A cassette ligation strategy with thioether replacement of three Gly-Gly peptide bonds: Total chemical synthesis of the 101 residue protein early pregnancy factor [psi(CH2S)(28-29,56-57,76-77)]

The 101 residue protein early pregnancy factor (EPF), also known as human chaperonin 10, was synthesized from four functionalized, but unprotected, peptide segments by a sequential thioether ligation strategy. The approach exploits the differential reactivity of a peptide-NHCH2CH2SH thiolate with XCH2CO-peptides, where X = Cl or I/Br. Initial model studies with short functionalized (but unprotected) peptides showed a significantly faster reaction of a peptide-NHCH2CH2SH thiolate with a BrCH2CO-peptide than with a CICH2CO-peptide, where thiolate displacement of the halide leads to chemoselective formation of a thioether surrogate for the Gly-Gly peptide bond. This rate difference was used as the basis of a novel sequential ligation approach to the synthesis of large polypeptide chains. Thus, ligation of a model bifunctional N-alpha-chloroacetyl, C-terminal thiolated peptide with a second N-alpha-bromoacetyl peptide demonstrated chemoselective bromide displacement by the thiol group. Further investigations showed that the relatively unreactive N-alpha-chloroacetyl peptides could be activated by halide exchange using saturated KI solutions to yield the highly reactive No-iodoacetyl peptides. These findings were used to formulate a sequential thioether ligation strategy for the synthesis of EPF, a 101 amino acid protein containing three Gly-Gly sites approximately equidistantly spaced within the peptide chain. Four peptide segments or cassettes comprising the EPF protein sequence (BrAc-[EPF 78-101] 12, ClAc-[EPF 58-75]-[NHCH2CH2SH] 13, ClAc-[EPF 30-55]-[NHCH2CH2SH] 14, and Ac-[EPF 1-27]-[NHCH2CH2SH] 15) of EPF were synthesized in high yield and purity using Boc SPPS chemistry. In the stepwise sequential ligation strategy, reaction of peptides 12 and 13 was followed by conversion of the N-terminal chloroacetyl functional group to an iodoacetyl, thus activating the product peptide for further ligation with peptide 14. The process of ligation followed by iodoacetyl activation was repeated to yield an analogue of EPF (EPF psi(CH2S)(28-29,56-57,76-77)) 19 in 19% overall yield.

Exploring the role of market learning capability in competitive strategy

It has been argued that a firm's capacity to learn from its market is a source of both innovation and competitive advantage. However, past research has failed to conceptualize market-focused learning activity as a capability having the potential to contribute to competitive advantage. Prior innovation research has been biased toward technological innovation. However, there is evidence to suggest that both technological and non-technological innovations contribute to competitive advantage reflecting the need for a broader conceptualization of the innovation construct. Past research has also overlooked the critical role of entrepreneurship in the capability building process. Competitive advantage has been predominantly measured in terms of financial indicators of performance. In general, the literature reflects the need for comprehensive measures of organizational innovation and competitive advantage. This paper examines the role of market-focused learning capability in organizational innovation-based competitive strategy. The paper contributes to the strategic marketing theory by developing and refining measures of entrepreneurship, market-focused learning capability, organizational innovation and sustained competitive advantage, testing relationships among these constructs.

Pseudo-randomness of round-off errors in discretized linear maps on the plane

We analyze the sequences of round-off errors of the orbits of a discretized planar rotation, from a probabilistic angle. It was shown [Bosio & Vivaldi, 2000] that for a dense set of parameters, the discretized map can be embedded into an expanding p-adic dynamical system, which serves as a source of deterministic randomness. For each parameter value, these systems can generate infinitely many distinct pseudo-random sequences over a finite alphabet, whose average period is conjectured to grow exponentially with the bit-length of the initial condition (the seed). We study some properties of these symbolic sequences, deriving a central limit theorem for the deviations between round-off and exact orbits, and obtain bounds concerning repetitions of words. We also explore some asymptotic problems computationally, verifying, among other things, that the occurrence of words of a given length is consistent with that of an abstract Bernoulli sequence.

Rio Branco, grand strategy and naval power

This article addresses Baron of Rio Branco's grand strategy and the role played by the naval reorganization program (1904-1910) in this context. The ensuing case study determined the domestic and international constraints that affected the program, as well as the worldview of the patron of Brazilian diplomacy regarding military power's instrumentality to foreign policy.

Swords into ploughshares? China's Soft Power strategy in Southeast Asia and its challenges1

Since the 1990s, alongside China's economic growth, the international community has fostered a general anxiety towards a "China threat." In order to relieve itself from suspicion, China adopted the dual strategies of "harmonious worldview" and "good neighbor policy." The strategies led to the use of soft power in China's foreign policy. China aimed to reduce security concerns implied by the threat theory by supporting an image that caters to international peace and development. This article seeks to explain how China achieves its interests in Southeast Asia through the use of soft power. The authors address the concepts of "harmonious worldview" and "good neighbor policy" and how the twin strategies and soft power have shaped China's foreign policy in recent years. This article aims to provide insights into China's policy options in Southeast Asia in the near future.

"Procedural Strategy" by Carlos Pinto de Abreu, lawyer

Como Carlos Pinto de Abreu refere e bem, no seu livro e no seminário, entre juízes, partes ou sujeitos processuais, advogados ou solicitadores, magistrados do Ministério Público ou testemunhas, peritos ou funcionários, encontramos “pessoas que podem ser mais ou menos sérias”, por sinal “motivadas por outros interesses que não os de servir a Verdade e a Justiça”; Abstract: Carlos Pinto de Abreu as regards and well in his book and seminar, between judges, parties or procedural subject, lawyers or solicitors, prosecutors and witnesses, experts or officials, found "people who may be more or less serious" , by the way "motivated by interests other than those serving the Truth and Justice".