Recent research has proposed integrating wastewater treatment with algae cultivation as a way of producing algal biofuels at a commercial scale more sustainably. This study evaluates the environmental performance of wastewater-based algal biofuels with a well-to-wheel life cycle assessment (LCA). Production pathways examined include different nutrient sources (municipal wastewater influent to the activated sludge process, centrate from the sludge drying process, swine manure, and freshwater with synthetic fertilizers) combined with emerging biomass conversion technologies (microwave pyrolysis, combustion, wet lipid extraction, and hydrothermal liquefaction). Results show that the environmental performance of wastewater-based algal biofuels is generally better than freshwater-based algal biofuels, but depends on the characteristics of the wastewater and the conversion technologies. Of 16 pathways compared, only the centrate cultivation with wet lipid extraction pathway and the centrate cultivation with combustion pathway have lower impacts than petroleum diesel in all environmental categories examined (fossil fuel use, greenhouse gas emissions, eutrophication potential, and consumptive water use). The potential for large-scale implementation of centrate-based algal biofuel, however, is limited by availability of centrate. Thus, it is unlikely that algal biofuels can provide a large-scale and environmentally preferable alternative to petroleum transportation fuels without considerable improvement in current production technologies. Additionally, the cobenefit of wastewater-based algal biofuel production as an alternate means of treating various wastewaters should be further explored.
The study's aim was to deepen our understanding of family physicians' perceptions of the strengths and weaknesses of the widely used US documentation, coding, and billing rules for primary care evaluation and management (E/M) services.
We tested the hypothesis that higher-intensity interval training (HIIT) could be deployed into a standard cardiac rehabilitation (CR) setting and would result in a greater increase in cardiorespiratory fitness (ie, peak oxygen uptake, (·)VO?) versus moderate-intensity continuous training (MCT).
Organisms can be affected by processes in the surrounding landscape outside the boundary of habitat areas and by local vegetation characteristics. There is substantial interest in understanding how these processes affect populations of grassland birds, which have experienced substantial population declines. Much of our knowledge regarding patterns of occupancy and density stem from prairie systems, whereas relatively little is known regarding how occurrence and abundance of grassland birds vary in reclaimed surface mine grasslands. Using distance sampling and single-season occupancy models, we investigated how the occupancy probability of Grasshopper (Ammodramus savannarum) and Henslow's Sparrows (A. henslowii) on 61 surface mine grasslands (1591 ha) in Pennsylvania changed from 2002 through 2011 in response to landscape, grassland, and local vegetation characteristics . A subset (n = 23; 784 ha) of those grasslands were surveyed in 2002, and we estimated changes in sparrow density and vegetation across 10 years. Grasshopper and Henslow's Sparrow populations declined 72% and 49%, respectively from 2002 to 2011, whereas overall woody vegetation density increased 2.6 fold. Henslow's Sparrows avoided grasslands with perimeter-area ratios ?0.141 km/ha and woody shrub densities ?0.04 shrubs/m(2). Both species occupied grasslands ?13 ha, but occupancy probability declined with increasing grassland perimeter-area ratio and woody shrub density. Grassland size, proximity to nearest neighboring grassland (x = 0.2 km), and surrounding landscape composition at 0.5, 1.5, and 3.0 km were not parsimonious predictors of occupancy probability for either species. Our results suggest that reclaimed surface mine grasslands, without management intervention, are ephemeral habitats for Grasshopper and Henslow's Sparrows. Given the forecasted decline in surface coal production for Pennsylvania, it is likely that both species will continue to decline in our study region for the foreseeable future.
A variety of clinical research training programs exist throughout the United States, although little is known about their methods, content, and outcomes. This report describes a model of clinical research training designed to teach medical students research processes in family medicine, while yielding data for research studies. Authors present a description and evaluation of the program, focusing on students' research productivity.
Grassland bird species have experienced substantial declines in North America. These declines have been largely attributed to habitat loss and degradation, especially from agricultural practices and intensification (the habitat-availability hypothesis). A recent analysis of North American Breeding Bird Survey (BBS) "grassland breeding" bird trends reported the surprising conclusion that insecticide acute toxicity was a better correlate of grassland bird declines in North America from 1980-2003 (the insecticide-acute-toxicity hypothesis) than was habitat loss through agricultural intensification. In this paper we reached the opposite conclusion. We used an alternative statistical approach with additional habitat covariates to analyze the same grassland bird trends over the same time frame. Grassland bird trends were positively associated with increases in area of Conservation Reserve Program (CRP) lands and cropland used as pasture, whereas the effect of insecticide acute toxicity on bird trends was uncertain. Our models suggested that acute insecticide risk potentially has a detrimental effect on grassland bird trends, but models representing the habitat-availability hypothesis were 1.3-21.0 times better supported than models representing the insecticide-acute-toxicity hypothesis. Based on point estimates of effect sizes, CRP area and agricultural intensification had approximately 3.6 and 1.6 times more effect on grassland bird trends than lethal insecticide risk, respectively. Our findings suggest that preserving remaining grasslands is crucial to conserving grassland bird populations. The amount of grassland that has been lost in North America since 1980 is well documented, continuing, and staggering whereas insecticide use greatly declined prior to the 1990s. Grassland birds will likely benefit from the de-intensification of agricultural practices and the interspersion of pastures, Conservation Reserve Program lands, rangelands and other grassland habitats into existing agricultural landscapes.
The Renewable Fuel Standard (RFS2) in the U.S. Energy Independence and Security Act of 2007 (EISA) sets annual volume targets for domestic renewable transportation fuel consumption through 2022, but allows for flexibility in the types of biomass used for biofuels and where and how they are grown. Spatially explicit feedstock scenarios for how the agricultural and forestry sectors can produce sufficient biomass to meet these targets have been developed by the U.S. Department of Energy (DOE), the U.S. Environmental Protection Agency (EPA), and the U.S. Department of Agriculture (USDA). Here we compare the models used to generate these scenarios and their underlying assumptions on crop yields, feedstock prices, biofuel conversion efficiencies, land availability, and other critical factors. We find key differences in the amount of land devoted to different biomass sources and their geographic distribution, most notably for perennial grasses. These different visions of land use and management for bioenergy in the U.S. are currently being used both for regulation and to set research funding priorities. Understanding the key assumptions and uncertainties that underlie these scenarios is important for accurate assessment of the potential economic and environmental impacts of RFS2, as well as for optimal design of future energy and agricultural policy.
The aim of our study was to deepen our understanding of the factors that may explain the observational literature that more primary care physicians in an area contribute to better population health outcomes and lower health care costs.
Greenhouse gas emissions associated with pesticide applications against invasive species constitute an environmental cost of species invasions that has remained largely unrecognized. Here we calculate greenhouse gas emissions associated with the invasion of an agricultural pest from Asia to North America. The soybean aphid, Aphis glycines, was first discovered in North America in 2000, and has led to a substantial increase in insecticide use in soybeans. We estimate that the manufacture, transport, and application of insecticides against soybean aphid results in approximately 10.6 kg of carbon dioxide (CO2) equivalent greenhouse gasses being emitted per hectare of soybeans treated. Given the acreage sprayed, this has led to annual emissions of between 6 and 40 million kg of CO2 equivalent greenhouse gasses in the United States since the invasion of soybean aphid, depending on pest population size. Emissions would be higher were it not for the development of a threshold aphid density below which farmers are advised not to spray. Without a threshold, farmers tend to spray preemptively and the threshold allows farmers to take advantage of naturally occurring biological control of the soybean aphid, which can be substantial. We find that adoption of the soybean aphid economic threshold can lead to emission reductions of approximately 300 million kg of CO2 equivalent greenhouse gases per year in the United States. Previous studies have documented that biological control agents such as lady beetles are capable of suppressing aphid densities below this threshold in over half of the soybean acreage in the U.S. Given the acreages involved this suggests that biological control results in annual emission reductions of over 200 million kg of CO2 equivalents. These analyses show how interactions between invasive species and organisms that suppress them can interact to affect greenhouse gas emissions.
Melioidosis is an emerging infectious disease of humans and animals in the tropics caused by the soil bacterium Burkholderia pseudomallei. Despite high fatality rates, the ecology of B.pseudomallei remains unclear. We used a combination of field and laboratory studies to investigate B.pseudomallei colonization of native and exotic grasses in northern Australia. Multivariable and spatial analyses were performed to determine significant predictors for B.pseudomallei occurrence in plants and soil collected longitudinally from field sites. In plant inoculation experiments, the impact of B.pseudomallei upon these grasses was studied and the bacterial load semi-quantified. Fluorescence in situ hybridization and confocal laser scanning microscopy were performed to localize the bacteria in plants. Burkholderia pseudomallei was found to inhabit not only the rhizosphere and roots but also aerial parts of specific grasses. This raises questions about the potential spread of B.pseudomallei by grazing animals whose droppings were found to be positive for these bacteria. In particular, B.pseudomallei readily colonized exotic grasses introduced to Australia for pasture. The ongoing spread of these introduced grasses creates new habitats suitable for B.pseudomallei survival and may be an important factor in the evolving epidemiology of melioidosis seen both in northern Australia and elsewhere globally.
The physiological reaction of CSF white blood cells (WBCs) over the course of treating a shunt infection is undefined. The authors speculated that the CSF WBC count varies with different infecting organisms in peak level and differential percentage of polymorphonuclear (PMN) leukocytes, lymphocytes, monocytes, and eosinophils. The authors hope to identify clinically useful trends in the progression of CSF WBCs by analyzing a large group of patients with successfully treated shunt infections.
Global food demand is increasing rapidly, as are the environmental impacts of agricultural expansion. Here, we project global demand for crop production in 2050 and evaluate the environmental impacts of alternative ways that this demand might be met. We find that per capita demand for crops, when measured as caloric or protein content of all crops combined, has been a similarly increasing function of per capita real income since 1960. This relationship forecasts a 100-110% increase in global crop demand from 2005 to 2050. Quantitative assessments show that the environmental impacts of meeting this demand depend on how global agriculture expands. If current trends of greater agricultural intensification in richer nations and greater land clearing (extensification) in poorer nations were to continue, ~1 billion ha of land would be cleared globally by 2050, with CO(2)-C equivalent greenhouse gas emissions reaching ~3 Gt y(-1) and N use ~250 Mt y(-1) by then. In contrast, if 2050 crop demand was met by moderate intensification focused on existing croplands of underyielding nations, adaptation and transfer of high-yielding technologies to these croplands, and global technological improvements, our analyses forecast land clearing of only ~0.2 billion ha, greenhouse gas emissions of ~1 Gt y(-1), and global N use of ~225 Mt y(-1). Efficient management practices could substantially lower nitrogen use. Attainment of high yields on existing croplands of underyielding nations is of great importance if global crop demand is to be met with minimal environmental impacts.
Increasing population and consumption are placing unprecedented demands on agriculture and natural resources. Today, approximately a billion people are chronically malnourished while our agricultural systems are concurrently degrading land, water, biodiversity and climate on a global scale. To meet the worlds future food security and sustainability needs, food production must grow substantially while, at the same time, agricultures environmental footprint must shrink dramatically. Here we analyse solutions to this dilemma, showing that tremendous progress could be made by halting agricultural expansion, closing yield gaps on underperforming lands, increasing cropping efficiency, shifting diets and reducing waste. Together, these strategies could double food production while greatly reducing the environmental impacts of agriculture.
The recent increase in liquid biofuel production has stemmed from a desire to reduce dependence on foreign oil, mitigate rising energy prices, promote rural economic development, and reduce greenhouse gas emissions. The growth of this industry has important implications for biodiversity, the effects of which depend largely on which biofuel feedstocks are being grown and the spatial extent and landscape pattern of land requirements for growing these feedstocks. Current biofuel production occurs largely on croplands that have long been in agricultural production. The additional land area required for future biofuels production can be met in part by reclaiming reserve or abandoned croplands and by extending cropping into lands formerly deemed marginal for agriculture. In the United States, many such marginal lands have been enrolled in the Conservation Reserve Program (CRP), providing important habitat for grassland species. The demand for corn ethanOl has changed agricultural commodity economics dramatically, already contributing to loss of CRP lands as contracts expire and lands are returned to agricultural production. Nevertheless, there are ways in which biofuels can be developed to enhance their coexistence with biodiversity. Landscape heterogeneity can be improved by interspersion of land uses, which is easier around facilities with smaller or more varied feedstock demands. The development of biofuel feedstocks that yield high net energy returns with minimal carbon debts or that do not require additional land for production, such as residues and wastes, should be encouraged. Competing land uses, including both biofuel production and biodiversity protection, should be subjected to comprehensive cost-benefit analysis, so that incentives can be directed where they will do the most good.
The cerebral cortex of the human infant at term is complexly folded in a similar fashion to adult cortex but has only one third the total surface area. By comparing 12 healthy infants born at term with 12 healthy young adults, we demonstrate that postnatal cortical expansion is strikingly nonuniform: regions of lateral temporal, parietal, and frontal cortex expand nearly twice as much as other regions in the insular and medial occipital cortex. This differential postnatal expansion may reflect regional differences in the maturity of dendritic and synaptic architecture at birth and/or in the complexity of dendritic and synaptic architecture in adults. This expression may also be associated with differential sensitivity of cortical circuits to childhood experience and insults. By comparing human and macaque monkey cerebral cortex, we infer that the pattern of human evolutionary expansion is remarkably similar to the pattern of human postnatal expansion. To account for this correspondence, we hypothesize that it is beneficial for regions of recent evolutionary expansion to remain less mature at birth, perhaps to increase the influence of postnatal experience on the development of these regions or to focus prenatal resources on regions most important for early survival.
The central role played by the class I(A) phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with "PI3K activated" tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize "PI3K activated" tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into "pathway on" and "pathway off" subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific "pathway on" patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.
The met proto-oncogene is functionally linked with tumorigenesis and metastatic progression. Validation of the receptor tyrosine kinase c-Met as a selective anticancer target has awaited the emergence of selective c-Met inhibitors. Herein, we report ARQ 197 as the first non-ATP-competitive small molecule that selectively targets the c-Met receptor tyrosine kinase. Exposure to ARQ 197 resulted in the inhibition of proliferation of c-Met-expressing cancer cell lines as well as the induction of caspase-dependent apoptosis in cell lines with constitutive c-Met activity. These cellular responses to ARQ 197 were phenocopied by RNAi-mediated c-Met depletion and further demonstrated by the growth inhibition of human tumors following oral administration of ARQ 197 in multiple mouse xenograft efficacy studies. Cumulatively, these data suggest that ARQ 197, currently in phase II clinical trials, is a promising agent for targeting cancers in which c-Met-driven signaling is important for their survival and proliferation.
Application of resting state functional connectivity magnetic resonance imaging (fcMRI) to the study of prematurely born infants enables assessment of the earliest forms of cerebral connectivity and characterization of its early development in the human brain. We obtained 90 longitudinal fcMRI data sets from a cohort of preterm infants aged from 26 weeks postmenstrual age (PMA) through term equivalent age at PMA-specific time points. Utilizing seed-based correlation analysis, we identified resting state networks involving varied cortical regions, the thalamus, and cerebellum. Identified networks demonstrated a regionally variable age-specific pattern of development, with more mature forms consisting of localized interhemispheric connections between homotopic counterparts. Anatomical distance was found to play a critical role in the rate of connection development. Prominent differences were noted between networks identified in term control versus premature infants at term equivalent, including in the thalamocortical connections critical for neurodevelopment. Putative precursors of the default mode network were detected in term control infants but were not identified in preterm infants, including those at term equivalent. Identified patterns of network maturation reflect the intricate relationship of structural and functional processes present throughout this important developmental period and are consistent with prior investigations of neurodevelopment in this population.
We have established a population average surface-based atlas of human cerebral cortex at term gestation and used it to compare infant and adult cortical shape characteristics. Accurate cortical surface reconstructions for each hemisphere of 12 healthy term gestation infants were generated from structural magnetic resonance imaging data using a novel segmentation algorithm. Each surface was inflated, flattened, mapped to a standard spherical configuration, and registered to a target atlas sphere that reflected shape characteristics of all 24 contributing hemispheres using landmark constrained surface registration. Population average maps of sulcal depth, depth variability, three-dimensional positional variability, and hemispheric depth asymmetry were generated and compared with previously established maps of adult cortex. We found that cortical structure in term infants is similar to the adult in many respects, including the pattern of individual variability and the presence of statistically significant structural asymmetries in lateral temporal cortex, including the planum temporale and superior temporal sulcus. These results indicate that several features of cortical shape are minimally influenced by the postnatal environment.
Differences across fields and experience levels are frequently considered in discussions of ethical decision-making and ethical behavior. In the present study, doctoral students in the health, biological, and social sciences completed measures of ethical decision-making. The effects of field and level of experience with respect to ethical decision-making, metacognitive reasoning strategies, social-behavioral responses, and exposure to unethical events were examined. Social and biological scientists performed better than health scientists with respect to ethical decision-making. Furthermore, the ethical decision-making of health science students decreased as experience increased. Moreover, these effects appeared to be linked to the specific strategies underlying participants ethical decision-making. The implications of these findings for ethical decision-making are discussed.
Antiproliferative effects of proteasome inhibitors are suggested to be primarily due to effects on nuclear factor-kappaB (NF-kappaB)-dependent pathways and the induction of apoptosis. The objective of this study was to elucidate the mechanistic basis for the antiproliferative effects of the proteasome inhibitor, bortezomib, in human clear cell renal cell cancer cells (CCRCC).
This paper used ordinary kriging to spatially map arsenic contamination in shallow aquifers of Northwestern Bangladesh (total area approximately 35,000 km(2)). The Northwestern region was selected because it represents a relatively safer source of large-scale and affordable water supply for the rest of Bangladesh currently faced with extensive arsenic contamination in drinking water (such as the Southern regions). Hence, the work appropriately explored sustainability issues by building upon a previously published study (Hossain et al., 2007; Water Resources Management, vol. 21: 1245-1261) where a more general nation-wide assessment afforded by kriging was identified. The arsenic database for reference comprised the nation-wide survey (of 3534 drinking wells) completed in 1999 by the British Geological Survey (BGS) in collaboration with the Department of Public Health Engineering (DPHE) of Bangladesh. Randomly sampled networks of zones from this reference database were used to develop an empirical variogram and develop maps of zonal arsenic concentration for the Northwestern region. The remaining non-sampled zones from the reference database were used to assess the accuracy of the kriged maps. Two additional criteria were explored: (1) the ability of geostatistical interpolators such as kriging to extrapolate information on spatial structure of arsenic contamination beyond small-scale exploratory domains; (2) the impact of a priori knowledge of anisotropic variability on the effectiveness of geostatistically based management. On the average, the kriging method was found to have a 90% probability of successful prediction of safe zones according to the WHO safe limit of 10ppb while for the Bangladesh safe limit of 50ppb, the safe zone prediction probability was 97%. Compared to the previous study by Hossain et al. (2007) over the rest of the contaminated country side, the probability of successful detection of safe zones in the Northwest is observed to be about 25% higher. An a priori knowledge of anisotropy was found to have inconclusive impact on the effectiveness of kriging. It was, however, hypothesized that a preferential sampling strategy that honored anisotropy could be necessary to reach a more definitive conclusion in regards to this issue.
Environmental impacts of energy use can impose large costs on society. We quantify and monetize the life-cycle climate-change and health effects of greenhouse gas (GHG) and fine particulate matter (PM(2.5)) emissions from gasoline, corn ethanol, and cellulosic ethanol. For each billion ethanol-equivalent gallons of fuel produced and combusted in the US, the combined climate-change and health costs are $469 million for gasoline, $472-952 million for corn ethanol depending on biorefinery heat source (natural gas, corn stover, or coal) and technology, but only $123-208 million for cellulosic ethanol depending on feedstock (prairie biomass, Miscanthus, corn stover, or switchgrass). Moreover, a geographically explicit life-cycle analysis that tracks PM(2.5) emissions and exposure relative to U.S. population shows regional shifts in health costs dependent on fuel production systems. Because cellulosic ethanol can offer health benefits from PM(2.5) reduction that are of comparable importance to its climate-change benefits from GHG reduction, a shift from gasoline to cellulosic ethanol has greater advantages than previously recognized. These advantages are critically dependent on the source of land used to produce biomass for biofuels, on the magnitude of any indirect land use that may result, and on other as yet unmeasured environmental impacts of biofuels.
Left vocal cord palsy is a well-recognised rare complication of SLE. We encountered a gentleman who during an acute flare developed left vocal fold palsy (VCP). Immunosuppression was increased, but this only produced partial improvement. VCP is commonly but not exclusively caused by recurrent laryngeal nerve palsy. Other causes may affect phonation, including mucosal ulceration, vasculitis and pulmonary hypertension. There is limited literature on the diagnosis of and treatment options for VCP in SLE.
The soil-dwelling saprophyte bacterium Burkholderia pseudomallei is the cause of melioidosis, a severe disease of humans and animals in southeast Asia and northern Australia. Despite the detection of B. pseudomallei in various soil and water samples from endemic areas, the environmental habitat of B. pseudomallei remains unclear.
Balancing productivity, profitability, and environmental health is a key challenge for agricultural sustainability. Most crop production systems in the United States are characterized by low species and management diversity, high use of fossil energy and agrichemicals, and large negative impacts on the environment. We hypothesized that cropping system diversification would promote ecosystem services that would supplement, and eventually displace, synthetic external inputs used to maintain crop productivity. To test this, we conducted a field study from 2003-2011 in Iowa that included three contrasting systems varying in length of crop sequence and inputs. We compared a conventionally managed 2-yr rotation (maize-soybean) that received fertilizers and herbicides at rates comparable to those used on nearby farms with two more diverse cropping systems: a 3-yr rotation (maize-soybean-small grain + red clover) and a 4-yr rotation (maize-soybean-small grain + alfalfa-alfalfa) managed with lower synthetic N fertilizer and herbicide inputs and periodic applications of cattle manure. Grain yields, mass of harvested products, and profit in the more diverse systems were similar to, or greater than, those in the conventional system, despite reductions of agrichemical inputs. Weeds were suppressed effectively in all systems, but freshwater toxicity of the more diverse systems was two orders of magnitude lower than in the conventional system. Results of our study indicate that more diverse cropping systems can use small amounts of synthetic agrichemical inputs as powerful tools with which to tune, rather than drive, agroecosystem performance, while meeting or exceeding the performance of less diverse systems.
The digital revolution is changing the manner in which patients communicate with their health care providers, yet many patients still lack access to communication technology. We conducted this study to evaluate access to, use of, and preferences for using communication technology among a predominantly low-income patient population. We determined whether access, use, and preferences were associated with type of health insurance, sex, age, and ethnicity.
The environmental health impacts of transportation depend in part on where and when emissions occur during fuel production and combustion. Here we describe spatially and temporally explicit life cycle inventories (LCI) of air pollutants from gasoline, ethanol derived from corn grain, and ethanol from corn stover. Previous modeling for the U.S. by Argonne National Laboratory (GREET: Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation) suggested that life cycle emissions are generally higher for ethanol from corn grain or corn stover than for gasoline. Our results show that for ethanol, emissions are concentrated in the Midwestern "Corn Belt". We find that life cycle emissions from ethanol exhibit different temporal patterns than from gasoline, reflecting seasonal aspects of farming activities. Enhanced chemical speciation beyond current GREET model capabilities is also described. Life cycle fine particulate matter emissions are higher for ethanol from corn grain than for ethanol from corn stover; for black carbon, the reverse holds. Overall, our results add to existing state-of-the-science transportation fuel LCI by providing spatial and temporal disaggregation and enhanced chemical speciation, thereby offering greater understanding of the impacts of transportation fuels on human health and opening the door to advanced air dispersion modeling of fuel life cycles.
We used an ensemble of aircraft measurements with the GEOS-Chem chemical transport model to constrain present-day North American ethanol sources, and gauge potential long-range impacts of increased ethanol fuel use. We find that current ethanol emissions are underestimated by 50% in Western North America, and overestimated by a factor of 2 in the east. Our best estimate for year-2005 North American ethanol emissions is 670 GgC/y, with 440 GgC/y from the continental U.S. We apply these optimized source estimates to investigate two scenarios for increased ethanol fuel use in the U.S.: one that assumes a complete transition from gasoline to E85 fuel, and one tied to the biofuel requirements of the U.S. Energy Indepence and Security Act (EISA). For both scenarios, increased ethanol emissions lead to higher atmospheric acetaldehyde concentrations (by up to 14% during winter for the All-E85 scenario and 2% for the EISA scenario) and an associated shift in reactive nitrogen partitioning reflected by an increase in the peroxyacetyl nitrate (PAN) to NO(y) ratio. The largest relative impacts occur during fall, winter, and spring because of large natural emissions of ethanol and other organic compounds during summer. Projected changes in atmospheric PAN reflect a balance between an increased supply of peroxyacetyl radicals from acetaldehyde oxidation, and the lower NO(x) emissions for E85 relative to gasoline vehicles. The net effect is a general PAN increase in fall through spring, and a weak decrease over the U.S. Southeast and the Atlantic Ocean during summer. Predicted NO(x) concentrations decrease in surface air over North America (by as much 5% in the All-E85 scenario). Downwind of North America this effect is counteracted by higher NO(x) export efficiency driven by increased PAN production and transport. From the point of view of NO(x) export from North America, the increased PAN formation associated with E85 fuel use thus acts to offset the associated lower NO(x) emissions.
This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.
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