Loss of BIM in T cells results in BCL-2 family BH3-member compensation but incomplete cell death sensitivity normalization.

BIM is the master BH3-only BCL-2 family regulator of lymphocyte survival. To understand how long-term loss of BIM affects apoptotic resistance in T cells we studied animals with T cell-specific deletion of Bim. Unlike CD19CREBimfl/fl animals, LCKCREBimfl/fl mice have pronounced early lymphocytosis followed by normalization of lymphocyte counts over time. This normalization occurred in mature T cells, as thymocyte development and apoptotic sensitivity remained abnormal in LCKCREBimfl/fl mice. T cells from aged mice experienced normalization of their absolute cell numbers and responses against various apoptotic stimuli. mRNA expression levels of BCL-2 family proteins in CD4+ and CD8+ T cells from young and old mice revealed upregulation of several BH3-only proteins, including Puma, Noxa, and Bmf. Despite upregulation of various BH3 proteins, there were no differences in anti-apoptotic BCL-2 protein dependency in these cells. However, T cells had continued resistance to direct BIM BH3-induced mitochondrial depolarization. This study further highlights the importance of BIM in cell death maintenance in T cells and provides new insight into the dynamism underlying BH3-only regulation of T cell homeostasis versus induced cell death and suggests that CD4+ and CD8+ T cells compensate differently in response to loss of Bim.

School-Based Interventions for Anxious Children: Long-Term Follow-Up.

This study examined the long-term outcomes of a nonclinical sample of anxious children (N = 61) who were randomized by school to 9 weeks of group cognitive-behavioral therapy (CBT) for children, group CBT for children plus parent training, or no-treatment control. Parents and children completed measures of anxiety symptoms at baseline, posttreatment, and at 3-, 6-, 12-month, 2-, and 3-year posttreatment follow-ups. Piecewise longitudinal growth curve analyses were applied to the data. When the two CBT groups were combined and compared with control, the combined treatment group showed significantly greater reduction in children's anxiety severity based on the parent ratings in the first longitudinal phase. However, on the parent Clinician Severity Rating, gains were maintained to 3 years. Child report revealed no significant differences between groups on anxiety reduction. This study maintained a small no-treatment control group during the entire follow-up period. From parental perspective only, school-based group CBT appeared to be beneficial in decreasing severity of anxiety symptoms and maintaining gains over time.

p19Arf represses platelet-derived growth factor receptor ß by transcriptional and posttranscriptional mechanisms.

In addition to cancer surveillance, p19(Arf) plays an essential role in blocking signals stemming from platelet-derived growth factor receptor ß (Pdgfrß) during eye development, but the underlying mechanisms have not been clear. We now show that without Arf, pericyte hyperplasia in the eye results from enhanced Pdgfrß-dependent proliferation from embryonic day 13.5 (E13.5) of mouse development. Loss of Arf in the eye increases Pdgfrß expression. In cultured fibroblasts and pericyte-like cells, ectopic p19(Arf) represses and Arf knockdown enhances the expression of Pdgfrß mRNA and protein. Ectopic Arf also represses primary Pdgfrß transcripts and a plasmid driven by a minimal promoter, including one missing the CCAAT element required for high-level expression. p19(Arf) uses both p53-dependent and -independent mechanisms to control Pdgfrß. In vivo, without p53, Pdgfrß mRNA is elevated and eye development abnormalities resemble the Arf (-/-) phenotype. However, effects of p53 on Pdgfrß mRNA do not appear to be due to direct p53 or RNA polymerase II recruitment to the promoter. Although p19(Arf) controls Pdgfrß mRNA in a p53-dependent manner, it also blunts Pdgfrß protein expression by blocking new protein synthesis in the absence of p53. Thus, our findings demonstrate a novel capacity for p19(Arf) to control Pdgfrß expression by p53-dependent and -independent mechanisms involving RNA transcription and protein synthesis, respectively, to promote the vascular remodeling needed for normal vision.