Parental breeding age effects on descendants' longevity interact over 2 generations in matrilines and patrilines

Individuals within populations vary enormously in mortality risk and longevity, but the causes of this variation remain poorly understood. A potentially important and phylogenetically widespread source of such variation is maternal age at breeding, which typically has negative effects on offspring longevity. Here, we show that paternal age can affect offspring longevity as strongly as maternal age does and that breeding age effects can interact over 2 generations in both matrilines and patrilines. We manipulated maternal and paternal ages at breeding over 2 generations in the neriid fly Telostylinus angusticollis. To determine whether breeding age effects can be modulated by the environment, we also manipulated larval diet and male competitive environment in the first generation. We found separate and interactive effects of parental and grand-parental ages at breeding on descendants' mortality rate and life span in both matrilines and patrilines. These breeding age effects were not modulated by grand-parental larval diet quality or competitive environment. Our findings suggest that variation in maternal and paternal ages at breeding could contribute substantially to intrapopulation variation in mortality and longevity

Preparation of highly substituted stereodefined dienes via cross-coupling of alpha-allenic acetate

International audienc

The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses

The complete inhibition of proteasome activities interferes with the production of most MHC class I peptide ligands as well as with cellular proliferation and survival. In this study we have investigated how partial and selective inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentation. At 0.5-1 μM lactacystin, the presentation of the lymphocytic choriomeningitis virus-derived epitopes NP118 and GP33 and the mouse CMV epitope pp89-168 were reduced and were further diminished in a dose-dependent manner with increasing concentrations. Presentation of the lymphocytic choriomeningitis virus-derived epitope GP276, in contrast, was markedly enhanced at low, but abrogated at higher, concentrations of either lactacystin or epoxomicin. The inhibitor-mediated effects were thus epitope specific and did not correlate with the degradation rates of the involved viral proteins. Although neither apoptosis induction nor interference with cellular proliferation was observed at 0.5-1 μM lactacystin in vivo, this concentration was sufficient to alter the fragmentation of polypeptides by the 20S proteasome in vitro. Our results indicate that partial and selective inhibition of proteasome activity in vivo is a valid approach to modulate Ag presentation, with potential applications for the treatment of autoimmune diseases and the prevention of transplant rejection

SES, Heart Failure, and N-terminal Pro-b-type Natriuretic Peptide: The Atherosclerosis Risk in Communities Study

INTRODUCTION: Compared with coronary heart disease and stroke, the association between SES and the risk of heart failure is less well understood. METHODS: In 12,646 participants of the Atherosclerosis Risk in Communities Study cohort free of heart failure history at baseline (1987-1989), the association of income, educational attainment, and area deprivation index with subsequent heart failure-related hospitalization or death was examined while accounting for cardiovascular disease risk factors and healthcare access. Because SES may affect threshold of identifying heart failure and admitting for heart failure management, secondarily the association between SES and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels, a marker reflecting cardiac overload, was investigated. Analysis was conducted in 2016. RESULTS: During a median follow-up of 24.3 years, a total of 2,249 participants developed heart failure. In a demographically adjusted model, the lowest-SES group had 2.2- to 2.5-fold higher risk of heart failure compared with the highest SES group for income, education, and area deprivation. With further adjustment for time-varying cardiovascular disease risk factors and healthcare access, these associations were attenuated but remained statistically significant (e.g., hazard ratio=1.92, 95% CI=1.69, 2.19 for the lowest versus highest income), with no racial interaction (p>0.05 for all SES measures). Similarly, compared with high SES, low SES was associated with both higher baseline level of NT-proBNP in a multivariable adjusted model (15% higher, p<0.001) and increase over time (~1% greater per year, p=0.023). CONCLUSIONS: SES was associated with clinical heart failure as well as NT-proBNP levels inversely and independently of traditional cardiovascular disease factors and healthcare access

Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic β subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor–1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and -4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation and that inhibition of specific components of this system may be useful therapeutically in common diseases of bone loss

PowerPoint Slides for: Dietary Magnesium and Kidney Function Decline: The Healthy Aging in Neighborhoods of Diversity across the Life Span Study

<p><b><i>Background:</i></b> Prior studies suggest that certain aspects of the diet related to magnesium intake, such as dietary acid load, protein intake and dietary patterns rich in fruits and vegetables, may impact kidney disease risk. We hypothesized that lower dietary magnesium intake would be prospectively associated with more rapid kidney function decline. <b><i>Methods:</i></b> Among participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m² at baseline (2004-2009), dietary magnesium intake was calculated from two 24-hour dietary recalls. Rapid decline was defined as ≥3% eGFR decline per year. <b><i>Results:</i></b> Median (25th-75th percentile) dietary magnesium intake was 116 (96-356) mg/1,000 kcal. Among 1,252 participants, those with lower dietary magnesium intake were younger, and were more likely to be African-American men. A total of 177 participants (14.1%) experienced rapid eGFR decline over a median follow-up of 5 years. Lower dietary magnesium intake was significantly associated with a greater odds of rapid eGFR decline (OR for tertile 1 vs. 3: 2.02, 95% CI 1.05-3.86, p value for trend across tertiles = 0.02) in analyses adjusted for sociodemographics (age, sex, race, education level, health insurance status, poverty status), kidney disease risk factors (smoking status, diabetes, hemoglobin A1c, hypertension, body mass index), baseline eGFR and dietary factors (total energy intake; diet quality; dietary intake of fiber, sodium, calcium, potassium and phosphorus). <b><i>Conclusions:</i></b> In this urban population, lower dietary magnesium intake was independently associated with greater odds of rapid kidney function decline.</p