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The sister queens
London, 1600. With no legitimate heir to Queen Elizabeth's throne, and no clear successor, England finds itself in a supremely perilous moment. When spymaster Anthony Bacon commands esteemed playwright William Shakespeare to write a play on the poisonous history of Queen Elizabeth and the rival monarch she executed, Catholic Mary Queen of Scots, Will knows that Elizabeth's one-time favourite, the powerful Earl of Essex, will use the play to try to seize her throne. Must Will be ensnared in a ruthless plot fated to tumble his country into civil war? Or can he navigate a treacherous path through the dark warrens of London and the tortuous world of Elizabethan politics to save his family, his country, and his Queen?
BOOK
Falls on an inpatient rehabilitation spinal injuries unit: the characteristics, circumstances, and consequences
Study designRetrospective auditObjectivesTo describe the nature of falls and fallers in a spinal injuries unit (SIU) and identify factors associated with having more than one fall (recurrent fallers) and falls with physical or psychological consequences (consequential falls).SettingAn Australian inpatient rehabilitation SIU.MethodsData were retrospectively extracted from falls incident reports and electronic medical records over a 5-year period. Data were analysed descriptively to summarise participant and fall details. Univariate analyses identified candidate variables for further investigation in a multivariate model for recurrent fallers and consequential falls.ResultsOf the 566 persons admitted to the SIU, 132 (23%) participants experienced 207 falls over the 5 years. Of the fallers, 41 (31%) were recurrent fallers experiencing between 2 and 7 falls and 78 (59%) experienced a consequential fall. No significant variables were identified for recurrent fallers. For consequential falls, older age (OR = 1.038, 95% CI, 1.012 to 1.064, p = 0.004) and female gender (OR = 3.581, 95% CI, 1.269 to 10.103, p = 0.016) were significant, as well as falls that occurred on a Sunday (OR = 0.196, 95% CI, 0.061 to 0.630, p = 0.006). Falls while transferring were less likely to be consequential (OR = 4.100, 95% CI, 1.706 to 9.856, p = 0.002).ConclusionsNearly one quarter of SIU inpatients experienced a fall with almost a third of those who fell experiencing recurrent falls. Older age, female gender, and Sundays were risk factors for falls with consequence.
Journal Article
The teen kitchen : recipes we love to cook
\"...teen stars The Kitchen Twins present a colorful and engaging cookbook with more than 75 accessible, fun, healthy, and delicious recipes for everyday cooking. As a bonus, virtually all of the recipes include vegetarian options and many have gluten-free or dairy-free options.\"-- Publisher's description.
Book
Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration
Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf. LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut–retina axis to protect against diet- and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.
Journal Article
Gut microbiome structure and metabolic activity in inflammatory bowel disease
The inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial chronic conditions of the gastrointestinal tract. While IBD has been associated with dramatic changes in the gut microbiota, changes in the gut metabolome—the molecular interface between host and microbiota—are less well understood. To address this gap, we performed untargeted metabolomic and shotgun metagenomic profiling of cross-sectional stool samples from discovery (
n
= 155) and validation (
n
= 65) cohorts of CD, UC and non-IBD control patients. Metabolomic and metagenomic profiles were broadly correlated with faecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While > 50% of differentially abundant metabolite features were uncharacterized, many could be assigned putative roles through metabolomic ‘guilt by association’ (covariation with known metabolites). Differentially abundant species and functions from the metagenomic profiles reflected adaptation to oxidative stress in the IBD gut, and were individually consistent with previous findings. Integrating these data, however, we identified 122 robust associations between differentially abundant species and well-characterized differentially abundant metabolites, indicating possible mechanistic relationships that are perturbed in IBD. Finally, we found that metabolome- and metagenome-based classifiers of IBD status were highly accurate and, like the vast majority of individual trends, generalized well to the independent validation cohort. Our findings thus provide an improved understanding of perturbations of the microbiome–metabolome interface in IBD, including identification of many potential diagnostic and therapeutic targets.
Using metabolomics and shotgun metagenomics on stool samples from individuals with and without inflammatory bowel disease, metabolites, microbial species and genes associated with disease were identified and validated in an independent cohort.
Journal Article
MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells
The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common \"passenger\" geomic alteration.
Journal Article
African American, low‐income mothers’ negative emotional reactivity, punishment, and children's externalizing and internalizing behavior
Objective In this study, we examined African American, low‐income mothers’ emotional reactivity and use of punishment in relation to determinants of parenting and children's behavior. Background More research is needed examining within‐group variation in parenting processes, including discipline, of African American parents. Parents’ negative emotion may have implications for children's behavior independent of punishment as a disciplinary strategy. Method Participants were 157 African American, low‐income mothers and their 4‐ to 7‐year‐old children. Mothers responded verbally to a questionnaire and were observed interacting in their natural home environment. Direct and indirect relations were examined from three determinants of parenting (i.e., depression, household disorganization, child difficulty) to negative emotional reactivity, punishment, sensitivity, and children's behavior. Results Depressive symptoms, household disorganization, and child difficulty were associated with children's externalizing and internalizing behavior indirectly through negative emotional reactivity. Household disorganization predicted externalizing behavior through verbal punishment. Physical punishment was not related to children's behavior above and beyond negative emotional reactivity. Conclusion This study supports the proposal that parents’ ability to regulate negative emotional reactivity in stressful contexts may have important implications for parenting and children's development above and beyond punishment. Implications Intervention and preventative parent education programs should consider adding components that help parents with emotion regulation during stressful parenting situations.
Journal Article