Molecular investigations into vaginal immunization with HIV gp41 antigenic construct H4A in a quick release solid dosage form

A robust vaginal immune response is considered essential for an effective prophylactic vaccine that prevents transmission of HIV and other sexually acquired diseases. Considerable attention has recently focused on the potential of vaginally administered vaccines as a means to induce such local immunity. However, the potential for vaccination at this site remains in doubt as the vaginal mucosa is generally considered to have low immune inductive potential. In the current study, we explored for the first time the use of a quick release, freeze-dried, solid dosage system for practical vaginal administration of a protein antigen. These solid dosage forms overcome the common problem associated with leakage and poor retention of vaginally administered antigen solutions. Mice were immunized vaginally with H4A, an HIV gp41 envelope based recombinant protein, using quick release, freeze-dried solid rods, and the immune responses compared to a control group immunized via subcutaneous H4A injection. Vaginally immunized mice failed to elicit robust immune responses. Our detailed investigations, involving cytokine analysis, the stability of H4A in mouse cervicovaginal lavage, and elucidation of the state of H4A protein in the immediate-release dosage form, revealed that antigen instability in vaginal fluid, the state of the antigen in the dosage form, and the cytokine profile induced are all likely to have contributed to the observed lack of immunogenicity. These are important factors affecting vaginal immunization and provide a rational basis for explaining the typically poor and variable elicitation of immunity at this site, despite the presence of immune responsive cells within the vaginal mucosae. In future mucosal vaccine studies, a more explicit focus on antigen stability in the dosage form and the immune potential of available antigen-responsive cells is recommended. © 2012 Elsevier Ltd. All rights reserved.

Our Construct or Theirs?

Identity is relational and a construct, and is expressed in a myriad of ways. For example, material culture and its pluralist meanings have been readily manipulated by humans in a prehistoric context in order to construct personal and group identities. Artefacts were often from or reminiscent of far-flung places and were used to demonstrate membership of an (imagined) regional, or European community. Earthworks frequently archive maximum visual impact through elaborate ramparts and entrances with the minimum amount of effort, indicating that the construction of identities were as much in the eye of the perceivor, as of the perceived. Variations in domestic architectural style also demonstrate the malleability of identity, and the prolonged, intermittent use of particular places for specific functions indicates that the identity of place is just as important in our archaeological understanding as the identity of people. By using a wide range of case studies, both temporally and spatially, these thought processes may be explored further and diachronic and geographic patterns in expressions of identity investigated.

Environmental and social supply chain management sustainability practices: construct development and measurement

The purpose of this paper is to conceptualise and operationalise the concept of supply chain management sustainability practices. Based on a multi-stage procedure involving a literature review, expert Q-sort and pre-test process, pilot test and survey of 156 supply chain directors and managers in Ireland, we develop a multidimensional conceptualisation and measure of social and environmental supply chain management sustainability practices. The research findings show theoretically sound constructs based on four underlying sustainable supply chain management practices: monitoring, implementing systems, new product and process development and strategy redefinition. A two-factor model is then identified as the most reliable: comprising process-based and market-based practices.

Total Synthesis of the Antitumor Macrolides, (+)-Brefeldin A and 4‑Epi-Brefeldin A from D‑Glucose: Use of the Padwa Anionic Allenylsulfone [3+2]-Cycloadditive Elimination To Construct Trans-Configured Chiral Cyclopentane Systems

A new synthesis of (+)-brefeldin A is reported via Padwa allenylsulfone [3+2]-cycloadditive elimination. Cycloadduct 13 was initially elaborated into iodide
27, which, following treatment with Zn, gave aldehyde 28 whose C(9) stereocenter was epimerized. Further elaboration into enoate 38 and Julia−Kocienski olefination with 5 subsequently afforded 39, which was deprotected at C(1) and O(15). Yamaguchi macrolactonization of the seco-acid thereafter afforded a macrocycle that underwent O-desilylation and inversion at C(4) to give (+)-brefeldin A following deprotection