Dissecting post-mating prezygotic speciation phenotypes.

Darwin's "mystery of mysteries," the origin of species, is caused by the evolution of speciation phenotypes, i.e. phenotypic differences that depress gene flow between daughter species during speciation. Postmating, prezygotic (PMPZ) differentiation characterizes many closely related species causing conspecific sperm precedence (CSP), wherein a female preferentially utilizes conspecific over heterospecific sperm in fertilization. Until recently, the components of CSP have been difficult to observe and study in internally fertilizing organisms. Research into the mechanisms of CSP is now progressing rapidly with the help of new innovative research tools. With the recent development of a sperm labeling system enabling distinct labels for different males, direct observations of competing male sperm within the female reproductive tract are possible, revealing multiple PMPZ phenotypes that combine to cause CSP. The discovery of mechanisms underlying CSP predicts an exciting future for studies of PMPZ speciation phenotypes and possible general principles underlying the origin of species.

Autologous stem cell transplantation outcomes in elderly patients with B cell Non-Hodgkin Lymphoma.

The precise role of autologous haematopoietic stem cell transplantation (ASCT) remains unclear in patients over 60 years of age. There is potential for increased procedural morbidity and mortality, and differences in disease biology that could impact outcomes. We performed a retrospective single-centre review of 81 elderly B-cell Non-Hodgkin Lymphoma patients undergoing ASCT. Five-year overall survival (OS) and progression-free survival (PFS) was 54·7% and 49·1% respectively. Non-relapse mortality (NRM) at 100 days and 1 year was 1·3% and 2·5%, suggesting no major excess compared to younger cohorts. OS and PFS were significantly worse in those over 65 years compared to those aged 60-64 (47·6% vs. 57·7%, P = 0·0437, and 27·6% vs. 57·7%, P = 0·0052 at 5 years). This resulted largely from an increased relapse risk (RR) (53·8% vs. 30·1%, P = 0·0511) rather than excess NRM, and age remained independently significant for PFS on multivariate analyses [Hazard ratio 2·56 (1·35-4·84, P = 0·0052) for PFS and 1·89 (0·99-3·61, P = 0·054) for OS]. Our data adds to the growing body of evidence demonstrating that ASCT can be an effective treatment strategy with an acceptable safety profile in selected elderly patients. Further evaluation of its overall benefit is warranted, however, in those over 65 years of age, as RR appears to be considerably higher.

The influence of beta-arrestin2 on cannabinoid CB1 receptor coupling to G-proteins and subcellular localization and relative levels of beta-arrestin1 and 2 in mouse brain.

CONTEXT: Beta-arrestins are known to couple to some G-protein-coupled receptors (GPCRs) to regulate receptor internalization, G-protein coupling and signal transduction, but have not been investigated for most receptors, and for very few receptors in vivo. Previous studies have shown that beta-arrestin2 deletion enhances the efficacy of specific cannabinoid agonists. OBJECTIVE: The present study hypothesized that brain cannabinoid CB1 receptors are regulated by beta-arrestin2. METHODS: Beta-arrestin2+/+ and -/- mice were used. Western blotting was used to determine the relative levels of each beta-arrestin subtype in mouse brain. Receptor binding was measured to determine whether deletion of beta-arrestin2 influences agonist binding to brain CB1 receptors, or the subcellular localization of CB1 in brain membranes subjected to differential centrifugation. A variety of cannabinoid agonists from different chemical classes were investigated for their ability to activate G-proteins in the presence and absence of beta-arrestin2 in cerebellum, hippocampus and cortex. RESULTS: No differences were found in the density of beta-arrestin1 or cannabinoid CB1 receptors in several brains of beta-arrestin2+/+ versus -/- mice. Differences between genotypes were found in the proportion of high- and low-affinity agonist binding sites in brain areas that naturally express higher levels of beta-arrestin2. Cortex from beta-arrestin2-/- mice contained less CB1 in the P1 fraction and more CB1 in the P2 fraction compared to beta-arrestin2+/+. Of the agonists assayed for activity, only Δ(9)-tetrahydrocannabinol (THC) exhibited a difference between genotypes, in that it was less efficacious in beta-arrestin2-/- than +/+ mouse membranes. CONCLUSION: Beta-arrestin2 regulates cannabinoid CB1 receptors in brain.

Sensitivity to delta9-tetrahydrocannabinol is selectively enhanced in beta-arrestin2 -/- mice.

Little is known about the roles of beta-arrestins in the regulation of brain CB1 cannabinoid receptors. This study investigated the role of beta-arrestin2 in cannabinoid behavioral effects using beta-arrestin2 -/- mice and their wild-type counterparts. A variety of cannabinoid ligands from different chemical classes that exhibit a variety of efficacies for activation of CB1 receptors were investigated, including Delta-tetrahydrocannabinol, CP55940, methanandamide, JWH-073, and O-1812. Delta-tetrahydrocannabinol produced both greater antinociception and greater decreases in body temperature in beta-arrestin2 -/- compared with beta-arrestin2 +/+ mice. No significant differences were, however, present in either assay for the other CB1 agonists. Antagonist radioligand binding indicated no difference in the density of cannabinoid CB1 receptors in the cerebellum, cortex, or hippocampus of beta-arrestin2 +/+ and -/- mice. These data demonstrate that beta-arrestin2 may regulate cannabinoid CB1 receptor sensitivity in an agonist-specific manner.