Green turtles shape the seascape through grazing patch formation around habitat features: Experimental evidence.

Understanding how megaherbivores incorporate habitat features into their foraging behavior is key toward understanding how herbivores shape the surrounding landscape. While the role of habitat structure has been studied within the context of predator-prey dynamics and grazing behavior in terrestrial systems, there is a limited understanding of how structure influences megaherbivore grazing in marine ecosystems. To investigate the response of megaherbivores (green turtles) to habitat features, we experimentally introduced structure at two spatial scales in a shallow seagrass meadow in The Bahamas. Turtle density increased 50-fold (to 311 turtles ha-1 ) in response to the structures, and turtles were mainly grazing and resting (low vigilance behavior). This resulted in a grazing patch exceeding the size of the experimental setup (242 m2 ), with reduced seagrass shoot density and aboveground biomass. After structure removal, turtle density decreased and vigilance increased (more browsing and shorter surfacing times), while seagrass within the patch partly recovered. Even at a small scale (9 m2 ), artificial structures altered turtle grazing behavior, resulting in grazing patches in 60% of the plots. Our results demonstrate that marine megaherbivores select habitat features as foraging sites, likely to be a predator refuge, resulting in heterogeneity in seagrass bed structure at the landscape scale.

GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and ß cells.

Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on ß cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid-stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in ß cells. Moreover, we demonstrate that GIP activity in α cells contributes to insulin secretion by invoking paracrine α to ß cell communication. Last, specific loss of GIPR activity in α cells prevents glucagon secretion in response to a meal stimulus, limiting insulin secretion and driving glucose intolerance. Together, these data uncover an important axis by which GIPR activity in α cells is necessary to coordinate the optimal level of both glucagon and insulin secretion to maintain postprandial homeostasis.

Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia.

There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.

Large historical growth in global terrestrial gross primary production.

Growth in terrestrial gross primary production (GPP)-the amount of carbon dioxide that is 'fixed' into organic material through the photosynthesis of land plants-may provide a negative feedback for climate change. It remains uncertain, however, to what extent biogeochemical processes can suppress global GPP growth. As a consequence, modelling estimates of terrestrial carbon storage, and of feedbacks between the carbon cycle and climate, remain poorly constrained. Here we present a global, measurement-based estimate of GPP growth during the twentieth century that is based on long-term atmospheric carbonyl sulfide (COS) records, derived from ice-core, firn and ambient air samples. We interpret these records using a model that simulates changes in COS concentration according to changes in its sources and sinks-including a large sink that is related to GPP. We find that the observation-based COS record is most consistent with simulations of climate and the carbon cycle that assume large GPP growth during the twentieth century (31% ± 5% growth; mean ± 95% confidence interval). Although this COS analysis does not directly constrain models of future GPP growth, it does provide a global-scale benchmark for historical carbon-cycle simulations.

A Review of Pharmacovigilance.

Pharmacovigilance supports safe and appropriate use of drugs. Spontaneous reporting of adverse drug reactions (ADRs) is an essential component of pharmacovigilance. However, there is significant underreporting of ADRs. Adverse drug reactions have become a major problem in developing countries. Knowledge of pharmacovigilance could form the basis for interventions aimed at improving reporting rates and decreasing ADRs.

Historical U.S. cropland areas and the potential for bioenergy production on abandoned croplands.

Agriculture is historically a dominant form of global environmental degradation, and the potential for increased future degradation may be driven by growing demand for food and biofuels. While these impacts have been explored using global gridded maps of croplands, such maps are based on relatively coarse spatial data. Here, we apply high-resolution cropland inventories for the conterminous U.S. with a land-use model to develop historical gridded cropland areas for the years 1850-2000 and year 2000 abandoned cropland maps. While the historical cropland maps are consistent with generally accepted land-use trends, our U.S. abandoned cropland estimates of 68 Mha are as much as 70% larger than previous gridded estimates due to a reduction in aggregation effects. Renewed cultivation on the subset of abandoned croplands that have not become forests or urban lands represents one approach to mitigating the future expansion of agriculture. Potential bioenergy production from these abandoned lands using a wide range of biomass yields and conversion efficiencies has an upper-limit of 5-30% of the current U.S. primary energy demand or 4-30% of the current U.S. liquid fuel demand.

Biofuels that cause land-use change may have much larger non-GHG air quality emissions than fossil fuels.

Although biofuels present an opportunity for renewable energy production, significant land-use change resulting from biofuels may contribute to negative environmental, economic, and social impacts. Here we examined non-GHG air pollution impacts from both indirect and direct land-use change caused by the anticipated expansion of Brazilian biofuels production. We synthesized information on fuel loading, combustion completeness, and emission factors, and developed a spatially explicit approach with uncertainty and sensitivity analyses to estimate air pollution emissions. The land-use change emissions, ranging from 6.7 to 26.4 Tg PM(2.5), were dominated by deforestation burning practices associated with indirect land-use change. We also found Brazilian sugar cane ethanol and soybean biodiesel including direct and indirect land-use change effects have much larger life-cycle emissions than conventional fossil fuels for six regulated air pollutants. The emissions magnitude and uncertainty decrease with longer life-cycle integration periods. Results are conditional to the single LUC scenario employed here. After LUC uncertainty, the largest source of uncertainty in LUC emissions stems from the combustion completeness during deforestation. While current biofuels cropland burning policies in Brazil seek to reduce life-cycle emissions, these policies do not address the large emissions caused by indirect land-use change.

Land-use and alternative bioenergy pathways for waste biomass.

Rapid escalation in biofuels consumption may lead to a trade regime that favors exports of food-based biofuels from tropical developing countries to developed countries. There is growing interest in mitigating the land-use impacts of these potential biofuels exports by converting biorefinery waste streams into cellulosic ethanol, potentially reducing the amount of land needed to meet production goals. This increased land-use efficiency for ethanol production may lower the land-use greenhouse gas emissions of ethanol but would come at the expense of converting the wastes into bioelectricity which may offset fossil fuel-based electricity and could provide a vital source of domestic electricity in developing countries. Here we compare these alternative uses of wastes with respect to environmental and energy security outcomes considering a range of electricity production efficiencies, ethanol yields, land-use scenarios, and energy offset assumptions. For a given amount of waste biomass, we found that using bioelectricity production to offset natural gas achieves 58% greater greenhouse gas reductions than using cellulosic ethanol to offset gasoline but similar emissions when cellulosic ethanol is used to offset the need for more sugar cane ethanol. If bioelectricity offsets low-carbon energy sources such as nuclear power then the liquid fuels pathway is preferred. Exports of cellulosic ethanol may have a small impact on the energy security of importing nations while bioelectricity production may have relatively large impacts on the energy security in developing countries.

Efficacy of embolic protection devices in renal artery stenting.

The efficacy of embolic protection devices (EPDs) have been studied extensively in coronary saphenous vein grafts and extra cranial cerebrovascular disease. Recent ex-vivo and in-vivo renal artery stenting studies suggest atheroembolism is not unique to the coronary and cerebrovascular domain and it seems intuitive, renal EPDs may be beneficial. In an attempt to better understand the current objective evidence regarding renal protection efficacy we systematically reviewed the contemporary literature and summarize the findings herein. There is increasing observational data suggesting the use of embolic protection devices decrease the risk of continued decline in renal function after renal artery stenting. There is also prospective randomized data to suggest that the use of adjuvant IIb/IIIa glycoprotein inhibitor and embolic protection has synergistic benefit, but this is a very small series. However, there are currently no well controlled prospective trials to conclude the added risk and expense of renal protection is countered by proven clinical benefit. Based on the literature compiled in this manuscript we do believe EPDs should be considered in some high-risk patients.

Greater transportation energy and GHG offsets from bioelectricity than ethanol.

The quantity of land available to grow biofuel crops without affecting food prices or greenhouse gas (GHG) emissions from land conversion is limited. Therefore, bioenergy should maximize land-use efficiency when addressing transportation and climate change goals. Biomass could power either internal combustion or electric vehicles, but the relative land-use efficiency of these two energy pathways is not well quantified. Here, we show that bioelectricity outperforms ethanol across a range of feedstocks, conversion technologies, and vehicle classes. Bioelectricity produces an average of 81% more transportation kilometers and 108% more emissions offsets per unit area of cropland than does cellulosic ethanol. These results suggest that alternative bioenergy pathways have large differences in how efficiently they use the available land to achieve transportation and climate goals.

Photosynthetic control of atmospheric carbonyl sulfide during the growing season.

Climate models incorporate photosynthesis-climate feedbacks, yet we lack robust tools for large-scale assessments of these processes. Recent work suggests that carbonyl sulfide (COS), a trace gas consumed by plants, could provide a valuable constraint on photosynthesis. Here we analyze airborne observations of COS and carbon dioxide concentrations during the growing season over North America with a three-dimensional atmospheric transport model. We successfully modeled the persistent vertical drawdown of atmospheric COS using the quantitative relation between COS and photosynthesis that has been measured in plant chamber experiments. Furthermore, this drawdown is driven by plant uptake rather than other continental and oceanic fluxes in the model. These results provide quantitative evidence that COS gradients in the continental growing season may have broad use as a measurement-based photosynthesis tracer.

Transcatheter therapy for the treatment of atherosclerotic renal artery stenosis.

UNLABELLED: The preemptory challenge in this invited review was to provide a contemporary evidence-based analysis of how renal artery intervention effects renal function and hypertension while also addressing the efficacy in transplanted kidneys. The authors tailored the paper architecture in a way that provides a systematic review of the randomized and observational data relating to the impact of renal stenting in each of these clinical domains. When appropriate the authors include data from their experience with over 1 200 renal stent procedures. This contemporary literature review provides objective insight into the procedural risk and early outcomes following renal intervention based on observational study RESULTS: However, well-controlled randomized trials and standardization of interventional technique with or without embolic protection is desperately needed.

Synthesis and structure-activity relationships of 5-substituted pyridine analogues of 3.

In an effort to probe the steric influence of C5 substitution of the pyridine ring on CNS binding affinity, analogues of 1 substituted with a bulky moiety--such as phenyl, substituted phenyl, or heteroaryl-were synthesized and tested in vitro for neuronal nicotinic acetylcholine receptor binding affinity. The substituted analogues exhibited Ki values ranging from 0.055 to 0.69 nM compared to a Ki value of 0.15 nM for compound 1. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors led to identify several agonists and antagonists.

Age variations in personal agency and self-esteem: the context of physical disability.

OBJECTIVES: This study examines how age patterns in health control, self-efficacy, and self-esteem are influenced by age-correlated social status, health, personality, and social integration variables. METHODS: Ordinary least squares regression documents age patterns in data from a 1985 community sample of 1,549 physically disabled and nondisabled individuals from southwestern Ontario, Canada. RESULTS: Older respondents report lower health control, self-efficacy, and self-esteem. Less education, more physical impairment, poorer global health, less empathy, and less introspectiveness explain about 43% of age's negative association with health control and more than half of its negative association with self-esteem. In addition, age is associated more negatively with self-efficacy among the disabled. Social status variables conceal the strength of the age-by-disability interaction coefficient, while health accounts for almost an equal amount. DISCUSSION: The findings describe how age-correlated personal and social factors contribute to, or statistically conceal, older adults' sense of health control, self-efficacy, and self-esteem.

Structure-activity studies on a novel series of cholinergic channel activators based on a heteroaryl ether framework.

Analogs of compound 1 with a variety of azacycles and heteroaryl groups were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 10,000 nM when tested in vitro for cholinergic channel receptor binding activity (displacement of [3H](-) cytisine from whole rat brain synaptic membranes).

ABT-594, a novel cholinergic channel modulator, is efficacious in nerve ligation and diabetic neuropathy models of neuropathic pain.

A novel cholinergic channel modulator, ABT-594, was tested in two established and distinct models of neuropathic pain; the Chung model (i.e., tight ligation of L5 and L6 spinal nerves) and a diabetic neuropathy model (i.e., streptozotocin-induced diabetes). Tactile allodynia and mechanical hyperalgesia were assessed in the Chung and diabetic neuropathy models, respectively. ABT-594 produced a significant antiallodynic effect following both oral (0.1-1 micromol/kg) and intraperitoneal (i.p.) (0.3 micromol/kg) administration. Equal efficacy was observed following both routes of administration. ABT-594 (0.3 micromol/kg, i.p.) maintained efficacy following repeated dosing (5 days; twice daily) in the Chung model, but the effect of morphine (21 micromol/kg, i.p.) was significantly reduced after repeated dosing. In the diabetic neuropathy model, ABT-594 (0.3 micromol/kg, i.p.) effectively reduced mechanical hyperalgesia. Morphine (21 micromol/kg, i.p.) was not effective in this model. Overall, these results suggest development of ABT-594 may provide a novel pharmacotherapy for the chronic treatment of neuropathic pain.

Nonmarital births in Oklahoma 1975-1995.

This report uses data from the Oklahoma State Department of Health to describe past trends and current patterns of nonmarital births in Oklahoma. Between 1975 and 1995, the percentage of unmarried women delivering a live birth in Oklahoma increased from 12% to 31%. Adult nonmarital births increased faster than teen nonmarital births, but teens had a higher percentage of nonmarital births. White rates increased faster than African-American and Native American rates, but African-Americans had a higher percentage of nonmarital births. Unmarried women who give birth were more likely to be poor and lack education; additionally, they were less likely to receive early prenatal care, more likely to have had low weight births, and more likely to have had an unintended pregnancy. Birth outcomes are poorer among unmarried women, but this may be due to poverty and education rather than marital status alone.

PIP: This study examined trends in nonmarital births during 1975-95 in Oklahoma. Data were obtained from the Oklahoma State Department of Health vital records and the Oklahoma Pregnancy Risk Assessment Monitoring System's annual surveys during 1988-95. Findings indicate that the percentage of unmarried women delivering a live birth in Oklahoma increased from 12% to 31% during 1975-99, a 158% increase. Nonmarital births rose from 5075 to 13,856. By 1995, almost one-third of births in Oklahoma were to unmarried women. Adult nonmarital births increased more rapidly than adolescent nonmarital births, especially among unmarried women aged 30-34 years. Most of the increase in older women with nonmarital births was from women who had nonmarital births as teens. Adolescents had a higher percentage of nonmarital births: 76% for women aged 15-17 years compared to 14.1% for women aged 30-34 years. White rates increased faster than African-American and Native-American rates (a 2.7-fold increase compared to 1.6- and 2.8-fold increases, respectively). African-Americans had a higher percentage of nonmarital births (69.2%) compared to White women (24.5%). Unmarried women were more likely to be poor and lack education and less likely to receive early prenatal care. 53.1% lived below the Federal Poverty Level. Unmarried mothers were more likely to have had a low-birth-weight baby and an unintended pregnancy. The percentage of nonmarital births in 1945 was only 3.4%, which means an 800% increase during 1945-95, a 50-year period of time. The state pattern followed a national pattern of increase.

ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization.

The discovery of (+/-)-epibatidine, a naturally occurring neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity 200-fold more potent than that of morphine, has renewed interest in the potential role of nAChRs in pain processing. However, (+/-)-epibatidine has significant side-effect liabilities associated with potent activity at the ganglionic and neuromuscular junction nAChR subtypes which limit its potential as a clinical entity. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine] is a novel, potent cholinergic nAChR ligand with analgesic properties (see accompanying paper by Bannon et al., 1998b) that shows preferential selectivity for neuronal nAChRs and a consequently improved in vivo side-effect profile compared with (+/-)-epibatidine. ABT-594 is a potent inhibitor of the binding of [3H](-)-cytisine to alpha 4 beta 2 neuronal nAChRs (Ki = 37 pM, rat brain; Ki = 55 pM, transfected human receptor). At the alpha 1 beta 1 delta gamma neuromuscular nAChR labeled by [125I] alpha-bungarotoxin (alpha-Btx), ABT-594 has a Ki value of 10,000 nM resulting in a greater than 180,000-fold selectivity of the compound for the neuronal alpha 4 beta 2 nAChR. In contrast, (+/-)-epibatidine has Ki values of 70 pM and 2.7 nM at the alpha 4 beta 2 and alpha 1 beta 1 delta gamma nAChRs, respectively, giving a selectivity of only 38-fold. The S-enantiomer of ABT-594, A-98593 has activity at the neuronal alpha 4 beta 2 nAChR identical with ABT-594 (Ki = 34-39 pM), which demonstrates a lack of stereospecific binding similar to that reported previously for (+/-)-epibatidine. A similar lack of stereoselectivity is seen at the human alpha 7 receptor. However, A-98593 is 3-fold more potent at the neuromuscular nAChR (Ki = 3420 nM) and the brain alpha-Btx-sensitive nAChR (Ki = 4620 nM) than ABT-594. ABT-594 has weak affinity in binding assays for adrenoreceptor subtypes alpha-1B (Ki = 890 nM), alpha-2B (Ki = 597 nM) and alpha-2C (Ki = 342 nM), and it has negligible affinity (Ki > 1000 nM) for approximately 70 other receptors, enzyme and transporter binding sites. Functionally, ABT-594 is an agonist. At the transfected human alpha 4 beta 2 neuronal nAChR (K177 cells), with increased 86Rb+ efflux as a measure of cation efflux, ABT-594 had an EC50 value of 140 nM with an intrinsic activity (IA) compared with (-)-nicotine of 130%; at the nAChR subtype expressed in IMR-32 cells (sympathetic ganglion-like), an EC50 of 340 nM (IA = 126%); at the F11 dorsal root ganglion cell line (sensory ganglion-like), an EC50 of 1220 nM (IA = 71%); and via direct measurement of ion currents, an EC50 value of 56,000 nM (IA = 83%) at the human alpha 7 homooligimeric nAChR produced in oocytes. A-98593 is 2- to 3-fold more potent and displays approximately 50% greater intrinsic activity than ABT-594 in all four functional assays. In terms of potency, ABT-594 is 8- to 64-fold less active than (+/-)-epibatidine and also has less IA in these functional assays. ABT-594 (30 microM) inhibits the release of calcitonin gene-related peptide from C-fibers terminating in the dorsal horn of the spinal cord, an effect mediated via nAChRs. Pharmacologically, ABT-594 has an in vitro profile distinct from that of the prototypic nicotinic analgesic (+/-)-epibatidine, with the potential for substantially reduced side-effect liability and, as such, represents a potentially novel therapeutic approach to pain management.

Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors.

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

Synthesis and structure-activity relationships of pyridine-modified analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, A-84543, a potent nicotinic acetylcholine receptor agonist.

Analogs of 3-[2-((S)-pyrrolidinyl)methoxy]pyridine, (A-84543, 1) with 2-, 4-, 5-, and 6-substituents on the pyridine ring were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 9,000 nM when tested in vitro for neuronal nicotinic acetylcholine receptor binding activity. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors indicates that pyridine substitution can have a profound effect on efficacy at these subtypes, and several subtype-selective agonists and antagonists have been identified.