Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo‐biosynthetic approach using an AHBA(?) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence‐labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell‐based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP‐binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets.     

The project-oriented organization and its contribution to innovation

This paper presents a new conceptualization of the project-oriented organization. The project-oriented organization is conceptualized as an entrepreneurial, future- and stakeholder-oriented innovating organization, which uses projects as temporary, task-focused organizations, to define, develop, and implement its strategies, to transform its structure, culture and behavior, and to define and develop new products, services, and business models. The concept of the project-oriented organization consists of the three segments (1) values, (2) structures, and (3) people. For each segment three important areas are described, which characterize a project-oriented organization. The model is theoretically based on a wide spectrum of management disciplines: (1) The orientations in the value segment have been developed in entrepreneurship, strategic management and technology and innovation management; (2) The foundations for the design of the socio-technical artefacts in the structure segment of derived from organizational design, planning and controlling, and ICT systems theory; (3) The foundations for the elements of the human side come from organizational behavior, human resource management, and knowledge management theories. Our model shows a clear linkage to these theories, references key articles, and gives special consideration to empirical studies in the realm of projects, programs, project portfolios, and project-based or project-oriented organizations. Thus, our assumption that the elements of our model are supposed to increase project success, innovation success, and business success is based on empirical evidence.     

A variable-depth search algorithm for the recursive bipartitioning of signal flow graphs

We discuss the use of local search techniques for mapping video algorithms onto programmable high-performance video signal processors. The mapping problem is very complex due to many constraints that need to be satisfied in order to obtain a feasible solution. The complexity is reduced by decomposing the mapping problem into three subproblems, namely delay management, partitioning, and scheduling. We present the partitioning problem and the representation of video algorithms by signal flow graphs. Furthermore, we propose a solution strategy that is based on recursive bipartitioning of these graphs. The bipartitions are generated using a variable-depth search algorithm. The results demonstrate that the frequently cited flexibility of local search techniques can be successfully exploited in handling complicated problems.     

Strategy and Structure in Developing Countries: Business Groups as an Evolutionary Response to Opportunities for Unrelated Diversification

Business groups are a common type of enterprise in lat-developingcountries, yet their existence appears to be at odds with extanttheory in strategic management. Drawing on Schumpeter, we suggestthat entrepreneurs in late development build a business groupby engaging in a distinct type of innovation. Instead of creatingnew products they leverage local and foreign contacts to combineforeign technology and local markets. The capability to leveragecontacts is broadly applicable to diverse industries, creatingincentives for unrelated diversification. We make two main arguments.First, the main (initial) cause for the creation of businessgroups can be traced to the selection environment at the beginningof economic development in late-industrializing countries, whenthe ability to use contacts outweighs other capabilities inimportance. Expanding businesses based on this core capability(which is different from the one underlying business successin developed countries) leads to unrelated diversification interms of products and technological and organizational capabilities,as well as a loose organizational structure. Secondly, we suggestthat the selection environment in late-industrializing countrieschanges systematically over time, altering the reasons underlyingthe continued existence and creation of business groups. Weformulate several testable propositions on the evolution ofbusiness groups predicting patterns of diversification and organizationalstructure over time. We illustrate our theory with two casestudies of business groups in lat-developing countries.     

FLIP: Prototyping multi-robot systems

The main objective of this article is to promote the use of inexpensive and realistic prototypes to verify the applicability of state-of-the-art technologies in the area of mobile robotics and intelligent manufacturing systems. We propose a toy prototype based on a LEGO^® Mindstorms™ RCX brick extended with a PDA and wireless LAN. We describe and evaluate the application of an agent-oriented approach for a prototype of an autonomous transportation system. This transportation system is an integral part of the FLIP project in which intelligent collaboration during transportation and processing of LEGO^® bricks is investigated.     

Design,Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents

7‐Chloroquinoline‐based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine‐sensitive (CQS) NF54 (IC₅₀: 4.2 nm ) and chloroquine‐resistant (CQR) Dd2 (IC₅₀: 33.7 nm ) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β‐hematin formation in an NP‐40 detergent assay, with IC₅₀ values ranging between 10.4 and 19.2 μm .