In this cross-sectional study, we aimed to predict age-related changes in bone microarchitecture and strength at the distal radius (DR) and distal tibia (DT) in 644 Canadian adults (n ¼ 442 women and 202 men) aged 20 to 99 years. We performed a standard morphologic analysis of the DR and DT with high-resolution peripheral quantitative computed tomography (pQCT) and used finite-element analysis (FEA) to estimate bone strength (failure load) and the load distribution. We also calculated a DR load-to-strength ratio as an estimate of forearm fracture risk. Total bone area, which was 33% larger in young men at both sites, changed similarly with age in women and men at the DT but increased 17% more in men than in women at the DR ( p < .001). Trabecular number and thickness (Tb.Th) were 7% to 20% higher in young men than in young women at both sites, and with the exception of Tb.Th at the DR, which declined more with age in men (À16%) than in women (À2%, p < .01), the age-related decline in these outcomes was similar in women and in men. In the cortex, porosity (Ct.Po) was 31% to 44% lower in young women than in young men but increased 92% to 176% more with age in women than in men ( p < .001). The DR cortex carried 14% more load in young women than in young men, and the percentage of load carried by the DR cortex did not change with age in women but declined by 17% in men ( p < .01). FEA-estimated bone strength was 34% to 47% greater in young men, but the predicted change with age was similar in both sexes. In contrast, the load-to-strength ratio increased 27% more in women than in men with age ( p < .01). These results highlight important site-and sex-specific differences in patterns of age-related bone loss. In particular, the trends for less periosteal expansion, more porous cortices, and a greater percentage of load carried by the DR cortex in women may underpin sex differences in forearm fracture risk. ß

p53-mediated transcription activity is essential for cell cycle arrest, but its importance for apoptosis remains controversial. To address this question, we employed homologous recombination and LoxP/Cre-mediated deletion to produce mutant murine embryonic stem (ES) cells that express p53 with Gln and Ser in place of Leu25 and Trp26, respectively. p53 Gln25Ser26 was stable but did not accumulate after DNA damage; the expression of p21/Waf1 and PERP was not induced, and p53-dependent repression of MAP4 expression was abolished. Therefore, p53 Gln25Ser26 is completely de®cient in transcriptional activation and repression activities. After DNA damage by UV radiation, p53 Gln25Ser26 was phosphorylated at Ser18 but was not acetylated at C-terminal sites, and its DNA binding activity did not increase, further supporting a role for p53 acetylation in the activation of sequence-speci®c DNA binding activity. Most importantly, p53 Gln25Ser26 mouse thymocytes and ES cells, like p53 ±/± cells, did not undergo DNA damage-induced apoptosis. We conclude that the transcriptional activities of p53 are required for p53-dependent apoptosis.

Impaired phosphorylation of ACE2 Ser680 by AMPK in pulmonary endothelium leads to a labile ACE2 and hence is associated with the pathogenesis of PH. Thus, AMPK regulation of the vasoprotective ACE2 is a potential target for PH treatment.

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