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On the molecular basis of the recognition of angiotensin II (AII) NMR structure of AII in solution compared with the X-ray structure of AII bound to the mAb Fab131 Andreas G. Tzakos 1 , Alexandre M. J. J. Bonvin 2 , Anasstasios Troganis 3 , Paul Cordopatis 4 , Mario L. Amzel 5 , Ioannis P. Gerothanassis 1 and Nico A. J. van Nuland 2 1 Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, GR-45110, Greece, 2 Bijvoet Center for Biomolecular Research, Department of NMR Spectroscopy, Utrecht, the Netherlands; 3 Department of Biological Applications and Technologies, University of Ioannina, Greece; 4 Department of Pharmacy, University of Patras, Greece; 5 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA The high-resolution 3D structure of the octapeptide hor- mone angiotensin II (AII) in aqueous solution has been obtained by simulated annealing calculations, using high- resolution NMR-derived restraints. After final refinement in explicit water, a family of 13 structures was obtained with a backbone RMSD of 0.73 ± 0.23 A ˚ . AII adopts a fairly compact folded structure, with its C-terminus and N-ter- minus approaching to within 7.2 A ˚ of each other. The side chains of Arg2, Tyr4, Ile5 and His6 are oriented on one side of a plane defined by the peptide backbone, and the Val3 and Pro7 are pointing in opposite directions. The stabilization of the folded conformation can be explained by the stacking of the Val3 side chain with the Pro7 ring and by a hydrophobic cluster formed by the Tyr4, Ile5 and His6 side chains. Comparison between the NMR-derived structure of AII in aqueous solution and the refined crystal structure of the complex of AII with a high-affinity mAb (Fab131) [Garcia, K.C., Ronco, P.M., Verroust, P.J., Brunger, A.T., Amzel, L.M. (1992) Science 257, 502–507] provides important quantitative information on two common structural fea- tures: (a) a U-shaped structure of the Tyr4-Ile5-His6-Pro7 sequence, which is the most immunogenic epitope of the peptide, with the Asp1 side chain oriented towards the interior of the turn approaching the C-terminus; (b) an Asx- turn-like motif with the side chain aspartate carboxyl group hydrogen-bonded to the main chain NH group of Arg2. It can be concluded that small rearrangements of the epitope 4–7 in the solution structure of AII are required by a mean value of 0.76 ± 0.03 A ˚ for structure alignment and 1.27 ± 0.02 A ˚ for sequence alignment with the X-ray structure of AII bound to the mAb Fab131. These data are interpreted in terms of a biological ÔnucleusÕ conformation of the hormone in solution, which requires a limited number of structural rearrangements for receptor–antigen recognition and binding. Keywords: angiotensin II; monoclonal antibody; NMR; peptide structure; VIb turn. Angiotensin II (AII), the main effector octapeptide hor- mone (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8) of the renin–angiotesin system [1], exerts a variety of actions on different target organs via specific receptors designated AT 1 and AT 2 [2,3]. Most of the known physiological effects of AII have been attributed to AT 1 , e.g. vasoconstriction, aldosterone release, renal The Structure of Costs in the Short Run The Structure of Costs in the Short Run By: OpenStaxCollege The cost of producing a firm’s output depends on how much labor and physical capital the firm uses A list of the costs involved in producing cars will look very different from the costs involved in producing computer software or haircuts or fast-food meals However, the cost structure of all firms can be broken down into some common underlying patterns When a firm looks at its total costs of production in the short run, a useful starting point is to divide total costs into two categories: fixed costs that cannot be changed in the short run and variable costs that can be changed Fixed and Variable Costs Fixed costs are expenditures that not change regardless of the level of production, at least not in the short term Whether you produce a lot or a little, the fixed costs are the same One example is the rent on a factory or a retail space Once you sign the lease, the rent is the same regardless of how much you produce, at least until the lease runs out Fixed costs can take many other forms: for example, the cost of machinery or equipment to produce the product, research and development costs to develop new products, even an expense like advertising to popularize a brand name The level of fixed costs varies according to the specific line of business: for instance, manufacturing computer chips requires an expensive factory, but a local moving and hauling business can get by with almost no fixed costs at all if it rents trucks by the day when needed Variable costs, on the other hand, are incurred in the act of producing—the more you produce, the greater the variable cost Labor is treated as a variable cost, since producing a greater quantity of a good or service typically requires more workers or more work hours Variable costs would also include raw materials As a concrete example of fixed and variable costs, consider the barber shop called “The Clip Joint” shown in [link] The data for output and costs are shown in [link] The fixed costs of operating the barber shop, including the space and equipment, are $160 per day The variable costs are the costs of hiring barbers, which in our example is $80 per barber each day The first two columns of the table show the quantity of haircuts the 1/11 The Structure of Costs in the Short Run barbershop can produce as it hires additional barbers The third column shows the fixed costs, which not change regardless of the level of production The fourth column shows the variable costs at each level of output These are calculated by taking the amount of labor hired and multiplying by the wage For example, two barbers cost: × $80 = $160 Adding together the fixed costs in the third column and the variable costs in the fourth column produces the total costs in the fifth column So, for example, with two barbers the total cost is: $160 + $160 = $320 Output and Total Costs Labor Quantity Fixed Cost Variable Cost Total Cost 16 $160 $80 $240 40 $160 $160 $320 60 $160 $240 $400 72 $160 $320 $480 80 $160 $400 $560 84 $160 $480 $640 82 $160 $560 $720 How Output Affects Total Costs At zero production, the fixed costs of $160 are still present As production increases, variable costs are added to fixed costs, and the total cost is the sum of the two The relationship between the quantity of output being produced and the cost of producing that output is shown graphically in the figure The fixed costs are always shown as the vertical intercept of the total cost curve; that is, they are the costs incurred when output is zero so there are no variable costs 2/11 The Structure of Costs in the Short Run You can see from the graph that once production starts, total costs and variable costs rise While variable costs may initially increase at a decreasing rate, at some point they begin increasing at an increasing rate This is caused by diminishing marginal returns, discussed in the chapter on Choice in a World of Scarcity, which is easiest to see with an example As the number of barbers increases from zero to one in the table, output increases from to 16 for a marginal gain of 16; as the number rises from one to two barbers, output increases from 16 to 40, a marginal gain of 24 From that point on, though, the marginal gain in output diminishes as each additional barber is added For example, as the number of barbers rises from two to three, the marginal output gain is only 20; and as the number rises from three to four, the marginal gain is only 12 To understand the reason behind this pattern, consider that a one-man barber shop is a very busy operation The single barber needs to everything: say hello to people entering, answer the phone, cut hair, sweep up, and run the cash register A second barber reduces the level of disruption from jumping back and forth between these tasks, and allows a greater division of labor and specialization The result can be greater increasing marginal returns However, as other ... Economic Impact of Investment in Public Higher Education in Massachusetts: Short-Run Employment Stimulus, Long-Run Public Returns Michael Ash, Ph.D. Professor of Economics and Public Policy Department of Economics and Center for Public Policy and Administration University of Massachusetts Amherst Shantel Palacio, MPPA Center for Public Policy and Administration University of Massachusetts Amherst April 2012 TABLE OF CONTENTS SUMMARY 1 1. IMMEDIATE JOB-CREATION 2 ▪ Quantitative methods used in analyzing short-term effects 3 ▪ Elements of the stimulus 5 ▪ Spending/investment choices for the commonwealth 7 ▪ What the data show about short-term benefits 8 Table 1. Jobs created by $800 million expenditure 9 Table 2. Quality of employment indicators, direct-effect industries 12 Table 3. Balanced Budget Higher Education Investment Program Massachusetts employment effect of increasing taxes and higher education investment by $800 million 14 2. LONG-TERM INCREASES IN TAX REVENUES AND OTHER GAINS 15 Table 4. Impact of higher education investment on annual earnings and tax revenue for Massachusetts 17 Table 5. Estimated Lifetime State and Local Taxes Across Education Categories in Massachusetts, 2010 18 3. REDUCTION IN OTHER AREAS OF STATE SPENDING 20 Table 6. Lifetime State and Local Expenditures Across Education Categories in Massachusetts 21 Table 7. Estimated Lifetime Fiscal Effects per Four-Year Equivalent Degree in Massachusetts 23 ▪ Higher education in the current economy 24 4. BROADER SOCIAL AND ECONOMIC BENEFITS 25 ▪ Advantages of greater access to higher education for all 29 ▪ Public spending is key to attracting students 31 Table 8. Estimated enrollment, expenditure, and tuition impact of $800 million public higher education investment program (PHEIP) 33 ▪ Higher education and long-term commitment to Massachusetts residents 34 CONCLUSIONS 35 Bibliography 37 Prepared with a grant from Massachusetts Society of Professors (MSP) Acknowledgments. We thank Zachary Phillis for excellent research assistance, Ferd Wulkan and John Stifler for editing, and Benjamin Taylor for public relations. We thank the advisory board for the project for guidance and comments: Professor Robert Pollin (Political Economy Research Institute and Department of Economics) and Professor Nancy Folbre (Department of Economics) both of the University of Massachusetts Amherst. We thank Philip Trostel (University of Maine) for comments and methodological contributions. [1] SUMMARY Extensive economic evidence makes it clear that increased state spending on public higher education in Massachusetts should be a top priority now and for the foreseeable future. This conclusion follows from an analysis of the economic impact of such spending, based on new research by economists measuring the quantitative relationships between the circulation of money, the overall health of a society, and the position of higher education in that relationship. In this report we examine both the short-run employment impact of additional Hitotsubashi University Repository Title Corporate governance in Vietnam : a system in transition Author(s) Hai, Bui Xuan; Nunoi, Chihiro Citation Hitotsubashi journal of commerce and management, 42(1): 45-66 Issue Date 2008-10 Type Departmental Bulletin Paper Text Version publisher URL http://hdl.handle.net/10086/16290 Right CORPORATE GOVERNANCE IN VIETNAM : A SYSTEM IN TRANSITION B UI X UAN H AI ＊ AND C HIHIRO N UNOI ＊＊ I. The Historical Background of Vietnamese Company Law and Corporate Governance 1 Historical influences have the potential to leave their mark on corporate governance practices and the development of a corporate governance system. 2 Before considering the existing Vietnamese corporate governance system, it is necessary to understand the history of Vietnamese company law and its corporate governance law regimes. The historical development of company law and corporate governance law regimes in Vietnam can be divided into three stages: the period of French colonisation, the period 1945-1990, and that from 1990 up to the present. Corporate forms and company law did not exist in Vietnam until the French occupation in thelate19 th century. 3 Following the French legal tradition, Vietnamese company legislation in this period appeared in civil and commercial codes. Hence, corporate forms and their corporate governance rules were prescribed by the North Civil Code 1931 and the Central Vietnam Commercial Code 1942. The two Codes provided for two company forms as copies of French company models: (1) human associations (cong ty hop nhan ̶ société de personnes or sociétés de personnes ou par interest) and (2) capital associations (cong ty hop co ̶ sociétés de capitaux). 4 After declaring independence in 1945, the Vietnamese government continued to implement company laws, which were enacted under French colonial rule. 5 In July 1954, after nine years Hitotsubashi Journal of Commerce and Management 42 (2008), pp.45-65. Hitotsubashi University ＊ Dean of the Commercial Law Faculty, Ho Chi Minh City University of Law, Vietnam ＊＊ Professor of Law, Hitotsubashi University 1 As for the development of company law in Vietnam, see Bui Xuan Hai, Vietnamese Company Law: The Development and Corporate Governance Issues, Bond Law Review, Australia, (2006) Vol. 18(1). 2 Sir Adrian Cadbury, ʻForewordʼ in Thomas Clarke (ed.), Theories of Corporate Governance: the Philosophical Foundations of Corporate Governance (2004) ix; Lucian Arye Bebchuk and Mark J. Roe, ʻA Theory of Path Dependence in Corporate Ownership and Governanceʼ in Jerey N. Gordon and Mark J. Roe, Convergence and Persistence in Corporate Governance (2004) 69, 69. 3 For a discussion of the history of state and law in Vietnam, see generally, Vu Quoc Thong, History of Vietnamese Law (Phap che su Viet Nam) (1971) 45-8. 4 For further details see, Article 22 of the Central Vietnam Commercial Code 1942; Articles 1238, 1247, 1257, 1261, 1263, 1264, and 1265 of the North Civil Code 1931. See also Le Tai Trien, Summary of Commercial Law (Luat Thuong mai toat yeu) (Vol. 2) (1959) 18. It should be noted that when these terms are translated from Vietnamese into English, the meanings are not precisely retained. For details of these company forms, see Articles 1238, 1247, 1257, 1261, 1263, 1264, and 1265 of the North Civil Code 1931. 5 After the Democratic Republic of van Gils et al. Cost Effectiveness and Resource Allocation 2010, 8:15 http://www.resource-allocation.com/content/8/1/15 Open Access REVIEW © 2010 van Gils et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Review The scope of costs in alcohol studies: Cost-of-illness studies differ from economic evaluations Paul F van Gils* †1 , Heleen H Hamberg-van Reenen †2 , Matthijs van den Berg †2 , Luqman Tariq †1 and G Ardine de Wit †1,3 Abstract Background: Alcohol abuse results in problems on various levels in society. In terms of health, alcohol abuse is not only an important risk factor for chronic disease, but it is also related to injuries. Social harms which can be related to drinking include interpersonal problems, work problems, violent and other crimes. The scope of societal costs related to alcohol abuse in principle should be the same for both economic evaluations and cost-of-illness studies. In general, economic evaluations report a small part of all societal costs. To determine the cost- effectiveness of an intervention it is necessary that all costs and benefits are included. The purpose of this study is to describe and quantify the difference in societal costs incorporated in economic evaluations and cost-of-illness studies on alcohol abuse. Method: To investigate the economic costs attributable to alcohol in cost-of-illness studies we used the results of a recent systematic review (June 2009). We performed a PubMed search to identify economic evaluations on alcohol interventions. Only economic evaluations in which two or more interventions were compared from a societal perspective were included. The proportion of health care costs and the proportion of societal costs were estimated in both type of studies. Results: The proportion of healthcare costs in cost-of-illness studies was 17% and the proportion of societal costs 83%. In economic evaluations, the proportion of healthcare costs was 57%, and the proportion of societal costs was 43%. Conclusions: The costs included in economic evaluations performed from a societal perspective do not correspond with those included in cost-of-illness studies. Economic evaluations on alcohol abuse underreport true societal cost of alcohol abuse. When considering implementation of alcohol abuse interventions, policy makers should take into account that economic evaluations from the societal perspective might underestimate the total effects and costs of interventions. Introduction Alcohol abuse results in problems on various levels in society. In terms of health, alcohol abuse is not only an important risk factor for chronic disease, but it is also related to unintentional and intentional injuries [1-3]. On the social level the WHO Expert Committee on Problems Related to Alcohol Consumption reported that social harms which can be related to drinking include interper- sonal problems, work problems, violent and other crimes [2]. From the economic point of view, the estimated tangi- ble costs of alcohol in the European Union were €125 bil- lion in 2003, including €59 billion worth of lost productivity through absenteeism, unemployment and lost working years due to premature death [4]. Another study reported that the weighted average costs in four high-income countries (France, USA, Scotland and Can- ada) were 1.4% of the gross domestic product [3]. To reduce the negative effect of alcohol abuse it is nec- essary for countries to develop an alcohol policy and implement prevention programs. An alcohol policy can be defined as a set of measures in a jurisdiction or society aimed at minimizing the health and social problems from alcohol consumption [2]. The alcohol abuse prevention * Correspondence: paul.van.gils@rivm.nl 1 International Financial market and Korean Economy Prepared by Seok-Kyun HUR Asset Approach in the Short Run Introduction • Substantial deviations from purchasing power parity (PPP) occur in the short run: the same basket of goods generally does not cost the same everywhere at all times • These short-run failures of the monetary approach prompted economists to develop an alternative theory to explain exchange rates in the short run: the asset approach to exchange rates, the subject of today’s lecure • The asset approach is based on the idea that currencies are assets • The price of the asset in this case is the spot exchange rate, the price of one unit of foreign exchange Exchange Rates and Interest Rates in the Short Run: UIP and FX Market Equilibrium Risky Arbitrage The uncovered interest parity (UIP) equation is the fundamental equation of the asset approach to exchange rates (15-1) FIGURE 15-1 Building Block: Uncovered Interest Parity—The Fundamental Equation of the Asset Approach In this model, the nominal interest rate and expected future exchange rate are treated as known exogenous variables (in green) The model uses these variables to predict the unknown endogenous variable (in red), the current spot exchange rate TABLE 15-1 Interest Rates, Exchange Rates, Expected Returns, and FX Market Equilibrium: A Numerical Example The foreign exchange (FX) market is in equilibrium when the domestic and foreign returns are equal In this example, the dollar interest rate is 5%, the euro interest rate is 3%, and the expected future exchange rate (one year ahead) is = 1.224 $/€ The equilibrium is highlighted in bold type, where both returns are 5% in annual dollar terms Figure 12-2 plots the domestic and foreign returns (columns and 6) against the spot exchange rate (column 3) Figures are rounded in this table Equilibrium in the FX Market: An Example FIGURE 15-2 FX Market Equilibrium: A Numerical Example The returns calculated in Table 15-1 are plotted in this figure The dollar interest rate is 5%, the euro interest rate is 3%, and the expected future exchange rate is 1.224 $/€ The foreign exchange market is in equilibrium at point 1, where the domestic returns DR and expected foreign returns FR are equal at 5% and the spot exchange rate is 1.20 $/€ Changes in Domestic and Foreign Returns and FX Market Equilibrium To gain greater familiarity with the model, let’s see how the FX market example shown in Figure 15-2 responds to three separate shocks: ■ A higher domestic interest rate, i$ = 7% ■ A lower foreign interest rate, i€ = 1% ■ A lower expected future exchange rate, Ee$/€ = 1.20 $/€ Changes in Domestic and Foreign Returns and FX Market Equilibrium A Change in the Domestic Interest Rate FIGURE 15-3 (1 of 3) (a) A Change in the Home Interest Rate A rise in the dollar interest rate from 5% to 7% increases domestic returns, shifting the DR curve up from DR1 to DR2 At the initial equilibrium exchange rate of 1.20 $/€ on DR2, domestic returns are above foreign returns at point Dollar deposits are more attractive and the dollar appreciates from 1.20 $/€ to 1.177 $/€ The new equilibrium is at point Changes in Domestic and Foreign Returns and FX Market Equilibrium A Change in the Foreign Interest Rate FIGURE 15-3 (2 of 3) (b) A Change in the Foreign Interest Rate A fall in the euro interest rate from 3% to 1% lowers foreign expected dollar returns, shifting the FR curve down from FR1 to FR2 At the initial equilibrium exchange rate of 1.20 $/€ on FR2, foreign returns are below domestic returns at point Dollar deposits are more attractive and the dollar appreciates from 1.20 $/€ to 1.177 $/€ The new equilibrium is at point Changes in Domestic and Foreign Returns and FX Market Equilibrium A Change in the Expected Future Exchange Rate FIGURE 15-3 (3 of 3) (c) A Change in the Expected Future Exchange Rate A fall in the expected future exchange rate from 1.224 to 1.20 lowers foreign expected dollar returns, shifting the FR curve down from ... cost then declines, as the fixed costs are spread over an increasing quantity 4/11 The Structure of Costs in the Short Run of output In the average cost calculation, the rise in the numerator of. .. upwardsloping in this zone The point of transition, between where MC is pulling ATC down and where it is pulling it up, must occur at the minimum point of the ATC curve 5/11 The Structure of Costs in the. .. be harder to 10/11 The Structure of Costs in the Short Run see since most of the marginal cost curve is increasing Why you think that average and marginal cost curves have the same general shape?