The patent expiry as a major inflection point in a branded Rx drug's life and strategies to counter generic competition - exemplified at Pfizer's blockbuster drug Lipitor in the USA

A large number of expensive, but highly profitable branded prescription drugs will go off-patent in the USA between 2011 and 2015. Their revenues are crucial to fund the immense costs associated with the development of an innovative drug. The rising cost pressure on pharmaceutical stakeholders has increased the demand for more affordable medications, as provided by the branded drug's generic counterpart. Yet, research based incumbents are moving beyond the traditional late lifecycle strategies and deploy more aggressive tactics in order to protect their brands, as seen with Pfizer's Lipitor!. It is doubtful, whether these efforts will help the blockbuster business model to resist current market conditions.

GyrI: a counter-defensive strategy against proteinaceous inhibitors of DNA gyrase

DNA gyrase is the target of two plasmid-encoded toxins CcdB and microcin B17, which ensure plasmid maintenance. These proteins stabilize gyrase-DNA covalent complexes leading to double-strand breaks in the genome. In contrast, the physiological role of chromosomally encoded inhibitor of DNA gyrase (Gyrl) in Escherichia coli is unclear and its mechanism of inhibition has not been established. We demonstrate that the mode of inhibition of GyrI is distinct from all other gyrase inhibitors. It inhibits DNA gyrase prior to, or at the step of, binding of DNA by the enzyme. Gyrl reduces intrinsic as well as toxin-stabilized gyrase-DNA covalent complexes. Furthermore, Gyri reduces microcin B17-mediated double-strand breaks in vivo, imparting protection to the cells against the toxin, substantiating the in vitro results. Thus, Gyrl is an antidote to DNA gyrase-specific proteinaceous poisons encoded by plasmid addiction systems.

An automatable generic strategy for dynamic load balancing in parallel structured mesh CFD codes

Parallel computing is now widely used in numerical simulation, particularly for application codes based on finite difference and finite element methods. A popular and successful technique employed to parallelize such codes onto large distributed memory systems is to partition the mesh into sub-domains that are then allocated to processors. The code then executes in parallel, using the SPMD methodology, with message passing for inter-processor interactions. In order to improve the parallel efficiency of an imbalanced structured mesh CFD code, a new dynamic load balancing (DLB) strategy has been developed in which the processor partition range limits of just one of the partitioned dimensions uses non-coincidental limits, as opposed to coincidental limits. The ‘local’ partition limit change allows greater flexibility in obtaining a balanced load distribution, as the workload increase, or decrease, on a processor is no longer restricted by the ‘global’ (coincidental) limit change. The automatic implementation of this generic DLB strategy within an existing parallel code is presented in this chapter, along with some preliminary results.

A generic strategy for dynamic load balancing of distributed memory parallel computational mechanics using unstructured meshes

A large class of computational problems are characterised by frequent synchronisation, and computational requirements which change as a function of time. When such a problem is solved on a message passing multiprocessor machine [5], the combination of these characteristics leads to system performance which deteriorate in time. As the communication performance of parallel hardware steadily improves so load balance becomes a dominant factor in obtaining high parallel efficiency. Performance can be improved with periodic redistribution of computational load; however, redistribution can sometimes be very costly. We study the issue of deciding when to invoke a global load re-balancing mechanism. Such a decision policy must actively weigh the costs of remapping against the performance benefits, and should be general enough to apply automatically to a wide range of computations. This paper discusses a generic strategy for Dynamic Load Balancing (DLB) in unstructured mesh computational mechanics applications. The strategy is intended to handle varying levels of load changes throughout the run. The major issues involved in a generic dynamic load balancing scheme will be investigated together with techniques to automate the implementation of a dynamic load balancing mechanism within the Computer Aided Parallelisation Tools (CAPTools) environment, which is a semi-automatic tool for parallelisation of mesh based FORTRAN codes.

State building as strategy: An interrogation of NATO's comprehensive approach in Afghanistan between 2006 and 2011

The core of this thesis is the study of NATO’s Comprehensive Approach strategy to state building in Afghanistan between 2006 and 2011. It argues that this strategy sustained operational and tactical practices which were ineffective in responding to the evolved nature of the security problem. The thesis interrogates the Comprehensive Approach along ontological, empirical and epistemological lines and concludes that the failure of the Comprehensive Approach in the specific Afghan case is, in fact, indicative of underlying theoretical and pragmatic flaws which, therefore, generalize the dilemma. The research is pragmatic in nature, employing mixed methods (quantitative and qualitative) concurrently. Qualitative methods include research into primary and secondary literature sources supplemented with the author’s personal experiences in Afghanistan in 2008 and various NATO HQ and Canadian settings. Quantitative research includes an empirical case study focussing on NATO’s Afghan experience and its attempt at state building between 2006 and 2011. This study incorporates a historical review of NATO’s evolutionary involvement in Afghanistan incorporating the subject timeframe; offers an analysis of human development and governance related data mapped to expected outcomes of the Afghan National Development Strategy and NATO’s comprehensive campaign design; and interrogates the Comprehensive Approach strategy by means of an analysis of conceptual, institutional and capability gaps in the context of an integrated investigational framework. The results of the case study leads to an investigation of a series of research questions related to the potential impact of the failure of the Comprehensive Approach for NATO in Afghanistan and the limits of state building as a means of attaining security for the Alliance.

Growing research where economies grow: essays on strategy and international expansion of companies from emerging countries

In recent years, emerging countries have assumed an increasingly prominent position in the world economy, as growth has picked up in these countries and slowed in developed economies. Two related phenomena, among others, can be associated with this growth: emerging countries were less affected by the 2008-2009 global economic recession; and they increased their participation in foreign direct investment, both inflows and outflows. This doctoral dissertation contributes to research on firms from emerging countries through four independent papers. The first group of two papers examines firm strategy in recessionary moments and uses Brazil, one of the largest emerging countries, as setting for the investigation. Data were collected through a survey on Brazilian firms referring to the 2008-2009 global recession, and 17 hypotheses were tested using structural equation modeling based on partial least squares. Paper 1 offered an integrative model linking RBV to literatures on entrepreneurship, improvisation, and flexibility to indicate the characteristics and capabilities that allow a firm to have superior performance in recessions. We found that firms that pre-recession have a propensity to recognize opportunities and improvisation capabilities for fast and creative actions have superior performance in recessions. We also found that entrepreneurial orientation and flexibility have indirect effects. Paper 2 built on business cycle literature to study which strategies - pro-cyclical or counter-cyclical – enable superior performance in recessions. We found that while most firms pro-cyclically reduce costs and investments during recessions, a counter-cyclical strategy of investing in opportunities created by changes in the environment enables superior performance. Most successful are firms with a propensity to recognize opportunities, entrepreneurial orientation to invest, and flexibility to efficiently implement these investments. The second group of two papers investigated international expansion of multinational enterprises, particularly the use of distance for their location decisions. Paper 3 proposed a conceptual framework to examine circumstances under which distance is less important for international location decisions, taking the new perspective of economic institutional distance as theoretical foundation. The framework indicated that the general preference for low-distance countries is lower: (1) when the company is state owned, rather than private owned; (2) when its internationalization motives are asset, resource, or efficiency seeking, as opposed to market seeking; and (3) when internationalization occurred after globalization and the advent of new technologies. Paper 4 compared five concurrent perspectives of distance and indicated their suitability to the study of various issues based on industry, ownership, and type, motive, and timing of internationalization. The paper also proposed that distance represents the disadvantages of host countries for international location decisions; as such, it should be used in conjunction with factors that represent host country attractiveness, or advantages as international locations. In conjunction, papers 3 and 4 provided additional, alternative explanations for the mixed empirical results of current research on distance. Moreover, the studies shed light into the discussion of differences between multinational enterprises from emerging countries versus those from advanced countries.

Suppression of gene silencing: A general strategy used by diverse DNA and RNA viruses of plants

In transgenic and nontransgenic plants, viruses are both initiators and targets of a defense mechanism that is similar to posttranscriptional gene silencing (PTGS). Recently, it was found that potyviruses and cucumoviruses encode pathogenicity determinants that suppress this defense mechanism. Here, we test diverse virus types for the ability to suppress PTGS. Nicotiana benthamiana exhibiting PTGS of a green fluorescent protein transgene were infected with a range of unrelated viruses and various potato virus X vectors producing viral pathogenicity factors. Upon infection, suppression of PTGS was assessed in planta through reactivation of green fluorescence and confirmed by molecular analysis. These experiments led to the identification of three suppressors of PTGS and showed that suppression of PTGS is widely used as a counter-defense strategy by DNA and RNA viruses. However, the spatial pattern and degree of suppression varied extensively between viruses. At one extreme, there are viruses that suppress in all tissues of all infected leaves, whereas others are able to suppress only in the veins of new emerging leaves. This variation existed even between closely related members of the potexvirus group. Collectively, these results suggest that virus-encoded suppressors of gene silencing have distinct modes of action, are targeted against distinct components of the host gene-silencing machinery, and that there is dynamic evolution of the host and viral components associated with the gene-silencing mechanism.

New challenges for the EU internal security strategy

In recent years, the EU and its member states have experienced a number of changes, as well as challenges, in the areas of politics, economics, security and law. As these areas are interconnected, changes and challenges to any of them have implications for the others, as well as implications for the populations and institutions of the EU or those coming into contact with its international power and influence. This edited collection focuses primarily on security and law, particularly the EU’s internal security strategy. The EU’s Internal Security Strategy, adopted by the Spanish presidency early in 2010, followed the Lisbon Treaty in 2009, building on previous developments within the EU in the Area of Freedom Security and Justice (AFSJ) policy. The focus of the EU Internal Security Strategy is to prevent and combat “serious and organised crime, terrorism and cybercrime, in strengthening the management of our external borders and in building resilience to natural and man-made disasters”. The Internal Security strategy intersects and overlaps with the European Union’s Counter-terrorism strategy, the Strategy for the External Dimension of JHA, and the EU’s Security Strategy. The role of and interaction between these strategies, their supplementing documents, and their implications for crime, victims, the law, political relations, democracy and human rights, form the backdrop against which the chapters in this collection are written. Building on original research by its contributors, this collection comprises work by authors from a wide variety of academic and professional areas and perspectives, as well as different countries, on a variety of areas and issues related to or raised by the EU’s Internal Security Strategy, from intelligence-led policing to human trafficking and port security. This book examines, from a wide variety of disciplinary perspectives including law, geography, politics and practice, both this further refinement of existing internal provisions on cross-border crime, and the increasing external relations of the EU in the AFSJ.

An investigation into resistance practices at an SME consultancy

Purpose Prior research emphasizes that organizational founders have a good deal of influence in organizational development and, where ICTs are involved, a generic strategy is usually deployed by managers in order to deal with any resistance that might occur. Cognisant of this, we investigated the role played by a Managing Director of an SME consultancy in an ICT project associated with organizational development. Design/methodology/approach This study is based on an ethnography of a ICT related change management initiative which, theoretically, takes into account though from the social shaping of technology – speifically the idea that technologies in their broadest sense are subject to ongoing work beyond the design stage. Findings We argue that Markus’ Interaction Theory of resistance still has relevance today and we extend it by emphasizing the problem of homogenizing users and downplaying their ability to appropriate resistance strategies in situ. Research limitations/implications Our study is based upon one group of individual’s experiences. Further case studies of resistance success are required which further highlight how such this is achieved and why. Practical implications Those engaged with organisational development projects need to be better educated as to the reasons for resistance, particularly positive ones, and the methods by which this might take place. Originality/value This study conceptualises strategies for ‘overcoming’ resistance as managerial technologies. Conceptualising them in this way, shows the deployement of such technologies to be a complicated and active process where the audience for such things are involved in how they are received and appropriated to suite differing agendas.

Cool Rationalities and Hot Air: A Rhetorical Approach to Understanding Debates on Renewable Energy.

A key obstacle to the wide-scale development of renewable energy is that public acceptability of wind energy cannot be taken for granted when wind energy moves from abstract support to local implementation. Drawing on a case study of opposition to the siting of a proposed off-shore wind farm in Northern Ireland, we offer a rhetorical analysis of a series of representative documents drawn from government, media, pro- and anti-wind energy sources, which identifies and interprets a number of discourses of objection and support. The analysis indicates that the key issue in terms of the transition to a renewable energy economy has little to do with the technology itself. Understanding the different nuances of pro- and anti-wind energy discourses highlights the importance of thinking about new ways of looking at these conflicts. These include adopting a “conflict resolution” approach and “upstreaming” public involvement in the decision-making process and also the counter-productive strategy of assuming that objection is based on ignorance (which can be solved by information) or NIMBY thinking (which can be solved by moral arguments about overcoming “free riders”).

Preliminary Overview of the Economies of Latin America and the Caribbean 2010

Includes bibliography

Cost Management Practices and Strategic Perspectives: a study in the construction industry of the State of Parana

The purpose of this paper is to investigate the cost management practices of building industry companies of Parana that follow the typology of Porter's strategies. The sample comprises member companies of the Association of Construction Industries of the State of Parana (PR-SINDUSCON) operating in the segment of residential buildings. The data were collected by means of questionnaires sent to 317 SINDUSCON members. 69 were returned and 54 used for our research. Exploratory Factorial Analysis of the data allowed us to identify two groups of cost management practices. Analyses suggest equality between the adopted cost management practices and the Cost Control Planning (CCP) practices among the companies of the Group 1, regardless of the generic strategy adopted. The companies of the Group 2 that adopted the differentiation strategy seem to use mainly the ACR cost management practice. Our findings differ from those obtained by Chenhall insofar as companies that adopt low cost strategies tend to use managerial controls focused on cost control and rigid budgetary controls.

Geminivirus Rep Protein Interferes with the Plant DNA Methylation Machinery and Modifies the Host Epigenome

The apparent simplicity of viruses hides the complexity of their interactions with their hosts. Viruses are masters at circumventing host defenses and manipulating the cellular environment for their own benefit. The replication of the largest known family of single-stranded DNA viruses, Geminiviridae, is impaired by DNA methylation and Arabidopsis mutants affected in cytosine methylation are hypersusceptible to geminivirus infection. This implies that plants might use methylation as a defense against geminiviruses and that the viral genome is a target for plant DNA methyltransferases. We have found a novel counter-defense strategy used by geminiviruses, that reduces the expression of the plant maintenance DNA methyltransferases, MET1 and CMT3, in both, locally and systemically infected tissues. Furthermore, we demonstrated that the virus-mediated repression of these two maintenance DNA methyltransferases is widely spread among different geminivirus species. Additionally, we identified Rep as the geminiviral protein responsible for the repression of MET1 and CMT3, and another viral protein, C4, as an ancillary player in MET1 downregulation. The presence of Rep, suppresses TGS of an Arabidopsis transgene and of host loci whose expression is strongly controlled by CG methylation. Bisulfite sequencing analyses showed that the expression of Rep caused a substantial reduction in the levels of DNA methylation at CG sites. Our findings suggest that Rep, the only viral protein essential for geminiviral replication, displays TGS suppressor activity through a mechanism distinct from the one thus far described for geminiviruses.

Diseño de una estrategia que posicione a Transporte Comercial la Estrella SAS como una empresa mas competitiva en el sector transporte

La elaboración de este proyecto busca explicar los factores que actualmente afectan al sector transporte (Costos elevados, sobreoferta, chatarrización, fletes elevados, hacinamiento, Etc.) y, a partir de esto, diseñar estrategias que le permitan a la empresa de transporte: TRANSPORTE COMERCIAL LA ESTRELLA SAS, convertirse en una empresa más competitiva dentro del sector en el que se desenvuelve. El planteamiento estratégico estudiado se fundamenta en el modelo de las 5 fuerzas de Michael Porter, y se obtiene como resultado una estrategia genérica de diferenciación, cuyo objetivo es la implementación de un sistema de carga consolidada, el cual le permitirá a la compañía aumentar sus ingresos y abarcar una mayor cantidad de clientes. Por último, se plantea un análisis cuantitativo de cada una de las fuerzas de Porter, mediante el cual se pueden tomar decisiones con respecto a cómo está funcionando la compañía, sus fortalezas y sus debilidades.