Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.

IntroductionDisruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).MethodsWe examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS-AD), 43 who met criteria for mild cognitive impairment (DS-MCI), and 211 who were cognitively unaffected and stable (CS).ResultsWe measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate-corrected q< 0.05. From the DE features, a nine-feature classifier model classified the CS and DS-AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two-feature model classified the DS-MCI and DS-AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism.DiscussionOur results reveal metabolic alterations in DS-AD that are similar to those seen in LOAD. The pattern of results in this cross-sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non-demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS-AD

Teaching and Learning In, With and For Community: Towards a pedagogy for education for sustainable development

The paper explores how one teaches and learns for sustainable development primarily through analysing education for sustainable development (ESD) initiatives in the Caribbean within the framework of service learning. The paper proposes that a pedagogy for ESD will require positioning education in the centre of community. What that means in terms of content and methodology is the focus of our discussion

Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling

To study the mechanisms of death following a single lethal dose of thoracic radiation, WAG/RijCmcr (Wistar) rats were treated with 15 Gy to the whole thorax and followed until they were morbid or sacrificed for invasive assays at 6 weeks. Lung function was assessed by breathing rate and arterial oxygen saturation. Lung structure was evaluated histologically. Cardiac structure and function were examined by echocardiography. The frequency and characteristics of pleural effusions were determined. Morbidity from 15 Gy radiation occurred in all rats 5 to 8 weeks after exposure, coincident with histological pneumonitis. Increases in breathing frequencies peaked at 6 weeks, when profound arterial hypoxia was also recorded. Echocardiography analysis at 6 weeks showed pulmonary hypertension and severe right ventricular enlargement with impaired left ventricular function and cardiac output. Histologic sections of the heart revealed only rare foci of lymphocytic infiltration. Total lung weight more than doubled. Pleural effusions were present in the majority of the irradiated rats and contained elevated protein, but low lactate dehydrogenase, when compared with serum from the same animal. Pleural effusions had a higher percentage of macrophages and large monocytes than neutrophils and contained mast cells that are rarely present in other pathological states. Lethal irradiation to rat lungs leads to hypoxia with infiltration of immune cells, edema and pleural effusion. These changes may contribute to pulmonary vascular and parenchymal injury that result in secondary changes in heart structure and function. We report that conditions resembling congestive heart failure contribute to death during radiation pneumonitis, which indicates new targets for therapy

Stone roller as mowing aid

The Avondale Research Station is situated on land typical of many thousands of -*- acres of the Avon Valley—jam, wattle and York-gum country liberally dotted with stony outcrops. Despite the expenditure over the years of many man-hours on stone-picking:, the cutting of meadow hay was always a task involving frayed tempers, loss of time and a heavy bill for replacements of mower parts. Small stones, which were of no consequence in the working of a paddock with other types of machinery, jammed the mower knives with exasperating frequency. It was not a practicable proposition to make hundreds of acres entirely stone-free, so following upon consultations with experienced farmers and engineers it was decided to test a heavy roller to press the stones into the ground before mowing, and incidentally to level out minor irregularities on the soil surface

Neck circumference and clustered cardiovascular risk factors in children and adolescents: Cross-sectional study.

OBJECTIVE: Early detection of cardiovascular disease (CVD) risk factors, such as obesity, is crucial to prevent adverse long-term effects on individuals' health. Therefore, the aims were: (1) to explore the robustness of neck circumference (NC) as a predictor of CVD and examine its association with numerous anthropometric and body composition indices and (2) to release sex and age-specific NC cut-off values to classify youths as overweight/obese. DESIGN: Cross-sectional study. SETTING: 23 primary schools and 17 secondary schools from Spain. PARTICIPANTS: 2198 students (1060 girls), grades 1-4 and 7-10. MEASURES: Pubertal development, anthropometric and body composition indices, systolic and diastolic blood pressure (SBP and DBP, respectively), cardiorespiratory fitness, blood sampling triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), glucose and inflammatory markers. Homoeostasis model assessment (HOMA-IR) and cluster of CVD risk factors were calculated. RESULTS: NC was negatively associated with maximum oxygen consumption (R2=0.231, P<0.001 for boys; R2=0.018, P<0.001 for girls) and adiponectin (R2=0.049, P<0.001 for boys; R2=0.036, P<0.001 for girls); and positively associated with SBP, DBP, TC/HDL-c, TG, HOMA, complement factors C-3 and C-4, leptin and clustered CVD risk factor in both sexes (R2 from 0.035 to 0.353, P<0.01 for boys; R2 from 0.024 to 0.215, P<0.001 for girls). Moreover, NC was positively associated with serum C reactive protein and LDL-c only in boys (R2 from 0.013 to 0.055, P<0.05). CONCLUSION: NC is a simple, low-cost and practical screening tool of excess of upper body obesity and CVD risk factors in children and adolescents. Paediatricians can easily use it as a screening tool for overweight/obesity in children and adolescents. For this purpose, sex and age-specific thresholds to classify children and adolescents as normal weight or overweight/obese are provided.This work was supported by the DEP 2010 21662 C04 00 (DEP 2010 21662 C04 01: DEP 2010 21662 C04 02: DEP 2010 21662 C04 03: DEP 2010 21662 C04 04) grant from the National Plan for Research: Development and Innovation (R+D+i) MICINN

A functional methylome map of ulcerative colitis

The etiology of inflammatory bowel diseases is only partially explained by the current genetic risk map. It is hypothesized that environmental factors modulate the epigenetic landscape and thus contribute to disease susceptibility, manifestation, and progression. To test this, we analyzed DNA methylation (DNAm), a fundamental mechanism of epigenetic long-term modulation of gene expression. We report a three-layer epigenome-wide association study (EWAS) using intestinal biopsies from 10 monozygotic twin pairs (n = 20 individuals) discordant for manifestation of ulcerative colitis (UC). Genome-wide expression scans were generated using Affymetrix UG 133 Plus 2.0 arrays (layer 1). Genome-wide DNAm scans were carried out using Illumina 27k Infinium Bead Arrays to identify methylation variable positions (MVPs, layer 2), and MeDIP-chip on Nimblegen custom 385k Tiling Arrays to identify differentially methylated regions (DMRs, layer 3). Identified MVPs and DMRs were validated in two independent patient populations by quantitative real-time PCR and bisulfite-pyrosequencing (n = 185). The EWAS identified 61 disease-associated loci harboring differential DNAm in cis of a differentially expressed transcript. All constitute novel candidate risk loci for UC not previously identified by GWAS. Among them are several that have been functionally implicated in inflammatory processes, e.g., complement factor CFI, the serine protease inhibitor SPINK4, and the adhesion molecule THY1 (also known as CD90). Our study design excludes nondisease inflammation as a cause of the identified changes in DNAm. This study represents the first replicated EWAS of UC integrated with transcriptional signatures in the affected tissue and demonstrates the power of EWAS to uncover unexplained disease risk and molecular events of disease manifestation

Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications.

Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression

Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data

Background: MicroRNAs (miRNAs) are short, non-coding RNA regulators of protein coding genes. miRNAs play a very important role in diverse biological processes and various diseases. Many algorithms are able to predict miRNA genes and their targets, but their transcription regulation is still under investigation. It is generally believed that intragenic miRNAs (located in introns or exons of protein coding genes) are co-transcribed with their host genes and most intergenic miRNAs transcribed from their own RNA polymerase II (Pol II) promoter. However, the length of the primary transcripts and promoter organization is currently unknown. Methodology: We performed Pol II chromatin immunoprecipitation (ChIP)-chip using a custom array surrounding regions of known miRNA genes. To identify the true core transcription start sites of the miRNA genes we developed a new tool (CPPP). We showed that miRNA genes can be transcribed from promoters located several kilobases away and that their promoters share the same general features as those of protein coding genes. Finally, we found evidence that as many as 26% of the intragenic miRNAs may be transcribed from their own unique promoters. Conclusion: miRNA promoters have similar features to those of protein coding genes, but miRNA transcript organization is more complex. © 2009 Corcoran et al

Potential effects of oilseed rape expressing oryzacystatin-1 (OC-1) and of purified insecticidal proteins on larvae of the solitary bee Osmia bicornis

Despite their importance as pollinators in crops and wild plants, solitary bees have not previously been included in non-target testing of insect-resistant transgenic crop plants. Larvae of many solitary bees feed almost exclusively on pollen and thus could be highly exposed to transgene products expressed in the pollen. The potential effects of pollen from oilseed rape expressing the cysteine protease inhibitor oryzacystatin-1 (OC-1) were investigated on larvae of the solitary bee Osmia bicornis (= O. rufa). Furthermore, recombinant OC-1 (rOC-1), the Bt toxin Cry1Ab and the snowdrop lectin Galanthus nivalis agglutinin (GNA) were evaluated for effects on the life history parameters of this important pollinator. Pollen provisions from transgenic OC-1 oilseed rape did not affect overall development. Similarly, high doses of rOC-1 and Cry1Ab as well as a low dose of GNA failed to cause any significant effects. However, a high dose of GNA (0.1%) in the larval diet resulted in significantly increased development time and reduced efficiency in conversion of pollen food into larval body weight. Our results suggest that OC-1 and Cry1Ab expressing transgenic crops would pose a negligible risk for O. bicornis larvae, whereas GNA expressing plants could cause detrimental effects, but only if bees were exposed to high levels of the protein. The described bioassay with bee brood is not only suitable for early tier non-target tests of transgenic plants, but also has broader applicability to other crop protection products

‘Sons of athelings given to the earth’: Infant Mortality within Anglo-Saxon Mortuary Geography

FOR 20 OR MORE YEARS early Anglo-Saxon archaeologists have believed children are underrepresented in the cemetery evidence. They conclude that excavation misses small bones, that previous attitudes to reporting overlook the very young, or that infants and children were buried elsewhere. This is all well and good, but we must be careful of oversimplifying compound social and cultural responses to childhood and infant mortality. Previous approaches have offered methodological quandaries in the face of this under-representation. However, proportionally more infants were placed in large cemeteries and sometimes in specific zones. This trend is statistically significant and is therefore unlikely to result entirely from preservation or excavation problems. Early medieval cemeteries were part of regional mortuary geographies and provided places to stage events that promoted social cohesion across kinship systems extending over tribal territories. This paper argues that patterns in early Anglo-Saxon infant burial were the result of female mobility. Many women probably travelled locally to marry in a union which reinforced existing social networks. For an expectant mother, however, the safest place to give birth was with experience women in her maternal home. Infant identities were affected by personal and legal association with their mother’s parental kindred, so when an infant died in childbirth or months and years later, it was their mother’s identity which dictated burial location. As a result, cemeteries central to tribal identities became places to bury the sons and daughters of a regional tribal aristocracy