No abstract

We show that changing the number and position of nitrogen atoms in the heteroatomic core of a pyrazolopyrimidine acetamide is sufficient to induce complex binding to wild type human TSPO. Only compounds with this complex binding profile lacked intrinsic effect on glioblastoma proliferation but positively modulated the antiproliferative effects of a synthetic TSPO ligand. To the best of our knowledge this is the first demonstration of allosteric-like interaction at the wild type human TSPO.

The 18kDa translocator protein (TSPO) is a target for novel glioblastoma therapies due to its upregulation in this cancer and relatively low levels of expression in the healthy cortex. The pyrazolo[1,5-a]pyrimidine acetamides, exemplified by DPA-713 and DPA-714, are a class of high affinity TSPO ligands with selectivity over the central benzodiazepine receptor. In this study we have explored the potential anti-glioblastoma activity of a library of DPA-713 and DPA-714 analogues, and investigated the effect of amending the alkyl ether chain on TSPO affinity and functional potential. All ligands demonstrated nanomolar affinity for TSPO, but showed diverse functional activity, for example DPA-713 and DPA-714 did not affect the proliferation or viability of human T98G glioblastoma cells, while the hexyl ether and benzyl ether derivatives decreased proliferation of T98G cells without affecting proliferation in human fetal glial SVGp12 cells. These ligands also induced apoptosis and dissipated T98G mitochondrial membrane potential. This suggests that the nature of the alkyl ether chain of pyrazolo[1,5-a]pyrimidine acetamides has little influence on TSPO affinity but is important for functional activity of this class of TSPO ligands.

Understanding ways to strengthen marriage in middle age and beyond is increasingly important as the population of older adults rises. Using couple-level growth curve modeling in a sample of 371 middle-aged husbands and wives in long-term, enduring relationships, we examined the association between "joint activities," an index of couple connectedness, and "couple religiosity," an index focused on active participation in organized religious activities, across a 10-year period, using data from the years of 1991, 1992, 1994, and 2001. Confirming expectations there was a bidirectional and positive relationship between couples' religiosity and joint activities. Follow-up analyses indicated that greater religiosity at baseline or greater levels of joint activities at baseline produced particularly strong cross-lagged effects when the other construct was initially low, suggesting that these constructs are mutually protective in long-term marital dyads and become more tightly connected across later middle age. Exploratory comparisons of separate models for husbands and wives indicated that effects were stronger among wives.

This study investigated the longitudinal associations between mastery, conflict management behaviors, and depressive symptoms using an actor–partner interdependence model with 371 middle‐aged couples over a span of 24 years. Results indicated that for both husbands and wives, individuals who possessed higher levels of mastery generally displayed more constructive conflict management behaviors during marital conflicts in middle years. In turn, individuals with more constructive behaviors averaged fewer depressive symptoms in their later adulthood. A partner effect was also noted, as individuals’ constructive behaviors were linked to their spouse's depressive symptoms. This finding emphasizes the importance of utilizing a dyadic context to understand intra‐individual and inter‐individual (or crossover) influences between husbands and wives in enduring marriages. A better understanding of how couples affect each other's mental health can inform the development and implementation of health promotion interventions and prevention efforts targeting middle‐aged couples.