Ardisinones A-E, novel diarylundecanones from Ardisia arborescens

A phytochemical study on an ethanol extract of Ardisia arborescens resulted in the isolation of five new diarylundecanones, named ardisinones A-E (1-5). The structures were established by HRESIMS and NMR (H-1, C-13, DEPT, HSQC, HMBC) as 11-(2-acetoxy-6-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)undecan-1-one (1), 11-(2-acetoxy-6-hydroxyphenyl)-1-(2,6-dihydroxy-4-methoxyphenyl)undecan- 1-one (2), 1-(2,6-dihydroxy-4-methoxyphenyl)-11-(2,6-dihydroxyphenyl)undecan-1-one (3), 1-(2,4,6-trihydroxyphenyl)-11-(2,6-dihydroxyphenyl)undecan-1-one (4), and 1-(2,4,6-trihydroxyphenyl)-11-(2-hydroxyphenyl)undecan-1-one (5). In our in vitro disk diffusion assay, compounds 1 and 4 showed some slight inhibition of three bacteria, while 2 and 3 did not show antimicrobial activity

Relationship between depressive symptoms and capability to live well in people with mild to moderate dementia and their carers: results from the Improving the experience of Dementia and Enhancing Active Life (IDEAL) programme

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThe datasets generated and analysed during the current study are not publicly available due to the restrictions imposed in the original study but are available from the IDEAL study team on reasonable request.Objectives: Depression is a common condition in dementia and has a substantial impact on quality of life and wellbeing. There is limited evidence on how depressive symptoms in the person with dementia impact on the carer, and vice versa. The aim of this study is to investigate dyadic relationships between depressive symptoms and capability to live well in both people with dementia and their carers and to examine whether people with dementia who do not have a carer are more vulnerable to the impact of depressive symptoms than those who have a carer. Methods: Using a large cohort study of 1547 community-dwelling people with mild to moderate dementia and 1283 carers in Great Britain, a Bayesian analysis framework was developed to incorporate dyads (N = 981), people with dementia whose carers did not participate (N = 127), people with dementia who did not have a carer (N = 137), and dyads with missing data (N = 302) and estimate actor and partner relationships between depressive symptoms and capability to live well, which was expressed as a latent factor derived from measures of quality of life, life satisfaction and wellbeing. Results: Depressive symptoms in people with dementia and carers had negative associations with capability to live well both for the individual and for the partner. Compared to those who had a carer, depressive symptoms had a greater impact on capability to live well in people with dementia who did not had a carer. Conclusions: The impact of depression may extend beyond the person experiencing the symptoms. Future interventions for depressive symptoms should utilise this potential wider impact to understand and optimise treatment effects.Economic and Social Research Council (ESRC)National Institute for Health Research (NIHR

RNA interference of argininosuccinate synthetase restores sensitivity to recombinant arginine deiminase (rADI) in resistant cancer cells

Background Sensitivity of cancer cells to recombinant arginine deiminase (rADI) depends on expression of argininosuccinate synthetase (AS), a rate- limiting enzyme in synthesis of arginine from citrulline. To understand the efficiency of RNA interfering of AS in sensitizing the resistant cancer cells to rADI, the down regulation of AS transiently and permanently were performed in vitro, respectively. Methods We studied the use of down-regulation of this enzyme by RNA interference in three human cancer cell lines (A375, HeLa, and MCF-7) as a way to restore sensitivity to rADI in resistant cells. The expression of AS at levels of mRNA and protein was determined to understand the effect of RNA interference. Cell viability, cell cycle, and possible mechanism of the restore sensitivity of AS RNA interference in rADI treated cancer cells were evaluated. Results AS DNA was present in all cancer cell lines studied, however, the expression of this enzyme at the mRNA and protein level was different. In two rADI-resistant cell lines, one with endogenous AS expression (MCF-7 cells) and one with induced AS expression (HeLa cells), AS small interference RNA (siRNA) inhibited 37-46% of the expression of AS in MCF- 7 cells. ASsiRNA did not affect cell viability in MCF-7 which may be due to the certain amount of residual AS protein. In contrast, ASsiRNA down- regulated almost all AS expression in HeLa cells and caused cell death after rADI treatment. Permanently down-regulated AS expression by short hairpin RNA (shRNA) made MCF-7 cells become sensitive to rADI via the inhibition of 4E-BP1-regulated mTOR signaling pathway. Conclusions Our results demonstrate that rADI-resistance can be altered via AS RNA interference. Although transient enzyme down- regulation (siRNA) did not affect cell viability in MCF-7 cells, permanent down- regulation (shRNA) overcame the problem of rADI-resistance due to the more efficiency in AS silencing

Dementia subtype and living well: results from the Improving the experience of Dementia and Enhancing Active Life (IDEAL) study

This is the final version of the article. Available from BMC via the DOI in this record.The datasets generated and analysed during the current study are not publicly available due to the restrictions imposed in the original study but are available from the IDEAL study team on reasonable request.BACKGROUND: The heterogeneity of symptoms across dementia subtypes has important implications for clinical practice and dementia research. Variation in subtypes and associated symptoms may influence the capability to live well for people with dementia and carers. The aim of this study is to investigate the potential impact of dementia subtypes on the capability to live well for both people with dementia and their carers. METHODS: The analysis was based on the 1283 dyads of community-dwelling people with dementia and carers in the Improving the experience of Dementia and Enhancing Active Life (IDEAL) project, a large cohort study in Great Britain. Capability to live well was defined using three measures: quality of life, life satisfaction and wellbeing. Structural equation modelling was used to investigate capability to live well in seven dementia subtypes: Alzheimer's disease (AD), Vascular dementia (VaD), mixed AD/VaD, frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), Lewy body dementia (LBD) and unspecified/other, accounting for dyadic data structure and adjusting for age and sex, type of relationship between person with dementia and their carer and the number of chronic conditions. RESULTS: The major subtypes in this study population were AD (56%), VaD (11%) and mixed AD/VaD (21%). Compared to participants with AD, people with non-AD subtypes generally reported a lower capability to live well. Carers for people with PDD (- 1.71; 95% confidence interval (CI) - 3.24, - 0.18) and LBD (- 2.29; 95% CI - 3.84, - 0.75) also reported a lower capability to live well than carers for people with AD. After adjusting for demographic factors and comorbidity, PDD (- 4.28; 95% CI - 5.65, - 2.91) and LBD (- 3.76; 95% CI - 5.14, - 2.39) continued to have the strongest impact on both people with dementia and their carers. CONCLUSIONS: This study suggests a variation in capability to live well across dementia subtypes. It is important for care providers to consider different needs across subtypes. Health professionals who provide post-diagnostic support may need to pay more attention to the complex needs of people living with PDD and LBD and their carers.This work was supported by the Economic and Social Research Council (UK) and the National Institute for Health Research (UK) through grant ES/L001853/2 ‘Improving the experience of dementia and enhancing active life: living well with dementia’ (investigators: L. Clare, I.R. Jones, C. Victor, J.V. Hindle, R.W. Jones, M. Knapp, M. Kopelman, R. Litherland, A. Martyr, F.E. Matthews, R.G. Morris, S.M. Nelis, J. Pickett, C. Quinn, J. Rusted, J. Thom)

Severe childhood malaria syndromes defined by plasma proteome profiles

BACKGROUND Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore it is important to understand the pathology underlying the development of CM and SMA, as opposed to uncomplicated malaria (UM). Different host responses to infection are likely to be reflected in plasma proteome-patterns that associate with clinical status and therefore provide indicators of the pathogenesis of these syndromes. METHODS AND FINDINGS Plasma and comprehensive clinical data for discovery and validation cohorts were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, an urban and densely populated holoendemic malaria area in Nigeria. A total of 946 children participated in this study. Plasma was subjected to high-throughput proteomic profiling. Statistical pattern-recognition methods were used to find proteome-patterns that defined disease groups. Plasma proteome-patterns accurately distinguished children with CM and with SMA from those with UM, and from healthy or severely ill malaria-negative children. CONCLUSIONS We report that an accurate definition of the major childhood malaria syndromes can be achieved using plasma proteome-patterns. Our proteomic data can be exploited to understand the pathogenesis of the different childhood severe malaria syndromes

Functional site prediction selects correct protein models

<p>Abstract</p> <p>Background</p> <p>The prediction of protein structure can be facilitated by the use of constraints based on a knowledge of functional sites. Without this information it is still possible to predict which residues are likely to be part of a functional site and this information can be used to select model structures from a variety of alternatives that would correspond to a functional protein.</p> <p>Results</p> <p>Using a large collection of protein-like decoy models, a score was devised that selected those with predicted functional site residues that formed a cluster. When tested on a variety of small <it>α</it>/<it>β</it>/<it>α </it>type proteins, including enzymes and non-enzymes, those that corresponded to the native fold were ranked highly. This performance held also for a selection of larger <it>α</it>/<it>β</it>/<it>α </it>proteins that played no part in the development of the method.</p> <p>Conclusion</p> <p>The use of predicted site positions provides a useful filter to discriminate native-like protein models from non-native models. The method can be applied to any collection of models and should provide a useful aid to all modelling methods from <it>ab initio </it>to homology based approaches.</p

Cognitive reserve as a moderator of the negative association between mood and cognition: evidence from a population-representative cohort

BACKGROUND: Cognitive reserve (CR) has been associated with better cognitive function and lower risk of depression in older people, yet it remains unclear whether CR moderates the association between mood and cognition. This study aimed to investigate whether a comprehensive indicator of CR, including education, occupation and engagement in cognitive and social activities, acts as a moderator of this association. METHODS: This was a cross-sectional study utilising baseline data from the Cognitive Function and Ageing Study II (CFAS II), a large population-based cohort of people aged 65+ in England. Complete data on the measures of CR, mood and cognition were available for 6565 dementia-free individuals. Linear regression models were used to investigate the potential modifying effect of CR on the association between cognition and mood with adjustment for age, sex and missing data. RESULTS: Levels of CR did moderate the negative association between mood and cognition; the difference in cognition between those with and without a clinical level mood disorder was significantly smaller in the middle (-2.28; 95% confidence interval (CI) -3.65 to -0.90) and higher (-1.30; 95% CI -2.46 to -0.15) CR groups compared with the lower CR group (-4.01; 95% CI -5.53 to -2.49). The individual components of CR did not significantly moderate the negative association between mood and cognition. CONCLUSION: These results demonstrate that CR, indexed by a composite score based on multiple indicators, can moderate the negative association between lowered mood and cognition, emphasising the importance of continuing to build CR across the lifespan in order to maintain cognitive health.CFAS II has been supported by the UK Medical Research Council (research grant: G06010220) and received additional support from the National Institute for Health Research (NIHR), comprehensive clinical research networks in West Anglia, Nottingham City and Nottinghamshire County NHS Primary Care trusts and the dementias and neurodegenerative disease research Network (DeNDRoN) in Newcastle. FEM is supported by the MRC (research grant, U105292687). The funders are represented on the CFAS management committee and the biological resource advisory committee but they had no role in the study design, data analysis, data interpretation, or writing of the report