Introduction to Special Theme Section “Accounting for Climate Change: Measurement,Management, Morality,and Myth”

This special section considers contemporary efforts to account for climate change through four frames: measurement, management, morality and myth. Our introduction briefly outlines these perspectives and the relevant literature, asking: 1) How have techniques of measurement and quantification emerged from and contributed to the particular politics of the “Anthropocene”?; 2) How have our efforts to measure socioclimatic systems facilitated new techniques of socio-environmental management and, at times, worked to reshape the very systems they describe?; 3) How have accounting practices worked to both elucidate and obscure questions of morality, value, responsibility and justice?; and 4) How we might address the critique that climate science is a myth and improve understanding with greater incorporation of historical and cross cultural knowledge from human ecology, human geography and anthropology.     

Improved Health among People Living with HIV/AIDS Who Received Packages of Proven Preventive Health Interventions,Amhara, Ethiopia

In 2009, basic care packages (BCP) containing health products were distributed to HIV-infected persons in Ethiopia who were clients of antiretroviral therapy clinics. To measure health impact, we enrolled clients from an intervention hospital and comparison hospital, and then conducted a baseline survey, and 7 bi-weekly home visits. We enrolled 405 intervention group clients and 344 comparison clients. Intervention clients were more likely than comparison clients to have detectable chlorine in stored water (40% vs. 1%, p<0.001), soap (51% vs. 36%, p<0.001), and a BCP water container (65% vs. 0%, p<0.001) at every home visit. Intervention clients were less likely than comparison clients to report illness (44% vs. 67%, p<0.001) or health facility visits for illness (74% vs. 95%, p<0.001), and had lower median illness scores (1.0 vs. 3.0, p<0.05). Participation in the BCP program appeared to improve reported health outcomes.     

ICln, a novel integrin alphaIIbbeta3-associated protein, functionally regulates platelet activation

A critical role for the conserved alpha-integrin cytoplasmic motif, KVGFFKR, is recognized in the regulation of activation of the platelet integrin alpha(IIb)beta(3). To understand the molecular mechanisms of this regulation, we sought to determine the nature of the protein interactions with this cytoplasmic motif. We used a tagged synthetic peptide, biotin-KVGFFKR, to probe a high density protein expression array (37,200 recombinant human proteins) for high affinity interactions. A number of potential integrin-binding proteins were identified. One such protein, a chloride channel regulatory protein, ICln, was characterized further because its affinity for the integrin peptide was highest as was its expression in platelets. We verified the presence of ICln in human platelets by PCR, Western blots, immunohistochemistry, and its co-association with alpha(IIb)beta(3) by surface plasmon resonance. The affinity of this interaction was 82.2 +/- 24.4 nm in a cell free assay. ICln co-immunoprecipitates with alpha(IIb)beta(3) in platelet lysates demonstrating that this interaction is physiologically relevant. Furthermore, immobilized KVGFFKR peptides, but not control KAAAAAR peptides, specifically extract ICln from platelet lysates. Acyclovir (100 microm to 5 mm), a pharmacological inhibitor of the ICln chloride channel, specifically inhibits integrin activation (PAC-1 expression) and platelet aggregation without affecting CD62 P expression confirming a specific role for ICln in integrin activation. In parallel, a cell-permeable peptide corresponding to the potential integrin-recognition domain on ICln (AKFEEE, 10-100 microm) also inhibits platelet function. Thus, we have identified, verified, and characterized a novel functional interaction between the platelet integrin and ICln, in the platelet membrane.     

A novel strategy for the targeted analysis of protein and peptide metabolites

In many biological applications such as epitope discovery or drug metabolism studies, the detection of naturally processed exogenous proteins (e.g. vaccines or peptide therapeutics) and their metabolites is frequently complicated by the presence of a complex endogenous mixture of closely related or even identical compounds. We describe a method that incorporates stable isotope labelling of the protein of interest, allowing the selective screening of the intact molecule and all metabolites using a modified precursor ion scan. This method involves monitoring the low-molecular-weight fragment ions produced during MS/MS that distinguish isotopically labelled peptides from related endogenous compounds. All isotopically labelled peptides can be selected using this method. The technique makes no assumptions about the processed or post-translational state of the peptide, and hence can selectively screen out modified peptides that would otherwise be missed by single reaction monitoring approaches. This method does not replace single reaction monitoring or regular precursor scanning techniques; instead, it is a method that can be used when the assumptions required for the former two techniques cannot be predicted. The potential for this technique to be used in metabolism and pharmacokinetic experiments is discussed with specific examples looking at the metabolism of α-synuclein in serum and the brain.     

Structure of a CXC chemokine-receptor fragment in complex with interleukin-8.

BACKGROUND: Interactions between CXC chemokines (e.g. interleukin-8, IL-8) and their receptors (e.g. CXCR-1) have a key role in host defense and disease by attracting and upregulating neutrophils to sites of inflammation. The transmembrane nature of the receptor impedes structure-based understanding of ligand interactions. Linear peptides based on the N-terminal, extracellular portion of the receptor CXCR-1 do bind to IL-8, however, and inhibit the binding of IL-8 to the full-length receptor. RESULTS: The NMR solution structure of the complex formed between IL-8 and one such receptor-based peptide indicates that a cleft between a loop and a beta hairpin constitute part of the receptor interaction surface on IL-8. Nine residues from the C terminus of the receptor peptide (corresponding to Pro21-Pro29 of CXCR-1) occupy the cleft in an extended fashion. Intermolecular contacts are mostly hydrophobic and sidechain mediated. CONCLUSIONS: The results offer the first details at an atomic level of the interaction between a chemokine and its receptor. Consideration of other biochemical data allow extrapolation to a model for the interaction of IL-8 with the full-length receptor. In this model, the heparin-binding residues of IL-8 are exposed, thereby allowing presentation of the chemokine from endothelial cell-surface glycosaminoglycans. This first glimpse of how IL-8 binds to its receptor provides a foundation for the structure-based design of chemokine antagonists.