title: A structural basis for the reduced toxicity of dinophysistoxin-2

authors: Huhn, Jason

subjects: dinophysistoxin

abstract: Okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) are algal toxins that can accumulate in shellfish and cause diarrhetic shellfish poisoning. Recent studies indicate that DTX-2 is about half as toxic and has about half the affinity for protein phosphatase 2A (PP2A) as OA. NMR structural studies showed that DTX-1 possessed an equatorial 35-methyl group but that DTX-2 had an axial 35-methyl group. Molecular modeling studies indicated that an axial 35-methyl could exhibit unfavorable interactions in the PP2A binding site, and this has been proposed as the reason for the reduced toxicity of DTX-2. Statistical analyses of published data indicate that the affinity of PP2A for DTX-1 is 1.6-fold higher, and for DTX-2 is 2-fold lower, than for OA. We obtained X-ray crystal structures of DTX-1 and DTX-2 bound to PP2A. The crystal structures independently confirm the C-35 stereochemistries determined in the earlier NMR study. The structure for the DTX-1 complex was virtually identical to that of the OA-PP2A complex, except for the presence of the equatorial 35-methyl on the ligand. The favorable placement of the equatorial 35-methyl group of DTX-1 against the aromatic π-bonds of His191 may account for the increased affinity of PP2A toward DTX-1. In contrast, the axial 35-methyl of DTX-2 caused the side chain of His191 to rotate 140° so that it pointed toward the solvent, thereby opening one end of the hydrophobic binding cage. This rearrangement to accommodate the unfavorable interaction from the axial 35-methyl of DTX-2 reduces the binding energy and appears to be responsible for the reduced affinity of PP2A for DTX-2. These results highlight the potential of molecular modeling studies for understanding the relative toxicity of analogues once the binding site at the molecular target has been properly characterized.

text: A structural basis for the reduced toxicity of dinophysistoxin-2 Okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) are algal toxins that can accumulate in shellfish and cause diarrhetic shellfish poisoning. Recent studies indicate that DTX-2 is about half as toxic and has about half the affinity for protein phosphatase 2A (PP2A) as OA. NMR structural studies showed that DTX-1 possessed an equatorial 35-methyl group but that DTX-2 had an axial 35-methyl group. Molecular modeling studies indicated that an axial 35-methyl could exhibit unfavorable interactions in the PP2A binding site, and this has been proposed as the reason for the reduced toxicity of DTX-2. Statistical analyses of published data indicate that the affinity of PP2A for DTX-1 is 1.6-fold higher, and for DTX-2 is 2-fold lower, than for OA. We obtained X-ray crystal structures of DTX-1 and DTX-2 bound to PP2A. The crystal structures independently confirm the C-35 stereochemistries determined in the earlier NMR study. The structure for the DTX-1 complex was virtually identical to that of the OA-PP2A complex, except for the presence of the equatorial 35-methyl on the ligand. The favorable placement of the equatorial 35-methyl group of DTX-1 against the aromatic π-bonds of His191 may account for the increased affinity of PP2A toward DTX-1. In contrast, the axial 35-methyl of DTX-2 caused the side chain of His191 to rotate 140° so that it pointed toward the solvent, thereby opening one end of the hydrophobic binding cage. This rearrangement to accommodate the unfavorable interaction from the axial 35-methyl of DTX-2 reduces the binding energy and appears to be responsible for the reduced affinity of PP2A for DTX-2. These results highlight the potential of molecular modeling studies for understanding the relative toxicity of analogues once the binding site at the molecular target has been properly characterized.

year: 2009

title: Health literacy as a complex practice

authors: Hunter, Judy

abstract: As attention to health literacy grows as an area for policy intervention, policy discourse continues to draw on skills deficit and patient compliance, buttressed by the dominant political discourse of individual responsibility. But for patients, the health domain is interwoven with linguistic challenges, significant affective issues, underlying cultural dimensions, political and economic exigencies, variable access to resources, and cognitive and situated complexity. From these perspectives, this article reports on findings of an ongoing study of health literacy demands in the Midlands region of the North Island of New Zealand, an area of high ethnic and socio-economic diversity. The study focuses on patients with diabetes and cardiovascular disease - two chronic areas strongly associated with ‘failure to care’ and identifed as having reached epidemic proportions. It analyses work to date: health professionals’ conceptions of and responses to perceived patients’ health literacy needs, and health information documents for patients. Implications of the study support the need for improvement in language and literacy skills among patients, but also the recognition of complexity and a collective responsibility for effective health communication.

text: Health literacy as a complex practice As attention to health literacy grows as an area for policy intervention, policy discourse continues to draw on skills deficit and patient compliance, buttressed by the dominant political discourse of individual responsibility. But for patients, the health domain is interwoven with linguistic challenges, significant affective issues, underlying cultural dimensions, political and economic exigencies, variable access to resources, and cognitive and situated complexity. From these perspectives, this article reports on findings of an ongoing study of health literacy demands in the Midlands region of the North Island of New Zealand, an area of high ethnic and socio-economic diversity. The study focuses on patients with diabetes and cardiovascular disease - two chronic areas strongly associated with ‘failure to care’ and identifed as having reached epidemic proportions. It analyses work to date: health professionals’ conceptions of and responses to perceived patients’ health literacy needs, and health information documents for patients. Implications of the study support the need for improvement in language and literacy skills among patients, but also the recognition of complexity and a collective responsibility for effective health communication.

year: 2012

title: Strategic framing: indigenous culture, identity, and politics

authors: Schoenberger-Orgad, Michèle Anne

subjects: New Zealand

abstract: This article analyses the role played by culture and the strategic communication of culture in the formation and establishment of the Māori Party. As an indigenous grassroots party, which achieved electoral success in the 2005, general election in New Zealand, the Māori Party offers an unusual case of cultural primacy as a political party for indigenous people. The Māori Party campaigned to be the first successful party to give a distinctive voice to Māori in a parliament dominated by Pakeha (New Zealand Europeans).

In examining the Māori Party's formation and campaign as a case study, the article focuses on socio-political conditions, issues of national identity, media changes, and the cultural relations between Māori and Pakeha. It pays particular attention to those that influenced public opinion during the 14 months of election campaigning. It argues that the strategic framing of the Māori Party as a movement giving a distinctive voice for Māori established the foundations for the campaign's success. In conclusion, the significance of the achievements of the Māori Party in the 2008 general election are discussed as evidence of the now distinct and recognized representation of Māori within the New Zealand democratic process.

text: Strategic framing: indigenous culture, identity, and politics This article analyses the role played by culture and the strategic communication of culture in the formation and establishment of the Māori Party. As an indigenous grassroots party, which achieved electoral success in the 2005, general election in New Zealand, the Māori Party offers an unusual case of cultural primacy as a political party for indigenous people. The Māori Party campaigned to be the first successful party to give a distinctive voice to Māori in a parliament dominated by Pakeha (New Zealand Europeans).

In examining the Māori Party's formation and campaign as a case study, the article focuses on socio-political conditions, issues of national identity, media changes, and the cultural relations between Māori and Pakeha. It pays particular attention to those that influenced public opinion during the 14 months of election campaigning. It argues that the strategic framing of the Māori Party as a movement giving a distinctive voice for Māori established the foundations for the campaign's success. In conclusion, the significance of the achievements of the Māori Party in the 2008 general election are discussed as evidence of the now distinct and recognized representation of Māori within the New Zealand democratic process.

year: 2011