Level and course of FEV1 in relation to polymorphisms in NFE2L2 and KEAP1 in the general population

<p>Abstract</p> <p>Background</p> <p>The metabolism of xenobiotics plays an essential role in smoking related lung function loss and development of Chronic Obstructive Pulmonary Disease. Nuclear Factor Erythroid 2-Like 2 (NFE2L2 or NRF2) and its cytosolic repressor Kelch-like ECH-associated protein-1 (KEAP1) regulate transcription of enzymes involved in cellular detoxification processes and <it>Nfe2l2</it>-deficient mice develop tobacco-induced emphysema. We assessed the impact of Single Nucleotide Polymorphisms (SNPs) in both genes on the level and longitudinal course of Forced Expiratory Volume in 1 second (FEV₁) in the general population.</p> <p>Methods</p> <p>Five <it>NFE2L2 </it>and three <it>KEAP1 </it>tagging SNPs were genotyped in the population-based Doetinchem cohort (n = 1,152) and the independent Vlagtwedde-Vlaardingen cohort (n = 1,390). On average 3 FEV₁measurements during 3 surveys, respectively 7 FEV₁measurements during 8 surveys were present. Linear Mixed Effect models were used to test cross-sectional and longitudinal genetic effects on repeated FEV₁measurements.</p> <p>Results</p> <p>In the Vlagtwedde-Vlaardingen cohort SNP rs11085735 in <it>KEAP1 </it>was associated with a higher FEV₁level (p = 0.02 for an additive effect), and SNP rs2364723 in <it>NFE2L2 </it>was associated with a lower FEV₁level (p = 0.06). The associations were even more significant in the pooled cohort analysis. No significant association of <it>KEAP1 </it>or <it>NFE2L2 </it>SNPs with FEV₁decline was observed.</p> <p>Conclusion</p> <p>This is the first genetic study on variations in key antioxidant transcriptional regulators <it>KEAP1 </it>and <it>NFE2L2 </it>and lung function in a general population. It identified 2 SNPs in <it>NFE2L2 </it>and <it>KEAP1 </it>which affect the level of FEV₁in the general population. It additionally shows that <it>NFE2L2 </it>and <it>KEAP1 </it>variations are unlikely to play a role in the longitudinal course of FEV₁in the general population.</p

Introduction to semantic e-Science in biomedicine

The Semantic Web technologies provide enhanced capabilities that allow data and the meaning of the data to be shared and reused across application, enterprise, and community boundaries, better enabling integrative research and more effective knowledge discovery. This special issue is intended to give an introduction of the state-of-the-art of Semantic Web technologies and describe how such technologies would be used to build the e-Science infrastructure for biomedical communities. Six papers have been selected and included, featuring different approaches and experiences in a variety of biomedical domains

The First 30 Years of GEWEX

The Global Energy and Water Cycle Exchanges (GEWEX) project was created more than 30 years ago within the framework of the World Climate Research Programme (WCRP). The aim of this initiative was to address major gaps in our understanding of Earth's energy and water cycles given a lack of information about the basic fluxes and associated reservoirs of these cycles. GEWEX sought to acquire and set standards for climatological data on variables essential for quantifying water and energy fluxes and for closing budgets at the regional and global scales. In so doing, GEWEX activities led to a greatly improved understanding of processes and our ability to predict them. Such understanding was viewed then, as it remains today, essential for advancing weather and climate prediction from global to regional scales. GEWEX has also demonstrated over time the importance of a wider engagement of different communities and the necessity of international collaboration for making progress on understanding and on the monitoring of the changes in the energy and water cycles under ever increasing human pressures. This paper reflects on the first 30 years of evolution and progress that has occurred within GEWEX. This evolution is presented in terms of three main phases of activity. Progress toward the main goals of GEWEX is highlighted by calling out a few achievements from each phase. A vision of the path forward for the coming decade, including the goals of GEWEX for the future, are also described.</p

The First 30 years of GEWEX

International audienceAbstract The Global Energy and Water Cycle EXchanges (GEWEX) project was created more than thirty years ago within the framework of the World Climate Research Programme (WCRP). The aim of this initiative was to address major gaps in our understanding of Earth’s energy and water cycles given a lack of information about the basic fluxes and associated reservoirs of these cycles. GEWEX sought to acquire and set standards for climatological data on variables essential for quantifying water and energy fluxes and for closing budgets at the regional and global scales. In so doing, GEWEX activities led to a greatly improved understanding of processes and our ability to predict them. Such understanding was viewed then, as it remains today, essential for advancing weather and climate prediction from global to regional scales. GEWEX has also demonstrated over time the importance of a wider engagement of different communities and the necessity of international collaboration for making progress on understanding and on the monitoring of the changes in the energy and water cycles under ever increasing human pressures. This paper reflects on the first 30 years of evolution and progress that has occurred within GEWEX. This evolution is presented in terms of three main phases of activity. Progress toward the main goals of GEWEX is highlighted by calling out a few achievements from each phase. A vision of the path forward for the coming decade, including the goals of GEWEX for the future, are also described

The importance of crop growth modeling to interpret the Δ14CO2 signature of annual plants

[1] The 14C/C abundance in CO2(¿14CO2) promises to provide useful constraints on regional fossil fuel emissions and atmospheric transport through the large gradients introduced by anthropogenic activity. The currently sparse atmospheric ¿14CO2 monitoring network can potentially be augmented by using plant biomass as an integrated sample of the atmospheric ¿14CO2. But the interpretation of such an integrated sample requires knowledge about the day¿to¿day CO2 uptake of the sampled plants. We investigate here the required detail in daily plant growth variations needed to accurately interpret regional fossil fuel emissions from annual plant samples. We use a crop growth model driven by daily meteorology to reproduce daily fixation of ¿14CO2 in maize and wheat plants in the Netherlands in 2008. When comparing the integrated ¿14CO2 simulated with this detailed model to the values obtained when using simpler proxies for daily plant growth (such as radiation and temperature), we find differences that can exceed the reported measurement precision of ¿14CO2(~2‰). Furthermore, we show that even in the absence of any spatial differences in fossil fuel emissions, differences in regional weather can induce plant growth variations that result in spatial gradients of up to 3.5‰ in plant samples. These gradients are even larger when interpreting separate plant organs (leaves, stems, roots, or fruits), as they each develop during different time periods. Not accounting for these growth¿induced differences in ¿14CO2 in plant samples would introduce a substantial bias (1.5–2¿ppm) when estimating the fraction of atmospheric CO2 variations resulting from nearby fossil fuel emission

Evaluation of safety and efficacy of gefitinib ('iressa', zd1839) as monotherapy in a series of Chinese patients with advanced non-small-cell lung cancer: experience from a compassionate-use programme

BACKGROUND: The gefitinib compassionate-use programme has enabled >39,000 patients worldwide to receive gefitinib ('Iressa', ZD1839) treatment. This paper reports the outcome of gefitinib treatment in Chinese patients who enrolled into the 'Iressa' Expanded Access Programme (EAP) at the Peking Union Medical College Hospital. METHODS: Thirty-one patients with advanced or metastatic non-small-cell lung cancer (NSCLC) that had progressed after prior systemic chemotherapy were eligible to receive oral gefitinib 250 mg/day as part of the EAP. Treatment was continued until disease progression or unacceptable toxicity occurred. The impact of treatment on disease-related symptoms and quality of life (QoL) was evaluated with the Chinese versions of European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and QLQ-LC13). RESULTS: Gefitinib was well tolerated. Adverse events (AEs) were generally mild (grade1 and 2) and reversible. The most frequent AEs were acneform rash and diarrhoea. Only one patient withdrew from the study due to a drug-related AE. The objective tumour response rate was 35.5% (95% confidence interval [CI]: 18.6–52.3); median progression-free survival was 5.5 months (95% CI, 1.6 to 9.4); median overall survival was 11.5 months (95% CI, 5.6 to 17.3). The QoL response rates for five functioning scales and global QoL varied from 56–88%. The main symptom response rates varied from 44–84%. QoL and symptom response were correlated with objective tumour response. CONCLUSION: Gefitinib demonstrated safety and efficacy as monotherapy in this series of Chinese patients with advanced NSCLC and was also associated with remarkable symptom relief and improvement in QoL. Although clinical trials are needed to confirm these positive findings, the data suggest that treatment with gefitinib may be beneficial for some Chinese patients who do not respond to chemotherapy and have poor prognosis

Win-stay, lose-switch and public information strategies for patch fidelity of songbirds with rare extra-pair paternity

Determining where organisms breed and understanding why they breed in particular locations are fundamental biological questions with conservation implications. Breeding-site fidelity is common in migratory, territorial songbirds and is typically thought to occur following reproductive success with a social mate and success of nearby conspecifics. It is currently unknown if frequency of extra-pair paternity in a population influences use of information about reproductive success of nearby conspecifics for site fidelity decisions. We investigated patch fidelity of white-eyed vireos (Vireo griseus) based on reproductive success and quantified frequency of extra-pair paternity. We found support only for females making patch fidelity decisions following reproductive success with a social mate. Patch fidelity of males was not associated with reproductive success of nearby conspecifics, suggesting males may not use this information when extra-pair paternity is infrequent or the association is non-existent in this species

Genomic Tools for Evolution and Conservation in the Chimpanzee: Pan troglodytes ellioti Is a Genetically Distinct Population

In spite of its evolutionary significance and conservation importance, the population structure of the common chimpanzee, Pan troglodytes, is still poorly understood. An issue of particular controversy is whether the proposed fourth subspecies of chimpanzee, Pan troglodytes ellioti, from parts of Nigeria and Cameroon, is genetically distinct. Although modern high-throughput SNP genotyping has had a major impact on our understanding of human population structure and demographic history, its application to ecological, demographic, or conservation questions in non-human species has been extremely limited. Here we apply these tools to chimpanzee population structure, using ∼700 autosomal SNPs derived from chimpanzee genomic data and a further ∼100 SNPs from targeted re-sequencing. We demonstrate conclusively the existence of P. t. ellioti as a genetically distinct subgroup. We show that there is clear differentiation between the verus, troglodytes, and ellioti populations at the SNP and haplotype level, on a scale that is greater than that separating continental human populations. Further, we show that only a small set of SNPs (10–20) is needed to successfully assign individuals to these populations. Tellingly, use of only mitochondrial DNA variation to classify individuals is erroneous in 4 of 54 cases, reinforcing the dangers of basing demographic inference on a single locus and implying that the demographic history of the species is more complicated than that suggested analyses based solely on mtDNA. In this study we demonstrate the feasibility of developing economical and robust tests of individual chimpanzee origin as well as in-depth studies of population structure. These findings have important implications for conservation strategies and our understanding of the evolution of chimpanzees. They also act as a proof-of-principle for the use of cheap high-throughput genomic methods for ecological questions

Policy Adjustment in a Dynamic Economic Game

Making sequential decisions to harvest rewards is a notoriously difficult problem. One difficulty is that the real world is not stationary and the reward expected from a contemplated action may depend in complex ways on the history of an animal's choices. Previous functional neuroimaging work combined with principled models has detected brain responses that correlate with computations thought to guide simple learning and action choice. Those works generally employed instrumental conditioning tasks with fixed action-reward contingencies. For real-world learning problems, the history of reward-harvesting choices can change the likelihood of rewards collected by the same choices in the near-term future. We used functional MRI to probe brain and behavioral responses in a continuous decision-making task where reward contingency is a function of both a subject's immediate choice and his choice history. In these more complex tasks, we demonstrated that a simple actor-critic model can account for both the subjects' behavioral and brain responses, and identified a reward prediction error signal in ventral striatal structures active during these non-stationary decision tasks. However, a sudden introduction of new reward structures engages more complex control circuitry in the prefrontal cortex (inferior frontal gyrus and anterior insula) and is not captured by a simple actor-critic model. Taken together, these results extend our knowledge of reward-learning signals into more complex, history-dependent choice tasks. They also highlight the important interplay between striatum and prefrontal cortex as decision-makers respond to the strategic demands imposed by non-stationary reward environments more reminiscent of real-world tasks