mis-function of the brain have not been fully researched. Research into quantitatively characterising the human brain proteome and using the analysis to understand important cell signalling mechanisms [16], is a very important area of neuropoteomics (i.e. proteomic research and development). The large scale use of stable isotope coded affinity tags in quantitative analysis of complex brain matrixes has helped to provide internal standards for relevant peptides that are chemically similar but isotopically different. These internal standards can be used to correctly identify important biomarkers present in the brain as in epilepsy[17]; or absent biomarkers as in the pathogenesis of Parkinsons disease[18]. E.5. Applications in the proteomic analysis of recombinant proteins High-throughput approaches to the quantification and identification of proteins, is widely applied in the industrial synthesis of therapeutic enzymes. [19] Proteomic analysis on most recombinant proteins, struggle with very low yields and poor solubility which greatly affects the ability to achieve high-throughput protein purification. Quantitative methods that employ isotope coded affinity tags have been documented to be the only way to achieve selective high-throughput protein purification with improved yields, solubility and folding of the recombinant protein, during the process [19]. This is because, purification processes by biotin affinity normal resulting in great yields of over 90%, making it very economically favourable. Combinations of two or more isotopic tags are typically needed to make the most of high-throughput screening.[1] THE FUTURE OF ISOTOPE CODED AFFINITY TAGS (ICATs) The main application area of isotope coded affinity approach is in the identification of biomarkers as a therapeutic target for disease treatment and prevention. The future of analytical techniques that use Isotope coded affinity tags for peptide-labelling includes:

Activity Based Costing – Essay 4

Topic Gateway Series Activity Based Costing Activity Based Costing Topic Gateway Series No. 1 1 Prepared by Stephanie Edwards and Technical Information Service Revised November 2008 Topic Gateway Series Activity Based Costing About Topic Gateways Topic Gateways are intended as a refresher or introduction to topics of interest to CIMA members. They include a basic definition, a brief overview and a fuller explanation of practical application. Finally they signpost some further resources for detailed understanding and research. Topic Gateways are available electronically to CIMA Members only in the CPD Centre on the CIMA website, along with a number of electronic resources. About the Technical Information Service CIMA supports its members and students with its Technical Information Service (TIS) for their work and CPD needs. Our information specialists and accounting specialists work closely together to identify or create authoritative resources to help members resolve their work related information needs. Additionally, our accounting specialists can help CIMA members and students with the interpretation of guidance on financial reporting, financial management and performance management, as defined in the CIMA Official Terminology 2005 edition. CIMA members and students should sign into My CIMA to access these services and resources. The Chartered Institute of Management Accountants 26 Chapter Street London SW1P 4NP United Kingdom T. +44 (0)20 8849 2259 F. +44 (0)20 8849 2468 E. [email  protected] com www. cimaglobal. com 2 Topic Gateway Series Activity Based Costing Activity based costing Definition and concept ‘An approach to the costing and monitoring of activities which involves tracing resource consumption and costing final outputs. Resources are assigned to activities, and activities to cost objects based on consumption estimates. The latter utilise cost drivers to attach activity costs to outputs. ’ CIMA Official Terminology, 2005 A development of the principles of activity based costing (ABC) is activity based management (ABM). Operational ABM is defined as: ‘Actions, based on activity driver analysis, that increase efficiency, lower costs and/or improve asset utilisation. CIMA Official Terminology, 2005 Strategic ABM is defined as: ‘Actions, based on activity based cost analysis, that aim to change the demand for activities so as to improve profitability. ’ CIMA Official Terminology, 2005 The main focus of this topic gateway is ABC. However, the development of ABC into ABM will be discussed further under Application. Context In the current syllabus, CIMA students will learn and may be examined on this topic in Paper P1, Management Accounting Performance Evaluation, Chapter 8, Developments in management accounting, and Paper P2, Management Accounting Decision Management, Chapter 10, Activity based approaches. Study systems for these papers are available from CIMA Publishing. Related concepts Activity based management; activity based budgeting; time driven activity based costing. Alternative approaches Traditional costing approaches. 3 Topic Gateway Series Activity Based Costing Overview The concept of ABC was first defined in the late 1980s by Robert Kaplan and William Burns. Initially ABC focused on manufacturing industry where technological developments and productivity improvements had reduced the proportion of direct labour and material costs, but increased the proportion of indirect or overhead costs. Comparison of traditional costing and ABC The traditional method of costing relied on the arbitrary addition of a proportion of overhead costs on to direct costs to attain a total product cost. The traditional approach to cost allocation relies on three basic steps. 1. Accumulate costs within a production or non-production department. 2. Allocate non-production costs to production departments. 3. Allocate the resulting production department costs to various products, services or customers. This type of costing system usually allocates costs based on a single volume measure, such as direct labour hours or machine hours. While using such a simplistic volume measure to allocate overheads as an overall cost driver, this approach seldom meets the cause-and-effect criteria desired in accurate cost allocation. This method of costing has become increasing inaccurate as the relative proportion of overhead costs has risen. This distortion of costs can result in inappropriate decision making. ABC is therefore an alternative approach to the traditional method or arbitrary allocation of overheads to product, services and customers. Stage 1. Activity cost pools Material Handling Stage 1. Activity cost pools Cost per material movement OVERHEAD COSTS Procurement Cost per purchase order Product lines Set-up Cost per set-up Figure 1. Framework of activity based costing 4 Topic Gateway Series Activity Based Costing Application In contrast to traditional cost accounting systems, ABC systems first accumulate overheads for each organisational activity. They then assign the costs of these activities to products, services or customers (referred to as cost objects) causing that activity. The initial activity analysis is clearly the most difficult aspect of ABC. Activity analysis is the process of identifying appropriate output measures of activities and resources (cost drivers) and their effects on the costs of making a product or providing a service. ABC systems have the flexibility to provide special reports so that management can take decisions about the costs of designing, selling and delivering a product or service. The key aspect is that ABC focuses on accumulating costs via activities, whereas traditional cost allocation focuses on accumulating costs within functional areas. The main advantage of ABC is that it minimises or avoids distortions on product costs that might occur from arbitrary allocation of overhead costs. Steps in development of an ABC System ABC uses cost drivers to assign the costs of resources to activities and unit cost as a way of measuring an output. There are four steps to implementing ABC. 1. Identify activities The organisation needs to undertake an in-depth analysis of the operating processes of each responsibility centre. Each process might consist of one or more activities required to produce an output. 2. Assign resource costs to activities This involves tracing costs to cost objects to determine why the cost occurred. Costs can be categorised in three ways: i. Direct – costs that can be traced directly to one output. For example, the wood and paint that it takes to make a chair. Indirect – costs that cannot be allocated to an individual output, that is, they benefit two or more outputs, but not all outputs. For example, maintenance costs or storage costs. ii. 5 Topic Gateway Series Activity Based Costing iii. General/administration – costs that cannot be associated with any product or service. These costs are likely to remain unchanged, whatever output is produced. For example, salaries of administration staff, security costs or depreciation. 3. Identify outputs Identify all of the output for which an activity segment performs activities and consumes resources. Outputs might be products, services or customers. 4. Assign activity costs to outputs This is done using activity drivers. Activity drivers assign activity costs to outputs (cost objects) based on the consumption or demand for activities. ABC in practice ABC activities have been around for nearly 20 years and many companies in a variety of sectors have implemented activity based thinking. ABC and ABM have brought about radical changes in cost management systems. The principles and philosophies of activity based thinking apply equally to service companies, government agencies, process and manufacturing industries. Management practices and methods have changed over the last decade and will continue to change. Organisations have moved from managing vertically to managing horizontally. There has also been a move from a function orientation to a process orientation. However, management information systems to track and provide information about the horizontal aspects of business have lagged significantly behind managers’ needs. ABC and ABM fill this information gap by providing cost and operation information that mirrors a horizontal view. ABC focuses on accurate information about the true cost of products, services, processes, activities and customers. Using ABC, organisations gain a thorough understanding of their business processes and cost behaviour during ABC analysis. Management then applies this insight to improve decision making at operating and strategic levels. This is then known as ABM. Simply, ABM is ABC in action. 6 Topic Gateway Series Activity Based Costing Better management activity based costing survey: how ABC is used in the organisation This detailed study of how organisations are practically applying ABC can be found on the BetterManagement. com website (to access this study you must register, and then click on the link to activity based management in the top left hand corner of the home page). Available from: www. bettermanagement. om [Accessed 4 November 2008] The study was carried out in July 2005 to determine the state of ABC within over 500 organisations across numerous industries of different sizes and locations. It provides a useful and interesting insight into how ABC is used in organisations. Reported benefits †¢ †¢ ABC provides a more accurate method of costing of products and services. It allows for a better and more comprehensive understanding of overheads and what causes them to occur. It makes costly and non-value adding activities more visible, so allowing managers to focus on these areas to reduce or eliminate them. It supports other management techniques such as continuous improvement, scorecards and performance management. †¢ †¢ Reported drawbacks †¢ ABC can be difficult and time consuming to collect the data about activities and cost drivers. It can be costly to implement, run and manage an ABC system. Even in ABC some overhead costs are difficult to assign to products and customers. These costs still have to be arbitrarily applied to products and customers. †¢ †¢ Case studies Technical Matters: Activity-based costing. (PDF 99KB). This article, published in Financial Management (March 2005), provides a case study of implementation of an activity based costing system in the Crown Prosecution Service (CPS). Available from: www. cimaglobal. com/financialmanagement [Accessed 8 November 2007]. 7 Topic Gateway Series Activity Based Costing The Value Creation Group website provides a comprehensive range of examples of case studies within different sectors where ABC has been implemented, including financial services and social services. Available from: www. valuecreationgroup. com [Accessed 4 November 2008] References Barrett, R. Getting a better view of business with activity based costing. CIMA Insight, February 2005. Available from: www. cimaglobal. com/insight [Accessed 4 November 2008]. CIMA Technical Services. (2001). Activity-based management – an overview. (PDF 69KB). CIMA Technical Briefing. Available from: www. cimaglobal. com/technicalreports [Accessed 4 November 2008]. Friedman, A. L. and Lyne, S. R. (1995). Activity-based techniques: the real life consequences. London: CIMA Publishing. Further information Articles Full text from Business Source Corporate through My CIMA www. cimaglobal. om/mycima [Accessed 4 November 2008] Allott, A. Activity Based Management can work for your company. CIMA Insight, January 2004. Available from: www. cimaglobal. com/insight [Accessed 4 November 2008]. Barrett, R. How ABC can make shared services work. CIMA Insight, March 2005. Available from: www. cimaglobal. com/insight [Accessed 4 November 2008]. Barrett, R. Get a better view of business with activity-based costing. CIMA Insight, February 2005. Available from: www. cimaglobal. com/insight [Accessed 4 November 2008]. Cleland, K. As easy as CBA? Financial Management, September 2004, pp 28-32 Available from: www. imaglobal. com/financialmanagement 8 Topic Gateway Series Activity Based Costing [Accessed 4 November 2008]. Johnson, B. and Glad, E. Spring chicken or dead lunch? Chartered Accountants Journal, March 2006, Volume 85, Issue 2, pp 35-36 Kaplan, R. S. and Anderson, S. R. Time-driven activity-based costing. Harvard Business Review, November 2004, Volume 82, Issue 11, p. 131 Larson, P. and Kerr, S. Integration of process management tools to support TQM implementation: ISO 9000 and activity-based costing. Total Quality Management & Business Excellence, January-March 2007, Volume 18, Issue 1-2, pp 201-207 Leahy, T. Where are you on the ABC learning curve? Business Finance, December 2004, Volume 10, Issue 12, p. 47 Liu, L. Activity-based costing. Financial Management, March 2005, pp 25-29 Max, M. Leveraging process documentation for time-driven activity based costing. Journal of Performance Management, November 2007, Volume 20, Issue 3, pp 16-28 Meelah, R. and Ibraham, D. N. Factors influencing activity based costing (ABC) adoption in manufacturing industry. Investment Management & Financial Innovations, 2007, Volume 4, Issue 2, pp 113-124 Plowman, B. Activity based management driving profitability. Accountancy Ireland, April 2007, Volume 39, Issue 2, pp 23-25 Abstract only from Business Source Corporate through My CIMA www. cimaglobal. com/mycima [Accessed 4 November 2008] Sandison, D. , Hansen, S. C. and Torok, R. G. Activity-based planning and budgeting: a new approach. Journal of Cost Management, March/April 2003, pp 16-22 Liu, L. Activity-based costing. Financial Management, March 2005, p. 29 Available from: www. cimaglobal. com/financialmanagement [Accessed 4 November 2008]. The competitive advantage of management accounting. Journal of Management Accounting Research, 2006, Volume 18, pp 127-135 Books Friedman, A. and Lyne, S. Success and failure of activity-based techniques: a long-term perspective. London: CIMA Publishing. (CIMA Research Series) 9 Topic Gateway Series Activity Based Costing Hansen, D. and Mowen, M. (2006). Cost management: accounting and control. Mason, OH: London: Thomson/South-Western Kaplan, R. and Anderson, S. (2007). Time-driven activity-based costing: a simpler and more powerful path to higher profits. Boston, MA: Harvard Business School Turney, P. (2005). Common cents: how to succeed with activity-based costing and activity-based management. New York: London: McGraw-Hill CIMA Publications CIMA Technical Services. (2001). Activity-based management – an overview. (PDF 69KB). CIMA Technical Briefing. Available from: www. cimaglobal. com/technicalreports [Accessed 4 November 2008]. Websites University of Pittsburgh: Introduction to ABC An online presentation on ABC, by Narcyz Roztocki of Pittsburgh University. Includes links to further sources of information on ABC. Available from: http://digbig. com/4xtmc [Accessed 4 November 2008] The Activity Based Costing Portal Global community portal explaining all aspects of Activity Based Costing. Available from: www. offtech. com. au/abc/Home. asp [Accessed 23 March 2009] The Value Creation Group – Activity Based Costing Gateway site on Activity Based Costing. Available from: http://digbig. com/4xtmg [Accessed 4 November 2008] Where are you on the ABC learning curve? An article by Tad Leahy in Business Finance Magazine. Business Finance Magazine and ALG Software recently surveyed more than 250 finance executives from companies of all sizes and types about the scope and current status of their organisation’s ABC efforts. Available from: www. businessfinancemag. com [Accessed 4 November 2008] 10 Topic Gateway Series Activity Based Costing Bain and Company's 2005 Management Tools and Trends Survey. Shows that usage of ABM is slightly below the mean, but satisfaction with it is considerably below the mean. Available from: http://digbig. com/4xtmk [Accessed 4 November 2008] Copyright  ©CIMA 2006 First published in 2006 by: The Chartered Institute of Management Accountants 26 Chapter Street London SW1P 4NP United Kingdom Printed in Great Britain No responsibility for loss occasioned to any person acting or refraining from action as a result of any material in this publication can be accepted by the authors or the publishers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means method or device, electronic (whether now or hereafter known or developed), mechanical, photocopying, recorded or otherwise, without the prior 11 permission of the publishers. Permission requests should be submitted to CIMA at [email  protected] com

Violence And Tragedy Staples Of Journalism - 1499 Words

Violence and tragedy are staples of journalism because readers are attracted to gruesome stories and photographs. â€Å"If it bleeds, it leads† is an undesirable rule of thumb. Ethical problems arise for photographers and editors because readers are also repulsed by such events. It is as if readers want to know that tragic circumstances take place, but do not want to face the uncomfortable details. After publication of a controversial picture that shows, for example, dead or grieving victims of violence, readers often attack the photographer as being tasteless and adding to suffering of those involved. Photographs such as Fig. 3 for example, which was published by the New York Times in 1993, received a vast amount of hate against the†¦show more content†¦Goodwin wrote, â€Å"Pictures usually have more impact on people than written words. Their capacity to shock exceeds that of language† [p.90]. Other researchers have noted the eye-catching ability of charity ad vertisements in newspapers. Miller (1975) wrote. â€Å"Photos are among the first news items to catch the reader’s eye, a photo may catch the eye of a reader who doesn’t read an accompanying story† [cited in: Lester, Paul. 1991. [p.44]]. Blackwood (1983) argued that â€Å"People who either can’t read, or who don’t take the time to read many of the stories about charity do however scan the photographs alongside it† [cited in: Lester, Paul. 1991. [p,44]]. Nora Ephron (1978) disputed against the negativity around printing graphic imagery in her publication ‘Scribble Scribble Notes on the Media’, and asserted that disturbing charity images should be printed, â€Å"They disturb readers.† Ephron wrote, â€Å"it is exactly as it should be: that’s why photojournalism is often more powerful than written journalism† [p.60]. During the 1980s newspapers would continuously print gruesome images of worldwide atrocities. George Beveridge (1980) of the redundant Washington Star defended his paper’s publication of such photographs by writing, â€Å"newspapers were obliged to print them because they gave readers a dimension of understanding of the situation and the people involved that written words could not possibly convey† [cited in: Lester, Paul.

The Life of Mass Murderer, Henry Lee Lucas Essay - 1037 Words

The Life of Mass Murderer, Henry Lee Lucas Henry Lee Lucas enjoyed holding the title of the most infamous man on death row. His fleeting fame did not evolve from the three cold-blooded murders he did commit, but from hundreds of murders he did not. (Bonnie Bobit) He confessed to hundreds of murders to prove several points, as well as to delay his death sentence. Lucas lived through a childhood of abuse and neglect. If there is a case that proves a persons childhood is reflected in their later actions this could certainly be one. He was never taught that life had any value and perhaps this led him into a life of crime. (killer index) Henry Lee Lucas was born on August 23, 1936, in Blacksburg Virginia. Lucass mother was an†¦show more content†¦(Bonnie Bobit) Henry became a career criminal at an early age and was in and out of correctional institutions, mostly for burglary. There are a lot of discrepancies to actually when Henrys first murder was or how many that were committed. Perhaps the first was his mother. On January 11, 1960 after a few drinks at a bar, Henry and his mother got into an argument and he staped her to death, he supposedly raped her dead corpse after that. Not only did Henry enjoy necrophile, but bestiality. Henry was sentenced to 40 years in prison, however he only severed 10, and shortly after he was in prison he was transferred to a mental institution. Lucas was diagnosed a suicidal psychopath, sadist, sexual deviant (including necrophilia, and bestiality) Henry and his half-brother, who he was supposedly sleeping with, enjoyed killing animals and having intercourse with them. (House of Horrors) Two murders that police are almost certain that Lucas did commit were his girlfriend Becky Powell and an elderly lady he was taking care of, Kate Rich. Becky was only seven years old when her and Lucas a young adult, started dating. A while after she was killed, Henry confessed to cutting her into pieces and placing her body parts in several pillowcases. He had met Powell through his sidekick, Ottis Toole. Toole was a cannibalist who supposedly committed several disturbing murders. The two together were known as The Tag Team from Hell: the Sadist King and the Generalissimo of Pain.Show MoreRelatedDifference Between Mass Killers And Serial Killers1819 Words   |  8 PagesThe following paper discusses the intricate differences between a mass murderer and a serial killer. The discussion of the mass murderer and the serial killer is backed up with three points in which significant differences are depicted, the intention, the experiences in the earlier stages of life and mass media. The three points will follow the ideals behind the murders and where that spark appear in a murderer’s life. 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