Editorial overview: Folding and binding: In silico, in vitro and in cellula

The essence of any biological processes relies on the conformational states of macromolecules and their interactions. It comes therefore with no surprises that the study of folding and binding has been centre stage since the birth of structural biology. In this context, the collaborative efforts of experimen- talists and theoreticians have tremendously increased our current knowl- edge on macromolecular structure and recognition. Nevertheless, several challenges and open questions are still present and a multidisciplinary approach would appear the most appropriate means to shed light onto the mechanisms of folding and binding to the highest level of detail. This thematic issue brings together a collection of reviews describing our current understanding of folding and binding, looking at these fundamental pro- blems from a wide perspective ranging from the single molecule to the complexity of the living cell, drawing on approaches that span from compu- tational (in silico), to the test tube (in vitro) and cell cultures (in cellula)

Radix Sorting With No Extra Space

It is well known that n integers in the range [1,n^c] can be sorted in O(n) time in the RAM model using radix sorting. More generally, integers in any range [1,U] can be sorted in O(n sqrt{loglog n}) time. However, these algorithms use O(n) words of extra memory. Is this necessary? We present a simple, stable, integer sorting algorithm for words of size O(log n), which works in O(n) time and uses only O(1) words of extra memory on a RAM model. This is the integer sorting case most useful in practice. We extend this result with same bounds to the case when the keys are read-only, which is of theoretical interest. Another interesting question is the case of arbitrary c. Here we present a black-box transformation from any RAM sorting algorithm to a sorting algorithm which uses only O(1) extra space and has the same running time. This settles the complexity of in-place sorting in terms of the complexity of sorting.Comment: Full version of paper accepted to ESA 2007. (17 pages

InSiDDe: A server for designing artificial disordered proteins

InSiDDe (In Silico Disorder Design) is a program for the in silico design of intrinsically disordered proteins of desired length and disorder probability. The latter is assessed using IUPred and spans values ranging from 0.55 to 0.95 with 0.05 increments. One to ten artificial sequences per query, each made of 50 to 200 residues, can be generated by InSiDDe. We describe the rationale used to set up InSiDDe and show that an artificial sequence of 100 residues with an IUPred score of 0.6 designed by InSiDDe could be recombinantly expressed in E. coli at high levels without degradation when fused to a natural molecular recognition element (MoRE). In addition, the artificial fusion protein exhibited the expected behavior in terms of binding modulation of the specific partner recognized by the MoRE. To the best of our knowledge, InSiDDe is the first publicly available software for the design of intrinsically disordered protein (IDP) sequences. InSiDDE is publicly available online

Problems Affecting Labor

Much experimental work has been devoted in comparing the folding behavior of proteins sharing the same fold but different sequence. The recent design of proteins displaying very high sequence identities but different 3D structure allows the unique opportunity to address the protein-folding problem from a complementary perspective. Here we explored by ℙ-value analysis the pathways of folding of three different heteromorphic pairs, displaying increasingly high-sequence identity (namely, 30%, 77%, and 88%), but different structures called G A (a 3-α helix fold) and G B (an α/β fold). The analysis, based on 132 site-directed mutants, is fully consistent with the idea that protein topology is committed very early along the pathway of folding. Furthermore, data reveals that when folding approaches a perfect two-state scenario, as in the case of the G A domains, the structural features of the transition state appear very robust to changes in sequence composition. On the other hand, when folding is more complex and multistate, as for the G Bs, there are alternative nuclei or accessible pathways that can be alternatively stabilized by altering the primary structure. The implications of our results in the light of previous work on the folding of different members belonging to the same protein family are discussed

Characterization of an emergent clone of enteroinvasive Escherichia coli circulating in Europe

Enteroinvasive Escherichia coli (EIEC) cause intestinal illness indistinguishable from that caused by Shigella, mainly in developing countries. Recently an upsurge of cases of EIEC infections has been observed in Europe, with two large outbreaks occurring in Italy and in the United Kingdom. We have characterized phenotypically and genotypically the strains responsible for these epidemics together with an additional isolate from a sporadic case isolated in Spain. The three isolates belonged to the same rare serotype O96:H19 and were of sequence type ST-99, never reported before in EIEC or Shigella. The EIEC strains investigated possessed all the virulence genes harboured on the large plasmid conferring the invasive phenotype to EIEC and Shigella while showing only some of the known chromosomal virulence genes and none of the described pathoadaptative mutations. At the same time, they displayed motility abilities and biochemical requirements resembling more closely those of the non-pathogenic E. coli rather than the EIEC and Shigella strains used as reference. Our observations suggested that the O96:H19 strains belong to an emerging EIEC clone, which could be the result of a recent event of acquisition of the invasion plasmid by commensal E. coli

Process issues in alliance management: A panel discussion.

The purpose in this series of papers is to examine different perspectives on the evolution of the process of collaboration and the management challenges therein by focusing on a single case experience. The literature on alliance and collaboration has grown immensely in the last few years. Much attention has been given to the economic rationale for intermediate organizational forms, the so-called «swollen middle» (Hennart, 1993) that lies between market and hierarchical solutions, and to the conditions under which such structures are optimal (Hennart, 1988; Balakrishnan & Koza, 1993; Buckley and Casson, 1996). More recently, there has been a virtual explosion in the treatment of the managerial challenges involved in inter-firm collaboration, ranging from issues of negotiation and conflict resolution to the role of strategic intent or prior experience, as well as numerous attempts to conceptualize and measure that most ephemeral and over-abused concept, trust. The initial paper in the series introduces the specifics of the case on which our discussion is based, and presents a view on the role that perceptions of efficiency and equity between the partners within a relationship have on the evolution of their collaboration. As elaborated in the paper, efficiency perceptions refer to the partners' views on the potential for value creation within the alliance, relative to other organizational choices. Equity perceptions relate to the expected balance between the partners' relative costs and benefits in the alliance, that is, the potential for fairness in value appropriation. The paper starts by summarizing the facts of a failed international joint venture, and chronicles the process of its disintegration through a series of events in its 3-year history. The concepts of efficiency and equity are then defined and formalized. Next, the authors provide their own interpretation of the case data and propose a structure for the analysis of the inter-partner relationship. Finally, they offer a model of the evolution of collaboration that is driven by the maintenance of relational quality among the partners, including the accommodation of changes in both the business environment and the strategies of the partners over time. The three other papers in the series elaborate on this interpretation and bring a broader set of concerns derived from each author's own research trajectory. Since two of these were responsible for earlier models on which the initial case analysis was based, they have a unique opportunity to revisit their original thinking and reinterpret it in view of the facts presented. They take a more dynamic view and incorporate more recent theoretical insights from the management process literature to the collaborative process. The last paper ventures beyond the dyadic framework of the original analysis to examine the lessons that can be drawn for broader networks of collaborative alliances. A final section on conclusions summarizes the arguments and suggests where there may be convergence, as well as proposing new avenues for research.alliances; evolution process collaboration; management challenges;