The functional interpretation of high throughput metabolomics by mass spectrometry is hindered by the identification of metabolites, a tedious and challenging task. We present a set of computational ...algorithms which, by leveraging the collective power of metabolic pathways and networks, predict functional activity directly from spectral feature tables without a priori identification of metabolites. The algorithms were experimentally validated on the activation of innate immune cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer's disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to ...develop new prognostic measures and enhanced stratification for clinical trials. Here, we studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer's disease pathology. Twenty-six patients (n = 12 with clinically probable Alzheimer's dementia and n = 14 with amyloid-positive mild cognitive impairment) and 29 healthy control subjects underwent baseline assessment with 18F-AV-1451 PET, 11C-PK11195 PET, and structural MRI. Cognition was examined annually over the subsequent 3 years using the revised Addenbrooke's Cognitive Examination. Regional grey matter volumes, and regional binding of 18F-AV-1451 and 11C-PK11195 were derived from 15 temporo-parietal regions characteristically affected by Alzheimer's disease pathology. A principal component analysis was used on each imaging modality separately, to identify the main spatial distributions of pathology. A latent growth curve model was applied across the whole sample on longitudinal cognitive scores to estimate the rate of annual decline in each participant. We regressed the individuals' estimated rate of cognitive decline on the neuroimaging components and examined univariable predictive models with single-modality predictors, and a multi-modality predictive model, to identify the independent and combined prognostic value of the different neuroimaging markers. Principal component analysis identified a single component for the grey matter atrophy, while two components were found for each PET ligand: one weighted to the anterior temporal lobe, and another weighted to posterior temporo-parietal regions. Across the whole-sample, the single-modality models indicated significant correlations between the rate of cognitive decline and the first component of each imaging modality. In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline. We conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer's disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer's disease, over and above MRI measures of brain atrophy and demographic data. Our findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer's disease.
Greenspace is theoretically a valuable resource for physical activity and hence has potential to contribute to reducing obesity and improving health. This paper reports on a systematic review of ...quantitative research examining the association between objectively measured access to greenspace and (i) Physical activity, (ii) Weight status and (iii) Health conditions related to elevated weight. Literature searches were conducted in SCOPUS, Medline, Embase and PYSCHINFO. Sixty studies met the inclusion criteria and were assessed for methodological quality and strength of the evidence. The majority (68%) of papers found a positive or weak association between greenspace and obesity-related health indicators, but findings were inconsistent and mixed across studies. Several studies found the relationship varied by factors such as age, socioeconomic status and greenspace measure. Developing a theoretical framework which considers the correlates and interactions between different types of greenspace and health would help study design and interpretation of reported findings, as would improvement in quality and consistency of greenspace access measures. Key areas for future research include investigating if and how people actually use greenspace and improving understanding of the mechanisms through which greenspace can improve health and, in particular, if physical activity is one such mechanism.
Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the ...mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.
Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review.
Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia.
Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
'Reactive oxygen species' (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell ...damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H
O
and O
. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H
O
, O
and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O
levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.
Genetics ultimately defines an individual, yet the phenotype of an adult is extensively determined by the sequence of lifelong exposures, termed the exposome. The redox theory of aging recognizes ...that animals evolved within an oxygen-rich environment, which created a critical redox interface between an organism and its environment. Advances in redox biology show that redox elements are present throughout metabolic and structural systems and operate as functional networks to support the genome in adaptation to environmental resources and challenges during lifespan. These principles emphasize that physical and functional phenotypes of an adult are determined by gene-environment interactions from early life onward. The principles highlight the critical nature of cumulative exposure memories in defining changes in resilience progressively during life. Both plasma glutathione and cysteine systems become oxidized with aging, and the recent finding that cystine to glutathione ratio in human plasma predicts death in coronary artery disease (CAD) patients suggests this could provide a way to measure resilience of redox networks in aging and disease. The emerging concepts of cumulative gene-environment interactions warrant focused efforts to elucidate central mechanisms by which exposure memory governs health and etiology, onset and progression of disease.
Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and ...treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.
This study is an extensive revision of the Climatic Research Unit (CRU) land station temperature database that has been used to produce a grid‐box data set of 5° latitude × 5° longitude temperature ...anomalies. The new database (CRUTEM4) comprises 5583 station records of which 4842 have enough data for the 1961–1990 period to calculate or estimate the average temperatures for this period. Many station records have had their data replaced by newly homogenized series that have been produced by a number of studies, particularly from National Meteorological Services (NMSs). Hemispheric temperature averages for land areas developed with the new CRUTEM4 data set differ slightly from their CRUTEM3 equivalent. The inclusion of much additional data from the Arctic (particularly the Russian Arctic) has led to estimates for the Northern Hemisphere (NH) being warmer by about 0.1°C for the years since 2001. The NH/Southern Hemisphere (SH) warms by 1.12°C/0.84°C over the period 1901–2010. The robustness of the hemispheric averages is assessed by producing five different analyses, each including a different subset of 20% of the station time series and by omitting some large countries. CRUTEM4 is also compared with hemispheric averages produced by reanalyses undertaken by the European Centre for Medium‐Range Weather Forecasts (ECMWF): ERA‐40 (1958–2001) and ERA‐Interim (1979–2010) data sets. For the NH, agreement is good back to 1958 and excellent from 1979 at monthly, annual, and decadal time scales. For the SH, agreement is poorer, but if the area is restricted to the SH north of 60°S, the agreement is dramatically improved from the mid‐1970s.
Key Points
Revised and updated version of a data set
Series robust to numerous choices
Series agrees with reanalysis output since 1970s
This study examines the association between objectively measured access to green space, frequency of green space use, physical activity, and the probability of being overweight or obese in the city ...of Bristol, England. Data from the 2005 Bristol Quality of Life in your Neighbourhood survey for 6821 adults were combined with a comprehensive GIS database of neighbourhood and green space characteristics. A range of green space accessibility measures were computed. Associations between accessibility and the odds of respondents achieving a recommended 30min or more of moderate activity five times a week, or being overweight or obese, were examined using logistic regression. Results showed that the reported frequency of green space use declined with increasing distance. The study also found that respondents living closest to the type of green space classified as a Formal park were more likely to achieve the physical activity recommendation and less likely to be overweight or obese. The association with physical activity, but not with overweight or obesity, remained after adjustment for respondent characteristics, area deprivation, and a range of characteristics of the neighbourhood environment. The findings suggest that the provision of good access to green spaces in urban areas may help promote population physical activity.
Redox theory of aging Jones, Dean P
Redox biology,
08/2015, Letnik:
5
Journal Article
Recenzirano
Odprti dostop
Metazoan genomes encode exposure memory systems to enhance survival and reproductive potential by providing mechanisms for an individual to adjust during lifespan to environmental resources and ...challenges. These systems are inherently redox networks, arising during evolution of complex systems with O2 as a major determinant of bioenergetics, metabolic and structural organization, defense, and reproduction. The network structure decreases flexibility from conception onward due to differentiation and cumulative responses to environment (exposome). The redox theory of aging is that aging is a decline in plasticity of genome-exposome interaction that occurs as a consequence of execution of differentiation and exposure memory systems. This includes compromised mitochondrial and bioenergetic flexibility, impaired food utilization and metabolic homeostasis, decreased barrier and defense capabilities and loss of reproductive fidelity and fecundity. This theory accounts for hallmarks of aging, including failure to maintain oxidative or xenobiotic defenses, mitochondrial integrity, proteostasis, barrier structures, DNA repair, telomeres, immune function, metabolic regulation and regenerative capacity.
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