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There are few changes in the history of human existence comparable to urbanization in scope and potential to bring about biologic change. The transition in the developed world from an agricultural to an industrial-urban society has already produced substantial changes in human health, morphology and growth (Schell, Smith and Bilsborough, 1993, p.1). By the year 2000, about 50% of the world s total population will be living crowded in urban areas and soon thereafter, by the year 2025 as the global urban population reaches the 5 billion mark more of the world s population will be living in urban areas. This has enormous health consequences. By the close of the twenty-first century, more people will be packed into the urban areas of the developing world than are alive on the planet today (UNCHS (Habitat), 1996, p.xxi). Africa presents a particularly poignant example of the problems involved, as it has the fastest population and urban growth in the world as well as the lowest economic development and growth and many of the poorest countries, especially in Tropical Africa. Thus it exemplifies in stark reality many of the worst difficulties of urban health and ecology (Clarke, 1993, p.260). This essay is therefore concerned to analyse the trends of urbanization in Africa. This is followed by an overview of the environmental conditions of Africa s towns and cities. The subsequent section explores the links between the urban environment and health. Although the focus is with physical hazards it is important to note that the social milieu is also vital in the reproduction of health. The paper concludes by providing some policy recommendations.
Characterised as the mighty capital of the eurozone (Sassen 1999, 83), Frankfurt is said to be a rising world city primarily due to its financial centre. This is reflected in the use of such common catchphrases as Bankfurt and Mainhattan for the city, as well as its reference in scientific publications. As Ronneberger and Keil (1995, 305) state, for instance, a service economy [...] mastered by the finance sector forms the basis for the continuing integration of Frankfurt into the international market. Frankfurt is the most important German as well as European financial centres. Thirteen of the 30 largest German banks and about two thirds of Germany s foreign banks are seated here. Frankfurt s stock exchange (ranked 4th in the world) is by far the biggest in Germany with a turnover-share of more than 80%. Its derivatives exchange (Eurex) aims to become the biggest in the world. As the host city for the European Central Bank, it is also the centre of European monetary policy. As a major node in the global financial network today, Frankfurt s specific functions within this network will be investigated in this paper. Unlike most other predominant national financial centres, Frankfurt has not continuously held this position in Germany s since the middle ages: It re-gained it s position from Berlin only after World War II. In contrast to the static phenomenon financial centre which is well covered in the literature emergence and development of financial centres is not as well understood. The study of the development of the financial centre Frankfurt after World War II gives insights into the dynamics of the self-reinforcing mechanisms within financial centres; the second topic covered in the paper. The paper is organised as follows: the remainder of this chapter looks at the method used in this study and the theory of financial centres with an emphasis on the basic approaches to the emergence of financial centres. After that it is asked whether Frankfurt meets the basic requirements for the concept of path dependence, i.e. that there are self-reinforcing mechanisms. After a positive answer to that, the development of Frankfurt as a financial centre is discussed as well as its role as a node in the world (financial) system today in chapter two. Chapter three provides some more or less speculative remarks about Frankfurt s future; the last chapter briefly summarises the findings of the paper.
One of the most important but less understood phenomena in the beginning of the 21st century has been a shift toward knowledge-based economic activity in the comparative advantage of modern industrialized countries. Two broad trends has been observed in the global economy. That is, the output from the world's science and technology system has been growing rapidly and the nature of investment has been changed (MILLER, 1996). The relative proportions of physical and intangible investment have changed considerably with the relative increase of intangible investments since the 1980s. In addition, there has been increased complementarity between physical and intangible investments and more important role of high technology in both kinds of investment (MILLER, 1996). Even in the newly industrialized countries, the growth of technology intensive industries, the increase of R&D activities and the growth of the knowledge intensive producer services have been common feature in recent years. In this change of the structure of productive assets, the role of knowledge is well recognized as the most fundamental resources in recent years (OECD, 1996; WORLD BANK, 1998). The development of information and communication technology (ICT) and globalisation trend have promoted this shift toward knowledge-based economy.
The globalisation of contemporary capitalism is bringing about at least two important implications for the emergence and significance of business services. First, the social division of labour steadily increases (ILLERIS 1996). Within the complex organisation of production and trade new intermediate actors emerge either from the externalisation of existing functions in the course of corporate restructuring policies or from the fragmentation of the production chain into newly defined functions. Second, competitive advantages of firms increasingly rest on their ability to innovate and learn. As global communication erodes knowledge advantages more quickly, product life cycles shorten and permanent organisational learning results to be crucial for the creation and maintenance of competitiveness. Intra- and interorganisational relations of firms now are the key assets for learning and reflexivity (STORPER 1997). These two aspects of globalisation help understand why management consulting - as only one among other knowledge intensive business services (KIBS) - has been experiencing such a boost throughout the last two decades. Throughout the last ten years, the business has grown annually by 10% on average in Europe. Management consulting can be seen first, as a new organisational intermediate and second, as an agent of change and reflexivity to business organisations. Although the KIBS industry may not take a great share of the national GDP its impact on national economies should not be underestimated. Estimations show that today up to 80% of the value added to industrial products stem from business services (ILLERIS 1996). Economic geographers have been paying more attention to KIBS since the late 1970s and focus on the transformation of the spatial economy through the emerging business services. This market survey is conceived as a first step of a research programme on the internationalisation of management consulting and as a contribution to the lively debate in economic geography. The management consulting industry is unlimited in many ways: There are only scarce institutional boundaries, low barriers to entry, a very heterogeneous supply structure and multiple forms of transaction. Official statistics have not yet provided devices of grasping this market and it may be therefore, that research and literature on this business are rather poor. The following survey is an attempt to selectively compile existing material, empirical studies and statistics in order to draw a sketchy picture of the European market, its institutional constraints, agents and dynamics. German examples will be employed to pursue arguments in more depth.
During the 1980s and early 1990s, the importance of small firm growth and industrial districts in Italy became the focus of a large number of regional development studies. According to this literature, successful industrial districts are characterized by intensive cooperation and market producer-user interaction between small and medium-sized, flexibly specialized firms (Piore and Sabel, 1984; Scott, 1988). In addition, specialized local labor markets develop which are complemented by a variety of supportive institutions and a tradition of collaboration based on trust relations (Amin and Robins, 1990; Amin and Thrift, 1995). It has also been emphasized that industrial districts are deeply embedded into the socio-institutional structures within their particular regions (Grabher, 1993). Many case studies have attempted to find evidence that the regional patterns identified in Italy are a reflection of a general trend in industrial development rather than just being historical exceptions. Silicon Valley, which is focused on high technology production, has been identified as being one such production complex similar to those in Italy (see, for instance, Hayter, 1997). However, some remarkable differences do exist in the institutional context of this region, as well as its particular social division of labor (Markusen, 1996). Even though critics, such as Amin and Robins (1990), emphasized quite early that the Italian experience could not easily be applied to other socio-cultural settings, many studies have classified other high technology regions in the U.S. as being industrial districts, such as Boston s Route 128 area. Too much attention has been paid to the performance of small and medium-sized firms and the regional level of industrial production in the ill-fated debate regarding industrial districts (Martinelli and Schoenberger, 1991). Harrison (1997) has provided substantial evidence that large firms continue to dominate the global economy. This does not, however, imply that a de-territorialization of economic growth is necessarily taking place as globalization tendencies continue (Storper, 1997; Maskell and Malmberg, 1998). In the case of Boston, it has been misleading to define its regional economy as being an industrial district. Neither have small and medium-sized firms been decisive in the development of the Route 128 area nor has the region developed a tradition of close communication between vertically-disintegrated firms (Dorfman, 1983; Bathelt, 1991a). Saxenian (1994) found that Boston s economy contrasted sharply with that of an industrial district. Specifically, the region has been dominated by large, vertically-integrated high technology firms which are reliant on proprietary technologies and autarkic firm structures. Several studies have tried to compare the development of the Route 128 region to Silicon Valley. These studies have shown that both regions developed into major 2 agglomerations of high technology industries in the post-World War II period. Due to their different traditions, structures and practices, Silicon Valley and Route 128 have followed divergent development paths which have resulted in a different regional specialization (Dorfman, 1983; Saxenian, 1985; Kenney and von Burg, 1999). In the mid 1970s, both regions were almost equally important in terms of the size of their high technology sectors. Since then, however, Silicon Valley has become more important and has now the largest agglomeration of leading-edge technologies in the U.S. (Saxenian, 1994). Saxenian (1994) argues that the superior performance of high technology industries in Silicon Valley over those in Boston is based on different organizational patterns and manufacturing cultures which are embedded in those socio-institutional traditions which are particular to each region. Despite the fact that Saxenian (1994) has been criticized for basing her conclusions on weak empirical research (i.e. Harrison, 1997; Markusen, 1998), she offers a convincing explanation as to why the development paths of both regions have differed.1 Saxenian s (1994) study does not, however, identify which structures and processes have enabled both regions to overcome economic crises. In the case of the Boston economy, high technology industries have proven that they are capable of readjusting and rejuvenating their product and process structures in such a way that further innovation and growth is stimulated. This is also exemplified by the region s recent economic development. In the late 1980s, Boston experienced an economic decline when the minicomputer industry lost its competitive basis and defense expenditures were drastically reduced. The number of high technology manufacturing jobs decreased by more than 45,000 between 1987 and 1995. By the mid 1990s, however, the regional economy began to recover. The rapidly growing software sector compensated for some of the losses experienced in manufacturing. In this paper, I aim to identify the forces behind this economic recovery. I will investigate whether high technology firms have uncovered new ways to overcome the crisis and the extent to which they have given up their focus on self-reliance and autarkic structures. The empirical findings will also be discussed in the context of the recent debate about the importance of regional competence and collective learning (Storper, 1997; Maskell and Malmberg, 1998). There is a growing body of literature which suggests that some regional economies During the 1980s and early 1990s, the importance of small firm growth and industrial districts in Italy became the focus of a large number of regional development studies. According to this literature, successful industrial districts are characterized by intensive cooperation and market producer-user interaction between small and medium-sized, flexibly specialized firms (Piore and Sabel, 1984; Scott, 1988). In addition, specialized local labor markets develop which are complemented by a variety of supportive institutions and a tradition of collaboration based on trust relations (Amin and Robins, 1990; Amin and Thrift, 1995). It has also been emphasized that industrial districts are deeply embedded into the socio-institutional structures within their particular regions (Grabher, 1993). Many case studies have attempted to find evidence that the regional patterns identified in Italy are a reflection of a general trend in industrial development rather than just being historical exceptions. Silicon Valley, which is focused on high technology production, has been identified as being one such production complex similar to those in Italy (see, for instance, Hayter, 1997). However, some remarkable differences do exist in the institutional context of this region, as well as its particular social division of labor (Markusen, 1996). Even though critics, such as Amin and Robins (1990), emphasized quite early that the Italian experience could not easily be applied to other socio-cultural settings, many studies have classified other high technology regions in the U.S. as being industrial districts, such as Boston s Route 128 area. Too much attention has been paid to the performance of small and medium-sized firms and the regional level of industrial production in the ill-fated debate regarding industrial districts (Martinelli and Schoenberger, 1991). Harrison (1997) has provided substantial evidence that large firms continue to dominate the global economy. This does not, however, imply that a de-territorialization of economic growth is necessarily taking place as globalization tendencies continue (Storper, 1997; Maskell and Malmberg, 1998). In the case of Boston, it has been misleading to define its regional economy as being an industrial district. Neither have small and medium-sized firms been decisive in the development of the Route 128 area nor has the region developed a tradition of close communication between vertically-disintegrated firms (Dorfman, 1983; Bathelt, 1991a). Saxenian (1994) found that Boston s economy contrasted sharply with that of an industrial district. Specifically, the region has been dominated by large, vertically-integrated high technology firms which are reliant on proprietary technologies and autarkic firm structures. Several studies have tried to compare the development of the Route 128 region to Silicon Valley. These studies have shown that both regions developed into major 2 agglomerations of high technology industries in the post-World War II period. Due to their different traditions, structures and practices, Silicon Valley and Route 128 have followed divergent development paths which have resulted in a different regional specialization (Dorfman, 1983; Saxenian, 1985; Kenney and von Burg, 1999). In the mid 1970s, both regions were almost equally important in terms of the size of their high technology sectors. Since then, however, Silicon Valley has become more important and has now the largest agglomeration of leading-edge technologies in the U.S. (Saxenian, 1994). Saxenian (1994) argues that the superior performance of high technology industries in Silicon Valley over those in Boston is based on different organizational patterns and manufacturing cultures which are embedded in those socio-institutional traditions which are particular to each region. Despite the fact that Saxenian (1994) has been criticized for basing her conclusions on weak empirical research (i.e. Harrison, 1997; Markusen, 1998), she offers a convincing explanation as to why the development paths of both regions have differed.1 Saxenian s (1994) study does not, however, identify which structures and processes have enabled both regions to overcome economic crises. In the case of the Boston economy, high technology industries have proven that they are capable of readjusting and rejuvenating their product and process structures in such a way that further innovation and growth is stimulated. This is also exemplified by the region s recent economic development. In the late 1980s, Boston experienced an economic decline when the minicomputer industry lost its competitive basis and defense expenditures were drastically reduced. The number of high technology manufacturing jobs decreased by more than 45,000 between 1987 and 1995. By the mid 1990s, however, the regional economy began to recover. The rapidly growing software sector compensated for some of the losses experienced in manufacturing. In this paper, I aim to identify the forces behind this economic recovery. I will investigate whether high technology firms have uncovered new ways to overcome the crisis and the extent to which they have given up their focus on self-reliance and autarkic structures. The empirical findings will also be discussed in the context of the recent debate about the importance of regional competence and collective learning (Storper, 1997; Maskell and Malmberg, 1998). There is a growing body of literature which suggests that some regional economies an develop into learning economies which are based on intra-regional production linkages, interactive technological learning processes, flexibility and proximity (Storper, 1992; Lundvall and Johnson, 1994; Gregersen and Johnson, 1997). In the next section of this paper, I will discuss some of the theoretical issues regarding localized learning processes, learning economies and learning regions (see, also, Bathelt, 1999). I will then describe the methodology used. What follows is a brief overview of how Boston s economy has specialized in high technology production. The main part of the paper will then focus on recent trends in Boston s high technology industries. It will be shown that the high technology economy consists of different subsectors which are not tied to a single technological development path. The various subsectors are, at least partially, dependent on different forces and unrelated processes. There is, however, tentative evidence which suggests that cooperative behavior and collective learning in supplierproducer- user relations have become important factors in securing reproductivity in the regional structure. The importance of these trends will be discussed in the conclusions.
Taking shareholder protection seriously? : Corporate governance in the United States and Germany
(2003)
The paper undertakes a comparative study of the set of laws affecting corporate governance in the United States and Germany, and an evaluation of their design if one assumes that their objective were the protection of the interests of minority outside shareholders. The rationale for such an objective is reviewed, in terms of agency cost theory, and then the institutions that serve to bound agency costs are examined and critiqued. In particular, there is discussion of the applicable legal rules in each country, the role of the board of directors, the functioning of the market for corporate control, and (briefly) the use of incentive compensation. The paper concludes with the authors views on what taking shareholder protection seriously, in each country s legal system, would require.
This memorandum describes the approach of the U.S. Securities and Exchange Commission (the "SEC") in monitoring and, where appropriate, regulating the use of research reports by investment banking firms in connection with securities transactions. The memorandum addresses the historical system of regulation, which continues in large measure to apply. It also examines the new initiatives taken, following a number of prominent corporate, accounting and banking scandals and a significant decline in U.S. and international capital markets, to supplement the current system in what some have dubbed the "post-Enron era".
Recent empirical work shows that a better legal environment leads to lower expected rates of return in an international cross-section of countries. This paper investigates whether differences in firm-specific corporate governance also help to explain expected returns in a cross-section of firms within a single jurisdiction. Constructing a corporate governance rating (CGR) for German firms, we document a positive relationship between the CGR and firm value. In addition, there is strong evidence that expected returns are negatively correlated with the CGR, if dividend yields and price-earnings ratios are used as proxies for the cost of capital. Most results are robust for endogeneity, with causation running from corporate governance practices to firm fundamentals. Finally, an investment strategy that bought high-CGR firms and shorted low-CGR firms would have earned abnormal returns of around 12 percent on an annual basis during the sample period. We rationalize the empirical evidence with lower agency costs and/or the removal of certain governance malfunctions for the high-CGR firms.
The corporate convergence debate is usually presented in terms of competing efficiency and political claims. Convergence optimists assert that an economic logic will promote convergence on the most efficient form of economic organization, usually taken to be the public corporation governed under rules designed to maximize shareholder value. Convergence skeptics counterclaim that organizational diversity is possible, even probable, because of path dependent development of institutional complementarities whose abandonment is likely to be inefficient. The skeptics also assert that existing elites will use their political and economic advantages to block reform; the optimists counterclaim that the spread of shareholding will reshape politics.
The venture capital market and firms whose creation and early stages were financed by venture capital are among the crown jewels of the American economy. Beyond representing an important engine of macroeconomic growth and job creation, these firms have been a major force in commercializing cutting edge science, whether through their impact on existing industries as with the radical changes in pharmaceuticals catalyzed by venture-backed firms commercialization of biotechnology, or by the their role in developing entirely new industries as with the emergence of the internet and world wide web. The venture capital market thus provides a unique link between finance and innovation, providing start-up and early stage firms - organizational forms particularly well suited to innovation - with capital market access that is tailored to the special task of financing these high risk, high return activities.
This article presents a structural overview of corporate disclosure in Germany against the background of a rapidly evolving European market. Professor Baums first makes the theoretical case for mandatory disclosure and outlines the standard, regulatory elements of market transparency. He then turns to German law and illustrates both how it attempts to meet the principle, theoretical demands of disclosure and how it should be improved. The article also presents in some detail the actual channels of corporate disclosure used in Germany and the manner in which German law now fits into the overall development of the broader, European Community scheme, as well as the contemplated changes and improvements both at the national and the supranational level.
The paper was submitted to the conference on company law reform at the University of Cambridge, July 4th, 2002. Since the introduction of corporation laws in the individual German states during the first half of the 19th century, Germany has repeatedly amended and reformed its company law. Such reforms and amendments were prompted in part by stock exchange fraud and the collapse of large corporations, but also by a routine adjustment of law to changing commercial and societal conditions. During the last ten years, a series of significant changes to German company law led one commentator to speak from a "company law in permanent reform". Two years ago, the German Federal Chancellor established a Regierungskommission Corporate Governance ("Government Commission on Corporate Governance") and instructed it to examine the German Corporate Governance system and German company law as a whole, and formulate recommendations for reform.
On April 24, 2001 the European Commission presented a proposal for a Directive1 introducing supplementary supervision of financial conglomerates (the Proposed Directive). The Proposed Directive requires a closer coordination among supervisory authorities of different sectors of the financial industry and leads to changes in the number of existing Directives relating to the supervision of credit institutions, insurance undertakings and investment firms.
It is an established policy in the United States to separate commercial banking (the business of taking deposits and making commercial loans) from other commercial activities. The separation of banking and commercial activities is achieved by federal and state banking laws, which enumerate the powers that banks may exercise, the activities that banks may engage in, and the investments that banks may lawfully make, and expressly exclude banks from certain activities or relationships. Some of these provisions could be circumvented if a nonbank company could carry on banking activities through a banking subsidiary and nonbanking activities either itself or through a nonbanking subsidiary.
The institutionalization and internationalization of shareholdings, the globalization of capital markets and the rapid development of information technologies have placed our corporate law system under increasing pressure to adapt to the ever changing requirements of the market. For this reason, in May 2000, the German government called together a group of industrialists, representatives of shareholder associations and institutional investors, trade unionists, politicians and scholars to form an expert Panel with the task of reviewing the German corporate governance system. This Government Panel on Corporate Governance prepared a questionnaire on key issues in the field, and solicited responses and input from numerous national and international experts and institutions. In July 2001, the Commission presented its 320 page report (available at www.ottoschmidt. de/corporate_governance.htm) to the German Chancellor. The Report made nearly 150 recommendations for amendments or changes to existing provisions of German law and also set forth proposals on how the German corporate governance system should be further developed in order to maintain a normative framework that is suitable and attractive not only for companies, but also for domestic and foreign investors. In order that the Panel s proposals may receive careful consideration from a diverse audience, it seems very useful to keep a wider public informed of the Panel s recommendations. Therefore, also on behalf of the Panel, I very much appreciate that the international law firm Shearman & Sterling has taken the initiative to have the summary of the Panel s recommendations translated into English.
The road to shareowner power
(1999)
A dramatic rise in shareowner power and improvements in corporate governance tan be achieved in the next few years by expanding the role of proxy advisory firms. This will require changing the way such firms are paid. They are now paid directly by investors who buy their advice; but this arrangement suffers from a free-rider problem. Instead, they should be paid by each corporation about which they are advising, in accordance with shareholder vote so as to preclude management influence. This arrangement would make it economically feasible for advisory firms to expand their services, becoming proactive like relational investors. Any proxy advisor other than the market leader Stands to gain tremendously by initiating this new System. lt would eliminate the natura1 monopoly feature of the current System, and spread the tost more equitably across all shareowners. lt would also enable proxy advisory ftrms to market their Services to individual investors via the internet.
Shareholder voting is back on the agenda of public debate for several reasons. One is the investors’ internationalization of capital investments and the raising of funds globally by companies. It can be predicted that considering the growing together of capital markets the trend to international investments will increase not least because the introduction of the Euro will create a uniform European stock market. This leads to the question how the law deals with this development and its problems. The EU Commission has commissioned a comparative study dealing, inter alia, with shareholders’ representation at general meetings in the EU member states.1 The aim is to simplify the operating regulations for public limited companies in the EU. Furthermore, the internationalization of shareholdings leads the investors to ask how their interests are protected abroad. Are the mechanisms of shareholder protection sufficient for foreign investors? In particular the formation of transnational companies like Daimler-Chrysler will change corporate governance systems. It remains to be seen whether and how foreign institutional investors will use measures of - in this case - German corporate law to control the management. From a microeconomic point of view the question is what specific features of a given corporate governance system might contribute to better performance of firms. The following remarks will however, be confined to one specific aspect of corporate governance only, the exercise of shareholders’ voting rights at the general meeting.
I analyze the most powerful shareholders in Germany to illustrate the concentration of control over listed corporations. Compared to other developed economies, the German stock market is dominated by large shareholders. I show that 77% of the median firm’s voting rights arecontrolled by large blockholders. This corresponds to 47% of the market value of all firms listed in Germany’s official markets. About two thirds of this amount is controlled by banks, industrial firms, holdings, and insurance companies. I show that due to current legislation it is clear for neither group who ultimate exerts control over the shareholding firm itself. For the remaining blockholders, only blocks controlled by voting pools and individuals can be traced back to the highest level of ownership. In the aggregate, both groups control only 5.6% of all reported blocks. The German government controls 8%, and it is not clear who ultimately is responsible for the consequences of decisions.
We first analyze legal provisions relating to corporate transparency in Germany. We show that despite the new securities trading law (WpHG) of 1995, the practical efficacy of disclosure regulation is very low. On the one hand, the formation of business groups involving less regulated legal forms as intermediate layers can substantially reduce transparency. On the other hand, the implementation of the law is not practical and not very effective. We illustrate these arguments using several examples of WpHG filings. To illustrate the importance of transparency, we show next that German capital markets are dominated by few large firms accounting for most of the market’s capitalization and trading volume. Moreover, the concentration of control is very high. First, 85% of all officially listed AGs have a dominant shareholder (controlling more than 25% of the voting rights). Second, few large blockholders control several deciding voting blocks in listed corporations, while the majority controls only one block.
The article describes the legal structure of the Daimler-Chrysler merger. It asks why this specific structure rather than another cheaper way was chosen. This leads to the more general question of the pros and cons of mandatory corporate law as a regulatory device. The article advocates an "optional" approach: The legislator should offer various menus or sets of binding rules among which the parties may choose. (JEL: ...)
The previous proposal for a company law directive on takeovers in 1990 was rejected in Germany almost unanimously for several different reasons. The new "slimmed down" draft proposal, in the light of the subsidiarity principle, takes the different approaches to investorprotection in the various member states better into account. Notably, the most controversial principle of the previous draft, viz. the mandatory bid rule as the only means of investorprotection in case of a change of control, has been given up. Therefore a much higher degree of acceptance seems likely. The Bundesrat (upper house) and the industry associations have already expressed their consent; the Bundestag (Federal Parliament) will deal with the proposal shortly. The technique of a "frame directive" leaves ample leeway for the member states. That will shift the discussion back to the national level and there will lead to the question as to how to make use of this leeway (cf. II, III, below) rather than to a debate about principles as in the past. It seems likely that criticism will confine itself to more technical questions (cf. IV, below).
The corporate governance systems in Europe differ markedly. Economists tend to use stylized models and distinguish between the Anglo-American, the German and the Latinist model.1 In this view, for instance, the Austrian, Dutch, German, and Swiss systems are said to be variations of one model. For lawyers the picture is of course, much more detailed as particular rules may vary even where common principles prevail. Many comparative studies on these differences have been undertaken meanwhile.2 I do not want to add another study but to treat a different question. Are there as a consequence of growing internationalization, globalization of markets and technological change, also tendencies of convergence of our corporate governance systems? My answer will be in two parts. As corporate governance systems are traditionally mainly shaped by legislation, the first part will analyze the influence of the economic and technological change on the rule-setting process itself. How does this process react to the fundamental environmental change? That includes a short analysis of the solution of centralized harmonizing of company law within the EU as well as the question of whether EU-wide competition between national corporate law legislators can be observed or be expected in the future. The second part will then turn to the national level. It deals with actual tendencies of convergence or, more correctly, of approach by the German corporate governance system to the Anglo-American one.
Universal banking means that banks are permitted to offer all of the various kinds of financial services. This includes classical banking activities like the credit and deposit business, as well as investment services, placement and brokerage of securities, and even insurance activities, trading in real estate and others. German universal banks also hold stock in nonfinancial firms and offer to vote their clients' shares in other firms. This paper deals with universal banks and their role in the investment business, more specifically, their links with investment companies and their various roles as shareholders and providers of financial services to such companies. Banks and investment companies have, as financial intermediaries, one trait in common: they both transform capital of investors (depositors and shareholders of investment funds, respectively) into funds (loans and equity or debt securities, respectively) that are channeled to other firms. So why should a regulation forbid to combine these transformation tasks in one institution or group, and why should the law not allow banks to establish investment companies and provide all kinds of financial services to them in addition to their banking services? German banking and investment company law have answered these questions in the affirmative. This paper argues that the existing regulation is not a sound and recommendable one. The paper is organized as follows: Sections II - V identify four areas where the combination of banking and investment might either harm the shareholders of the investment funds and/or negatively affect other constituencies such as the shareholders of the banking institution. These sections will at the same time explore whether there are institutional or regulatory provisions in place or market forces at work that adequately protect investors and the other constituencies in question. Concluding remarks follow (VI.).
For the German observer the idea of a Company repurchasing its own shares seems to resemble the picture of a snake eating its own tail. It appears to be highly unnatura1 and one wonders how the tail tan possibly be eatable for the snake. Not in the United States. Although repurchases have once been subject to the most stubbornly fought conflict in US Company law only some modest disclosure requirements and safeguards against overt market manipulation exist today. Large repurchases are an almost everyday event and there is an increasing tendency. The aggregate value of shares repurchased by NYSE listed companies has increased from $ 1 .l billion in 1975 to $ 6.3 billion in 1982 to $ 37.1 billion in 1985*. Few examples may illustrate this practice further: Within three years Ford Motor Corp. repurchased 30 million shares for $ 1.2 billion. In 1985 Phillips Petroleum Corp. was faced with two hostile bids and took several defensive Steps, one of which was to tender for 20 million of its own shares at a total tost of $ 1 billion. And by the end of 1988 Exxon Corp. retired 28 percent of its shares that had once been outstanding at an aggregate tost of $ 14.5 billion. The Situation in Germany is completely different. As it will be shown under German law repurchases are severely restricted and do appreciable amount at all. not take place at an In contrast to German law the United Kingdom does not prohibit repurchases but requires companies to comply with such complex rules that US companies would regard simply as limiting their economic freedom. Therefore UK companies very seldom repurchase their own shares, too. This Paper deals with repurchases by quoted companies, in particular the UK public Company and the more or less German equivalent, the Aktiengesellschaft (AG). It seeks to ascertain the reasons why companies might want to engage in those activities. Moreover, it tries to analyse the Problems which may arise from repurchases and the safeguards which the UK and German legal Systems provide for these Problems.This Paper deals with repurchases by quoted companies, in particular the UK public Company and the more or less German equivalent, the Aktiengesellschaft (AG). It seeks to ascertain the reasons why companies might want to engage in those activities. Moreover, it tries to analyse the Problems which may arise from repurchases and the safeguards which the UK and German legal Systems provide for these Problems.
Until the late 1980s, asset securitisation was an US-American finance technique. Meanwhile this technique has been used also in some European countries, although to a much lesser extent. While some of them have adopted or developed their legal and regulatory framework, others remain on earlier stages. That may be because of the lack of economic incentives, but also because of remaining regulatory or legal impediments. The following overview deals with the legal and regulatory environment in five selected European countries. It is structured as follows: First, this finance technique will be described in outline to the benefit of the reader who might not be familiar with it. A further part will report the recent development and the underlying economic reasons that drive this development. The main part will then deal with international aspects and give an overview of some legal and regulatory issues in five European legislations. Tax and accounting questions are, however, excluded. Concluding remarks follow.
The following descriptive overview of the German corporate governance system and the current debate is structured as follows. Part II will give some information on the empirical background. Part III will describe the formal legal setting as well as actual practices in some key areas. Part IV will then deal with some issues of the current debate.
In my following remarks I will focus on a differente which we find in German law as well as in other legislations, the differente b e t w e e n entrepreneurial investments among firms and merely financial investments. Whereas OUT law of groups of companies o f Konzernrecht contains quite an elaborated set of rules, the rules governing financial investments, especially Cross-border financial investments, seems to be somewhat underdeveloped.
In early 1991 the United States Treasury Department of the Bush Administration recommended in ib proposal for Modemizing The FinancialSystem l that, in addition to other remarkable breaks with the traditional United States financial Services framework, the current bank holding Company structure be replaced with a new financial Services holding Company that would reward banks with the ability to engage in a broad new range of financial activities through separate afbliates, including full-service securities, insurance, and mutual fund activities. The Treaaury Department pointed out that commercial banking and investment banking are complementary Services and that the Glass-Steagall Separation was unnecessary. The Treasury Department gave many reasons for the need for financial modernization and why such a modemized System would work better. As an example that demonstrates the advantages of the System proposed by the Treasury Department, the proposal pointed to the German banks and called the German model of a universal banking System the most liberal banking System in the world. -What makes the German universal banking System so unique and desirable? The following outline of the history and the current structure of the Getman banking System is intended to give readers a background tc determine whether the German banking System could be a model for the System of the future.
The task of this Paper as originally described in the outline of the current project was to compare the German banking System, as one type of relationship banking , with the Japanese main bank System. This was, of course, not simply meant in the sense of a mere description and comparison of different institutions. A meaningful contribution rather has to look at the functions of a given banking System as a provider of capital or other financial Services to their client firms, has to ask in what respect the one or the other System might be superior or less efficient, and has to analyze the reasons for this. Such a thorough analysis would have to answer questions like, for instance, to what extent investment is financed by (lang or short term-)bank loans, whether German banks have, because of specific institutional arrangements like own equity holdings, seats on Company boards or other links with their borrowers, informational or other advantages that make bank finance eheaper or easier available; how such banks behave with respect to financial distress and bankruptcy of their client firms, and what their exact role in corporate governance is. While preparing this Paper I found that in Order to give reliable answers to these questions there had to be several other conferences comparable to the present one that had to focus exclusively on our domestic System. Hence what this Paper only tan provide for at this moment is a short overview of the German banking System and its special t r a i t s ( Universalbankensystem and Group Banking ; part I), describe and analyse some aspects of bank lending to firms (Part II), and the role of German banks as delegated monitors in widely held firms (Part Ill). A description of the historical development of the specific links between banks and industry and their impact on the economic growth of Germany during the period of the industrialization and later on would be specifically interesting within the framework of a Conference that discusses the lessons and relevante of banking Systems for developing market economies and for transforming socialist economies. However, historical remarks had to be omitted completely, not least because of lack of own knowledge, time and space, but also because this history is already well documented and available in English publications, too.
Other than in Belgium, German banks may hold even controlling equity participations in industrial firms (and such firms may own banks) and do so to a large extent. Vis-a-vis the European development this leads to two questions: From the perspective of the (Belgian and other) competitors of these banks, whether their own domestic System might be disadvantageous to them. And from a public interest perspective, which advantages and drawbacks are connected with the different regulations in Europe. The article first informs about the legal framework and some statistical facts. Then the various and different reasons why banks acquire and hold shares on own account are analyzed. The following Parts deal with the various public policy arguments whether equity links between banks and industrial firms should be prohibited or not (safety and soundness of banking; autonomie de Ia fonction bancaire ; abuse of confidential information and conflicts of interest; antitrust considerations; negative and positive impacts on the respective firm). In its last part the article deals with recent proposals in the German political debate to limit stockholdings of banks. The article argues that a step-by-step approach to the Single Problems and issues (conflict of interests; anticompetitive effects etc.) should be preferred to a general limitation of stock ownership of banks.
The corporate governance Systems in the U.K. and in Germany differ markedly. German large firms have a two-board structure, they are subject to employee codetermination, their managements are not confronted with public hostile takeover bids, and banks play a major role in corporate governance, through equity stakes, through proxies given to them by small investors, and through bankers positions on the supervisory boards of these firms. One of the main issues of corporate governance in large firms, the Problem of shareholders passivity in monitoring management in Berle-Means type corporations, is thus addressed by an institutional Provision, the role of the banks, rather than by a market-oriented Solution as we find it in the U.K. with its market for corporate control through the threat of hostile takeovers. These two different approaches to corporate governance have been compared several times recently, and it was argued that a bank-based or institutional Solution has clear advantages and should be preferred. Cosh, Hughes and Singh, for example, argue at the conclusion of their discussion of takeovers and short-termism in the U.K. that the institutional shareholder [in the UK] should take a much more active and vigorous part in the internal governance of corporations. . . . In Order for such a proposal to be effective both in disciplining inefficient managements and promoting long-term investments, far reaching changes in the internal workings and behaviour of the financial institutions would be required. The financial institutions would need to pool their resources together, set up specialised departments for promoting investment and innovations - in other words behave like German banks. The following remarks seek to continue this discussion from the German perspective. The article will first attempt to evaluate the monitoring potential of our domestic bank or institution-oriented corporate governance System and then, in a further patt, compare it with that of a market-oriented Solution. lt will be argued that both Systems focus on different Problems and have specific advantages and drawbacks, and that there are still quite a few puzzles to be solved until all pros and cons of each of these monitoring devices tan be assessed. The perception that both Systems focus on different Problems suggests combining institutional monitoring with a market for corporate control rather than considering them to be contrasting and incompatible approaches. The article is organized as follows. Section II will describe the legal structure of the large corporation in Germany in more detail. Section Ill explains why a market for corporate control by the threat of public hostile takeover bids does not exist in Germany. Section IV then Shows how corporate governance in publicly held corporations with small investors is organized instead, and deals with the role of banks in corporate governance in these firms. Section V of the atticle then will try to compare the monitoring potential of a marketoriented and our bank or institution-oriented corporate governance System. Concluding remarks follow.
The hypothesis that oxidative stress plays a role in the pathogenesis of Alzheimer’s disease (AD) was tested by studying oxidative damage, acitvities of antioxidant enzymes and levels of reactive oxygen species (ROS) in several models. To this end, mouse models transgenic for mutant presenilin (PS1M146L) as well as mutant amyloid precursor protein (APP) and human post mortem brain tissue from sporadic AD patients and age-matched controls were studied. Aging leads to an upregulation of antioxidant enzyme activities of Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) in brains from C57BL/6J mice. Simultaneously, levels of lipid peroxidation products malondialdehyde MDA and 4-hydroxynonenal HNE were reduced. Additionally, pronounced gender effects were observed, as female mice display better protection against oxidative damage due to higher activity of GPx. Hence, antioxidant enzymes provide an important contribution to the protection against oxidative damage. In PS1M146L transgenic mice oxidative damage was only detectable in 19-22 months old mice, arguing for an additive effect of aging and the PS1 mutation. Both HNE levels in brain tissue as well as mitochondrial and cytosolic levels of ROS in splenic lymphocytes were increased in PS1M146L mice. Antioxidant defences were unaltered. In PDGF-APP and PDGF-APP/PS1 trangenic mice no changes in any of the parameters studied were observed in any age group. In contrast, Thy1-APP transgenic mice display oxidative damage as assessed by increased HNE levels. Reduced activity of Cu/Zn-SOD may explain this observation. Additionally, gender modified this effect, as female APP transgenic mice display higher b-secretase cleavage of APP and simultaneously increased HNE levels and reduced Cu/Zn-SOD activity earlier than male mice, i.e. from an age of 3 months and before the formation of Ab plaques. Reduced Cu/Zn-SOD activity was also found in another APP transgenic mouse model, in APP23 mice. In post mortem brain tissue from sporadic AD patients activities of Cu/Zn-SOD and GPx were however increased, and changes were most pronounced in temporal cortex. Simultaneously, levels of HNE but not MDA were elevated. Additionally, in vitro stimulation of lipid peroxidation led to increased MDA formation in samples from AD patients, indicating that increased activity of Cu/Zn-SOD and GPx are insufficient to protect against oxidative damage. Furthermore, the observed changes were subject to a gender effect, as samples from female AD patients showed increased activities of Cu/Zn-SOD and GPx as well as increased HNE levels, indicating that brain tissue from females is more sensitive towards oxidative damage. Levels of soluble Ab1-40 were positively correlated with with MDA levels and activities of Cu/Zn-SOD and GPx. Additionally, levels of lipid peroxidation products MDA and HNE are gene-dose-dependently modulated by the Apolipoprotein E4 allele, the most important genetic risk factor for AD known so far. While MDA levels were negatively correlated with MMSE scores, a measure for cognitive function, HNE levels were highest in AD patients with moderate cognitive impairment. Hence, increased HNE levels may play an important role in neurodegenerative events at an early disease stage. In summary, oxidative damage, as assessed by increased HNE levels, could be detected in sporadic AD patients and in different transgenic mouse models. The results of this thesis therefore support the further research of pharmacological targets aiming at augmentation of antioxidant defences for therapy or prophylaxis of Alzheimer’s disease.
The cytochrome bc1 complex is a cornerstone in bioenergetic electron transfer chains, where it carries out tasks as diverse as respiration, photosynthesis, and nitrogen fixation. This homodimeric multisubunit membrane protein has been studied extensively for several decades and the enzyme mechanism is described with the modified protonmotive Q cycle. Still, the molecular and kinetic description of the catalytic cycle is not complete and questions remain regarding the bifurcation of electron transfer at the quinol oxidation (Qo) site, substrate occupancy, pathways of proton conduction, and the nature of the Rieske protein domain movement. We used competitive inhibitors to study the molecular architecture at the Qo site with X-ray crystallography. The structure of the enzyme with the substrate analog 5-n-heptyl-6-hydroxy-4,7-dioxobenzothiazole (HHDBT) bound at the Qo site was determined at 2.5 Å resolution. Spectroscopic studies showed that HHDBT is negatively charged when bound at the active site. Mechanistic interpretations from inhibitor binding are in line with single occupancy model for quinol oxidation and structural analysis supports the proposed proton transfer pathway. For functional insight into the enzyme mechanism, redox-sensitive protonation changes were studied by Fourier transform infrared spectroscopy. The protein purification procedure was optimized for less delipidation and the isolated enzyme was more active. Furthermore, two new phospholipids were identified in the X-ray structures, including a cardiolipin. Strikingly, conserved lipid binding cavities were observed in structural comparison with homologous enzymes. The functional role of tightly bound phospholipids will be discussed. Finally, the Qo site is a target for various compounds of agricultural and pharmaceutical importance. Importantly, the X-ray structures permit detailed analysis of the molecular reasons for acquired resistance to and treatment failure of Qo site inhibitors, such as atovaquone, that is used to treat malaria and pneumonia, as discussed herein.
The cytochrome bc1 complex or ubiquinol:cytochrome c oxidoreductase (QCR) catalyses electron transfer from ubiquinol to cytochrome c in respiration and photosynthesis coupled to a vectorial proton transport across the membrane, in which the enzyme resides. In both bacteria and eukaryotic organisms, QCR participates in supramolecular assembly of membrane proteins that comprise the respiratory or photosynthetic chain. In the present work, proton transfer pathways, substrate binding and the supramolecular assembly of the respiratory chain in yeast were probed by structure-based site-directed mutagenesis and characterization of the variants. Both active sites centre P, the place of quinol oxidation, and centre N, where quinone reduction takes place, lack direct access to the bulk solvent necessary for proton release and uptake. Based on the X-ray structure, proton transfer pathways were postulated. Analysis at centre P showed, that E272 and Y132 of cytochrome b are important for QCR catalysis as indicated by increased superoxide production and lowered Cyc1p reductase activity in these variants. Pre-steady state heme reduction kinetics in combination with stigmatellin resistance indicated that charge and length of the side chain at position 272 are crucial for efficient docking of the ISP to form the enzyme substrate complex and for electron bifurcation at centre P. Variants of Y312 and F129, both residues of cytochrome b, showed an increased Km indicating participation of these residues in coordination of ubiquinol or the possible intermediate semiquinone anion radical. F129 proved to be crucial for a functional Q-cycle as indicated by respiratory negative growth phenotype and a lowered H+/e- stoichiometry of F129 variants. At centre N, the postulated CL/K and E/R proton transfer pathways are located at opposite sites of the bound ubiquinone. Variants in the surface residues R218 (cytochrome b) and E52 (Qcr7) of the E/R pathway and E82 (Qcr7) of the CL/K pathway showed instability upon purification indicating an important role of these residues for QCR integrity. The slowed down centre N reduction kinetics in H85 (CL/K), R218 and N208 (both E/R) variant was attributed to a destabilised semiquinone anion consistent with the observed decreased sensitivity towards the site-specific inhibitor antimycin and an increased Km. Variants of residues of both pathway, E82Q and R218M, exhibited a decreased H+/e- stoichiometry indicating a crucial role of both residue for maintaining a working Q-cycle and supporting the proposed protonation of the substrate via the Cl/K and the E/R pathway. Long-range interaction between centre N and centre P were observed by altered reduction kinetics of the high potential chain and increased superoxide production in the centre N variants. The role of the cation-pi-interaction between F230 of Cyt1p and R19 of cytochrome c in binding of the redox carrier to QCR was analysed. In F230L hydrophobic interaction were partially lost as was deduced from the ionic strength dependence of Cyc1p reductase activity and Cycp1 binding, as detected by ionic strength sensitive Kd and Km for Cyc1p. The decreased enzymatic rate of F230W could be explained by a disturbed binding of Cyc1p to the variant enzyme. F230 may influence the heme mid point potential and thereby the electron transfer rate to Cyc1p. Reduction of Cobp via both centre P and centre N was disturbed suggesting an interaction between high and low potential chain. Supramolecular association between QCR and cytochrome c oxidase (COX) in yeast mitochondria was probed by affinity chromatography of a his-tagged QCR in the presence of the mild detergent digitonin. In comparison to purification with laurylmaltoside, the presence of both QCR and COX subunits was detected in the elution fractions by SDS-PAGE, Cyc1p reductase and TMPD oxidase activity assays and immunoblot analysis. The CL-dependent formation of the supercomplex between QCR and COX was analysed by replacement variants in the CL-binding site of QCR in CL containing and CL free environment. With an increasing number of replacements of the three lysines the CL-binding pocket supercomplex formation was not abolished, when CL is present as shown by BN-PAGE analysis. This was supported by the synergetic decrease in enzyme activity for both enzymes upon increased number of replacements. In the CL-free environment, no supracomplex formation was observed for a wildtype CL binding site. By replacements of two lysines in the CL-binding pocket, supercomplex formation could be recovered as revealed by BN-PAGE. This indicates, that CL may serve as a charge neutralizer for the lysines near the presumed interaction domain between complex III and complex IV. The obtained results for centre P provide new information of residues critical for stabilisation of ubiquinol and controlling electron short circuit reactions. The observations for centre N variants clearly support the proposed two proton transfer pathways and the role of the bound phospholipids in centre N kinetics. Variants in the Cyc1p binding site suggest a role for F230 both in Cyc1p binding and electron transfer. Clear interaction between the high and low potential chain in both Cyt1p and centre N variants strongly support long-range interactions in the complex. Studies on the supramolecular association of complex III and complex IV indicate a new role of Cl in stabilising a supracomplex.
The enzyme quinol:fumarate reductase (QFR) from the anaerobic e-proteobacterium Wolinella succinogenes is part of the anaerobic respiratory system of this organism. It couples the reduction of fumarate to succinate to the oxidation of menaquinol to menaquinone. W. succinogenes uses fumarate as terminal electron acceptor and can use various substrates (e.g., formate or molecular hydrogen) as electron donors. The concerted catalytic substrate turnover of either a hydrogenase or a formate dehydrogenase in conjunction with QFR contributes to the generation of an electrochemical potential gradient across the bacterial plasma membrane, which is used for the phosphorylation of ADP with inorganic phosphate, Pi, to ATP. In addition to an FAD (in subunit A) and three iron-sulfur clusters (in subunit B), QFR binds a low- and a high-potential heme b group in its transmembrane subunit C, as was ultimately shown in the crystal structure at 2.2 Å resolution (Lancaster et al., 1999, Nature 402, 377– 385). Both hemes are part of the electron transport chain between the two catalytic sites of this redox enzyme. The midpoint potentials of the hemes are well established but their assignment to the distal and proximal positions in the structure had not yet been determined. Furthermore, QFR from W. succinogenes has been proposed to exhibit a novel coupling mechanism of transmembrane electron and proton transfer, which has been described in the so-called “E-pathway” hypothesis (Lancaster, 2002, Biochim. Biophys. Acta 1565, 215–231). The aim of this project was to characterize the relationship between structure and function of QFR and to investigate the details of the proposed coupling mechanism (“Epathway”) with the help of computer-based electrostatic calculations on the QFR wild-type (WT) coordinates, and electrochemically induced FTIR and VIS difference spectroscopy on the QFR WT and available variant enzymes (in particular enzyme variant E180Q, in which the glutamic acid at position C180 has been replaced by a glutamine). 1.) It was demonstrated in this study that the diheme-containing QFR exhibits stable and reproducible electrochemically induced FTIR difference bands in the midinfrared range from 1800 cm-1 to 1000 cm-1 that reflect transitions from the reduced to the oxidized state of the enzyme. The spectral features that were observed in the FTIR difference spectra are fully reversible when changing from a reductive to an oxidative reference potential at the working electrode and vice versa. This indicates that the underlying redox reactions of the enzyme at the gold grid working electrode are also fully reversible under the applied experimental conditions. The same reversible spectral redox behavior in the visible range could also be ascertained for the Soret- and a-band of the two heme b groups of QFR. This behavior allowed to reliably determine the heme b midpoint potentials of QFR at various pH values. Analysis of the FTIR difference spectra in the amide I range yields evidence for structural reorganizations of the polypeptide backbone upon the electrochemically induced redox reaction. 2.) The redox titrations of the high- and low-potential heme b of QFR as simulated by multiconformation continuum electrostatics (MCCE) calculations showed a very high level of agreement with respect to the experimentally observed midpoint potentials of the heme b groups at pH 7. As determined with the help of the theoretical calculations, prominent features governing the differences in redox potential between the two hemes are the higher loss of reaction field energy for the proximal heme and the stronger destabilization of the oxidized form of the proximal heme due to several buried and ionized Arg and Lys residues. The explicit incorporation of crystallographically identified water molecules in the calculations had a noticeable effect on the absolute values of the determined midpoint potentials, although the relative difference of the two obtained midpoints did not change significantly. The results of the electrostatic calculations clearly showed that the lowpotential heme corresponds to the distal position bD in the structure, and that the high-potential heme is identical to the proximal heme bP. This assignment could previously not be achieved unequivocally with experimental methods. 3.) In addition, the currently discussed mechanism of coupled electron and proton transfer in the QFR of W. succinogenes (i.e., the “E-pathway” hypothesis) is further supported by the results of this study. The simulations of intermediate states of electron transfer via the heme b groups show that the protonation state of the key amino acid residue Glu C180 depends on the redox states of the heme groups as suggested in the “E-pathway” hypothesis. This result yields a possible mechanism for the coupling of transient transmembrane proton transfer via Glu C180 to the electron transfer via the heme b groups, since Glu C180 could be part of a “proton wire” and its redox-dependent protonation state could serve as the regulatory element of the “E-pathway”. Furthermore, the results of simulated heme reduction indicate that the side chain of Glu C180 also changes its conformation with respect to the redox state of the hemes. Both major results concerning the role of Glu C180, the change of protonation as well as the reorientation of the side chain upon reduction of the heme groups, are consistent with the results from electrochemically induced FTIR difference spectroscopy: Of particular interest was the spectral range above 1710 cm-1, where C=O stretching vibrations of protonated COOH carboxyl groups absorb, because those groups can act as proton donors, respectively acceptors, and can be involved in intra-protein proton transfer reactions. It was possible to observe signals of such protonated carboxyl groups originating from QFR enzyme, which either change their protonation state and/or experience an environmental change in the course of the induced redox reaction. This finding was supported by the fact that the relevant FTIR difference signals are sensitive to an isotopic hydrogen/deuterium (1H/2H) exchange via the buffer solution, since they were shifted towards lower wavenumbers in D2O. Furthermore, it could be shown with the help of site-directed mutagenesis that the acidic residue Glu C180, which is located in the membranespanning, diheme-containing subunit C of QFR, is contributing to the redox dependent signal of protonated carboxyl groups. The observed residual signal in the FTIR double-difference spectrum of QFR wild-type and enzyme variant E180Q (Glu C180 has been replaced with a Gln residue) could be interpreted as a protonation/deprotonation event that is superimposed by an environmental effect on the specific C=O vibration. This result strongly supports the proposed “E-pathway” of coupled transmembrane electron and proton transfer in the QFR enzyme, which states that residue Glu C180 is an essential constituent of a transient redox-controlled transmembrane proton transfer pathway. 4.) As a second possible constituent of the suggested “E-pathway”, the ring C propionate of the distal heme was found to be unusually fully protonated in all simulated redox states, indicating a possible role as a transient proton donor/acceptor in the “E-pathway”. Similarly to Glu C180, experimental evidence from FTIR difference spectroscopy on a modified QFR with 13C-labeled heme propionates was obtained, which indicates an involvement of at least one of the two propionates of heme bD in proton transfer. The observed signals can tentatively be interpreted as a redox-coupled (de)protonation of the ring C propionate of bD, which is possibly xiii superimposed by a conformational or environmental change of the specific propionate. 5.) Also the observation of a strong redox Bohr effect for both heme b groups in QFR is in line with the proposed “E-pathway” hypothesis, as this effect yields a possible and well-established mechanism for the coupling of proton transfer and redox changes of the heme groups. The comparison of the observed effect in QFR WT and E180Q together with the results from FTIR spectroscopy and MCCE calculation indicate that the ring C propionate of the distal heme is dominating the pHdependence of the midpoint potential of bD, and that the corresponding group for bP is Glu C180. The origin of the redox Bohr effect for bP in the enzyme variant E180Q (which is dramatically changed with respect to the WT) could not be identified unequivocally, but the observation of this redox Bohr effect in the variant implies the presence of other protolytic groups, which interact with heme bP and which may be necessary for a functional “E-pathway”.
Die vorliegende Arbeit soll einen Beitrag zur Erforschung der Verarbeitungsmechanismen des Gehirns leisten. Die Erregung des komplexen Systems "Hirn" liefert Antworten, deren Analyse zu einem besseren Verständnis dieser Informationsverarbeitung führt. Zu diesem Zweck wurde das Gehirn mit unterschiedlichen visuellen Stimuli angeregt und die hirnelektrischen Signale gemessen, die von Nervenzellgruppen (Multiunits) im visuellen Kortex der Katze ausgesandt wurden.Die verwendeten Stimuli waren ein Streifenmuster sowie eine Zufallspunktverteilung, deren Kohärenz beliebig geändert werden konnte. Darüber hinaus wurden die Antworten auf eine Vielzahl von Stimuli analysiert, die nur aufgrund des Bewegungskontrastes zwischen punktdefiniertem Objekt und Hintergrund zu erkennen sind (Shape-from-Motion- (SFM-) Stimuli). Die aufgenommenen Daten wurden mit Hilfe einer umfangreichen Signalanalyse untersucht. So wurden in Abhängigkeit von der Stimulusbedingung die Anzahl der Nervenimpulse pro Zeiteinheit (Feuerraten), Synchronisation, Frequenzverteilung sowie Kopplung von Aktionspotenzialen und LFPDaten analysiert. Die Experimente im ersten Teil dieser Arbeit untersuchten den Einfluss von Kohärenz auf die Verarbeitung von Bewegungsinformation im primären visuellen Areal (A17) und im posteromedialen lateralen suprasylvischen Sulcus (Area PMLS) der Katze. Es konnte gezeigt werden, dass Multiunits in A17 und PMLS sowohl auf Streifenmuster als auch auf Zufallspunktverteilungen antworten und dass die Stärke der Antwort als eine Funktion der Stimulusrichtung variiert. Die Vorzugsrichtung ist in beiden Arealen weitgehend unabhängig von der Art des verwendeten Stimulus, was darauf hindeutet, dass die Stimulusrichtung für Streifenmuster und Zufallspunktmuster in diesen Arealen durch einen einheitlichen Mechanismus bestimmt wird. Bei einer Abnahme der Stimuluskohärenz zeigen die Multiunits eine Abnahme der Feuerrate, wobei im Vergleich zu PMLS in A17 eine stärkere Abnahme der Kohärenz nötig ist, um die gleiche Abnahme der Feuerrate zu erreichen. Dieses Ergebnis konnte durch die unterschiedlichen Größen der rezeptiven Felder der beiden Areale erklärt werden und ist ein weiterer Hinweis darauf, dass eine wichtige Funktion von PMLS in der Analyse von Bewegung und räumlich verteilter Information liegt. Da beide Areale keine signifikante Änderungen der Feuerrate bei Inkohärenzniveaus von mehr als 50% zeigten, scheinen sie nicht in der Lage zu sein, die Bewegungsrichtung eines inkohärenten Zufallspunktmusters nahe der psychophysischen Detektionsschwelle von 95% auf der Basis von Feuerraten zu erkennen. Die Korrelation der Aktionspotenziale unterschiedlicher Multiunits zeigte bereits bei einer geringen Abnahme der Stimuluskohärenz eine monotone Verbreiterung des zentralen Maximums in den Korrelogrammen beider Areale. Die Stärke der Synchronisation hingegen war kaum beeinflusst. Darüberhinaus kam es zu einer Verschiebung der Leistung im lokalen Feldpotential (LFP) von hohen hin zu niedrigen Frequenzbereichen. Diese Verschiebung wurde auch für die Kopplung zwischen LFP und Akvi tionspotenzialen nachgewiesen. Diese Resultate unterstützen die Theorie, dass präzise Synchronisation und hochfrequente Oszillationen ein Mechanismus für die Bindung kohärenter Objekte sind. Sie zeigen darüber hinaus, dass Synchronisation auch nicht kohärente Stimuli binden kann und dass die Verschiebung im LFP hin zu niedrigeren Frequenzen wichtig für die Integration verteilter Information über einen größeren visuellen Raum sein kann. Da bei hohen Inkohärenzniveaus keine präzise Synchronisation mehr nachgewiesen werden konnte, kann jedoch auch die Synchronisation nicht als alleiniger Mechanismus zum Erkennen einer Bewegungsrichtung eines inkohärenten Zufallspunktmusters herangezogen werden. In den Experimenten im zweiten Teil dieser Arbeit wurde untersucht, wie das Gehirn SFM-Stimuli verarbeitet. Die Auswertungen der Feuerraten haben gezeigt, dass Multiunits in PMLS sowohl auf helligkeitsdefinierte Kontrastbalken als auch auf SFM-Balken reagieren. Die Stärke der Antwort hängt von der Kombination von Stimulus und Hintergrund und von der relativen Bewegungsrichtung zueinander ab. Während ähnliche Feuerraten für Balken mit hohem Kontrast relativ zum Hintergrund und für punktdefinierte Balken gefunden wurde, die sich über einen dunklen Hintergrund bewegten, führte ein statischer Zufallspunkthintergrund zu einer starken Abnahme der von dem SFM-Balken hervorgerufenen Antwort. Ein in die Gegenrichtung bewegter Hintergrund sowie ein reduziertes Kohärenzniveau des Zufallspunkthintergrundes führten dazu, dass die Multiunits auf den SFM- Balken nicht mehr mit einer Zunahme der Feuerraten reagierten. Um die hemmende Wirkung des Hintergrundes aufzuheben, musste der Hintergrund auf einer Fläche des visuellen Feldes, die der Größe des rezeptiven Feldes entsprach, abgedeckt werden. Dieses Ergebnis zeigt, dass die Feuerraten für diese Art Stimulus nicht wesentlich von Arealen außerhalb des rezeptiven Feldes beeinflusst werden. Zur weiteren Analyse der Fähigkeit von PMLS, SFM-Balken nur aufgrund des Bewegungskontrastes zwischen punktdefiniertem Objekt und Hintergrund zu erkennen, wurde mit Hilfe von zwei Tuningkurven-Stimuli, bei denen sich die Bewegungsrichtung der Punkte innerhalb des Balkens um 90° unterschied, die Vorzugsrichtung der Multiunits bestimmt. Die Auswertung ergab, dass sich die gemessene Vorzugsrichtung der Multiunit um 45° drehte, obwohl sich die Bewegungsrichtung des Balkens selbst nicht änderte. Darüber hinaus wurden verschiedene SFM-Stimuli untersucht, die alle dieselbe Bewegungsrichtung des Balkens, jedoch unterschiedliche Bewegungsrichtungen der Punkte innerhalb des Balkens aufwiesen. Wenn PMLS die Bewegung des SFM-Objekts statt der Bewegung der einzelnen Punkte verarbeitet, sollte die Feuerrate für alle diese Bedingungen identisch sein. Die Ergebnisse zeigen jedoch, dass sich die durch die verschiedenen SFM-Stimuli hervorgerufenen Feuerraten verringerten, je weiter sich die Punkte, die den Balken bildeten, von der Bewegungsrichtung des Balkens – und damit von der Vorzugsrichtung der Multiunit – weg bewegten. Durch dieses Ergebnis konnte gezeigt werden, dass Multiunits in PMLS nicht in der Lage sind, die Richtung von kinetisch definierten Balken zu analysieren und statt dessen nur die Bewegung der einzelnen Komponenten erfassen.
Proton-translocating NADH:ubiquinone oxidoreductase (complex I) transports two electrons from NADH to membranal ubiquinone: in this process protons are translocated across the membrane, producing 40% of the total proton gradient between matrix side and intermembrane space. Mitochondrial complex I contains at least 46 subunits in mammals, and has a molecular weight of around 1000 kDa. Electronic microscopy analysis showed that complex I has an L-form, which consists of two domains: a peripheral “arm” (hydrophilic domain) and a membrane “arm” (hydrophobic domain). The peripheral domain, which protrudes into the matrix, contains one non-covalently bound flavin mononucleotide (FMN) and the iron-sulfur clusters N1a, N1b, N2, N3, N4 and N5 as redox active groups. They transport electrons from NADH to ubiquinone. Cluster N2 is supposed to be the immediate electron donor to ubiquinone by virtue of its highest and pH dependent redox midpoint potential (Em,7 –150 mV). The exact location of the tetra-nuclear cluster N2 is still object of discussion. The TYKY and the PSST subunits contain three binding motifs for tetranuclear clusters which are formed by twelve cysteins. In an effort to investigate the “ubiquinone reduction module” of complex I, in the first part of this work site directed mutagenesis of the TYKY and PSST subunits has been carried out. Mutant strains were characterised in terms of complex I content, catalytic activity and EPR signature of cluster N2. The second part of this work was aimed at developing a substrate inducible version of the internal alternative NADH:ubiquinone oxidoreductase (NDH2i). A substrate inducible NDH2i is expected to offer a “switch” between complex I activity dependent (no NDH2i activity) and independent (NDH2i activity) cell growth, by changing between activating and non-activating substrates. This strategy would allow the screening for two types of complex I mutants, which is a prerequisite for realising a random PCR mutagenesis of single subunits of complex I, that allows the production of a high number of point mutations in relatively short time. Y. lipolytica complex I deficiency mutant strains could be easily identified, by virtue of their inability to survive under complex I dependent growth conditions (no NDH2i activity). By this way, amino acids that have an important role for complex I structure or function could be identified by subsequent sequence analysis. Each of the twelve cysteines that form the above mentioned three binding motifs for iron-sulfur cluster have been mutagenised. In mutant mitochondrial membranes, no assembled complex I could be detected. From these data one may conclude that the mutagenised 6 SUMMARY 92 cysteines play an important role for complex I stability, or that are a prerequisite for complex I assembly in Y. lipolytica, but there is not direct evidence indicating that any of the four mutagenised residues acts as a ligand. Two aspartates in the PSST subunit, Asp-99 and Asp-115, were found to be essential for complex I catalytic activity. EPR spectroscopic analysis indicated that the electron transfer to N2 cluster was not blocked and implied that this was not the reason for the loss of catalytic activity. From these data it can be concluded that D99 and D115 play a vital role for complex I NADH:ubiquinone reductase activity, but are not ligands for cluster N2 and that their position is not close enough to the cluster to influence directly its electromagnetic environment. Three mutations, identified in the PSST and TYKY homologous subunits of patients affected with Leigh syndrome (V119M in PSST, P78L and R101H in TYKY) were reconstructed in the obligate aerobic yeast Y. lipolytica. This approach may help to understand the aetiology of the Leigh syndrome, in terms of the ability of complex I to oxidize NADH and to transport electrons. In fact, all three mutations showed effects on electron transport, reducing the VMax by about 50%. Mutant V119M in the PSST subunit, which had a lethal effect in two patients that were homozygous for this mutation, affects a fully conserved residue. Overall, the results from site directed mutagenesis carried out so far support the theory that the “catalytic core ” (N2 cluster and quinone binding site) of complex I has been evolved from the electron transfer module of the [Ni-Fe] hydrogenases. In fact, mutagenesis of residues that are fully conserved between complex I and [Ni-Fe] hydrogenases, showed dramatic effects on complex I in terms of assembly (cysteine mutants) or catalytic activity (D99-D115). Differently, changing aspartate 174 and glutamic acid 185 (not fully conserved, Fig 4.1A) had little or no effect on the Michaelis-Menten parameters and N2 EPR signal. In recent years Y. lipolytica has been developed as a yeast genetic system to study mitochondrial complex I. The present work introduced the promoter for the isocitrate lyase (pICL1) as a useful tool for the substrate selective expression of the internal version of the alternative NADH:ubiquinone oxidoreductase (pICL1-NDH2i). This allows to rescue complex I deficiencies “in vivo” selectively by growth on acetate (or ethanol) medium. The integration of the pICL1-NDH2i construct into the genome of Y. lipolytica and subsequent deletion of nuclear-coded subunits like PSST, TYKY and 49 kDa, would contribute to further develop this organism as a useful genetic model for studying subunits of mitochondrial complex I by site directed mutagenesis.
Stability, unfolding and refolding of the outer membrane protein porin from Paracoccus denitrificans was investigated using genetic and spectroscopic methods. Structural and functional activity studies on wild type and mutant porins: The site-directed mutants were constructed based on conserved residues and evidences on the role of certain amino acids from previous studies with OmpF. Secondary structure analysis of wild type and mutants E81Q, W74C, E81Q/D148N, E81Q/D148N/W74C by FTIR and CD spectroscopy are in line with the fact that porins are predominantly ß-sheet structure. The functional activity studies by black lipid bilayer techniques showed that the wild type and mutants W74C, E81Q/D148N, E81Q/D148N/W74C have a conductance of 3.25 nS. For mutant E81Q conductance of 1.25nS was more predominant over 3.25 nS. The activity of the mutants was observed to be far less than the wild type. This indicates that structural similarities does not implies similar functional activity. Thermal stability analysis of porin in detergent micelles and reconstituted into liposomes: Thermal stability analysis of wild type and mutants in detergent micelles showed changes in secondary and quaternary structure. It was found that wild type porin unfolds into aggregated structure with a high transition temperature of 86.2 °C. For mutants E81Q, W74C, E81Q/D148N the transition temperature was found to be 84.2 °C, 80.3 °C and 80.2 °C respectively. Functional activity assays at high temperatures revealed that the protein tends to loose its activity on heating up to 50 °C. This shows that structural stability does not imply functionality in the case of porins. Thermal stability analysis of porin reconstituted into liposomes showed that there was no change in the secondary and quaternary structure of the protein up to 100 °C, revealing that the protein becomes more thermostable when it is reconstituted into liposomes. Refolding of aggregated porin: This study shows that disaggregation of ß-sheet membrane protein porin is possible by changing its chemical and thermodynamic parameters. An increase of the solution pH to 12 or above results in opening up of the aggregated protein into unordered structure, as observed by FTIR and CD spectroscopy. This unordered structure could be refolded into native-like structure forming trimers. The secondary structure of the refolded protein deviated slightly from the native one. The thermal stability analysis of the native-like refolded proteins showed that the unfolding pattern is entirely different when compared to the native porins. pH dependent unfolding of porin: Thermal stability of porin at different pH values showed that the protein is stable in a pH range of 1-11. At pH 12 and above the protein unfolds into unordered structure instead of aggregating. The high pH unfolding of porin is a reversible process. The secondary structure of the refolded protein varied slightly from the native-one. Whereas thermal stability was entirely different. This shows that even though the unfolding of porin at high pH is reversible, it results in changes in local interaction between the amino acids resulting in a difference in stability. Unfolding in presence of urea and guanidinium hydrochloride (GuHCl): Denaturation of porin in the presence of chemical denaturants like urea and GuHCl showed that porin unfold into unordered structure. The unfolding is a reversible process. Unfolded protein was refolded into detergent micelles and liposomes. Refolding into detergent micelles was faster compared to refolding into liposomes, as seen by kinetic gel shift assays. The refolding into liposomes showed the presence of intermediates similar to those reported for OmpF. This study shows the difference in thermal stability of the outer membrane protein porin from Paracoccus denitrificans in detergent micelles and native-like liposomes. It suggests various unfolding pathways, which can be further investigated for unfolding and refolding kinetics. This report also suggests that it is possible to refold a heat-aggregated protein.