The politics of disease surveillance

The capacity to conduct international disease outbreak surveillance and share information about outbreaks quickly has empowered both State and Non-State Actors to take an active role in stopping the spread of disease by generating new technical means to identify potential pandemics through the creation of shared reporting platforms. Despite all the rhetoric about the importance of infectious disease surveillance, the concept itself has received relatively little critical attention from academics, practitioners, and policymakers. This book asks leading contributors in the field to engage with five key issues attached to international disease outbreak surveillance - transparency, local engagement, practical needs, integration, and appeal - to illuminate the political effect of these technologies on those who use surveillance, those who respond to surveillance, and those being monitored.

Cloud computing services for the small and medium enterprises: Key considerations for sourcing sustainable business value

The concept of cloud computing services (CCS) is appealing to small and medium enterprises (SMEs). However, while there is a significant push by various authorities on SMEs to adopt the CCS, knowledge of the key considerations to adopt the CCS is very limited. We use the technology-organization-environment (TOE) framework to suggest that a strategic and incremental intent, understanding the organizational structure and culture, understanding the external factors, and consideration of the human resource capacity can contribute to sustainable business value from CCS. Using survey data, we find evidence of a positive association between these considerations and the CCS-related business objectives. We also find evidence of positive association between the CCS-related business objectives and CCS-related financial objectives. The results suggest that the proposed considerations can ensure sustainable business value from the CCS. This study provides guidance to SMEs on a path to adopting the CCS with the intention of a long-term commitment and achieving sustainable business value from these services.

Holistic Spirituality in the Thinking of Ellen White

Spiritualiteetti viittaa syvälliseen, inhimilliseen ulottuvuuteen ja ominaisuuteen, jonka tarkka määritteleminen on haasteellista, ellei mahdotonta. Sitä vastaa yhtäältä uskonnollisuuden kautta toteutuva, elämän tarkoitukseen ja syvemmän olemuksen etsintään liittyvä hengellisyys, mutta toisaalta myös kaikkea muuta hengen viljelyä ja mielekkään olemisen tavoittelua tarkoittava henkisyys. John Swintonin mukaan hengen ulottuvuus on se inhimilliseen olemukseen kuuluva, dynaaminen elinvoima, joka virkistää ja elävöittää ihmistä ja motivoi häntä etsimään Jumalaa, arvoja, merkitystä, tarkoitusta ja toivoa. Tämä tutkimus nostaa tarkastelun kohteeksi kokonaisvaltaisen hengellisyyden, jolloin huomio kiinnitetään niihin sidoksiin, joiden kautta hengen ulottuvuus liittyy muihin inhimillisen elämän olennaisiin toimintoihin ja näkökulmiin. Tällaisia ovat 1) ajattelu 2) teot ja käytännön toiminta 3) suhteet ja vuorovaikutusverkostot 4) tunteet ja kanssakäymistä ohjaavat asenteet 5) olemassaolon ja olemisen ulottuvuudet. Kokemusten merkitys, arvo ja mielekkyys hahmottuvat juuri hengen alueella, toisin sanoen sisäisesti, hengellisenä ja henkisenä asiana. Tutkimusmateriaalina tässä tutkimuksessa on amerikkalaisen vuosina 1827 1915 eläneen Ellen Whiten kuusi myöhäiskauden teosta vuosilta 1892 1905 ja tutkimusmenetelmänä on käytetty systemaattista analyysiä. Olennaista Whiten tavassa käsitellä uskonnon harjoitukseen liittyviä aiheita on hänen käytännöllinen ja elämän arkeen kiinteästi niveltyvä otteensa. Tutkimus paljastaa, että Martti Lutherin käsitykset ovat merkittävästi vaikuttaneet Whiten ajatteluun. Lähteistä paljastuu samankaltaisuutta hänen näkemystensä ja uusimman suomalaisen Luther-tutkimuksen Martti Lutherin tuotannosta esiin nostaman ajattelutavan välillä. Vaikka teologisen oppineisuuden kannalta White ja Luther ovat eri tasoilla, kummankin käsitys ihmisen ja Jumalan välisen suhteen perusolemuksesta on samankaltainen: Lähtökohtana sille on Jumalan rakkaus ja hänen armostaan lähtenyt toiminta. Toiseksi, ihmisen ja Kristuksen välinen, olemuksellinen yhteys, unio , on perustana sille, että Jumala hyväksyy ihmisen ja huolehtii hänestä nyt ja ikuisesti. Kolmanneksi, tämä ihmisen ja Kristuksen liittoutuminen ja yhdistyminen ilmenee yhteistoimintana ja kumppanuutena yhteisten tavoitteiden saavuttamiseksi maailmassa. White korostaa ihmisen ja Kristuksen välisen hengellisen suhteen vuorovaikutteista ja toiminnallista luonnetta, joka tulee ilmi epäitsekkyytenä, toisten ihmisten ja heidän tarpeittensa huomioimisena sekä myötätuntona ja kykynä asettua toisen asemaan. Terveellistä elämäntapaa ja kasvatusta koskevat ajatuksensa White liittää siihen laaja-alaiseen näkemykseen hengellisyydestä, jonka tavoitteena on ihmisen kokonaisvaltainen hyvinvointi. Hän ei näe spiritualiteettia elämän arjesta irrallisena tai erillisenä saarekkeena, vaan ihmistä kaikessa ohjaavana, voimaannuttavana ja mielekkyyttä tuottavana, ensisijaisena ulottuvuutena. Tutkimuksen kuluessa myös Whiten usein käyttämät Jumalalle antautumisen ja luonteen käsitteet nousevat tarkastelun kohteiksi. Hänen mukaansa ihminen ei tahdonponnistuksillaan yksin pysty tavoittamaan Jumalaa vaan hänen on lakattava Jumalan rakastavan kutsun edessä itse tahtomasta ja suostuttava liittymään Jumalan tahtoon ja tarkoitukseen. Tämä liittyy siihen sisäiseen muutokseen, jota White kuvaa luonteen käsitteen avulla. Jumalan armon vaikuttama tahdon uudelleen suuntaaminen muuttaa ihmisen olemusta, arvoja, asennoitumisen tapaa ja myötätuntoisen vuorovaikutuksen kykyä niin ettei ihminen ole enää aivan sama kuin ennen. Kysymys on toisaalta yhtäkkisestä ja kertakaikkisesta olemuksellisesta muuttumisesta, mutta samalla myös hiljaisesta, elämänmittaisesta kasvusta ja kypsymisestä. Juuri luonteen käsitteen avulla White kuvaa hengellisyyttä ja siihen kuuluvaa sisästä matkaa. Tässä tutkimuksessa spiritualiteettia lähestytään yleisinhimillisenä piirteenä ja ominaisuutena, jolloin huomio ei ole ensisijaisesti yksittäisissä opillisissa käsityksissä tai uskonnollisuuden harjoittamisen muodoissa. Tarkoituksena on luoda kokoava rakenne, jonka puitteissa holistinen spiritualiteetti voidaan selkeämmin hahmottaa ja yksilöidymmin ymmärtää.

Theological Exegesis in the Canonical Context : Brevard S. Childs' Methodology of Biblical Theology

Modern Christian theology has been at pain with the schism between the Bible and theology, and between biblical studies and systematic theology. Brevard Springs Childs is one of biblical scholars who attempt to dismiss this “iron curtain” separating the two disciplines. The present thesis aims at analyzing Childs’ concept of theological exegesis in the canonical context. In the present study I employ the method of systematic analysis. The thesis consists of seven chapters. Introduction is the first chapter. The second chapter attempts to find out the most important elements which exercise influence on Childs’ methodology of biblical theology by sketching his academic development during his career. The third chapter attempts to deal with the crucial question why and how the concept of the canon is so important for Childs’ methodology of biblical theology. In chapter four I analyze why and how Childs is dissatisfied with historical-critical scholarship and I point out the differences and similarities between his canonical approach and historical criticism. The fifth chapter attempts at discussing Childs’ central concepts of theological exegesis by investigating whether a Christocentric approach is an appropriate way of creating a unified biblical theology. In the sixth chapter I present a critical evaluation and methodological reflection of Childs’ theological exegesis in the canonical context. The final chapter sums up the key points of Childs’ methodology of biblical theology. The basic results of this thesis are as follows: First, the fundamental elements of Childs’ theological thinking are rooted in Reformed theological tradition and in modern theological neo-orthodoxy and in its most prominent theologian, Karl Barth. The American Biblical Theological Movement and the controversy between Protestant liberalism and conservatism in the modern American context cultivate his theological sensitivity and position. Second, Childs attempts to dismiss negative influences of the historical-critical method by establishing canon-based theological exegesis leading into confessional biblical theology. Childs employs terminology such as canonical intentionality, the wholeness of the canon, the canon as the most appropriate context for doing a biblical theology, and the continuity of the two Testaments, in order to put into effect his canonical program. Childs demonstrates forcefully the inadequacies of the historical-critical method in creating biblical theology in biblical hermeneutics, doctrinal theology, and pastoral practice. His canonical approach endeavors to establish and create post-critical Christian biblical theology, and works within the traditional framework of faith seeking understanding. Third, Childs’ biblical theology has a double task: descriptive and constructive, the former connects biblical theology with exegesis, the later with dogmatic theology. He attempts to use a comprehensive model, which combines a thematic investigation of the essential theological contents of the Bible with a systematic analysis of the contents of the Christian faith. Childs also attempts to unite Old Testament theology and New Testament theology into one unified biblical theology. Fourth, some problematic points of Childs’ thinking need to be mentioned. For instance, his emphasis on the final form of the text of the biblical canon is highly controversial, yet Childs firmly believes in it, he even regards it as the corner stone of his biblical theology. The relationship between the canon and the doctrine of biblical inspiration is weak. He does not clearly define whether Scripture is God’s word or whether it only “witnesses” to it. Childs’ concepts of “the word of God” and “divine revelation” remain unclear, and their ontological status is ambiguous. Childs’ theological exegesis in the canonical context is a new attempt in the modern history of Christian theology. It expresses his sincere effort to create a path for doing biblical theology. Certainly, it was just a modest beginning of a long process.

Ethics in a Technological World : Framing the Questions and Three Approaches

This study addresses the following question: How to think about ethics in a technological world? The question is treated first thematically by framing central issues in the relationship between ethics and technology. This relationship has three distinct facets: i) technological advance poses new challenges for ethics, ii) traditional ethics may become poorly applicable in a technologically transformed world, and iii) the progress in science and technology has altered the concept of rationality in ways that undermine ethical thinking itself. The thematic treatment is followed by the description and analysis of three approaches to the questions framed. First, Hans Jonas s thinking on the ontology of life and the imperative of responsibility is studied. In Jonas s analysis modern culture is found to be nihilistic because it is unable to understand organic life, to find meaning in reality, and to justify morals. At the root of nihilism Jonas finds dualism, the traditional Western way of seeing consciousness as radically separate from the material world. Jonas attempts to create a metaphysical grounding for an ethic that would take the technologically increased human powers into account and make the responsibility for future generations meaningful and justified. The second approach is Albert Borgmann s philosophy of technology that mainly assesses the ways in which technological development has affected everyday life. Borgmann admits that modern technology has liberated humans from toil, disease, danger, and sickness. Furthermore, liberal democracy, possibilities for self-realization, and many of the freedoms we now enjoy would not be possible on a large scale without technology. Borgmann, however, argues that modern technology in itself does not provide a whole and meaningful life. In fact, technological conditions are often detrimental to the good life. Integrity in life, according to him, is to be sought among things and practices that evade technoscientific objectification and commodification. Larry Hickman s Deweyan philosophy of technology is the third approach under scrutiny. Central in Hickman s thinking is a broad definition of technology that is nearly equal to Deweyan inquiry. Inquiry refers to the reflective and experiential way humans adapt to their environment by modifying their habits and beliefs. In Hickman s work, technology consists of all kinds of activities that through experimentation and/or reflection aim at improving human techniques and habits. Thus, in addition to research and development, many arts and political reforms are technological for Hickman. He argues for recasting such distinctions as fact/value, poiesis/praxis/theoria, and individual/society. Finally, Hickman does not admit a categorical difference between ethics and technology: moral values and norms need to be submitted to experiential inquiry as well as all the other notions. This study mainly argues for an interdisciplinary approach to the ethics of technology. This approach should make use of the potentialities of the research traditions in applied ethics, the philosophy of technology, and the social studies on science and technology and attempt to overcome their limitations. This study also advocates an endorsement of mid-level ethics that concentrate on the practices, institutions, and policies of temporal human life. Mid-level describes the realm between the instantaneous and individualistic micro-level and the universal and global macro level.

The church must become the people of Soweto : Manas Buthelezi’s existential-Christocentric understanding of the church

The aim of this study has been to discern what Manas Buthelezi (1935-), a black South African Lutheran theologian and later also a bishop, regards as the requirements a church has to fulfill in order to be credible in the apartheid society. Buthelezi’s dissertation and several articles written between the years 1968 and 1993 are the sources of this study. Also the lectures held in Heidelberg in 1972 are referred to. Systematic analysis is the method used. The question of the credibility of the church is studied through three concepts that play an important role in Buthelezi’s ecclesiological thought, namely the wholeness of life, incarnation and liberation. The notion of the wholeness of life stems from the African tradition. Buthelezi takes the concept into the Christian church: the church should realize that God is the Creator of all life and Christ the lord of every aspect of human existence. Life is one entity coram Deo. However, the church is not to become the world; solidarity between the two must remain critical as the church is also called to play a prophetic role in the society. The church is in an open relationship with the world. It has a unique message of forgiveness and reconciliation. Nevertheless, the message is not a possession of the church but it is addressed to the whole world. The meaning of incarnation comes close to that of the wholeness of life. Following the example of Christ’s incarnation, the church must become human in the reality of the people. The church in Soweto is to become the people of Soweto, that is, the church must become as vulnerable as the people are. An incarnate church cannot be immune to the oppression that people experience, because the people are the church. The church is therefore bound to suffer. Buthelezi’s theology of the cross is pragmatic: the suffering of the church aims at the liberation of the oppressed. At times the physical presence of the church by the side of the suffering people is the only way to preach the incarnate gospel. In the South Africa of the late 1960s onwards the liberation of the oppressed black people was high on the agenda of Black Theology. As a leader of the early South African Black Theology, Buthelezi is concerned about the racial injustice in his country. He urges the churches to join the struggle against it as one people of God. The notions of liberation and the wholeness of life emerge in Buthelezi’s holistic understanding of liberation that involves the inner liberation of the black spirit and the liberation of the economic, social and political aspects of life. Interpreting Tillich’s correlation method in the South African situation, and also paralleling other liberation theologians, Buthelezi takes the existential situation of the people as the starting point for liberation. The gospel has to respond to the existential questions of people. The church is called to work for the liberation of society but it must also be liberated itself. Buthelezi initiated the LWF statement on the status confessionis in South Africa (1977). In line with the statement, he calls for church unity on the human level. For the unity to be true, it has to be experienced on the grassroots’ level. All the three concepts covered urge the church to come down from any ivory tower and out of any spiritual haven it might hide in. A lot of the credibility of the church derives from the behavior of the people. Buthelezi’s concentration on how the people who constitute the church should live their faith leaves less attention to how God constitutes the church. I have labeled Buthelezi’s understanding of the church existential-Christocentric due to the emphasis he lays on the need of the church to take the existential situation of the people seriously and on the other hand, on Christ as the exemplar for the church.

Living Poetically in the Modern Age : The Situational Aspects of Kierkegaard's Thought

How did Søren Kierkegaard (1813 1855) situate the human subject into historical and social actuality? How did he take into consideration his own situatedness? As key for understanding these questions the research takes the ideal of living poetically that Kierkegaard outlined in his dissertation. In The Concept of Irony (1841) Kierkegaard took up this ideal of the Romantic ironists and made it into an ethical-religious ideal. For him the ideal of living poetically came to mean 1) becoming brought up by God, while 2) assuming ethical-religiously one s role and place in the historical actuality. Through an exegesis of Kierkegaard s texts from 1843 to 1851 it is shown how this ideal governed Kierkegaard s thought and action throughout his work. The analysis of Kierkegaard s ideal of living poetically not only a) shows how the Kierkegaardian subject is situated in its historical context. It also b) sheds light on Kierkegaard s social and political thought, c) helps to understand Kierkegaard s character as a religious thinker, and d) pits his ethical-religious orientation in life against its scientific and commonsense alternatives. The research evaluates the rationality of the way of life championed by Kierkegaard by comparing it with ways of life dominated by reflection and reasoning. It uses Kierkegaard s ideal of living poetically in trying to understand the tensions between religious and unreligious ways of life.

Small State Cultures of Consensus : State Traditions and Consensus-Seeking in the Neo-Corporatist and Neutrality Policies in Post-1945 Austria and Finland

Austria and Finland are persistently referred to as the “success stories” of post-1945 European history. Notwithstanding their different points of departure, in the course of the Cold War both countries portrayed themselves as small and neutral border-states in the world dictated by superpower politics. By the 1970s, both countries frequently ranked at the top end in various international classifications regarding economic development and well-being in society. This trend continues today. The study takes under scrutiny the concept of consensus which figures centrally in the two national narratives of post-1945 success. Given that the two domestic contexts as such only share few direct links with one another and are more obviously different than similar in terms of their geographical location, historical experiences and politico-cultural traditions, the analogies and variations in the anatomies of the post-1945 “cultures of consensus” provide an interesting topic for a historical comparative and cross-national examination. The main research question concerns the identification and analysis of the conceptual and procedural convergence points of the concepts of the state and consensus. The thesis is divided into six main chapters. After the introduction, the second chapter presents the theoretical framework in more detail by focusing on the key concepts of the study – the state and consensus. Chapter two also introduces the comparative historical and cross-national research angles. Chapter three grounds the key concepts of the state and consensus in the historical contexts of Austria and Finland by discussing the state, the nation and democracy in a longer term comparative perspective. The fourth and fifth chapter present case studies on the two policy fields, the “pillars”, upon which the post-1945 Austrian and Finnish cultures of consensus are argued to have rested. Chapter four deals with neo-corporatist features in the economic policy making and chapter five discusses the building up of domestic consensus regarding the key concepts of neutrality policies in the 1950s and 1960s. The study concludes that it was not consensus as such but the strikingly intense preoccupation with the theme of domestic consensus that cross-cut, in a curiously analogous manner, the policy-making processes studied. The main challenge for the post-1945 architects of Austrian and Finnish cultures of consensus was to find strategies and concepts for consensus-building which would be compatible with the principles of democracy. Discussed at the level of procedures, the most important finding of the study concerns the triangular mechanism of coordination, consultation and cooperation that set into motion and facilitated a new type of search for consensus in both post-war societies. In this triangle, the agency of the state was central, though in varying ways. The new conceptions concerning a small state’s position in the Cold War world also prompted cross-nationally perceivable willingness to reconsider inherited concepts and procedures of the state and the nation. At the same time, the ways of understanding the role of the state and its relation to society remained profoundly different in Austria and Finland and this basic difference was in many ways reflected in the concepts and procedures deployed in the search for consensus and management of domestic conflicts. For more detailed information, please consult the author.

EU Multi-level Governance in the Making - The Community Initiative LEADER+ in Finland and Germany

In order to fully understand the process of European integration it is of paramount importance to consider developments at the sub-national and local level. EU integration scholars shifted their attention to the local level only at the beginning of the 1990s with the concept of multi-level governance (MLG). While MLG is the first concept to scrutinise the position of local levels of public administration and other actors within the EU polity, I perceive it as too optimistic in the degree of influence it ascribes to local levels. Thus, learning from and combining MLG with other concepts, such as structural constructivism, helps to reveal some of the hidden aspects of EU integration and paint a more realistic picture of multi-level interaction. This thesis also answers the call for more case studies in order to conceptualise MLG further. After a critical study of theories and concepts of European integration, above all, MLG, I will analyse sub-national and local government in Finland and Germany. I show how the sub-national level and local governments are embedded in the EU s multi-level structure of governance and how, through EU integration, those levels have been empowered but also how their scope of action has partially decreased. After theoretical and institutional contextualisation, I present the results of my empirical study of the EU s Community Initiative LEADER+. LEADER stands for Liaison Entre Actions de Développement de l'Économie Rurale , and aims at improving the economic conditions in Europe s rural areas. I was interested in how different actors construct and shape EU financed rural development, especially in how local actors organised in so-called local action groups (LAGs) cooperate with other administrative units within the LEADER+ administrative chain. I also examined intra-institutional relations within those groups, in order to find out who are the most influential and powerful actors within them. Empirical data on the Finnish and German LAGs was first gathered through a survey, which was then supplemented and completed by interviewing LAG members, LAG-managers, several civil servants from Finnish and German decision-making and managing authorities and a civil servant from the EU Commission. My main argument is that in both Germany and Finland, the Community Initiative LEADER+ offered a space for multi-level interaction and local-level involvement, a space that on the one hand consists of highly motivated people actively contributing to the improvement of the quality of life and economy in Europe s countryside but which is dependent and also restricted by national administrative practices, implementation approaches and cultures on the other. In Finland, the principle of tri-partition (kolmikantaperiaatte) in organising the executive committees of LAGs is very noticeable. In comparison to Germany, for instance, the representation of public administration in those committees is much more limited due to this principle. Furthermore, the mobilisation of local residents and the bringing together of actors from the local area with different social and institutional backgrounds to become an active part of LEADER+ was more successful in Finland than in Germany. Tri-partition as applied in Finland should serve as a model for similar policies in other EU member states. EU integration changed the formal and informal inter-institutional relations linking the different levels of government. The third sector including non-governmental institutions and interest groups gained access to policy-making processes and increasingly interact with government institutions at all levels of public administration. These developments do not necessarily result in the empowering of the local level.

An innovative clustering technique for unsupervized learning in the context of remotely sensed earth resources data analysis

A new clustering technique, based on the concept of immediato neighbourhood, with a novel capability to self-learn the number of clusters expected in the unsupervized environment, has been developed. The method compares favourably with other clustering schemes based on distance measures, both in terms of conceptual innovations and computational economy. Test implementation of the scheme using C-l flight line training sample data in a simulated unsupervized mode has brought out the efficacy of the technique. The technique can easily be implemented as a front end to established pattern classification systems with supervized learning capabilities to derive unified learning systems capable of operating in both supervized and unsupervized environments. This makes the technique an attractive proposition in the context of remotely sensed earth resources data analysis wherein it is essential to have such a unified learning system capability.

Cues in the environment: A design principle for ambient intelligence

The aim of this paper is to propose design principles for ambient intelligence (AmI) environments. The question we are investigating is how these environments can be designed to support a group to be able to carry out common goal-oriented activities. The approach we are taking in answering this question is informed by the concept of collective intelligence (CI). We are applying the concept of CI to AmI as we have found it works well in biological and social systems. Examples from nature demonstrate the power of CI stimulated by implicit cues in the environment. We use these examples to derive design principles for AmI environments. By applying these design principles to a concrete scenario, we are able to propose ways to help decrease environmental pollution within urban areas.

A model for doped-oxide-source diffusion with a chemical reaction at the silicon-silicon dioxide interface

A mathematical model for doped-oxide-source diffusion is proposed. In this model the concept of segregation of impurity at the silicon-silicon dioxide is used and also a constant of “rate limitation” is introduced through a chemical reaction at the interface.

Liquid-liquid critical phenomena. The coexistence curve of n-heptane-acetic anhydride

The coexistence curve of the binary liquid mixture n-heptane-acetic anhydride has been determined by the observation of the transition temperatures of 76 samples over the range of compositions. The functional form of the difference in order parameter, in terms of either the mole fraction or the volume fraction, is consistent with theoretical predictions invoking the concept of universality at critical points. The average value of the order parameter, the diameter of the coexistence curve, shows an anomaly which can be described by either an exponent 1 - a, as predicted by various theories (where a is the critical exponent of the specific heat), or by an exponent 20 (where P is the coexistence curve exponent), as expected when the order parameter used is not the one the diameter of which diverges asymptotically as 1 - a.

Conservation law with the flux function discontinuous in the space variable- II - Convex-concave type fluxes and generalized entropy solutions

We deal with a single conservation law with discontinuous convex-concave type fluxes which arise while considering sign changing flux coefficients. The main difficulty is that a weak solution may not exist as the Rankine-Hugoniot condition at the interface may not be satisfied for certain choice of the initial data. We develop the concept of generalized entropy solutions for such equations by replacing the Rankine-Hugoniot condition by a generalized Rankine-Hugoniot condition. The uniqueness of solutions is shown by proving that the generalized entropy solutions form a contractive semi-group in L-1. Existence follows by showing that a Godunov type finite difference scheme converges to the generalized entropy solution. The scheme is based on solutions of the associated Riemann problem and is neither consistent nor conservative. The analysis developed here enables to treat the cases of fluxes having at most one extrema in the domain of definition completely. Numerical results reporting the performance of the scheme are presented. (C) 2006 Elsevier B.V. All rights reserved.

Structural Insights into the acyl-intermediates of plasmodium falciparum fatty acid synthesis pathway; the mechanism of expansion of acyl carrier protein core

Acyl carrier protein (ACP) plays a central role in fatty acid biosynthesis. However, the molecular machinery that mediates its function is not yet fully understood. Therefore, structural studies were carried out on the acyl-ACP intermediates of Plasmodium falciparum using NMR as a spectroscopic probe. Chemical shift perturbation studies put forth a new picture of the interaction of ACP molecule with the acyl chain, namely, the hydrophobic core can protect up to 12 carbon units, and additional carbons protrude out from the top of the hydrophobic cavity. The latter hypothesis stems from chemical shift changes observed in C-alpha and C-beta of Ser-37 in tetradecanoyl-ACP. C-13, N-15-Double-filtered nuclear Overhauser effect (NOE) spectroscopy experiments further substantiate the concept; in octanoyl (C-8)- and dodecanoyl (C-12)-ACP, a long range NOE is observed within the phosphopantetheine arm, suggesting an arch-like conformation. This NOE is nearly invisible in tetradecanoyl (C-14)-ACP, indicating a change in conformation of the prosthetic group. Furthermore, the present study provides insights into the molecular mechanism of ACP expansion, as revealed from a unique side chain-to-backbone hydrogen bond between two fairly conserved residues, Ile-55 HN and Glu-48 O. The backbone amide of Ile-55 HN reports a pK(a) value for the carboxylate, similar to 1.9 pH units higher than model compound value, suggesting strong electrostatic repulsion between helix II and helix III. Charge-charge repulsion between the helices in combination with thrust from inside due to acyl chain would energetically favor the separation of the two helices. Helix III has fewer structural restraints and, hence, undergoes major conformational change without altering the overall-fold of P. falciparum ACP.