New Approaches to the Total Synthesis of the Bryostatin Antitumour Macrolides

In this Focus Review, we give an overview of various bryostatin total syntheses. We also discuss the synthesis of various bryostatin analogues and their biological activity. Work reviewed includes that of Masamune, Evans, Nishiyama and Yamamura, Hale and Manaviazar, Trost, Wender, Keck, Burke, Thomas, and Krische. Our coverage is primarily for the period 2001–2009, since detailed reviews already exist on bryostatin total synthesis work and biology up to this time.

Seen but never heard: rethinking approaches to researching racism and young children

This paper is concerned with the methodology underlying attempts to understand the nature and impact of racism among young children. In drawing upon data gathered from a year-long ethnographic study of five- and six-year-old children in an English multi-ethnic, inner-city primary school, the paper provides a critique of traditional approaches to the study of racial attitudes among young children. It is argued that such research has been conceived through the articulation of two, inter-related discourses on children and on 'race'; the former couched in traditional socialisation and developmental models of childhood with their tendency to neglect the agency and social competency of young children and the latter being embedded within essentialist notions of 'race' and ethnicity that tend to deny the contingent and context-specific nature of racialised identities. The paper argues that the result of this has been that while children have often been the objects of research they have rarely been the subjects; in other words they are often seen but never heard. The paper argues for the need to move beyond the methodological confines set by these discourses and rethink alternative approaches that begin with the assumption that young children are socially competent. One such approach, drawing upon ethnographic methods and fore-grounding the importance of largely unstructured small group interviews with young children, is illustrated. Through the use of a number of examples, it is shown how this approach can help to emphasise the ability of children as young as five and six to respond to and negotiate their social worlds and more specifically within this the competency with which they are able to appropriate, rework and reproduce a number of discourses on 'race' to make sense of their own social experiences. In doing this the paper also illustrates the way in which it provides a methodology able to draw out and highlight the contradictions, contingency and complexity of racialised identities among young children. Ultimately, it is an approach concerned with placing the children themselves central within the research processes and foregrounding their voices and experiences.

Burkholderia cenocepacia-induced delay of acidification and phagolysosomal fusion in cystic fibrosis transmembrane conductance regulator (CFTR)-defective macrophages

The Burkholderia cepacia complex (Bcc) is a group of opportunistic bacteria chronically infecting the airways of patients with cystic fibrosis (CF). Several laboratories have shown that Bcc members, in particular B. cenocepacia, survive within a membrane-bound vacuole inside phagocytic and epithelial cells. We have previously demonstrated that intracellular B. cenocepacia causes a delay in phagosomal maturation, as revealed by impaired acidification and slow accumulation of the late phagolysosomal marker LAMP-1. In this study, we demonstrate that uninfected cystic fibrosis transmembrane conductance regulator (CFTR)-defective macrophages or normal macrophages treated with a CFTR-specific drug inhibitor display normal acidification. However, after ingestion of B. cenocepacia, acidification and phagolysosomal fusion of the bacteria-containing vacuoles occur in a lower percentage of CFTR-negative macrophages than CFTR-positive cells, suggesting that loss of CFTR function contributes to enhance bacterial intracellular survival. The CFTR-associated phagosomal maturation defect was absent in macrophages exposed to heat-inactivated B. cenocepacia and macrophages infected with a non-CF pathogen such as Salmonella enterica, an intracellular pathogen that once internalized rapidly traffics to acidic compartments that acquire lysosomal markers. These results suggest that not only a defective CFTR but also viable B. cenocepacia are required for the altered trafficking phenotype. We conclude that CFTR may play a role in the mechanism of clearance of the intracellular infection, as we have shown before that B. cenocepacia cells localized to the lysosome lose cell envelope integrity. Therefore, the prolonged maturation arrest of the vacuoles containing B. cenocepacia within cftr(-/-) macrophages could be a contributing factor in the persistence of the bacteria within CF patients.

Burkholderia cenocepacia requires RpoE for growth under stress conditions and delay of phagolysosomal fusion in macrophages

Burkholderia cenocepacia is an opportunistic pathogen causing serious infections in patients with cystic fibrosis. The widespread distribution of this bacterium in the environment suggests that it must adapt to stress to be able to survive. We identified in B. cenocepacia K56-2 a gene predicted to encode RpoE, the extra-cytoplasmic stress response regulator. The rpoE gene is the first gene of a predicted operon encoding proteins homologous to RseA, RseB, MucD and a protein of unknown function. The genomic organization and the co-transcription of these genes were confirmed by PCR and RT-PCR. The mucD and rpoE genes were mutated, giving rise to B. cenocepacia RSF24 and RSF25, respectively. While mutant RSF24 did not demonstrate any growth defects under the conditions tested, RSF25 was compromised for growth under temperature (44 degrees C) and osmotic stress (426 mM NaCl). Expression of RpoE in trans could complement the osmotic growth defect but exacerbated temperature sensitivity in both RSF25 and wild-type K56-2. Inactivation of rpoE altered the bacterial cell surface, as indicated by increased binding of the fluorescent dye calcofluor white and by an altered outer-membrane protein profile. These cell surface changes were restored by complementation with a plasmid encoding rpoE. Macrophage infections in which bacterial colocalization with fluorescent dextran was examined demonstrated that the rpoE mutant could not delay the fusion of B. cenocepacia-containing vacuoles with lysosomes, in contrast to the parental strain K56-2. These data show that B. cenocepacia rpoE is required for bacterial growth under certain stress conditions and for the ability of intracellular bacteria to delay phagolysosomal fusion in macrophages.

The Ties That Bind Us: Ritual, Fusion, and Identification

Most social scientists endorse some version of the claim that participating in collective rituals promotes social cohesion. The systematic testing and evaluation of this claim, however, has been prevented by a lack of precision regarding the nature of both ‘ritual’and ‘social cohesion’ as well as a lack of integration between the theories and findings of the social and evolutionary sciences. By directly addressing these challenges, we argue that a systematic investigation and evaluation of the claim that ritual promotes social cohesion is achievable.

We present a general and testable theory of the relationship between ritual, cohesion, and cooperation that more precisely connects particular elements of ‘ritual,’ such as causal opacity and emotional arousal, to two particular forms
of ‘social cohesion’: group identification and identity fusion. Further, we ground this theory in an evolutionary account of why particular modes of ritual practice would be adaptive for societies with particular resource acquisition strategies. In setting out our conceptual framework we report numerous ongoing investigations that test our hypotheses against data from controlled psychological experiments as well as from theethnographic, archaeological, and historical records.