Identifying individual differences of fluoxetine response in juvenile rhesus monkeys by metabolite profiling

Fluoxetine is the only psychopharmacological agent approved for depression by the US Food and Drug Administration for children and is commonly used therapeutically in a variety of neurodevelopmental disorders. Therapeutic response shows high individual variability, and severe side effects have been observed. In the current study we set out to identify biomarkers of response to fluoxetine as well as biomarkers that correlate with impulsivity, a measure of reward delay behavior and potential side effect of the drug, in juvenile male rhesus monkeys. The study group was also genotyped for polymorphisms of monoamine oxidase A (MAOA), a gene that has been associated with psychiatric disorders. We used peripheral metabolite profiling of blood and cerebrospinal fluid (CSF) from animals treated daily with fluoxetine or vehicle for one year. Fluoxetine response metabolite profiles and metabolite/reward delay behavior associations were evaluated using multivariate analysis. Our analyses identified a set of plasma and CSF metabolites that distinguish fluoxetine-from vehicle-treated animals and metabolites that correlate with impulsivity. Some metabolites displayed an interaction between fluoxetine and MAOA genotype. The identified metabolite biomarkers belong to pathways that have important functions in central nervous system physiology. Biomarkers of response to fluoxetine in the normally functioning brain of juvenile nonhuman primates may aid in finding predictors of response to treatment in young psychiatric populations and in progress toward the realization of a precision medicine approach in the area of neurodevelopmental disorders

Simulating Changes in Regional Air Pollution over the Eastern United States Due to Changes in Global and Regional Climate and Emissions

[1] To simulate ozone (O3) air quality in future decades over the eastern United States, a modeling system consisting of the NASA Goddard Institute for Space Studies Atmosphere-Ocean Global Climate Model, the Pennsylvania State University/National Center for Atmospheric Research mesoscale regional climate model (MM5), and the Community Multiscale Air Quality model has been applied. Estimates of future emissions of greenhouse gases and ozone precursors are based on the A2 scenario developed by the Intergovernmental Panel on Climate Change (IPCC), one of the scenarios with the highest growth of CO2 among all IPCC scenarios. Simulation results for five summers in the 2020s, 2050s, and 2080s indicate that summertime average daily maximum 8-hour O3 concentrations increase by 2.7, 4.2, and 5.0 ppb, respectively, as a result of regional climate change alone with respect to five summers in the 1990s. Through additional sensitivity simulations for the five summers in the 2050s the relative impact of changes in regional climate, anthropogenic emissions within the modeling domain, and changed boundary conditions approximating possible changes of global atmospheric composition was investigated. Changed boundary conditions are found to be the largest contributor to changes in predicted summertime average daily maximum 8-hour O3 concentrations (5.0 ppb), followed by the effects of regional climate change (4.2 ppb) and the effects of increased anthropogenic emissions (1.3 ppb). However, when changes in the fourth highest summertime 8-hour O3 concentration are considered, changes in regional climate are the most important contributor to simulated concentration changes (7.6 ppb), followed by the effect of increased anthropogenic emissions (3.9 ppb) and increased boundary conditions (2.8 ppb). Thus, while previous studies have pointed out the potentially important contribution of growing global emissions and intercontinental transport to O3 air quality in the United States for future decades, the results presented here imply that it may be equally important to consider the effects of a changing climate when planning for the future attainment of regional-scale air quality standards such as the U.S. national ambient air quality standard that is based on the fourth highest annual daily maximum 8-hour O3 concentration

Computationally designed libraries of fluorescent proteins evaluated by preservation and diversity of function

To determine which of seven library design algorithms best introduces new protein function without destroying it altogether, seven combinatorial libraries of green fluorescent protein variants were designed and synthesized. Each was evaluated by distributions of emission intensity and color compiled from measurements made in vivo. Additional comparisons were made with a library constructed by error-prone PCR. Among the designed libraries, fluorescent function was preserved for the greatest fraction of samples in a library designed by using a structure-based computational method developed and described here. A trend was observed toward greater diversity of color in designed libraries that better preserved fluorescence. Contrary to trends observed among libraries constructed by error-prone PCR, preservation of function was observed to increase with a library's average mutation level among the four libraries designed with structure-based computational methods

Frequency analysis of air quality time series for traffic related pollutants

In the present work, annual time series of traffic related pollutants (CO and PM10) were considered for frequency analysis (Fourier series) with the aim to understand the underlying physical processes and the influence of emission sources on the variability of the air pollutant concentrations. Several urban traffic and suburban background air quality stations located in Porto metropolitan area (Portugal) were analysed. The results obtained for CO and PM10 reveal the important contributions of short-term fluctuations (12 h and 24 h periods). However, the spectrum signals at low frequencies are significantly different between these pollutants thus stressing that temporal variations of CO and PM10 are influenced by different processes. Cross-spectrum analysis of the air quality time series against wind measurements and traffic counts allowed us to identify the contribution of long-range transport over a period of about 21 days to the PM10 fluctuations. Also, a correlation of over 80% between the pollution levels in the vicinity of traffic sources and suburban background levels are found for these harmonic components in the PM10 spectrum, while correlations for CO is below a significant level. Thus, the spectrum and cross-spectrum analysis performed in this study reveal the distinct influence of local traffic emissions and long-range transport to CO and PM10 fluctuations in the polluted urban area. The methodology shows to be a powerful tool for the analysis of the causes of air pollution

Crystal structure of a thermostable Bacillus DNA polymerase l large fragment at 2.1 Å resolution

AbstractBackground: The study of DNA polymerases in the Pol l family is central to the understanding of DNA replication and repair. DNA polymerases are used in many molecular biology techniques, including PCR, which require a thermostable polymerase. In order to learn about Pol l function and the basis of thermostability, we undertook structural studies of a new thermostable DNA polymerase.Results: A DNA polymerase large, Klenow-like, fragment from a recently identified thermostable strain of Bacillus stearothermophilus (BF) was cloned, sequenced, overexpressed and characterized. Its crystal structure was determined to 2.1 Å resolution by the method of multiple isomorphous replacement.Conclusions: This structure represents the highest resolution view of a Pol l enzyme obtained to date. Comparison of the three Pol l structures reveals no compelling evidence for many of the specific interactions that have been proposed to induce thermostability, but suggests that thermostability arises from innumerable small changes distributed throughout the protein structure. The polymerase domain is highly conserved in all three proteins. The N-terminal domains are highly divergent in sequence, but retain a common fold. When present, the 3′-5′ proofreading exonuclease activity is associated with this domain. Its absence is associated with changes in catalytic residues that coordinate the divalent ions required for activity and in loops connecting homologous secondary structural elements. In BF, these changes result in a blockage of the DNA-binding cleft

Air quality assessment for Portugal

According to the Air Quality Framework Directive, air pollutant concentration levels have to be assessed and reported annually by each European Union member state, taking into consideration European air quality standards. Plans and programmes should be implemented in zones and agglomerations where pollutant concentrations exceed the limit and target values. The main objective of this study is to perform a long-term air quality simulation for Portugal, using the CHIMERE chemistry-transport model, applied over Portugal, for the year 2001. The model performance was evaluated by comparing its results to air quality data from the regional monitoring networks and to data from a diffusive sampling experimental campaign. The results obtained show a modelling system able to reproduce the pollutant concentrations' temporal evolution and spatial distribution observed at the regional networks of air quality monitoring. As far as the fulfilment of the air quality targets is concerned, there are excessive values for nitrogen and sulfur dioxides, ozone also being a critical gaseous pollutant in what concerns hourly concentrations and AOT40 (Accumulated Over Threshold 40 ppb) values

Climate Change, Tropospheric Ozone and Particulate Matter, and Health Impacts

We review how climate change could affect future concentrations of tropospheric ozone and particulate matter (PM), and what changing concentrations could mean for population health, as well as studies projecting the impacts of climate change on air quality and the impacts of these changes on morbidity/mortality. Climate change could affect local to regional air quality through changes in chemical reaction rates, boundary layer heights that affect vertical mixing of pollutants, and changes in synoptic airflow patterns that govern pollutant transport. Sources of uncertainty are the degree of future climate change, future emissions of air pollutants and their precursors, and how population vulnerability may change in the future. Given the uncertainties, projections suggest that climate change will increase concentrations of tropospheric ozone, at least in high-income countries when precursor emissions are held constant, increasing morbidity/mortality. There are few projections for low- and middle-income countries. The evidence is less robust for PM, because few studies have been conducted. More research is needed to better understand the possible impacts of climate change on air pollution-related health impacts

Long-term trends in total inorganic nitrogen and sulfur deposition in the US from 1990 to 2010

Excess deposition (including both wet and dry deposition) of nitrogen and sulfur is detrimental to ecosystems. Recent studies have investigated the spatial patterns and temporal trends of nitrogen and sulfur wet deposition, but few studies have focused on dry deposition due to the scarcity of dry deposition measurements. Here, we use long-term model simulations from the coupled Weather Research and Forecasting and the Community Multiscale Air Quality (WRF-CMAQ) model covering the period from 1990 to 2010 to study changes in spatial distribution as well as temporal trends in total (TDEP), wet (WDEP), and dry deposition (DDEP) of total inorganic nitrogen (TIN) and sulfur (TS) in the United States (US). We first evaluate the model's performance in simulating WDEP over the US by comparing the model results with observational data from the US National Atmospheric Deposition Program. The coupled model generally underestimates the WDEP of both TIN (including both the oxidized nitrogen deposition, TNO3, and the reduced nitrogen deposition, NHx) and TS, with better performance in the eastern US than the western US. The underestimation of the wet deposition by the model is mainly caused by the coarse model grid resolution, missing lightning NOx emissions, and the poor temporal and spatial representation of NH3 emissions. TDEP of both TIN and TS shows significant decreases over the US, especially in the east, due to the large emission reductions that occurred in that region. The decreasing trends of TIN TDEP are caused by decreases in TNO3, and the increasing trends of TIN deposition over the Great Plains and Tropical Wet Forests (Southern Florida Coastal Plain) regions are caused by increases in NH3 emissions, although it should be noted that these increasing trends are not significant. TIN WDEP shows decreasing trends throughout the US, except for the Marine West Coast Forest region. TIN DDEP shows significant decreasing trends in the Eastern Temperate Forests, Northern Forests, Mediterranean California, and Marine West Coast Forest and significant increasing trends in the Tropical Wet Forests, Great Plains and Southern Semi-arid Highlands. For the other three regions (North American Deserts, Temperate Sierras, and Northwestern Forested Mountains), the decreasing or increasing trends are not significant. Both the WDEP and DDEP of TS have decreases across the US, with a larger decreasing trend in the DDEP than that in the WDEP. Across the US during the 1990–2010 period, DDEP of TIN accounts for 58–65 % of TDEP of TIN. TDEP of TIN over the US is dominated by deposition of TNO3 during the first decade, which then shifts to reduced nitrogen (NHx) dominance after 2003, resulting from a combination of NOx emission reductions and NH3 emission increases. The sulfur DDEP is usually higher than the sulfur WDEP until recent years, as the sulfur DDEP has a larger decreasing trend than WDEP

Myocardial Perfusion Reserve but not fibrosis predicts outcomes in initially asymptomatic patients with moderate to severe aortic stenosis : the PRognostic Importance of MIcrovascular Dysfunction in AS study- PRIMID AS

Peer reviewedPublisher PD