Self-condensation of a thiazole-peptide bearing a 21-membered loop into a library of giant macrocycles with multiple orthogonal loops

Tetrapeptide analogue H-[Glu-Ser-Lys(Thz)]-OH, containing a turn-inducing thiazole constraint, was used as a template to produce a 21-membered structurally characterized loop by linking Glu and Lys side chains with a Val-Ile dipeptide. This template was oligomerized in one pot to a library (cyclo-[1](n), n = 2-10) of giant symmetrical macrocycles (up to 120-membered rings), fused to 2-10 appended loops that were carried intact through multiple oligomerization (chain extension) and cyclization (chain terminating) reactions of the template. A three-dimensional solution structure for cyclo-[1](3) shows all three appended loops projecting from the same face of the macrocycle. This is a promising approach to separating pepticle motifs over large distances.

Implantation of a scaffold following bulbectomy induces laminar organization of regenerating olfactory axons

Primary olfactory axons expressing different odorant receptors are interspersed within the olfactory nerve. However, upon reaching the outer nerve fiber layer of the olfactory bulb they defasciculate, sort out, and refasciculate prior to targeting glomeruli in fixed topographic positions. While odorant receptors are crucial for the final targeting of axons to glomeruli, it is unclear what directs the formation of the nerve fiber and glomerular layers of the olfactory bulb. While the olfactory bulb itself may provide instructive cues for the development of these layers, it is also possible that the incoming axons may simply require the presence of a physical scaffold to establish the outer laminar cytoarchitecture. In order to begin to understand the underlying role of the olfactory bulb in development of the outer layers of the olfactory bulb, we physically ablated the olfactory bulbs in OMP-IRES-LacZ and P2-IRES-tau-LacZ neonatal mice and replaced them with artificial biological scaffolds molded into the shape of an olfactory bulb. Regenerating axons projected around the edge of the cranial cavity at the periphery of the artificial scaffold and were able to form an olfactory nerve fiber layer and, to some extent, a glomerular layer. Our results reveal that olfactory axons are able to form rudimentary cytoarchitectonic layers if they are provided with an appropriately shaped biological scaffold. Thus, the olfactory bulb does not appear to provide any tropic substance that either attracts regenerating olfactory axons into the cranial cavity or induces these axons to form a plexus around its outer surface. (c) 2006 Elsevier B.V. All rights reserved.

A political analysis of the PRSP initiative: Social struggles and the organization of persistent relations of inequality

The current global development project appears to be premised on the assumption that underlying political debates over development have been settled. An upshot of this is that development is reduced to the theoretical, ideological and legal framework of a neo-liberal political order. However, implicit, and sometimes explicit, political dynamics of development can be rendered from a perspective that foregrounds social struggles. I offer a political analysis of the PRSP initiative by examining its evolution and implications considered within social and political contexts, and by specific reference to the 'poverty reduction' interventions that emerged in the 1980s. I argue that the PRSP initiative is best understood as the formation of a comprehensive extension of neo-liberal strategic responses that emerged in the 1980s. In this context, I discuss the example of microcredit schemes in relation to the PRSP process and demonstrate the analytical significance of micro-political social relations for political analyses of development. The approach I adopt reveals social struggles as relationally constitutive of formations of a hegemonic development discourse otherwise ostensibly rendered in de-contextualized terms. From the perspective of critical development analysis such struggles are the concrete expressions of the contradictions immanent to the dialectic of development through inequality and immiseration in the (re)production of social power.

The observant mind:self-awareness of attentional status

Visual perception is dependent not only on low-level sensory input but also on high-level cognitive factors such as attention. In this paper, we sought to determine whether attentional processes can be internally monitored for the purpose of enhancing behavioural performance. To do so, we developed a novel paradigm involving an orientation discrimination task in which observers had the freedom to delay target presentation--by any amount required--until they judged their attentional focus to be complete. Our results show that discrimination performance is significantly improved when individuals self-monitor their level of visual attention and respond only when they perceive it to be maximal. Although target delay times varied widely from trial-to-trial (range 860 ms-12.84 s), we show that their distribution is Gaussian when plotted on a reciprocal latency scale. We further show that the neural basis of the delay times for judging attentional status is well explained by a linear rise-to-threshold model. We conclude that attentional mechanisms can be self-monitored for the purpose of enhancing human decision-making processes, and that the neural basis of such processes can be understood in terms of a simple, yet broadly applicable, linear rise-to-threshold model.

Improper organization of the actin cytoskeleton affects protein synthesis at initiation

Although the actin cytoskeleton and the translation machinery are considered to be separate cellular complexes, growing evidence supports overlapping regulation of the two systems. Because of its interaction with actin, the eukaryotic translation elongation factor 1A (eEF1A) is proposed to be a regulator or link between these processes. Using a genetic approach with the yeast Saccharomyces cerevisiae, specific regions of eEF1A responsible for actin interactions and bundling were identified. Five new mutations were identified along one face of eEF1A. Dramatic changes in cell growth, cell morphology, and actin cable and patch formation as well as a unique effect on total translation in strains expressing the F308L or S405P eEF1A mutant form were observed. The translation effects do not correlate with reduced translation elongation but instead include an initiation defect. Biochemical analysis of the eEF1A mutant forms demonstrated reduced actin-bundling activity in vitro. Reduced total translation and/or the accumulation of 80S ribosomes in strains with either a mutation or a null allele of genes encoding actin itself or actin-regulating proteins Tpm1p, Mdm20p, and Bnirp/Bni1p was observed. Our data demonstrate that eEF1A, other actin binding proteins, and actin mutants affect translation initiation through the actin cytoskeleton.

Self measurement of blood pressure:A community survey

New technology means that self-measurement or testing of blood pressure (BP) is potentially available for many people but few data exist on how common it is. A community survey in Birmingham, UK in June 2005 (2931 responders; response rate 54%) of self-testing of BP showed that 9% of a randomly selected population sample had self-tested their own BP. Greater public awareness of BP through self-testing has the potential to improve the detection and treatment of BP but this will only be possible if professionals are aware of it.

Self monitoring of blood glucose in type 2 diabetes:Longitudinal qualitative study of patients' perspectives

Objective: To explore views of patients with type 2 diabetes about self monitoring of blood glucose over time. Design: Longitudinal, qualitative study. Setting: Primary and secondary care settings across Lothian, Scotland. Participants: 18 patients with type 2 diabetes. Main outcome measures: Results from repeat in-depth interviews with patients over four years after clinical diagnosis. Results: Analysis revealed three main themes - the role of health professionals, interpreting readings and managing high values, and the ongoing role of blood glucose self monitoring. Self monitoring decreased over time, and health professionals' behaviour seemed crucial in this: participants interpreted doctors' focus on levels of haemoglobin A1c, and lack of perceived interest in meter readings, as indicating that self monitoring was not worth continuing. Some participants saw readings as a proxy measure of good and bad behaviour - with women especially, chastising themselves when readings were high. Some participants continued to find readings difficult to interpret, with uncertainty about how to respond to high readings. Reassurance and habit were key reasons for continuing. There was little indication that participants were using self monitoring to effect and maintain behaviour change. Conclusions: Clinical uncertainty about the efficacy and role of blood glucose self monitoring in patients with type 2 diabetes is mirrored in patients' own accounts. Patients tended not to act on their self monitoring results, in part because of a lack of education about the appropriate response to readings. Health professionals should be explicit about whether and when such patients should self monitor and how they should interpret and act upon the results, especially high readings.

The limits of open innovation:openness and (quasi-)markets in the organization of innovation

Recent studies have stressed the importance of ‘open innovation’ as a means of enhancing innovation performance. The essence of the open innovation model is to take advantage of external as well as internal knowledge sources in developing and commercialising innovation, so avoiding an excessively narrow internal focus in a key area of corporate activity. Although the external aspect of open innovation is often stressed, another key aspect involves maximising the flow of ideas and knowledge from different sources within the firm, for example through knowledge sharing via the use of cross-functional teams. A fully open innovation approach would therefore combine both aspects i.e. cross-functional teams with boundary-spanning knowledge linkages. This suggests that there should be complementarities between the use cross-functional teams with boundary-spanning knowledge linkages i.e. the returns to implementing open innovation in one innovation activity is should be greater if open innovation is already in place in another innovation activity. However, our findings – based on a large sample of UK and German manufacturing plants – do not support this view. Our results suggest that in practice the benefits envisaged in the open innovation model are not generally achievable by the majority of plants, and that instead the adoption of open innovation across the whole innovation process is likely to reduce innovation outputs. Our results provide some guidance on the type of activities where the adoption of a market-based governance structure such as open innovation may be most valuable. This is likely to be in innovation activities where search is deterministic, activities are separable, and where the required level of knowledge sharing is correspondingly moderate – in other words those activities which are more routinized. For this type of activity market-based governance mechanisms (i.e. open innovation) may well be more efficient than hierarchical governance structures. For other innovation activities where outcomes are more uncertain and unpredictable and the risks of knowledge exchange hazards are greater, quasi-market based governance structures such as open innovation are likely to be subject to rapidly diminishing returns in terms of innovation outputs.

'I felt that I do live in the UK now':international students' self-reports of their English language speaking experiences on a pre-sessional programme

This article focuses on the English language experiences of a group of pre-sessional students, an under-represented group in the literature on language and education. In particular, it investigates the opportunities that such students have to use English outside the classroom, shown to be a key factor in student satisfaction with their study abroad experience. Drawing on data from questionnaires, interviews and on-line diaries, we show that students have a variety of opportunities to use English; however, these opportunities may require students to engage in complex negotiations right from the beginning of their sojourn in the UK. Micro-analysis of the data shows that agency is a key construct in understanding students' representations of their English encounters as they begin their lives in the UK. The article concludes with some suggestions as to how pre-sessional courses may develop students' linguistic and socio-cultural skills in order that they may interact successfully in English outside the classroom. © 2011 Taylor &Francis.

The effect of PEO length on the self-assembly of poly(ethylene oxide)−tetrapeptide conjugates prepared by “click” chemistry

Two series of poly(ethylene oxide)-tetrapeptide conjugates have been prepared using a “Click” reaction between an alkyne-modified tetra(phenylalanine) or tetra(valine) and various azide-terminated poly(ethylene oxide) (PEO) oligomers. Three different PEO precursors were used to prepare these conjugates, with number-average molecular weights of 350, 1200, and 1800 Da. Assembly of mPEO-F4-OEt and mPEO-V4-OEt conjugates was achieved by dialysis of a THF solution of the conjugate against water or by direct aqueous rehydration of a thin film. The PEO length has a profound effect on the outcome of the self-assembly, with the F4 conjugates giving rise to nanotubes, fibers, and wormlike micelles, respectively, as the length of the PEO block is increased. For the V4 series, the propensity to form ß-sheets dominates, and hence, the self-assembled structures are reminiscent of those formed by peptides alone, even at the longer PEO lengths. Thus, this systematic study demonstrates that the self-assembly of PEO-peptides depends on both the nature of the peptides and the relative PEO block length.

The perceptual organization of sine-wave speech under competitive conditions

Speech comprises dynamic and heterogeneous acoustic elements, yet it is heard as a single perceptual stream even when accompanied by other sounds. The relative contributions of grouping “primitives” and of speech-specific grouping factors to the perceptual coherence of speech are unclear, and the acoustical correlates of the latter remain unspecified. The parametric manipulations possible with simplified speech signals, such as sine-wave analogues, make them attractive stimuli to explore these issues. Given that the factors governing perceptual organization are generally revealed only where competition operates, the second-formant competitor (F2C) paradigm was used, in which the listener must resist competition to optimize recognition [Remez et al., Psychol. Rev. 101, 129-156 (1994)]. Three-formant (F1+F2+F3) sine-wave analogues were derived from natural sentences and presented dichotically (one ear = F1+F2C+F3; opposite ear = F2). Different versions of F2C were derived from F2 using separate manipulations of its amplitude and frequency contours. F2Cs with time-varying frequency contours were highly effective competitors, regardless of their amplitude characteristics. In contrast, F2Cs with constant frequency contours were completely ineffective. Competitor efficacy was not due to energetic masking of F3 by F2C. These findings indicate that modulation of the frequency, but not the amplitude, contour is critical for across-formant grouping.

Self-association of calcium-binding protein S100A4 and metastasis

Elevated levels of the calcium-binding protein S100A4 promote metastasis and in carcinoma cells are associated with reduced survival of cancer patients. S100A4 interacts with target proteins that affect a number of activities associated with metastatic cells. However, it is not known how many of these interactions are required for S100A4-promoted metastasis, thus hampering the design of specific inhibitors of S100A4-induced metastasis. Intracellular S100A4 exists as a homodimer through previously identified, well conserved, predominantly hydrophobic key contacts between the subunits. Here it is shown that mutating just one key residue, phenylalanine 72, to alanine is sufficient to reduce the metastasis-promoting activity of S100A4 to 50% that of the wild type protein, and just 2 or 3 specific mutations reduces the metastasis-promoting activity of S100A4 to less than 20% that of the wild type protein. These mutations inhibit the self-association of S100A4 in vivo and reduce markedly the affinity of S100A4 for at least two of its protein targets, a recombinant fragment of non-muscle myosin heavy chain isoform A, and p53. Inhibition of the self-association of S100 proteins might be a novel means of inhibiting their metastasis-promoting activities.