The human brainome: network analysis identifies \u3ci\u3eHSPA2\u3c/i\u3e as a novel Alzheimer’s disease target

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-B40 and amyloid-B42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes

Quantifying variation in the ability of yeasts to attract Drosophila melanogaster

Yeasts that invade and colonise fruit significantly enhance the volatile chemical diversity of this ecosystem. These modified bouquets are thought to be more attractive to Drosophila flies than the fruit alone, but the variance of attraction in natural yeast populations is uncharacterised. Here we investigate how a range of yeast isolates affect the attraction of female D. melanogaster to fruit in a simple two choice assay comparing yeast to sterile fruit. Of the 43 yeast isolates examined, 33 were attractive and seven repellent to the flies. The results of isolate-versus-isolate comparisons provided the same relative rankings. Attractiveness varied significantly by yeast, with the strongly fermenting Saccharomyces species generally being more attractive than the mostly respiring non-Saccharomyces species (P = 0.0035). Overall the habitat (fruit or other) from which the isolates were directly sampled did not explain attraction (P = 0.2352). However, yeasts isolated from fruit associated niches were more attractive than those from non-fruit associated niches (P = 0.0188) regardless of taxonomic positioning. These data suggest that while attractiveness is primarily correlated with phylogenetic status, the ability to attract Drosophila is a labile trait among yeasts that is potentially associated with those inhabiting fruit ecosystems. Preliminary analysis of the volatiles emitted by four yeast isolates in grape juice show the presence/absence of ethanol and acetic acid were not likely explanations for the observed variation in attraction. These data demonstrate variation among yeasts for their ability to attract Drosophila in a pattern that is consistent with the hypothesis that certain yeasts are manipulating fruit odours to mediate interactions with their Drosophila dispersal agent. © 2013 Palanca et al

The human brainome: network analysis identifies HSPA2 as a novel Alzheimer's disease target

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer's disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer's disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65-105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66-107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-b40 and amyloid-b42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer's disease processes

The prevalence and social patterning of chronic diseases among older people in a population undergoing health transition. A 10/66 Group cross-sectional population-based survey in the Dominican Republic

BACKGROUND: Very little of the increased attention towards chronic diseases in countries with low and middle incomes has been directed towards older people, who contribute 72% of all deaths, and 14% of all Disability Adjusted Life Years linked to this group of conditions in those regions. We aimed to study the prevalence of physical, mental and cognitive diseases and impairments among older people in the Dominican Republic, their social patterning, and their relative contributions to disability. METHODS: A cross-sectional catchment area one-phase survey of chronic disease diagnoses, physical impairments, risk factors and associated disability among 2011 people aged 65 years and over (of whom 1451 gave fasting blood samples) in Santo Domingo, Dominican Republic. RESULTS: The most prevalent diagnoses were hypertension (73.0%), anaemia (35.0%), diabetes (17.5%), depression (13.8%) and dementia (11.7%), with 39.6% meeting criteria for metabolic syndrome. After direct standardization (for age and sex) the prevalences of stroke (standardized morbidity ratio [SMR] 100) and hypertension (SMR 108) were similar to those in the United States of America National Health and Nutrition Examination Survey (NHANES reference SMR 100), while those of diabetes (SMR 83) and metabolic syndrome (SMR 72) were somewhat lower. Anaemia was three times more common than in the USA (SMR 310). Diabetes, hypertension, dyslipidaemia, obesity and the metabolic syndrome were associated with affluence and female sex. Arthritis, anaemia, dementia and stroke were strongly age-associated and these conditions were also the main independent contributors to disability. CONCLUSIONS: The prevalence of many chronic diseases is similar in predominately low socioeconomic status neighbourhoods in the Dominican Republic to that in the USA. Prevalence of age-associated conditions is likely to increase with demographic ageing. There is also scope for increases in cardiovascular disease prevalence, if, as observed in other settings undergoing the epidemiologic transition, the burden of risk factors shifts towards the less affluent. Monitoring future trends in the prevalence and social patterning of chronic diseases may help to assess the effectiveness and equity of primary and secondary prevention strategies. Specific recommendations from our research include identifying and targeting the causes of anaemia among older people, and addressing women's health disadvantages