921 resultados para Elaine Albirght
Resumo:
Understanding the metabolic processes associated with aging is key to developing effective management and treatment strategies for age-related diseases. We investigated the metabolic profiles associated with age in a Taiwanese and an American population. 1H NMR spectral profiles were generated for urine specimens collected from the Taiwanese Social Environment and Biomarkers of Aging Study (SEBAS; n = 857; age 54–91 years) and the Mid-Life in the USA study (MIDUS II; n = 1148; age 35–86 years). Multivariate and univariate linear projection methods revealed some common age-related characteristics in urinary metabolite profiles in the American and Taiwanese populations, as well as some distinctive features. In both cases, two metabolites—4-cresyl sulfate (4CS) and phenylacetylglutamine (PAG)—were positively associated with age. In addition, creatine and β-hydroxy-β-methylbutyrate (HMB) were negatively correlated with age in both populations (p < 4 × 10–6). These age-associated gradients in creatine and HMB reflect decreasing muscle mass with age. The systematic increase in PAG and 4CS was confirmed using ultraperformance liquid chromatography–mass spectrometry (UPLC–MS). Both are products of concerted microbial–mammalian host cometabolism and indicate an age-related association with the balance of host–microbiome metabolism.
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The pig is a single-stomached omnivorous mammal and is an important model of human disease and nutrition. As such, it is necessary to establish a metabolic framework from which pathology-based variation can be compared. Here, a combination of one and two-dimensional 1H and 13C nuclear magnetic resonance spectroscopy (NMR) and high-resolution magic angle spinning (HR-MAS) NMR was used to provide a systems overview of porcine metabolism via characterisation of the urine, serum, liver and kidney metabolomes. The metabolites observed in each of these biological compartments were found to be qualitatively comparable to the metabolic signature of the same biological matrices in humans and rodents. The data were modelled using a combination of principal components analysis and Venn diagram mapping. Urine represented the most metabolically distinct biological compartment studied, with a relatively greater number of NMR detectable metabolites present, many of which are implicated in gut-microbial co-metabolic processes. The major interspecies differences observed were in the phase II conjugation of extra-genomic metabolites; the pig was observed to conjugate p-cresol, a gut microbial metabolite of tyrosine, with glucuronide rather than sulfate as seen in man. These observations are important to note when considering the translatability of experimental data derived from porcine models.
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Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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Concordance in global office market cycles, Regional Studies. A large proportion of international real estate investment is concentrated in the office markets of the world's largest cities. However, many of these global cities are also key financial services centres, highlighting the possibility of reduced economic diversification from an investor's perspective. This paper assesses the degree of synchronization in cycles across twenty of the world's largest office markets, finding evidence of significant concordance across a large number of markets. The results highlight the problems associated with commonalities in the underlying economic bases of the markets. The concentration of investment also raises the possibility of common flow of funds effects that may further reduce diversification opportunities.
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Modeling aging and age-related pathologies presents a substantial analytical challenge given the complexity of gene−environment influences and interactions operating on an individual. A top-down systems approach is used to model the effects of lifelong caloric restriction, which is known to extend life span in several animal models. The metabolic phenotypes of caloric-restricted (CR; n = 24) and pair-housed control-fed (CF; n = 24) Labrador Retriever dogs were investigated by use of orthogonal projection to latent structures discriminant analysis (OPLS-DA) to model both generic and age-specific responses to caloric restriction from the 1H NMR blood serum profiles of young and older dogs. Three aging metabolic phenotypes were resolved: (i) an aging metabolic phenotype independent of diet, characterized by high levels of glutamine, creatinine, methylamine, dimethylamine, trimethylamine N-oxide, and glycerophosphocholine and decreasing levels of glycine, aspartate, creatine and citrate indicative of metabolic changes associated largely with muscle mass; (ii) an aging metabolic phenotype specific to CR dogs that consisted of relatively lower levels of glucose, acetate, choline, and tyrosine and relatively higher serum levels of phosphocholine with increased age in the CR population; (iii) an aging metabolic phenotype specific to CF dogs including lower levels of liproprotein fatty acyl groups and allantoin and relatively higher levels of formate with increased age in the CF population. There was no diet metabotype that consistently differentiated the CF and CR dogs irrespective of age. Glucose consistently discriminated between feeding regimes in dogs (≥312 weeks), being relatively lower in the CR group. However, it was observed that creatine and amino acids (valine, leucine, isoleucine, lysine, and phenylalanine) were lower in the CR dogs (<312 weeks), suggestive of differences in energy source utilization. 1H NMR spectroscopic analysis of longitudinal serum profiles enabled an unbiased evaluation of the metabolic markers modulated by a lifetime of caloric restriction and showed differences in the metabolic phenotype of aging due to caloric restriction, which contributes to longevity studies in caloric-restricted animals. Furthermore, OPLS-DA provided a framework such that significant metabolites relating to life extension could be differentiated and integrated with aging processes.
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The Plaut, McClelland, Seidenberg and Patterson (1996) connectionist model of reading was evaluated at two points early in its training against reading data collected from British children on two occasions during their first year of literacy instruction. First, the network’s non-word reading was poor relative to word reading when compared with the children. Second, the network made more non-lexical than lexical errors, the opposite pattern to the children. Three adaptations were made to the training of the network to bring it closer to the learning environment of a child: an incremental training regime was adopted; the network was trained on grapheme– phoneme correspondences; and a training corpus based on words found in children’s early reading materials was used. The modifications caused a sharp improvement in non-word reading, relative to word reading, resulting in a near perfect match to the children’s data on this measure. The modified network, however, continued to make predominantly non-lexical errors, although evidence from a small-scale implementation of the full triangle framework suggests that this limitation stems from the lack of a semantic pathway. Taken together, these results suggest that, when properly trained, connectionist models of word reading can offer insights into key aspects of reading development in children.
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Animal models are invaluable tools which allow us to investigate the microbiome-host dialogue. However, experimental design introduces biases in the data that we collect, also potentially leading to biased conclusions. With obesity at pandemic levels animal models of this disease have been developed; we investigated the role of experimental design on one such rodent model. We used 454 pyrosequencing to profile the faecal bacteria of obese (n = 6) and lean (homozygous n = 6; heterozygous n = 6) Zucker rats over a 10 week period, maintained in mixed-genotype cages, to further understand the relationships between the composition of the intestinal bacteria and age, obesity progression, genetic background and cage environment. Phylogenetic and taxon-based univariate and multivariate analyses (non-metric multidimensional scaling, principal component analysis) showed that age was the most significant source of variation in the composition of the faecal microbiota. Second to this, cage environment was found to clearly impact the composition of the faecal microbiota, with samples from animals from within the same cage showing high community structure concordance, but large differences seen between cages. Importantly, the genetically induced obese phenotype was not found to impact the faecal bacterial profiles. These findings demonstrate that the age and local environmental cage variables were driving the composition of the faecal bacteria and were more deterministically important than the host genotype. These findings have major implications for understanding the significance of functional metagenomic data in experimental studies and beg the question; what is being measured in animal experiments in which different strains are housed separately, nature or nurture?
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The school has been identified as a key setting to promote physical activity. The purpose of this study was to evaluate the effect of a classroom-based activity break on in-school step counts of primary school children. Data for 90 children (49 boys, 41 girls, 9.3 ± 1.4 years) from three Irish primary schools is presented. In each school one class was randomly assigned as the intervention group and another as controls. Children's step counts were measured for five consecutive days during school hours at baseline and follow-up. Teachers of the intervention classes led a 10 min activity break in the classroom each day (Bizzy Break!). Mean daily in-school steps for the intervention at baseline and follow-up were 5351 and 5054. Corresponding values for the control group were 5469 and 4246. There was a significant difference in the change in daily steps from baseline to follow-up between groups (p < .05). There was no evidence that girls and boys responded differently to the intervention (p > .05). Children participating in a daily 10 min classroom-based activity break undertake more physical activity during school hours than controls.
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The postnatal environment, including factors such as weaning and acquisition of the gut microbiota, has been causally linked to the development of later immunological diseases such as allergy and autoimmunity, and has also been associated with a predisposition to metabolic disorders. We show that the very early-life environment influences the development of both the gut microbiota and host metabolic phenotype in a porcine model of human infants. Farmpiglets were nursed by their mothers for 1 day, before removal to highly controlled, individual isolators where they received formula milk until weaning at 21 days. The experiment was repeated, to create two batches, which differed only in minor environmental fluctuations during the first day. At day 1 after birth, metabolic profiling of serum by 1H nuclear magnetic resonance spectroscopy demonstrated significant, systemic, inter-batch variation which persisted until weaning. However, the urinary metabolic profiles demonstrated that significant inter-batch effects on 3-hydroxyisovalerate, trimethylamine-N-oxide and mannitol persisted beyond weaning to at least 35 days. Batch effects were linked to significant differences in the composition of colonic microbiota at 35 days, determined by 16 S pyrosequencing. Different weaning diets modulated both the microbiota and metabolic phenotype independently of the persistent batch effects. We demonstrate that the environment during the first day of life influences development of the microbiota and metabolic phenotype and thus should be taken into account when interrogating experimental outcomes. In addition, we suggest that intervention at this early time could provide ‘metabolic rescue’ for at-risk infants who have undergone aberrant patterns of initial intestinal colonisation.
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The Pleasance was a ’virandarium’ or pleasure garden, constructed by Henry V in the grounds of his castle at Kenilworth. Despite its high academic profile and the survival of well-preserved earthwork remains, the Pleasance has never previously been subjected to a programme of detailed archaeological survey and investigation. This article discusses the results of a new analytical earthwork survey undertaken by staff from English Heritage in 2012. It considers the contribution that these new findings make to the wider debate on medieval designed landscapes, with a particular focus on mobility and its role in unlocking the meaning and symbolism embedded in elite landscapes.
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When travelling north-east across the Somerset Levels and Moors the eye is drawn to the dark mass of the Mendip Hills, a Carboniferous Limestone ridge which rises abruptly from the flatness of its surroundings. The Historic Landscape of the Mendip Hills explores the archaeology and architecture of this remarkable corner of England, beginning with evidence for the first hunting groups who passed through the region over half a million years ago. Succeeding generations have left their mark on the Hills, from the enigmatic ceremonial structures of the Neolithic and Early Bronze Age, to the ancient farming landscapes and brooding hillforts of the Later Prehistoric period. Field archaeology, combined with architectural and historical enquiry, has also allowed a complex narrative to be constructed for more recent periods of history. This is a story dominated by adaptation and change, evidenced by the developing architecture of manorial centres and the shadowy remains of earlier structures fossilized within village houses. This volume presents a synthesis of the results of recent fieldwork undertaken by English Heritage and traces this region’s remarkable past, revealing ways in which it has shaped the landscape we see and value today.
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Nitric oxide synthase (NOS) has been reported to be involved with both bone healing and bone metabolism. The aim of this study was to test the null hypothesis that there is no correlation between new bone formation during mandibular distraction osteogenesis and NOS expression in the trigeminal ganglion of rats. Newly formed tissue during distraction osteogenesis and trigeminal NOS expression measured by the NADPH-diaphorase (NADPH-d) reaction were evaluated in 72 male Wistar rats by histomorphometric and histochemical methods. In animals submitted to 0.5 mm/day distraction osteogenesis, the percentage of bone tissue was higher in the basal area of the mandibles compared with the center and significantly increased through the experimental periods (P < 0.05). At the sixth postoperative week, the difference in bone formation between the continuous and acute distraction osteogenesis groups was the highest. Significant correlation between new bone formation by distraction osteogenesis and NADPH-d-reactive neurons was found, varying according to neuronal cell size (r = -0.6, P = 0.005, small cells strongly stained; r = 0.5, P = 0.018, large cells moderately stained). The results suggest that NOS may play a role in the bone healing process via neurogenic pathways, and the phenomenon seems to be neuronal cell morphotype-dependent. Further studies are now warranted to investigate the mechanistic link between the expression of trigeminal NOS and mandibular new bone formation by distraction osteogenesis.