RANKL-Targeted Therapies: The Next Frontier in the Treatment of Male Osteoporosis

Male osteoporosis is an increasingly recognized problem in aging men. A common cause of male osteoporosis is hypogonadism. Thousands of men with prostate cancer are treated with androgen deprivation therapy, a treatment that dramatically reduces serum testosterone and causes severe hypogonadism. Men treated with androgen deprivation therapy experience a decline in bone mineral density and have an increased rate of fracture. This paper describes prostate cancer survivors as a model of hypogonadal osteoporosis and discusses the use of RANKL-targeted therapies in osteoporosis. Denosumab, the only RANKL-targeted therapy currently available, increases bone mineral density and decreases fracture rate in men with prostate cancer. Denosumab is also associated with delayed time to first skeletal-related event and an increase in bone metastasis-free survival in these men. It is reasonable to investigate the use of RANKL-targeted therapy in male osteoporosis in the general population

Gene ontology analysis for RNA-seq: accounting for selection bias

GOseq is a method for GO analysis of RNA-seq data that takes into account the length bias inherent in RNA-se

Prehypertensive blood pressures and regional cerebral blood flow independently relate to cognitive performance in midlife

Background High blood pressure is thought to contribute to dementia in late life, but our understanding of the relationship between individual differences in blood pressure ( BP ) and cognitive functioning is incomplete. In this study, cognitive performance in nonhypertensive midlife adults was examined as a function of resting BP and regional cerebral blood flow ( rCBF ) responses during cognitive testing. We hypothesized that BP would be negatively related to cognitive performance and that cognitive performance would also be related to rCBF responses within areas related to BP control. We explored whether deficits related to systolic BP might be explained by rCBF responses to mental challenge. Methods and Results Healthy midlife participants (n=227) received neuropsychological testing and performed cognitive tasks in a magnetic resonance imaging scanner. A pseudocontinuous arterial spin labeling sequence assessed rCBF in brain areas related to BP in prior studies. Systolic BP was negatively related to 4 of 5 neuropsychological factors (standardized β&gt;0.13): memory, working memory, executive function, and mental efficiency. The rCBF in 2 brain regions of interest was similarly related to memory, executive function, and working memory (standardized β&gt;0.17); however, rCBF responses did not explain the relationship between resting systolic BP and cognitive performance. Conclusions Relationships at midlife between prehypertensive levels of systolic BP and both cognitive and brain function were modest but suggested the possible value of midlife intervention. </jats:sec

Carbon dioxide mediates the response to temperature and water activity levels in Aspergillus flavus during infection of maize kernels

Aspergillus flavus is a saprophytic fungus that may colonize several important crops, including cotton, maize, peanuts and tree nuts. Concomitant with A. flavus colonization is its potential to secrete mycotoxins, of which the most prominent is aflatoxin. Temperature, water activity (aw) and carbon dioxide (CO2) are three environmental factors shown to influence the fungus-plant interaction, which are predicted to undergo significant changes in the next century. In this study, we used RNA sequencing to better understand the transcriptomic response of the fungus to aw, temperature, and elevated CO2 levels. We demonstrate that aflatoxin (AFB1) production on maize grain was altered by water availability, temperature and CO2. RNA-Sequencing data indicated that several genes, and in particular those involved in the biosynthesis of secondary metabolites, exhibit different responses to water availability or temperature stress depending on the atmospheric CO2 content. Other gene categories affected by CO2 levels alone (350 ppm vs. 1000 ppm at 30 °C/0.99 aw), included amino acid metabolism and folate biosynthesis. Finally, we identified two gene networks significantly influenced by changes in CO2 levels that contain several genes related to cellular replication and transcription. These results demonstrate that changes in atmospheric CO2 under climate change scenarios greatly influences the response of A. flavus to water and temperature when colonizing maize grain

Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease

Interactions between water activity and temperature on the Aspergillus flavus transcriptome and aflatoxin B1 production

Effects of Aspergillus flavus colonization of maize kernels under different water activities (aw; 0.99 and 0.91) and temperatures (30, 37 °C) on (a) aflatoxin B1 (AFB1) production and (b) the transcriptome using RNAseq were examined. There was no significant difference (p = 0.05) in AFB1 production at 30 and 37 °C and 0.99 aw. However, there was a significant (p = 0.05) increase in AFB1 at 0.91 aw at 37 °C when compared with 30 °C/0.99 aw. Environmental stress effects using gene ontology enrichment analysis of the RNA-seq results for increasing temperature at 0.99 and 0.91 aw showed differential expression of 2224 and 481 genes, respectively. With decreasing water availability, 4307 were affected at 30 °C and 702 genes at 37 °C. Increasing temperature from 30 to 37 °C at both aw levels resulted in 12 biological processes being upregulated and 9 significantly downregulated. Decreasing aw at both temperatures resulted in 22 biological processes significantly upregulated and 25 downregulated. The interacting environmental factors influenced functioning of the secondary metabolite gene clusters for aflatoxins and cyclopiazonic acid (CPA). An elevated number of genes were co-regulated by both aw and temperature. An interaction effect for 4 of the 25 AFB1 genes, including regulatory and transcription activators occurred. For CPA, all 5 biosynthetic genes were affected by aw stress, regardless of temperature. The molecular regulation of A. flavus in maize is discussed

Interactions between water activity and temperature on the Aspergillus flavus transcriptome and aflatoxin B1 production

Effects of Aspergillus flavus colonization of maize kernels under different water activities (aw; 0.99 and 0.91) and temperatures (30, 37 °C) on (a) aflatoxin B1 (AFB1) production and (b) the transcriptome using RNAseq were examined. There was no significant difference (p = 0.05) in AFB1 production at 30 and 37 °C and 0.99 aw. However, there was a significant (p = 0.05) increase in AFB1 at 0.91 aw at 37 °C when compared with 30 °C/0.99 aw. Environmental stress effects using gene ontology enrichment analysis of the RNA-seq results for increasing temperature at 0.99 and 0.91 aw showed differential expression of 2224 and 481 genes, respectively. With decreasing water availability, 4307 were affected at 30 °C and 702 genes at 37 °C. Increasing temperature from 30 to 37 °C at both aw levels resulted in 12 biological processes being upregulated and 9 significantly downregulated. Decreasing aw at both temperatures resulted in 22 biological processes significantly upregulated and 25 downregulated. The interacting environmental factors influenced functioning of the secondary metabolite gene clusters for aflatoxins and cyclopiazonic acid (CPA). An elevated number of genes were co-regulated by both aw and temperature. An interaction effect for 4 of the 25 AFB1 genes, including regulatory and transcription activators occurred. For CPA, all 5 biosynthetic genes were affected by aw stress, regardless of temperature. The molecular regulation of A. flavus in maize is discussed