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Methadone remains the most common form of pharmacological therapy for opioid dependence; however, there is a lack of explanation for the reports of its relatively low success rate in achieving complete abstinence. One hypothesis is that in vivo binding of methadone to the plasma glycoprotein alpha-1-acid glycoprotein (AGP), to a degree dependent on the molecular structure, may render the drug inactive. This study sought to determine whether alterations present in the glycosylation pattern of AGP in patients undergoing various stages of methadone therapy (titration < two weeks, harm reduction < one year, long-term > one and a half years) could affect the affinity of the glycoprotein to bind methadone. The composition of AGP glycosylation was determined using high pH anion exchange chromatography (HPAEC) and intrinsic fluorescence analysed to determine the extent of binding to methadone. The monosaccharides galactose and N-acetyl-glucosamine were elevated in all methadone treatment groups indicating alterations in AGP glycosylation. AGP from all patients receiving methadone therapy exhibited a greater degree of binding than the normal population. This suggests that analysing the glycosylation of AGP in patients receiving methadone may aid in determining whether the therapy is likely to be effective.

Dependence on heroin and other opioids represents a considerable problem worldwide. There is a continual need to improve therapy and/ or find more efficacious alternatives if these issues are to be addressed. The most commonly implemented pharmacological therapy in treating said dependencies is methadone; however its success is the subject of ongoing debate. Certain plasma proteins including alpha1-acid glycoprotein (AGP) bind to drugs which causes inactivation and, if low enough, may prevent a therapeutic effect being attained. The hepatic synthesis of AGP increases two- to five-fold during numerous physiological and pathophysiological conditions, becoming the most prevalent acute phase protein in the blood. Additionally, the structure of the sugar chains (glycans) attached to the surface of underlying polypeptide backbones can differ, potentially altering the functions performed. AGP was isolated from blood samples obtained from patients undergoing various stages and types of opioid-replacement therapy and from heparinised blood samples provided by the Blood Transfusion Service. Structural analysis of the glycans was undertaken primarily through the use of high pH anion-exchange chromatography (HPAEC) and intrinsic fluorescence used as a measure of drug binding. The composition of glycans attached to the polypeptide backbone of AGP isolated from patient samples was found to markedly differ from that of a ‘normal' healthy population. Levels of galactose and N-acetyl-glucosamine were amplified in all methadone treatment groups which suggested increased branching of glycans; this was supported by HPAEC analysis of complete glycan chains. Binding of methadone to all isolated AGP samples was elevated at the highest drug concentrations tested; however the degree of quenching appeared to be greater in patients. Therefore, the glycoforms expressed by AGP appear to be associated with the subsequent binding of the glycoprotein to methadone. It is possible that altered glycosylation could increase affinity for the drug, reducing its bioactive concentration to below that required to produce the pharmacological effect. Currently, the doses of methadone used in opioid replacement therapy are primarily influenced by the expression of physical symptoms, however this preliminary study has indicated that determination of the level and glycoform expression of AGP may offer potential use when determining the most effective therapy and dosage regimen.

Space‐use and demographic processes are critical to the persistence of populations across space and time. Despite their importance, estimates of these processes are often derived from a limited number of populations spanning broad habitat or environmental gradients. With increasing appreciation of the role fine‐scale environmental variation in microgeographic adaptation, there is a need and value to assessing within‐site variation in space‐use and demographic patterns. In this study, we analyze 3 years of spatial capture–recapture data on the Eastern Red‐backed Salamander collected from a mixed‐use deciduous forest site in central Ohio, USA. Study plots were situated in both a mature forest stand and successional forest stand separated by <100‐m distance. Our results showed that salamander density was reduced on successional plots, which corresponded with greater distance between nearest neighbors, less overlap in core use areas, greater space‐use, and greater shifts in activity centers when compared to salamanders occupying the mature habitat. By contrast, individual growth rates of salamanders occupying the successional forest were significantly greater than salamanders in the mature forest. These estimates result in successional plot salamanders reaching maturity more than 1 year earlier than salamanders on the mature forest plots and increasing their estimated lifetime fecundity by as much as 43%. The patterns we observed in space‐use and individual growth are likely the result of density‐dependent processes, potentially reflecting differences in resource availability or quality. Our study highlights how fine‐scale, within‐site variation can shape population demographics. As research into the demographic and population consequences of climate change and habitat loss and alteration continue, future research should take care to acknowledge the role that fine‐scale variation may play, especially for abiotically sensitive organisms with limited vagility. Time to maturity is a critical life history trait. In this study, we find that salamanders occupying mature and successional forest habitats separated by <100 m differed in their time to maturity by over a year. The delayed time to maturity of individuals in the mature forest results in a 43% reduction in lifetime fecundity for salamanders inhabiting the mature forest.

Mutations in the lozenge gene of Drosophila melanogaster elicit a pleiotropic set of adult phenotypes, including severe compound eye perturbations resulting from the defective recruitment of photoreceptors R1/6 and R7, cone and pigment cells. In this study, we show that excessive patterned apoptosis is evident at the same developmental stage in these lozenge mutants. In lozenge null mutants, apoptosis occurs prior to lozenge-dependent cell fate specification. A second gene, D-Pax2, genetically interacts with lozenge. Interestingly, D-Pax2 mutants also exhibit increased cell death, but slightly later in development than that in lozenge mutants. Although expression of the caspase inhibitor p35 eliminates death in both lozenge and D-Pax2 mutants, the lozenge mutant eye phenotypes persist because other normal Lozenge functions are still lacking. D-Pax2 eye phenotypes, in contrast, are dramatically altered in a p35 background, because cells that normally differentiate as cone and primary pigment cells are subsequently transformed into secondary pigment cells. This study leads us to propose that Lozenge, aside from its known role in gene regulation of cell-specific transcription factors, is required to contribute to the repression of cell death mechanisms, creating a permissive environment for the survival of undifferentiated cells in early eye development. Lack of lozenge expression increases the likelihood that an undifferentiated cell will initiate its default death program and die prematurely. The ectopic cell death evident in D-Pax2 mutants appears to arise from the cell fate transformation of cone cells into secondary pigment cells, either autonomously or as a result of defective signalling.