Pharmacological characterization of extracellular acidification rate responses in human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells

PubMed Central

Coldwell, M C; Boyfield, I; Brown, A M; Stemp, G; Middlemiss, D N

1999-01-01

This study characterized pharmacologically the functional responses to agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) zreceptors separately expressed in cloned cells using the cytosensor microphysiometer. Dopaminergic receptor agonists caused increases in extracellular acidification rate in adherent Chinese hamster ovary (CHO) clones expressing hD2, hD3 or hD4 receptors. Acidification rate responses to agonists in other cell lines expressing these receptors were smaller than those in adherent CHO cells. The time courses and maximum increases in acidification rate of the agonist responses in adherent CHO cells were different between the three dopamine receptor clones. Responses were blocked by pretreatment of cells with pertussis toxin or amiloride analogues. Most agonists had full intrinsic activity at each of the dopamine receptor subtypes, as compared to quinpirole, however both enantiomers of UH-232 and (−)3-PPP were partial agonists in this assay system. The functional potency of full agonists at each of the three receptors expressed in CHO cells was either higher than, or similar to, the apparent inhibition constants (Ki) determined in [125I]-iodosulpride competition binding studies. Functional selectivities of the agonists were less than radioligand binding selectivities. The rank orders of agonist potencies and selectivities were similar, but not identical, to the rank orders of radioligand binding affinities and selectivities. The dopamine receptor antagonists, iodosulpride and clozapine, had no effect on basal acidification rates but inhibited acidification responses in CHO cells to quinpirole in an apparently competitive manner. Antagonist potencies closely matched their radioligand binding affinities in these cells. PMID:10455259

Structure-activity relationships of phenothiazines and related drugs for inhibition of protein kinase C.

PubMed

Aftab, D T; Ballas, L M; Loomis, C R; Hait, W N

1991-11-01

Phenothiazines are known to inhibit the activity of protein kinase C. To identify structural features that determine inhibitory activity against the enzyme, we utilized a semiautomated assay [Anal. Biochem. 187:84-88 (1990)] to compare the potency of greater than 50 phenothiazines and related compounds. Potency was decreased by trifluoro substitution at position 2 on the phenothiazine nucleus and increased by quinoid structures on the nucleus. An alkyl bridge of at least three carbons connecting the terminal amine to the nucleus was required for activity. Primary amines and unsubstituted piperazines were the most potent amino side chains. We selected 7,8-dihydroxychlorpromazine (DHCP) (IC50 = 8.3 microM) and 2-chloro-9-(3-[1-piperazinyl]propylidene)thioxanthene (N751) (IC50 = 14 microM) for further study because of their potency and distinct structural features. Under standard (vesicle) assay conditions, DHCP was noncompetitive with respect to phosphatidylserine and a mixed-type inhibitor with respect to ATP. N751 was competitive with respect to phosphatidylserine and noncompetitive with respect to ATP. Using the mixed micelle assay, DHCP was a competitive inhibitor with respect to both phosphatidylserine and ATP. DHCP was selective for protein kinase C compared with cAMP-dependent protein kinase, calmodulin-dependent protein kinase type II, and casein kinase. N751 was more potent against protein kinase C compared with cAMP-dependent protein kinase and casein kinase but less potent against protein kinase C compared with calmodulin-dependent protein kinase type II. DHCP was analyzed for its ability to inhibit different isoenzymes of protein kinase C, and no significant isozyme selectivity was detected. These data provide important information for the rational design of more potent and selective inhibitors of protein kinase C.

Brevenal is a natural inhibitor of brevetoxin action in sodium channel receptor binding assays.

PubMed

Bourdelais, Andrea J; Campbell, Susan; Jacocks, Henry; Naar, Jerome; Wright, Jeffery L C; Carsi, Jigani; Baden, Daniel G

2004-08-01

1. Florida red tides produce profound neurotoxicity that is evidenced by massive fish kills, neurotoxic shellfish poisoning, and respiratory distress. Red tides vary in potency, potency that is not totally governed by toxin concentration. The purpose of the study was to understand the variable potency of red tides by evaluating the potential for other natural pharmacological agents which could modulate or otherwise reduce the potency of these lethal environmental events. 2. A synaptosome binding preparation with 3-fold higher specific brevetoxin binding was developed to detect small changes in toxin binding in the presence of potential antagonists. Rodent brain labeled in vitro with tritiated brevetoxin shows high specific binding in the cerebellum as evidenced by autoradiography. Synaptosome binding assays employing cerebellum-derived synaptosomes illustrate 3-fold increased specific binding. 3. A new polyether natural product from Florida's red tide dinoflagellate Karenia brevis, has been isolated and characterized. Brevenal, as the nontoxic natural product is known, competes with tritiated brevetoxin for site 5 associated with the voltage-sensitive sodium channel (VSSC). Brevenal displacement of specific brevetoxin binding is purely competitive in nature. 4. Brevenal, obtained from either laboratory cultures or field collections during a red tide, protects fish from the neurotoxic effects of brevetoxin exposure. 5. Brevenal may serve as a model compound for the development of therapeutics to prevent or reverse intoxication in red tide exposures.

An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1.

PubMed

Dinkova-Kostova, Albena T; Talalay, Paul; Sharkey, John; Zhang, Ying; Holtzclaw, W David; Wang, Xiu Jun; David, Emilie; Schiavoni, Katherine H; Finlayson, Stewart; Mierke, Dale F; Honda, Tadashi

2010-10-29

The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.

ABOVE- AND BELOWGROUND CONTROLS ON FOREST TREE GROWTH, MORTALITY AND SPATIAL PATTERN

EPA Science Inventory

We investigated the relative importance of above- and belowground competition in controlling growth, mortality and spatial patterns of trees in a nitrogen-limited, old-growth forest in western Oregon. To assess the effects of competition for light, we applied a spatially-explici...

Interaction of fenoterol stereoisomers with β2-adrenoceptor-G sα fusion proteins: antagonist and agonist competition binding.

PubMed

Reinartz, Michael T; Kälble, Solveig; Wainer, Irving W; Seifert, Roland

2015-05-01

The specific interaction between G-protein-coupled receptors and ligand is the starting point for downstream signaling. Fenoterol stereoisomers were successfully used to probe ligand-specific activation (functional selectivity) of the β2-adrenoceptor (β2AR) (Reinartz et al. 2015). In the present study, we extended the pharmacological profile of fenoterol stereoisomers using β2AR-Gsα fusion proteins in agonist and antagonist competition binding assays. Dissociations between binding affinities and effector potencies were found for (R,S')- and (S,S')-isomers of 4'-methoxy-1-naphthyl-fenoterol. Our data corroborate former studies on the importance of the aminoalkyl moiety of fenoterol derivatives for functional selectivity.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zask, Arie; Verheijen, Jeroen C.; Curran, Kevin

The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.

Nitric Oxide Mediates Glutamate-Linked Enhancement of cGMP Levels in the Cerebellum

NASA Astrophysics Data System (ADS)

Bredt, David S.; Snyder, Solomon H.

1989-11-01

Nitric oxide, which mediates influences of numerous neurotransmitters and modulators on vascular smooth muscle and leukocytes, can be formed in the brain from arginine by an enzymatic activity that stoichiometrically generates citrulline. We show that glutamate and related amino acids, such as N-methyl-D-aspartate, markedly stimulate arginine-citrulline transformation in cerebellar slices stoichiometrically with enhancement of cGMP levels. Nω-monomethyl-L-arginine blocks the augmentation both of citrulline and cGMP with identical potencies. Arginine competitively reverses both effects of Nω-monomethyl-L-arginine with the same potencies. Hemoglobin, which complexes nitric oxide, prevents the stimulation by N-methyl-D-aspartate of cGMP levels, and superoxide dismutase, which elevates nitric oxide levels, increases cGMP formation. These data establish that nitric oxide mediates the stimulation by glutamate of cGMP formation.

Big data on a big new market: Insights from Washington State's legal cannabis market.

PubMed

Caulkins, Jonathan P; Bao, Yilun; Davenport, Steve; Fahli, Imane; Guo, Yutian; Kinnard, Krista; Najewicz, Mary; Renaud, Lauren; Kilmer, Beau

2018-07-01

Voters in eight U.S. states have passed initiatives to legalize large-scale commercial production of cannabis for non-medical use. All plan or require some form of "seed-to-sale" tracking systems, which provide a view of cannabis market activity at a heretofore unimagined level of detail. Legal markets also create a range of new matters for policy makers to address. Publicly available data were obtained on approximately 45 million individually priced items purchased in the 35 million retail transactions that took place during the first two and a half years of Washington State's legal cannabis market. Records include product type (flower, extract, lotion, liquid edible, etc.), product name, price, and potency with respect to multiple cannabinoids, notably THC and CBD. Items sold can be traced back up the supply chain through the store to the processor and producer, to the level of identifying the specific production batch and mother plant, the firm that tested the product, and test results. Data visualization methods are employed to describe spatial-temporal patterns of multiple correlated attributes (e.g., price and potency) broken down by product. Text-analytic methods are used to subdivide the broad category of "extracts for inhalation" into more homogeneous sub-categories. To understand the competitiveness of the legal cannabis market in Washington we calculate the Herfindahl-Hirschman index (HHI) for processors and retailers. Cannabis prices fell steadily and proportionally at the processor and retailer levels. Retail and wholesale price maintained a roughly 3:1 ratio for multiple product types after some initial fluctuations. Although a wide range of edibles are sold, they account for a modest share of consumer spending; extracts for inhalation are a larger and heterogeneous market segment. The HHI indicates the cannabis market is highly competitive at the processor level, but less so for retail markets at the county level. Washington's state-legal cannabis market is diverse and rapidly evolving in terms of pricing, products, and organization. Post-legalization, researchers and policy makers may need to think in terms of a family of cannabis products, akin to how we think of new psychoactive substances and amphetamine-type stimulants, not a single drug "cannabis." Copyright © 2018 Elsevier B.V. All rights reserved.

Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine.

PubMed

Walter, Niklas M; Wentsch, Heike K; Bührmann, Mike; Bauer, Silke M; Döring, Eva; Mayer-Wrangowski, Svenja; Sievers-Engler, Adrian; Willemsen-Seegers, Nicole; Zaman, Guido; Buijsman, Rogier; Lämmerhofer, Michael; Rauh, Daniel; Laufer, Stefan A

2017-10-12

We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I 1 / 2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.

Competitive exclusion over broad spatial extents is a slow process: Evidence and implications for species distribution modeling

USGS Publications Warehouse

Yackulic, Charles B.

2016-01-01

There is considerable debate about the role of competition in shaping species distributions over broad spatial extents. This debate has practical implications because predicting changes in species' geographic ranges in response to ongoing environmental change would be simpler if competition could be ignored. While this debate has been the subject of many reviews, recent literature has not addressed the rates of relevant processes. This omission is surprising in that ecologists hypothesized decades ago that regional competitive exclusion is a slow process. The goal of this review is to reassess the debate under the hypothesis that competitive exclusion over broad spatial extents is a slow process.Available evidence, including simulations presented for the first time here, suggests that competitive exclusion over broad spatial extents occurs slowly over temporal extents of many decades to millennia. Ecologists arguing against an important role for competition frequently study modern patterns and/or range dynamics over periods of decades, while much of the evidence for competition shaping geographic ranges at broad spatial extents comes from paleoecological studies over time scales of centuries or longer. If competition is slow, as evidence suggests, the geographic distributions of some, perhaps many species, would continue to change over time scales of decades to millennia, even if environmental conditions did not continue to change. If the distributions of competing species are at equilibrium it is possible to predict species distributions based on observed species–environment relationships. However, disequilibrium is widespread as a result of competition and many other processes. Studies whose goal is accurate predictions over intermediate time scales (decades to centuries) should focus on factors associated with range expansion (colonization) and loss (local extinction), as opposed to current patterns. In general, understanding of modern range dynamics would be enhanced by considering the rates of relevant processes.

In Vitro Screening of Opiod Antagonist Effectiveness

DTIC Science & Technology

2018-04-01

with a co-administration of acrylfentanyl and naloxone. Reversibility of acrylfentanyl was achieved at naloxone concentrations comparable to those of...EC50, EC90, and efficacy values were calculated (Figure 4). These values were compared to those of fentanyl (Table 1). 1 2 3 4 5 6 7 8 9 10 11 12... compare that to the metabolic rate of the reversal agent, itself. Metabolic clearance data, when combined with a potency and competition assay

Spatial vegetation patterns and neighborhood competition among woody plants in an East African savanna.

PubMed

Dohn, Justin; Augustine, David J; Hanan, Niall P; Ratnam, Jayashree; Sankaran, Mahesh

2017-02-01

The majority of research on savanna vegetation dynamics has focused on the coexistence of woody and herbaceous vegetation. Interactions among woody plants in savannas are relatively poorly understood. We present data from a 10-yr longitudinal study of spatially explicit growth patterns of woody vegetation in an East African savanna following exclusion of large herbivores and in the absence of fire. We examined plant spatial patterns and quantified the degree of competition among woody individuals. Woody plants in this semiarid savanna exhibit strongly clumped spatial distributions at scales of 1-5 m. However, analysis of woody plant growth rates relative to their conspecific and heterospecific neighbors revealed evidence for strong competitive interactions at neighborhood scales of up to 5 m for most woody plant species. Thus, woody plants were aggregated in clumps despite significantly decreased growth rates in close proximity to neighbors, indicating that the spatial distribution of woody plants in this region depends on dispersal and establishment processes rather than on competitive, density-dependent mortality. However, our documentation of suppressive effects of woody plants on neighbors also suggests a potentially important role for tree-tree competition in controlling vegetation structure and indicates that the balanced-competition hypothesis may contribute to well-known patterns in maximum tree cover across rainfall gradients in Africa. © 2016 by the Ecological Society of America.

Sulfated Pentagalloylglucoside is a Potent, Allosteric, and Selective Inhibitor of Factor XIa

PubMed Central

Al-Horani, Rami A.; Ponnusamy, Pooja; Mehta, Akul Y.; Gailani, David; Desai, Umesh R.

2013-01-01

Inhibition of factor XIa (FXIa) is a novel paradigm for developing anticoagulants without major bleeding consequences. We present the discovery of sulfated pentagalloylglucoside (6) as a highly selective inhibitor of human FXIa. Biochemical screening of a focused library led to the identification of 6, a sulfated aromatic mimetic of heparin. Inhibitor 6 displayed a potency of 551 nM against FXIa, which was at least 200-fold more selective than other relevant enzymes. It also prevented activation of factor IX and prolonged human plasma and whole blood clotting. Inhibitor 6 reduced VMAX of FXIa hydrolysis of chromogenic substrate without affecting the KM suggesting an allosteric mechanism. Competitive studies showed that 6 bound in the heparin-binding site of FXIa. No allosteric small molecule has been discovered to date that exhibits equivalent potency against FXIa. Inhibitor 6 is expected to open up a major route to allosteric FXIa anticoagulants with clinical relevance. PMID:23316863

Decavanadate, a P2X receptor antagonist, and its use to study ligand interactions with P2X7 receptors.

PubMed

Michel, Anton D; Xing, Mengle; Thompson, Kyla M; Jones, Clare A; Humphrey, Patrick P A

2006-03-18

In this study we have studied decavanadate effects at P2X receptors. Decavanadate competitively blocked 2'- and 3'-O-(4benzoylbenzoyl) ATP (BzATP) stimulated ethidium accumulation in HEK293 cells expressing human recombinant P2X7 receptors (pK(B) 7.5). The effects of decavanadate were rapid (minutes) in both onset and offset and contrasted with the much slower kinetics of pyridoxal 5-phosphate (P5P), Coomassie brilliant blue (CBB) and 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN62). Decavanadate competitively blocked the slowly reversible, or irreversible, blockade of the P2X7 receptor produced by P5P and oxidised ATP suggesting competition for a common binding site. However, the interaction between decavanadate and KN62 was non-competitive. Decavanadate also blocked P2X2 and P2X4 receptors but with slightly lower potency. These data demonstrate that decavanadate is the first reversible and competitive antagonist of the P2X7 receptor and is a useful tool for studying the mechanism of interaction of ligands with the P2X7 receptor.

Instabilities and spatiotemporal patterns behind predator invasions with nonlocal prey competition.

PubMed

Merchant, Sandra M; Nagata, Wayne

2011-12-01

We study the influence of nonlocal intraspecies prey competition on the spatiotemporal patterns arising behind predator invasions in two oscillatory reaction-diffusion integro-differential models. We use three common types of integral kernels as well as develop a caricature system, to describe the influence of the standard deviation and kurtosis of the kernel function on the patterns observed. We find that nonlocal competition can destabilize the spatially homogeneous state behind the invasion and lead to the formation of complex spatiotemporal patterns, including stationary spatially periodic patterns, wave trains and irregular spatiotemporal oscillations. In addition, the caricature system illustrates how large standard deviation and low kurtosis facilitate the formation of these spatiotemporal patterns. This suggests that nonlocal competition may be an important mechanism underlying spatial pattern formation, particularly in systems where the competition between individuals varies over space in a platykurtic manner. Copyright © 2011 Elsevier Inc. All rights reserved.

Spatial heterogeneity of plant-soil feedback affects root interactions and interspecific competition.

PubMed

Hendriks, Marloes; Ravenek, Janneke M; Smit-Tiekstra, Annemiek E; van der Paauw, Jan Willem; de Caluwe, Hannie; van der Putten, Wim H; de Kroon, Hans; Mommer, Liesje

2015-08-01

Plant-soil feedback is receiving increasing interest as a factor influencing plant competition and species coexistence in grasslands. However, we do not know how spatial distribution of plant-soil feedback affects plant below-ground interactions. We investigated the way in which spatial heterogeneity of soil biota affects competitive interactions in grassland plant species. We performed a pairwise competition experiment combined with heterogeneous distribution of soil biota using four grassland plant species and their soil biota. Patches were applied as quadrants of 'own' and 'foreign' soils from all plant species in all pairwise combinations. To evaluate interspecific root responses, species-specific root biomass was quantified using real-time PCR. All plant species suffered negative soil feedback, but strength was species-specific, reflected by a decrease in root growth in own compared with foreign soil. Reduction in root growth in own patches by the superior plant competitor provided opportunities for inferior competitors to increase root biomass in these patches. These patterns did not cascade into above-ground effects during our experiment. We show that root distributions can be determined by spatial heterogeneity of soil biota, affecting plant below-ground competitive interactions. Thus, spatial heterogeneity of soil biota may contribute to plant species coexistence in species-rich grasslands. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

Divergent modes of enzyme inhibition in a homologous structure-activity series.

PubMed

Ferreira, Rafaela S; Bryant, Clifford; Ang, Kenny K H; McKerrow, James H; Shoichet, Brian K; Renslo, Adam R

2009-08-27

A docking screen identified reversible, noncovalent inhibitors (e.g., 1) of the parasite cysteine protease cruzain. Chemical optimization of 1 led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending on the assay conditions employed.

A new ELISA for determination of potency in snake antivenoms.

PubMed

Rial, A; Morais, V; Rossi, S; Massaldi, H

2006-09-15

A competitive ELISA for potency determination of bothropic equine antivenom was developed and compared to the conventional in vivo ED(50) assay, with the aim of partially substituting the in vivo assay in the monitoring of antivenom immunoglobulin levels. On this purpose, blood samples were taken at different times during and after the immunization protocol of the lot of horses used for production of snake antivenom at the Instituto de Higiene, Uruguay. Both the competitive ELISA and the ED(50) assay were performed on those samples. In addition, a group of five commercial pepsin-digested antivenoms were tested by both methods. A significant (P<0.001) correlation (Pearson's r=0.957) was found between the ELISA titres and the corresponding ED(50) values, indicating that the in vitro test can estimate the neutralizing antibody capacity of the sera as well as the in vivo assay. By means of this new ELISA, it was found that the immunized animals maintained good venom antibody titres, in the order of 20-50% of the maximum achieved, even 10 month after the end of the immunization schedule. The main advantage of our ELISA design is its ability to correctly estimate the neutralization capacity of crude hyperimmune plasma and antivenom sera independently of their antibody composition in terms of whole IgG or F(ab')(2) fragment.

The role of competition – colonization tradeoffs and spatial heterogeneity in promoting trematode coexistence

USGS Publications Warehouse

Mordecai, Erin A.; Jaramillo, Alejandra G.; Ashford, Jacob E.; Hechinger, Ryan F.; Lafferty, Kevin D.

2016-01-01

Competition – colonization tradeoffs occur in many systems, and theory predicts that they can strongly promote species coexistence. However, there is little empirical evidence that observed competition – colonization tradeoffs are strong enough to maintain diversity in natural systems. This is due in part to a mismatch between theoretical assumptions and biological reality in some systems. We tested whether a competition – colonization tradeoff explains how a diverse trematode guild coexists in California horn snail populations, a system that meets the requisite criteria for the tradeoff to promote coexistence. A field experiment showed that subordinate trematode species tended to have higher colonization rates than dominant species. This tradeoff promoted coexistence in parameterized models but did not fully explain trematode diversity and abundance, suggesting a role of additional diversity maintenance mechanisms. Spatial heterogeneity is an alternative way to promote coexistence if it isolates competing species. We used scale transition theory to expand the competition – colonization tradeoff model to include spatial variation. The parameterized model showed that spatial variation in trematode prevalence did not isolate most species sufficiently to explain the overall high diversity, but could benefit some rare species. Together, the results suggest that several mechanisms combine to maintain diversity, even when a competition – colonization tradeoff occurs.

Dampened regulates the activating potency of Bicoid and the embryonic patterning outcome in Drosophila

PubMed Central

Liu, Junbo; Ma, Jun

2014-01-01

The Drosophila morphogen gradient of Bicoid (Bcd) initiates anterior-posterior (AP) patterning, but it is poorly understood how its ability to activate a target gene may impact this process. Here we report an F-box protein, Dampened (Dmpd) as a nuclear co-factor of Bcd that can enhance its activating potency. We establish a quantitative platform to specifically investigate two parameters of a Bcd target gene response, expression amplitude and boundary position. We show that embryos lacking Dmpd have a reduced amplitude of Bcd-activated hunchback (hb) expression at a critical time of development. This is due to a reduced Bcd-dependent transcribing probability. This defect is faithfully propagated further downstream of the AP patterning network to alter the spatial characteristics of even-skipped (eve) stripes. Thus, unlike another Bcd-interacting F-box protein Fates-shifted (Fsd), which controls AP patterning through regulating the Bcd gradient profile, Dmpd achieves its patterning role through regulating the activating potency of Bcd. PMID:24336107

Spatial and temporal patterns of coexistence between competing Aedes mosquitoes in urban Florida

PubMed Central

Juliano, S. A.

2009-01-01

Understanding mechanisms fostering coexistence between invasive and resident species is important in predicting ecological, economic, or health impacts of invasive species. The mosquito Aedes aegypti coexists at some urban sites in southeastern United States with invasive Aedes albopictus, which is often superior in interspecific competition. We tested predictions for three hypotheses of species coexistence: seasonal condition-specific competition, aggregation among individual water-filled containers, and colonization–competition tradeoff across spatially partitioned habitat patches (cemeteries) that have high densities of containers. We measured spatial and temporal patterns of abundance for both species among water-filled resident cemetery vases and experimentally positioned standard cemetery vases and ovitraps in metropolitan Tampa, Florida. Consistent with the seasonal condition-specific competition hypothesis, abundances of both species in resident and standard cemetery vases were higher early in the wet season (June) versus late in the wet season (September), but the proportional increase of A. albopictus was greater than that of A. aegypti, presumably due to higher dry-season egg mortality and strong wet-season competitive superiority of larval A. albopictus. Spatial partitioning was not evident among cemeteries, a result inconsistent with the colonization-competition tradeoff hypothesis, but both species were highly independently aggregated among standard cemetery vases and ovitraps, which is consistent with the aggregation hypothesis. Densities of A. aegypti but not A. albopictus differed among land use categories, with A. aegypti more abundant in ovitraps in residential areas compared to industrial and commercial areas. Spatial partitioning among land use types probably results from effects of land use on conditions in both terrestrial and aquatic-container environments. These results suggest that both temporal and spatial variation may contribute to local coexistence between these Aedes in urban areas. PMID:19263086

Spatial and temporal patterns of coexistence between competing Aedes mosquitoes in urban Florida.

PubMed

Leisnham, Paul T; Juliano, S A

2009-05-01

Understanding mechanisms fostering coexistence between invasive and resident species is important in predicting ecological, economic, or health impacts of invasive species. The mosquito Aedes aegypti coexists at some urban sites in southeastern United States with invasive Aedes albopictus, which is often superior in interspecific competition. We tested predictions for three hypotheses of species coexistence: seasonal condition-specific competition, aggregation among individual water-filled containers, and colonization-competition tradeoff across spatially partitioned habitat patches (cemeteries) that have high densities of containers. We measured spatial and temporal patterns of abundance for both species among water-filled resident cemetery vases and experimentally positioned standard cemetery vases and ovitraps in metropolitan Tampa, Florida. Consistent with the seasonal condition-specific competition hypothesis, abundances of both species in resident and standard cemetery vases were higher early in the wet season (June) versus late in the wet season (September), but the proportional increase of A. albopictus was greater than that of A. aegypti, presumably due to higher dry-season egg mortality and strong wet-season competitive superiority of larval A. albopictus. Spatial partitioning was not evident among cemeteries, a result inconsistent with the colonization-competition tradeoff hypothesis, but both species were highly independently aggregated among standard cemetery vases and ovitraps, which is consistent with the aggregation hypothesis. Densities of A. aegypti but not A. albopictus differed among land use categories, with A. aegypti more abundant in ovitraps in residential areas compared to industrial and commercial areas. Spatial partitioning among land use types probably results from effects of land use on conditions in both terrestrial and aquatic-container environments. These results suggest that both temporal and spatial variation may contribute to local coexistence between these Aedes in urban areas.

The contribution of competition to tree mortality in old-growth coniferous forests

USGS Publications Warehouse

Das, A.; Battles, J.; Stephenson, N.L.; van Mantgem, P.J.

2011-01-01

Competition is a well-documented contributor to tree mortality in temperate forests, with numerous studies documenting a relationship between tree death and the competitive environment. Models frequently rely on competition as the only non-random mechanism affecting tree mortality. However, for mature forests, competition may cease to be the primary driver of mortality.We use a large, long-term dataset to study the importance of competition in determining tree mortality in old-growth forests on the western slope of the Sierra Nevada of California, U.S.A. We make use of the comparative spatial configuration of dead and live trees, changes in tree spatial pattern through time, and field assessments of contributors to an individual tree's death to quantify competitive effects.Competition was apparently a significant contributor to tree mortality in these forests. Trees that died tended to be in more competitive environments than trees that survived, and suppression frequently appeared as a factor contributing to mortality. On the other hand, based on spatial pattern analyses, only three of 14 plots demonstrated compelling evidence that competition was dominating mortality. Most of the rest of the plots fell within the expectation for random mortality, and three fit neither the random nor the competition model. These results suggest that while competition is often playing a significant role in tree mortality processes in these forests it only infrequently governs those processes. In addition, the field assessments indicated a substantial presence of biotic mortality agents in trees that died.While competition is almost certainly important, demographics in these forests cannot accurately be characterized without a better grasp of other mortality processes. In particular, we likely need a better understanding of biotic agents and their interactions with one another and with competition. ?? 2011.

Unique DC-SIGN clustering activity of a small glycomimetic: A lesson for ligand design.

PubMed

Sutkeviciute, Ieva; Thépaut, Michel; Sattin, Sara; Berzi, Angela; McGeagh, John; Grudinin, Sergei; Weiser, Jörg; Le Roy, Aline; Reina, Jose J; Rojo, Javier; Clerici, Mario; Bernardi, Anna; Ebel, Christine; Fieschi, Franck

2014-06-20

DC-SIGN is a dendritic cell-specific C-type lectin receptor that recognizes highly glycosylated ligands expressed on the surface of various pathogens. This receptor plays an important role in the early stages of many viral infections, including HIV, which makes it an interesting therapeutic target. Glycomimetic compounds are good drug candidates for DC-SIGN inhibition due to their high solubility, resistance to glycosidases, and nontoxicity. We studied the structural properties of the interaction of the tetrameric DC-SIGN extracellular domain (ECD), with two glycomimetic antagonists, a pseudomannobioside (1) and a linear pseudomannotrioside (2). Though the inhibitory potency of 2, as measured by SPR competition experiments, was 1 order of magnitude higher than that of 1, crystal structures of the complexes within the DC-SIGN carbohydrate recognition domain showed the same binding mode for both compounds. Moreover, when conjugated to multivalent scaffolds, the inhibitory potencies of these compounds became uniform. Combining isothermal titration microcalorimetry, analytical ultracentrifugation, and dynamic light scattering techniques to study DC-SIGN ECD interaction with these glycomimetics revealed that 2 is able, without any multivalent presentation, to cluster DC-SIGN tetramers leading to an artificially overestimated inhibitory potency. The use of multivalent scaffolds presenting 1 or 2 in HIV trans-infection inhibition assay confirms the loss of potency of 2 upon conjugation and the equal efficacy of chemically simpler compound 1. This study documents a unique case where, among two active compounds chemically derived, the compound with the lower apparent activity is the optimal lead for further drug development.

Discovery of a novel general anesthetic chemotype using high-throughput screening.

PubMed

McKinstry-Wu, Andrew R; Bu, Weiming; Rai, Ganesha; Lea, Wendy A; Weiser, Brian P; Liang, David F; Simeonov, Anton; Jadhav, Ajit; Maloney, David J; Eckenhoff, Roderic G

2015-02-01

The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-aminoanthracene-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for γ-aminobutyric acid type A receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. From an initial chemical library of more than 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-aminoanthracene binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based on a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. The authors demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype.

Preemptive spatial competition under a reproduction-mortality constraint.

PubMed

Allstadt, Andrew; Caraco, Thomas; Korniss, G

2009-06-21

Spatially structured ecological interactions can shape selection pressures experienced by a population's different phenotypes. We study spatial competition between phenotypes subject to antagonistic pleiotropy between reproductive effort and mortality rate. The constraint we invoke reflects a previous life-history analysis; the implied dependence indicates that although propagation and mortality rates both vary, their ratio is fixed. We develop a stochastic invasion approximation predicting that phenotypes with higher propagation rates will invade an empty environment (no biotic resistance) faster, despite their higher mortality rate. However, once population density approaches demographic equilibrium, phenotypes with lower mortality are favored, despite their lower propagation rate. We conducted a set of pairwise invasion analyses by simulating an individual-based model of preemptive competition. In each case, the phenotype with the lowest mortality rate and (via antagonistic pleiotropy) the lowest propagation rate qualified as evolutionarily stable among strategies simulated. This result, for a fixed propagation to mortality ratio, suggests that a selective response to spatial competition can extend the time scale of the population's dynamics, which in turn decelerates phenotypic evolution.

THE EVOLUTION OF RESTRAINT IN BACTERIAL BIOFILMS UNDER NONTRANSITIVE COMPETITION

PubMed Central

Prado, Federico; Kerr, Benjamin

2009-01-01

Theoretical and empirical evidence indicates that competing species can coexist if dispersal, migration, and competitive interactions occur over relatively small spatial scales. In particular, spatial structure appears to be critical to certain communities with nontransitive competition. A typical nontransitive system involves three competing species that satisfy a relationship similar to the children’s game of rock–paper–scissors. Although the ecological dynamics of nontransitive systems in spatially structured communities have received some attention, fewer studies have incorporated evolutionary change. Here we investigate evolution within toxic bacterial biofilms using an agent-based simulation that represents a nontransitive community containing three populations of Escherichia coli. In structured, nontransitive communities, strains evolve that do not maximize their competitive ability: They do not reduce their probability of death to a minimum or increase their toxicity to a maximum. That is, types evolve that exercise restraint. We show that nontransitivity and spatial structure (in the form of localized interactions) are both necessary for the evolution of restraint in these biofilms. PMID:18039324

The evolution of restraint in bacterial biofilms under nontransitive competition.

PubMed

Prado, Federico; Kerr, Benjamin

2008-03-01

Theoretical and empirical evidence indicates that competing species can coexist if dispersal, migration, and competitive interactions occur over relatively small spatial scales. In particular, spatial structure appears to be critical to certain communities with nontransitive competition. A typical nontransitive system involves three competing species that satisfy a relationship similar to the children's game of rock-paper-scissors. Although the ecological dynamics of nontransitive systems in spatially structured communities have received some attention, fewer studies have incorporated evolutionary change. Here we investigate evolution within toxic bacterial biofilms using an agent-based simulation that represents a nontransitive community containing three populations of Escherichia coli. In structured, nontransitive communities, strains evolve that do not maximize their competitive ability: They do not reduce their probability of death to a minimum or increase their toxicity to a maximum. That is, types evolve that exercise restraint. We show that nontransitivity and spatial structure (in the form of localized interactions) are both necessary for the evolution of restraint in these biofilms.

Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors.

PubMed

Labadie, Sharada S; Dragovich, Peter S; Cummings, Richard T; Deshmukh, Gauri; Gustafson, Amy; Han, Ning; Harmange, Jean-Christophe; Kiefer, James R; Li, Yue; Liang, Jun; Liederer, Bianca M; Liu, Yichin; Manieri, Wanda; Mao, Wiefeng; Murray, Lesley; Ortwine, Daniel F; Trojer, Patrick; VanderPorten, Erica; Vinogradova, Maia; Wen, Li

2016-09-15

Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG). Copyright © 2016 Elsevier Ltd. All rights reserved.

Competitive intransitivity, population interaction structure, and strategy coexistence.

PubMed

Laird, Robert A; Schamp, Brandon S

2015-01-21

Intransitive competition occurs when competing strategies cannot be listed in a hierarchy, but rather form loops-as in the game rock-paper-scissors. Due to its cyclic competitive replacement, competitive intransitivity promotes strategy coexistence, both in rock-paper-scissors and in higher-richness communities. Previous work has shown that this intransitivity-mediated coexistence is strongly influenced by spatially explicit interactions, compared to when populations are well mixed. Here, we extend and broaden this line of research and examine the impact on coexistence of intransitive competition taking place on a continuum of small-world networks linking spatial lattices and regular random graphs. We use simulations to show that the positive effect of competitive intransitivity on strategy coexistence holds when competition occurs on networks toward the spatial end of the continuum. However, in networks that are sufficiently disordered, increasingly violent fluctuations in strategy frequencies can lead to extinctions and the prevalence of monocultures. We further show that the degree of disorder that leads to the transition between these two regimes is positively dependent on population size; indeed for very large populations, intransitivity-mediated strategy coexistence may even be possible in regular graphs with completely random connections. Our results emphasize the importance of interaction structure in determining strategy dynamics and diversity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Spatial competition dynamics between reef corals under ocean acidification.

PubMed

Horwitz, Rael; Hoogenboom, Mia O; Fine, Maoz

2017-01-09

Climate change, including ocean acidification (OA), represents a major threat to coral-reef ecosystems. Although previous experiments have shown that OA can negatively affect the fitness of reef corals, these have not included the long-term effects of competition for space on coral growth rates. Our multispecies year-long study subjected reef-building corals from the Gulf of Aqaba (Red Sea) to competitive interactions under present-day ocean pH (pH 8.1) and predicted end-of-century ocean pH (pH 7.6). Results showed coral growth is significantly impeded by OA under intraspecific competition for five out of six study species. Reduced growth from OA, however, is negligible when growth is already suppressed in the presence of interspecific competition. Using a spatial competition model, our analysis indicates shifts in the competitive hierarchy and a decrease in overall coral cover under lowered pH. Collectively, our case study demonstrates how modified competitive performance under increasing OA will in all likelihood change the composition, structure and functionality of reef coral communities.

Spatial competition dynamics between reef corals under ocean acidification

NASA Astrophysics Data System (ADS)

Horwitz, Rael; Hoogenboom, Mia O.; Fine, Maoz

2017-01-01

Climate change, including ocean acidification (OA), represents a major threat to coral-reef ecosystems. Although previous experiments have shown that OA can negatively affect the fitness of reef corals, these have not included the long-term effects of competition for space on coral growth rates. Our multispecies year-long study subjected reef-building corals from the Gulf of Aqaba (Red Sea) to competitive interactions under present-day ocean pH (pH 8.1) and predicted end-of-century ocean pH (pH 7.6). Results showed coral growth is significantly impeded by OA under intraspecific competition for five out of six study species. Reduced growth from OA, however, is negligible when growth is already suppressed in the presence of interspecific competition. Using a spatial competition model, our analysis indicates shifts in the competitive hierarchy and a decrease in overall coral cover under lowered pH. Collectively, our case study demonstrates how modified competitive performance under increasing OA will in all likelihood change the composition, structure and functionality of reef coral communities.

It's About Time: A Critique of Macroecological Inferences Concerning Plant Competition.

PubMed

Damgaard, Christian; Weiner, Jacob

2017-02-01

Several macroecological studies have used static spatial data to evaluate plant competition in natural ecosystems and to investigate its role in plant community dynamics and species assembly. The assumptions on which the inferences are based have not been consistent with ecological knowledge. Inferences about processes, such as competition, from static data are weak. Macroecology will benefit more from dynamic data, even if limited, than from increasingly sophisticated analyses of static spatial patterns. Copyright © 2016 Elsevier Ltd. All rights reserved.

Two-track virtual screening approach to identify both competitive and allosteric inhibitors of human small C-terminal domain phosphatase 1

NASA Astrophysics Data System (ADS)

Park, Hwangseo; Lee, Hye Seon; Ku, Bonsu; Lee, Sang-Rae; Kim, Seung Jun

2017-08-01

Despite a wealth of persuasive evidence for the involvement of human small C-terminal domain phosphatase 1 (Scp1) in the impairment of neuronal differentiation and in Huntington's disease, small-molecule inhibitors of Scp1 have been rarely reported so far. This study aims to the discovery of both competitive and allosteric Scp1 inhibitors through the two-track virtual screening procedure. By virtue of the improvement of the scoring function by implementing a new molecular solvation energy term and by reoptimizing the atomic charges for the active-site Mg2+ ion cluster, we have been able to identify three allosteric and five competitive Scp1 inhibitors with low-micromolar inhibitory activity. Consistent with the results of kinetic studies on the inhibitory mechanisms, the allosteric inhibitors appear to be accommodated in the peripheral binding pocket through the hydrophobic interactions with the nonpolar residues whereas the competitive ones bind tightly in the active site with a direct coordination to the central Mg2+ ion. Some structural modifications to improve the biochemical potency of the newly identified inhibitors are proposed based on the binding modes estimated with docking simulations.

Optimized Target Residence Time: Type I1/2 Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R-Spine.

PubMed

Wentsch, Heike K; Walter, Niklas M; Bührmann, Mike; Mayer-Wrangowski, Svenja; Rauh, Daniel; Zaman, Guido J R; Willemsen-Seegers, Nicole; Buijsman, Rogier C; Henning, Melanie; Dauch, Daniel; Zender, Lars; Laufer, Stefan

2017-05-02

Skepinone-L was recently reported to be a p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, this class of compounds still act as fully ATP-competitive Type I binders which, furthermore, suffer from short residence times at the enzyme. We herein describe a further development with the first Type I1/2 binders for p38α MAP kinase. Type I1/2 inhibitors interfere with the R-spine, inducing a glycine flip and occupying both hydrophobic regions I and II. This design approach leads to prolonged target residence time, binding to both the active and inactive states of the kinase, excellent selectivity, excellent potency on the enzyme level, and low nanomolar activity in a human whole blood assay. This promising binding mode is proven by X-ray crystallography. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Monocarbonyl Curcumin Analogs: Heterocyclic Pleiotropic Kinase Inhibitors that Mediate Anti-Cancer Properties

PubMed Central

Brown, Andrew; Shi, Qi; Moore, Terry W.; Yoon, Younghyoun; Prussia, Andrew; Maddox, Clinton; Liotta, Dennis C.; Shim*, Hyunsuk; Snyder*, James P.

2014-01-01

Curcumin is a biologically active component of curry powder. A structurally-related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed ≥85% inhibition for ten of the enzymes at 5 μM, while twenty-two of the proteins were blocked at ≥40%. IC50’s for an expanded set of curcumin analogs established a rank order of potencies, and analyses of IKKβ and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogs are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways. PMID:23550937

Monocarbonyl curcumin analogues: heterocyclic pleiotropic kinase inhibitors that mediate anticancer properties.

PubMed

Brown, Andrew; Shi, Qi; Moore, Terry W; Yoon, Younghyoun; Prussia, Andrew; Maddox, Clinton; Liotta, Dennis C; Shim, Hyunsuk; Snyder, James P

2013-05-09

Curcumin is a biologically active component of curry powder. A structurally related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed ≥85% inhibition for 10 of the enzymes at 5 μM, while 22 of the proteins were blocked at ≥40%. IC50 values for an expanded set of curcumin analogues established a rank order of potencies, and analyses of IKKβ and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogues are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways.

High-throughput screening to identify selective inhibitors of microbial sulfate reduction (and beyond)

NASA Astrophysics Data System (ADS)

Carlson, H. K.; Coates, J. D.; Deutschbauer, A. M.

2015-12-01

The selective perturbation of complex microbial ecosystems to predictably influence outcomes in engineered and industrial environments remains a grand challenge for geomicrobiology. In some industrial ecosystems, such as oil reservoirs, sulfate reducing microorganisms (SRM) produce hydrogen sulfide which is toxic, explosive and corrosive. Current strategies to selectively inhibit sulfidogenesis are based on non-specific biocide treatments, bio-competitive exclusion by alternative electron acceptors or sulfate-analogs which are competitive inhibitors or futile/alternative substrates of the sulfate reduction pathway. Despite the economic cost of sulfidogenesis, there has been minimal exploration of the chemical space of possible inhibitory compounds, and very little work has quantitatively assessed the selectivity of putative souring treatments. We have developed a high-throughput screening strategy to target SRM, quantitatively ranked the selectivity and potency of hundreds of compounds and identified previously unrecognized SRM selective inhibitors and synergistic interactions between inhibitors. Once inhibitor selectivity is defined, high-throughput characterization of microbial community structure across compound gradients and identification of fitness determinants using isolate bar-coded transposon mutant libraries can give insights into the genetic mechanisms whereby compounds structure microbial communities. The high-throughput (HT) approach we present can be readily applied to target SRM in diverse environments and more broadly, could be used to identify and quantify the potency and selectivity of inhibitors of a variety of microbial metabolisms. Our findings and approach are relevant for engineering environmental ecosystems and also to understand the role of natural gradients in shaping microbial niche space.

Density dependence, spatial scale and patterning in sessile biota.

PubMed

Gascoigne, Joanna C; Beadman, Helen A; Saurel, Camille; Kaiser, Michel J

2005-09-01

Sessile biota can compete with or facilitate each other, and the interaction of facilitation and competition at different spatial scales is key to developing spatial patchiness and patterning. We examined density and scale dependence in a patterned, soft sediment mussel bed. We followed mussel growth and density at two spatial scales separated by four orders of magnitude. In summer, competition was important at both scales. In winter, there was net facilitation at the small scale with no evidence of density dependence at the large scale. The mechanism for facilitation is probably density dependent protection from wave dislodgement. Intraspecific interactions in soft sediment mussel beds thus vary both temporally and spatially. Our data support the idea that pattern formation in ecological systems arises from competition at large scales and facilitation at smaller scales, so far only shown in vegetation systems. The data, and a simple, heuristic model, also suggest that facilitative interactions in sessile biota are mediated by physical stress, and that interactions change in strength and sign along a spatial or temporal gradient of physical stress.

Comparative reactivity of human IgE to cynomolgus monkey and human effector cells and effects on IgE effector cell potency

PubMed Central

Saul, Louise; Saul, Louise; Josephs, Debra H; Josephs, Debra H; Cutler, Keith; Cutler, Keith; Bradwell, Andrew; Bradwell, Andrew; Karagiannis, Panagiotis; Karagiannis, Panagiotis; Selkirk, Chris; Selkirk, Chris; Gould, Hannah J; Gould, Hannah J; Jones, Paul; Jones, Paul; Spicer, James F; Spicer, James F; Karagiannis, Sophia N; Karagiannis, Sophia N

2014-01-01

Background: Due to genetic similarities with humans, primates of the macaque genus such as the cynomolgus monkey are often chosen as models for toxicology studies of antibody therapies. IgE therapeutics in development depend upon engagement with the FcεRI and FcεRII receptors on immune effector cells for their function. Only limited knowledge of the primate IgE immune system is available to inform the choice of models for mechanistic and safety evaluations.   Methods: The recognition of human IgE by peripheral blood lymphocytes from cynomolgus monkey and man was compared. We used effector cells from each species in ex vivo affinity, dose-response, antibody-receptor dissociation and potency assays. Results: We report cross-reactivity of human IgE Fc with cynomolgus monkey cells, and comparable binding kinetics to peripheral blood lymphocytes from both species. In competition and dissociation assays, however, human IgE dissociated faster from cynomolgus monkey compared with human effector cells. Differences in association and dissociation kinetics were reflected in effector cell potency assays of IgE-mediated target cell killing, with higher concentrations of human IgE needed to elicit effector response in the cynomolgus monkey system. Additionally, human IgE binding on immune effector cells yielded significantly different cytokine release profiles in each species. Conclusion: These data suggest that human IgE binds with different characteristics to human and cynomolgus monkey IgE effector cells. This is likely to affect the potency of IgE effector functions in these two species, and so has relevance for the selection of biologically-relevant model systems when designing pre-clinical toxicology and functional studies. PMID:24492303

Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening

PubMed Central

McKinstry-Wu, Andrew R.; Bu, Weiming; Rai, Ganesha; Lea, Wendy A.; Weiser, Brian P.; Liang, David F.; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.; Eckenhoff, Roderic G.

2014-01-01

Background The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Methods Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene (1-AMA) and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-AMA-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for γ-aminobutyric acid type A-receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. Results From an initial chemical library of over 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-AMA binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based upon a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. Conclusions We demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype. PMID:25603205

Hospital staffing and local pay: an investigation into the impact of local variations in the competitiveness of nurses' pay on the staffing of hospitals in France.

PubMed

Combes, Jean-Baptiste; Delattre, Eric; Elliott, Bob; Skåtun, Diane

2015-09-01

Spatial wage theory suggests that employers in different regions may offer different pay rates to reflect local amenities and cost of living. Higher wages may be required to compensate for a less pleasant environment or a higher cost of living. If wages in a competing sector within an area are less flexible and therefore less competitive this may lead to an inability to employ staff. This paper considers the market for nursing staff in France where there is general regulation of wages and public hospitals compete for staff with the private hospital and non-hospital sectors. We consider two types of nursing staff, registered and assistant nurses and first establish the degree of spatial variation in the competitiveness of pay of nurses in public hospitals. We then consider whether these spatial variations are associated with variation in the employment of nursing staff. We find that despite regulation of pay in the public and private sector, there are substantial local variations in the competitiveness of nurses' pay. We find evidence that the spatial variations in the competitiveness of pay are associated with relative numbers of assistant nurses but not registered nurses. While we find the influence of the competitiveness of pay is small, it suggests that nonpay conditions may be an important factor in adjusting the labour market as might be expected in such a regulated market.

Does Competition Improve Public School Efficiency? A Spatial Analysis

ERIC Educational Resources Information Center

Misra, Kaustav

2010-01-01

Proponents of educational reform often call for policies to increase competition between schools. It is argued that market forces naturally lead to greater efficiencies, including improved student learning, when schools face competition. In many parts of the country, public schools experience significant competition from private schools; however,…

Coexistence of species with different dispersal across landscapes: a critical role of spatial correlation in disturbance.

PubMed

Liao, Jinbao; Ying, Zhixia; Woolnough, Daelyn A; Miller, Adam D; Li, Zhenqing; Nijs, Ivan

2016-05-11

Disturbance is key to maintaining species diversity in plant communities. Although the effects of disturbance frequency and extent on species diversity have been studied, we do not yet have a mechanistic understanding of how these aspects of disturbance interact with spatial structure of disturbance to influence species diversity. Here we derive a novel pair approximation model to explore competitive outcomes in a two-species system subject to spatially correlated disturbance. Generally, spatial correlation in disturbance favoured long-range dispersers, while distance-limited dispersers were greatly suppressed. Interestingly, high levels of spatial aggregation of disturbance promoted long-term species coexistence that is not possible in the absence of disturbance, but only when the local disperser was intrinsically competitively superior. However, spatial correlation in disturbance led to different competitive outcomes, depending on the disturbed area. Concerning ecological conservation and management, we theoretically demonstrate that introducing a spatially correlated disturbance to the system or altering an existing disturbance regime can be a useful strategy either to control species invasion or to promote species coexistence. Disturbance pattern analysis may therefore provide new insights into biodiversity conservation. © 2016 The Author(s).

Role of intraspecific competition in the coexistence of mobile populations in spatially extended ecosystems.

PubMed

Yang, Rui; Wang, Wen-Xu; Lai, Ying-Cheng; Grebogi, Celso

2010-06-01

Evolutionary-game based models of nonhierarchical, cyclically competing populations have become paradigmatic for addressing the fundamental problem of species coexistence in spatially extended ecosystems. We study the role of intraspecific competition in the coexistence and find that the competition can strongly promote the coexistence for high individual mobility in the sense that stable coexistence can arise in parameter regime where extinction would occur without the competition. The critical value of the competition rate beyond which the coexistence is induced is found to be independent of the mobility. We derive a theoretical model based on nonlinear partial differential equations to predict the critical competition rate and the boundaries between the coexistence and extinction regions in a relevant parameter space. We also investigate pattern formation and well-mixed spatiotemporal population dynamics to gain further insights into our findings. (c) 2010 American Institute of Physics.

Effects of perfluoroalkyl substances on neurosteroid synthetic enzymes in the rat.

PubMed

Xu, Renai; Shen, Qiuxia; Li, Senlin; Li, Xiaojun; Li, Huitao; Lü, Yao; Lian, Qing-Quan; Ge, Ren-Shan

2017-06-25

Perfluoroalkylated substances (PFASs), including perfluorooctyl sulphonate (PFOS) and perfluorooctane acid (PFOA), have been classified as persistent organic pollutants and are known to cause endocrine-disrupting effects in humans. The objective of the present study was to compare the potencies of four different PFASs, PFOS, PFOA, perfluorohexyl sulfonate (PFHxS), and perfluorobutyl sulfonate (PFBS), to inhibit neurosteroidogenic 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C9), and retinol dehydrogenase 2 (RoDH2) in rats. The potencies of PFASs to inhibit SRD5A1 are PFOS > PFOA > PFHxS = PFBS, with IC 50 values of PFOS and PFOA of 1.92 ± 0.07 and 14.24 ± 0.07 μM and no effects for PFHxS and PFBS at 100 μM, respectively. The potencies of PFASs to inhibit AKR1C9 and RoDH2 are PFOS > PFOA > PFHxS = PFBS, with IC 50 values of PFOS and PFOA on these two enzymes about 100 μM and no effects for PFHxS and PFBS at 100 μM, respectively. PFOS and PFOA competitively inhibited rat SRD5A1. In conclusion, PFOS and PFOA are potent inhibitors of rat SRD5A1, thereby controlling the biosynthesis of neurosteroids. Copyright © 2017 Elsevier B.V. All rights reserved.

Antagonist interaction with the human 5-HT7 receptor mediates the rapid and potent inhibition of non-G-protein-stimulated adenylate cyclase activity: a novel GPCR effect

PubMed Central

Klein, MT; Teitler, M

2011-01-01

BACKGROUND AND PURPOSE The human 5-hydroxytryptamine7 (h5-HT7) receptor is Gs-coupled and stimulates the production of the intracellular signalling molecule cAMP. Previously, we reported a novel property of the h5-HT7 receptor: pseudo-irreversible antagonists irreversibly inhibit forskolin-stimulated (non-receptor-mediated) cAMP production. Herein, we sought to determine if competitive antagonists also affect forskolin-stimulated activity and if this effect is common among other Gs-coupled receptors. EXPERIMENTAL APPROACH Recombinant cell lines expressing h5-HT7 receptors or other receptors of interest were briefly exposed to antagonists; cAMP production was then stimulated by forskolin and quantified by an immunocompetitive assay. KEY RESULTS In human embryonic kidney 293 cells stably expressing h5-HT7 receptors, all competitive antagonists inhibited nearly 100% of forskolin-stimulated cAMP production. This effect was insensitive to pertussis toxin, that is, not Gi/o-mediated. Potency to inhibit forskolin-stimulated activity strongly correlated with h5-HT7 binding affinity (r2= 0.91), indicating that the antagonists acted through h5-HT7 receptors to inhibit forskolin. Potency and maximal effects of clozapine, a prototypical competitive h5-HT7 antagonist, were unaffected by varying forskolin concentration. Antagonist interaction with h5-HT6, human β1, β2, and β3 adrenoceptors did not inhibit forskolin's activity. CONCLUSIONS AND IMPLICATIONS The inhibition of adenylate cyclase, as measured by forskolin's activity, is an underlying property of antagonist interaction with h5-HT7 receptors; however, this is not a common property of other Gs-coupled receptors. This phenomenon may be involved in the roles played by h5-HT7 receptors in human physiology. Development of h5-HT7 antagonists that do not elicit this effect would aid in the elucidation of its mechanisms and shed light on its possible physiological relevance. PMID:21198551

Characterization of kinin receptors by bioassays.

PubMed

Gobeil, F; Regoli, D

1994-08-01

1. Using the classical pharmacological criteria recommended by Schild, namely the order of potency of selective agonists (e.g., bradykinin, desArg9-bradykinin, [Hyp3]BK and [Aib7]BK) and the apparent affinity of competitive antagonists (e.g., DArg[Hyp3,DPhe7,Leu8]BK and WIN 64338), we have attempted to characterize B2 receptor subtypes. It has been shown that vascular tissues (e.g., dog carotid and renal arteries, rabbit jugular vein and rabbit aorta) are very sensitive to kinin agonists and antagonists (pD2 and pA2 values for BK and HOE 140 on B2 receptors are 8.5-10.1 and 9.2-9.4, respectively, and for desArg9BK and desArg9[Leu8]BK on B1 receptors they are 7.3-8.6 and 7.3-7.8, respectively). Mechanisms of action of kinins differ between pharmacological preparations. Kinin may act directly on the smooth muscle (e.g., rabbit jugular vein and rabbit aorta) as well as indirectly through other endogenous mediators such as nitric oxide (EDRF) (e.g., dog carotid and renal arteries) and prostaglandins (e.g., dog renal artery). 2. Pharmacological analysis of rabbit jugular vein (RJV) and guinea pig ileum (GPI) has revealed different sensitivities to certain synthetic analogs of BK and to competitive B2 receptor antagonists between the two tissues. 3. Agonist order of potency ([Hyp3]BK > BK > [Aib7]BK) obtained for RJV differed from that obtained for GPI (BK > or = [Aib7]BK > [Hyp3]BK). Competitive antagonists such as DArg[Hyp3, DPhe7, Leu8]BK and WIN 64338 discriminate in favor of B2A (RJV) and B2B (GPI) receptor subtypes, respectively. These data demonstrate the existence of B2 receptor subtypes. Correlation between data obtained in the present study and those reported for binding to the human B2 receptor support the view that the human receptor is similar to that of the rabbit.

Virtual screening for potential inhibitors of bacterial MurC and MurD ligases.

PubMed

Tomašić, Tihomir; Kovač, Andreja; Klebe, Gerhard; Blanot, Didier; Gobec, Stanislav; Kikelj, Danijel; Mašič, Lucija Peterlin

2012-03-01

Mur ligases are bacterial enzymes involved in the cytoplasmic steps of peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have performed virtual screening for potential ATP-competitive inhibitors targeting MurC and MurD ligases, using a protocol of consecutive hierarchical filters. Selected compounds were evaluated for inhibition of MurC and MurD ligases, and weak inhibitors possessing dual inhibitory activity have been identified. These compounds represent new scaffolds for further optimisation towards multiple Mur ligase inhibitors with improved inhibitory potency.

Glycogen synthase kinase-3β inhibition of 6-(methylsulfinyl)hexyl isothiocyanate derived from wasabi (Wasabia japonica Matsum).

PubMed

Yoshida, Jun; Nomura, Satomi; Nishizawa, Naoyuki; Ito, Yoshiaki; Kimura, Ken-ichi

2011-01-01

A new biological activity of 6-(methylsulfinyl)hexyl isothiocyanate derived from Wasabia japonica was discovered as an inhibitor of glycogen synthase kinase-3β. The most potent isothiocyanate, 9-(methylsulfinyl)hexyl isothiocyanate, inhibited glycogen synthase kinase-3β at a K(i) value of 10.5 µM and showed ATP competitive inhibition. The structure-activity relationship revealed an inhibitory potency of methylsulfinyl isothiocyanate dependent on the alkyl chain length and the sulfoxide, sulfone, and/or the isothiocyanate moiety.

Spatial competition dynamics between reef corals under ocean acidification

PubMed Central

Horwitz, Rael; Hoogenboom, Mia O.; Fine, Maoz

2017-01-01

Climate change, including ocean acidification (OA), represents a major threat to coral-reef ecosystems. Although previous experiments have shown that OA can negatively affect the fitness of reef corals, these have not included the long-term effects of competition for space on coral growth rates. Our multispecies year-long study subjected reef-building corals from the Gulf of Aqaba (Red Sea) to competitive interactions under present-day ocean pH (pH 8.1) and predicted end-of-century ocean pH (pH 7.6). Results showed coral growth is significantly impeded by OA under intraspecific competition for five out of six study species. Reduced growth from OA, however, is negligible when growth is already suppressed in the presence of interspecific competition. Using a spatial competition model, our analysis indicates shifts in the competitive hierarchy and a decrease in overall coral cover under lowered pH. Collectively, our case study demonstrates how modified competitive performance under increasing OA will in all likelihood change the composition, structure and functionality of reef coral communities. PMID:28067281

Both your intention and mine are reflected in the kinematics of my reach-to-grasp movement.

PubMed

Becchio, Cristina; Sartori, Luisa; Bulgheroni, Maria; Castiello, Umberto

2008-02-01

The aim of the present study is to ascertain whether in a social context the kinematic parameters are influenced by the stance of the participants. In particular, we consider two basic modes of social cognition, namely cooperation and competition. Naïve subjects were asked either to cooperate or to compete with a partner (a professional female actor), whose attitude could be either congruent or incongruent with the task instructions. Thus, on congruent conditions, subjects cooperated or competed with a partner showing a congruent cooperative or competitive attitude. On incongruent trials, the partner assumed an attitude that was manifestly in contrast with the instruction: competitive for the cooperative task, cooperative for the competitive task. We hypothesized that this mismatch between partner's attitude and instruction would produce a sort of unexpected social situation, affecting the kinematics of reach-to-grasp movement performed by the agents. If cooperative and competitive kinematic patterns are sensitive to the partner's attitude, then we should expect that an incongruent attitude have the potency to determine a reversal in kinematic patterning. Results revealed that for the incongruent trials the specific kinematic patterns for cooperation and competition found for the congruent conditions where modified according to the incongruent attitude assumed by the model actor. We suggest that this 'attitude' contagion is part of a sophisticated system that allows us to infer about the intention to act in a social context.

The centrifugal and centripetal force influence on spatial competition of agricultural land in Bandung Metropolitan Region

NASA Astrophysics Data System (ADS)

Sadewo, E.

2017-06-01

Agricultural activity has suffered a massive land functional shift caused by market mechanism in Bandung metropolitan region (BMR). We argue that the existence of agricultural land in urban spatial structure is the result of interaction between centrifugal and centripetal force on spatial competition. This research aims to explore how several recognized centrifugal and centripetal force influence to the existence of agricultural land in BMR land development. The analysis using multivariate regression indicates that there exists spatial competition between population density and degree of urbanization with agricultural land areas. Its extended spatial regression model suggested that neighboring situation plays an important role to preserve agricultural land areas existences in BMR. Meanwhile, the influence of distance between the location of the city center and employment opportunities is found to be insignificant in the spatial competition. It is opposed to the theory of von Thünen and monocentric model in general. One of the possible explanation of such condition is that the assumption of centrality does not met. In addition, the agricultural land density decay in the southern parts of the area was related to its geographical conditions as protected areas or unfavorable for farming activity. It is suggested that BMR was in the early phase of polycentric development. Hence, better policies that lead redirected development to the southern part of the region is needed as well as population control and regulation of land use.

Developing tools for risk assessment in protected species: relative potencies inferred from competitive binding of halogenated aromatic hydrocarbons to aryl hydrocarbon receptors from beluga (Delphinapterus leucas) and mouse

PubMed Central

Jensen, Brenda A.; Reddy, Christopher M.; Nelson, Robert K.; Hahn, Mark E.

2011-01-01

Persistent organic pollutants such as halogenated aromatic hydrocarbons (HAHs) biomagnify in food webs and accumulate to high concentrations in top predators like odontocete cetaceans (toothed whales). The most toxic HAHs are the 2,3,7,8-substituted halogenated dibenzo-p-dioxins and furans, and non-ortho-substituted polychlorinated biphenyls (PCBs), which exert their effects via the aryl hydrocarbon receptor (AHR). Understanding the impact of HAHs in wildlife is limited by the lack of taxon-specific information about the relative potencies of toxicologically important congeners. To assess whether Toxic Equivalency Factors (TEFs) determined in rodents are predictive of HAH relative potencies in a cetacean, we used beluga and mouse AHRs expressed in vitro from cloned cDNAs to measure the relative AHR-binding affinities of ten HAHs from five different structural classes. The rank order of mean IC50s for competitive binding to beluga AHR was: TCDD

Developing tools for risk assessment in protected species: Relative potencies inferred from competitive binding of halogenated aromatic hydrocarbons to aryl hydrocarbon receptors from beluga (Delphinapterus leucas) and mouse.

PubMed

Jensen, Brenda A; Reddy, Christopher M; Nelson, Robert K; Hahn, Mark E

2010-11-01

Persistent organic pollutants such as halogenated aromatic hydrocarbons (HAHs) biomagnify in food webs and accumulate to high concentrations in top predators like odontocete cetaceans (toothed whales). The most toxic HAHs are the 2,3,7,8-substituted halogenated dibenzo-p-dioxins and furans, and non-ortho-substituted polychlorinated biphenyls (PCBs), which exert their effects via the aryl hydrocarbon receptor (AHR). Understanding the impact of HAHs in wildlife is limited by the lack of taxon-specific information about the relative potencies of toxicologically important congeners. To assess whether Toxic Equivalency Factors (TEFs) determined in rodents are predictive of HAH relative potencies in a cetacean, we used beluga and mouse AHRs expressed in vitro from cloned cDNAs to measure the relative AHR-binding affinities of ten HAHs from five different structural classes. The rank order of mean IC(50)s for competitive binding to beluga AHR was: TCDD

Competitive Stem Cell Recruitment by Multiple Cytotactic Cues

PubMed Central

Mendelson, Avital; Cheung, Yukkee; Paluch, Kamila; Chen, Mo; Kong, Kimi; Tan, Jiali; Dong, Ziming; Sia, Samuel K.; Mao, Jeremy J.

2014-01-01

A multitude of cytotactic cues direct cell migration in development, cancer metastasis and wound healing. However, our understanding of cell motility remains fragmented partially because current migration devices only allow the study of independent factors. We developed a cell motility assay that allows competitive recruitment of a given cell population simultaneously by gradients of multiple cytotactic cues, observable under real-time imaging. Well-defined uniform gradients of cytotactic cues can be independently generated and sustained in each channel. As a case study, bone marrow mesenchymal stem/stromal cells (MSCs) were exposed to 15 cytokines that are commonly present in arthritis. Cytokines that induced robust recruitment of MSCs in multiple groups were selected to ‘compete’ in a final round to yield the most chemotactic factor(s) based on cell migration numbers, distances, migration indices and motility over time. The potency of a given cytokine in competition frequently differed from its individual action, substantiating the need to test multiple cytokines concurrently due to synergistic or antagonistic effects. This new device has the rare capacity to screen molecules that induce cell migration in cancer therapy, drug development and tissue regeneration. PMID:23364311

Spatial Structures of the Environment and of Dispersal Impact Species Distribution in Competitive Metacommunities

PubMed Central

Ai, Dexiecuo; Gravel, Dominique; Chu, Chengjin; Wang, Gang

2013-01-01

The correspondence between species distribution and the environment depends on species’ ability to track favorable environmental conditions (via dispersal) and to maintain competitive hierarchy against the constant influx of migrants (mass effect) and demographic stochasticity (ecological drift). Here we report a simulation study of the influence of landscape structure on species distribution. We consider lottery competition for space in a spatially heterogeneous environment, where the landscape is represented as a network of localities connected by dispersal. We quantified the contribution of neutrality and species sorting to their spatial distribution. We found that neutrality increases and the strength of species-sorting decreases with the centrality of a community in the landscape when the average dispersal among communities is low, whereas the opposite was found at elevated dispersal. We also found that the strength of species-sorting increases with environmental heterogeneity. Our results illustrate that spatial structure of the environment and of dispersal must be taken into account for understanding species distribution. We stress the importance of spatial geographic structure on the relative importance of niche vs. neutral processes in controlling community dynamics. PMID:23874815

Spatial structures of the environment and of dispersal impact species distribution in competitive metacommunities.

PubMed

Ai, Dexiecuo; Gravel, Dominique; Chu, Chengjin; Wang, Gang

2013-01-01

The correspondence between species distribution and the environment depends on species' ability to track favorable environmental conditions (via dispersal) and to maintain competitive hierarchy against the constant influx of migrants (mass effect) and demographic stochasticity (ecological drift). Here we report a simulation study of the influence of landscape structure on species distribution. We consider lottery competition for space in a spatially heterogeneous environment, where the landscape is represented as a network of localities connected by dispersal. We quantified the contribution of neutrality and species sorting to their spatial distribution. We found that neutrality increases and the strength of species-sorting decreases with the centrality of a community in the landscape when the average dispersal among communities is low, whereas the opposite was found at elevated dispersal. We also found that the strength of species-sorting increases with environmental heterogeneity. Our results illustrate that spatial structure of the environment and of dispersal must be taken into account for understanding species distribution. We stress the importance of spatial geographic structure on the relative importance of niche vs. neutral processes in controlling community dynamics.

Elucidating the interaction between light competition and herbivore feeding patterns using functional–structural plant modelling

PubMed Central

de Vries, Jorad; Poelman, Erik H; Anten, Niels; Evers, Jochem B

2018-01-01

Abstract Background and Aims Plants usually compete with neighbouring plants for resources such as light as well as defend themselves against herbivorous insects. This requires investment of limiting resources, resulting in optimal resource distribution patterns and trade-offs between growth- and defence-related traits. A plant’s competitive success is determined by the spatial distribution of its resources in the canopy. The spatial distribution of herbivory in the canopy in turn differs between herbivore species as the level of herbivore specialization determines their response to the distribution of resources and defences in the canopy. Here, we investigated to what extent competition for light affects plant susceptibility to herbivores with different feeding preferences. Methods To quantify interactions between herbivory and competition, we developed and evaluated a 3-D spatially explicit functional–structural plant model for Brassica nigra that mechanistically simulates competition in a dynamic light environment, and also explicitly models leaf area removal by herbivores with different feeding preferences. With this novel approach, we can quantitatively explore the extent to which herbivore feeding location and light competition interact in their effect on plant performance. Key Results Our results indicate that there is indeed a strong interaction between levels of plant–plant competition and herbivore feeding preference. When plants did not compete, herbivory had relatively small effects irrespective of feeding preference. Conversely, when plants competed, herbivores with a preference for young leaves had a strong negative effect on the competitiveness and subsequent performance of the plant, whereas herbivores with a preference for old leaves did not. Conclusions Our study predicts how plant susceptibility to herbivory depends on the composition of the herbivore community and the level of plant competition, and highlights the importance of considering the full range of dynamics in plant–plant–herbivore interactions. PMID:29373660

Interspecific interactions in phytophagous insects revisited: a quantitative assessment of competition theory.

PubMed

Kaplan, Ian; Denno, Robert F

2007-10-01

The importance of interspecific competition is a highly controversial and unresolved issue for community ecology in general, and for phytophagous insects in particular. Recent advancements, however, in our understanding of indirect (plant- and enemy-mediated) interactions challenge the historical paradigms of competition. Thus, in the context of this rapidly developing field, we re-evaluate the evidence for interspecific competition in phytophagous insects using a meta-analysis of published studies. Our analysis is specifically designed to test the assumptions underlying traditional competition theory, namely that competitive interactions are symmetrical, necessitate spatial and temporal co-occurrence, and increase in intensity as the density, phylogenetic similarity, and niche overlap of competing species increase. Despite finding frequent evidence for competition, we found very little evidence that plant-feeding insects conform to theoretical predictions for interspecific competition. Interactions were highly asymmetrical, similar in magnitude within vs. between feeding guilds (chewers vs. sap-feeders), and were unaffected by the quantity of resources removed (% defoliation). There was mixed support for the effects of phylogeny, spatial/temporal separation, and the relative strength of intra- vs. interspecific competition. Clearly, a new paradigm that accounts for indirect interactions and facilitation is required to describe how interspecific competition contributes to the organization of phytophagous insect communities, and perhaps to other plant and animal communities as well.

Natural flavonoids as antidiabetic agents. The binding of gallic and ellagic acids to glycogen phosphorylase b.

PubMed

Kyriakis, Efthimios; Stravodimos, George A; Kantsadi, Anastassia L; Chatzileontiadou, Demetra S M; Skamnaki, Vassiliki T; Leonidas, Demetres D

2015-07-08

We present a study on the binding of gallic acid and its dimer ellagic acid to glycogen phosphorylase (GP). Ellagic acid is a potent inhibitor with Kis of 13.4 and 7.5 μM, in contrast to gallic acid which displays Kis of 1.7 and 3.9 mM for GPb and GPa, respectively. Both compounds are competitive inhibitors with respect to the substrate, glucose-1-phoshate, and non-competitive to the allosteric activator, AMP. However, only ellagic acid functions with glucose in a strongly synergistic mode. The crystal structures of the GPb-gallic acid and GPb-ellagic acid complexes were determined at high resolution, revealing that both ligands bind to the inhibitor binding site of the enzyme and highlight the structural basis for the significant difference in their inhibitory potency. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Palytoxin isolated from marine coelenterates. The inhibitory action on (Na,K)-ATPase.

PubMed

Ishida, Y; Takagi, K; Takahashi, M; Satake, N; Shibata, S

1983-07-10

Palytoxin (PTX), C129H223N3O54, a highly toxic substance isolated from zoanthids of Palythoa tuberculosa, inhibited (Na,K)-ATPase (ATP phosphohydrolase, EC 3.6.1.3) prepared from guinea pig heart and hog cerebral cortex in a dose-dependent manner at concentrations greater than 10(-8) M. In the presence of Na (100 mM) and K (20 mM), PTX showed potency nearly equal to that of ouabain. When the ATPase was activated by the various Na concentrations at a constant K concentration, both PTX and ouabain inhibited the ATPase activity noncompetitively. On the other hand, when K concentration was changed at a constant Na concentration, PTX caused a competitive inhibition in all ranges of K concentrations employed, whereas ouabain caused a competitive inhibition at low concentrations and a noncompetitive inhibition at high concentrations.

Does Competition Improve Public School Efficiency? A Spatial Analysis

ERIC Educational Resources Information Center

Misra, Kaustav; Grimes, Paul W.; Rogers, Kevin E.

2012-01-01

Advocates for educational reform frequently call for policies to increase competition between schools because it is argued that market forces naturally lead to greater efficiencies, including improved student learning, when schools face competition. Researchers examining this issue are confronted with difficulties in defining reasonable measures…

Spatial effects in discrete generation population models.

PubMed

Carrillo, C; Fife, P

2005-02-01

A framework is developed for constructing a large class of discrete generation, continuous space models of evolving single species populations and finding their bifurcating patterned spatial distributions. Our models involve, in separate stages, the spatial redistribution (through movement laws) and local regulation of the population; and the fundamental properties of these events in a homogeneous environment are found. Emphasis is placed on the interaction of migrating individuals with the existing population through conspecific attraction (or repulsion), as well as on random dispersion. The nature of the competition of these two effects in a linearized scenario is clarified. The bifurcation of stationary spatially patterned population distributions is studied, with special attention given to the role played by that competition.

Xenobiotic interaction with and alteration of channel catfish estrogen receptor.

PubMed

Nimrod, A C; Benson, W H

1997-12-01

In teleostean in vivo studies, the vitellogenin response to environmental estrogens is not completely predicted by mammalian literature. One possible explanation for differences is heterogeneity of the estrogen receptor (ER) structure between species. Therefore, ER from channel catfish (Ictalurus punctatus) hepatic tissue was characterized by binding affinity for several compounds. Affinity was indirectly measured as potency of the chemical for inhibiting binding of radiolabeled estradiol (E2) to specific binding sites. The order of potency among therapeutic chemicals was ethinylestradiol > unlabeled E2 = diethylstilbestrol > mestranol > tamoxifen > testosterone. Unlabeled E2 had an IC50 of 2.2 nM. Several environmentally relevant chemicals were evaluated in a similar manner and the order of potency established was the o-demethylated metabolite of methoxychlor (MXC) > nonylphenol (NP) > chlordecone > MXC > o,p'-DDT > o,p'-DDE > beta-hexachlorocyclohexane. Demethylated MXC had an IC50 1000-fold greater than that of E2. Of the most potent inhibitors, NP appeared to be a competitive inhibitor for the same binding site as E2, while o-demethylated MXC had a more complex interaction with the receptor protein. ER from nonvitellogenic females was determined to have a Kd value of 1.0 to 1.3 nM. Because E2 has been reported to up-regulate teleostean ER, the hepatic ER population following in vivo xenobiotic exposure was assessed. NP significantly increased ER per milligram hepatic protein almost to the same extent as E2, but did not increase Kd to the same extent as E2.

Discovery of HDAC Inhibitors That Lack an Active Site Zn(2+)-Binding Functional Group.

PubMed

Vickers, Chris J; Olsen, Christian A; Leman, Luke J; Ghadiri, M Reza

2012-06-14

Natural and synthetic histone deacetylase (HDAC) inhibitors generally derive their strong binding affinity and high potency from a key functional group that binds to the Zn(2+) ion within the enzyme active site. However, this feature is also thought to carry the potential liability of undesirable off-target interactions with other metalloenzymes. As a step toward mitigating this issue, here, we describe the design, synthesis, and structure-activity characterizations of cyclic α3β-tetrapeptide HDAC inhibitors that lack the presumed indispensable Zn(2+)-binding group. The lead compounds (e.g., 15 and 26) display good potency against class 1 HDACs and are active in tissue culture against various human cancer cell lines. Importantly, enzymological analysis of 26 indicates that the cyclic α3β-tetrapeptide is a fast-on/off competitive inhibitor of HDACs 1-3 with K i values of 49, 33, and 37 nM, respectively. Our proof of principle study supports the idea that novel classes of HDAC inhibitors, which interact at the active-site opening, but not with the active site Zn(2+), can have potential in drug design.

Temporal analysis and spatial mapping of Lymantria dispar nuclear polyhedrosis virus transcripts and in-vitro translation products

Treesearch

James M. Slavicek; Nancy Hayes-Plazolles

1991-01-01

The Lymantria dispar nuclear polyhedrosis virus LdNPV) is being used as a biopesticide against the gypsy moth. We are attempting to enhance the potency of the LdNPV through recombinant DNA technology. As a prerequisite to genetic manipulation, we have characterized LdNPV gene expression in cell culture through the generation of transcription and...

The Spatial Power Motivation Scale: a semi-implicit measure of situational power motivation.

PubMed

Schoel, Christiane; Zimmer, Katharina; Stahlberg, Dagmar

2015-01-01

We introduce a new nonverbal and unobtrusive measure to assess power motive activation, the Spatial Power Motivation Scale (SPMS). The unique features of this instrument are that it is (a) very simple and economical, (b) reliable and valid, and (c) sensitive to situational changes. Study 1 demonstrates the instrument's convergent and discriminant validity with explicit measures. Study 2 demonstrates the instrument's responsiveness to situational power motive salience: anticipating and winning competition versus losing competition and watching television. Studies 3 and 4 demonstrate that thoughts of competition result in higher power motivation specifically for individuals with a high dispositional power motive.

Time, Not Sleep, Unbinds Contexts from Item Memory

PubMed Central

Cox, Roy; Tijdens, Ron R.; Meeter, Martijn M.; Sweegers, Carly C. G.; Talamini, Lucia M.

2014-01-01

Contextual cues are known to benefit memory retrieval, but whether and how sleep affects this context effect remains unresolved. We manipulated contextual congruence during memory retrieval in human volunteers across 12 h and 24 h intervals beginning with either sleep or wakefulness. Our data suggest that whereas contextual cues lose their potency with time, sleep does not modulate this process. Furthermore, our results are consistent with the idea that sleep's beneficial effect on memory retention depends on the amount of waking time that has passed between encoding and sleep onset. The findings are discussed in the framework of competitive consolidation theory. PMID:24498441

Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors.

PubMed

Grimster, Neil P; Anderson, Erica; Alimzhanov, Marat; Bebernitz, Geraldine; Bell, Kirsten; Chuaqui, Claudio; Deegan, Tracy; Ferguson, Andrew D; Gero, Thomas; Harsch, Andreas; Huszar, Dennis; Kawatkar, Aarti; Kettle, Jason Grant; Lyne, Paul D; Read, Jon A; Rivard Costa, Caroline; Ruston, Linette; Schroeder, Patricia; Shi, Jie; Su, Qibin; Throner, Scott; Toader, Dorin; Vasbinder, Melissa Marie; Woessner, Richard; Wang, Haixia; Wu, Allan; Ye, Minwei; Zheng, Weijia; Zinda, Michael

2018-06-01

Herein, we report the discovery and characterization of a novel series of pyrimidine based JAK1 inhibitors. Optimization of these ATP competitive compounds was guided by X-ray crystallography and a structure-based drug design approach, focusing on selectivity, potency, and pharmaceutical properties. The best compound, 24, displayed remarkable JAK1 selectivity (~1000-fold vs JAK2,3 and TYK2), as well as a good kinase selectivity profile. Moreover, a dose-dependent reduction in pSTAT3, a downstream marker of JAK1 inhibition, was observed when 24 was examined in vivo.

Niches and Interspecific Competitive Relationships of the Parasitoids, Microplitis prodeniae and Campoletis chlorldeae, of the Oriental Leafworm Moth, Spodoptera litura, in Tobacco

PubMed Central

Zhou, Zhong-Shi; Chen, Ze-Peng; Xu, Zai-Fu

2010-01-01

Both Microplitis prodeniae Rao and Chandry (Hymenoptera: Bracondidae) and Campoletis chlorideae Uchida (Hymenoptera: Ichnumonidae) are major parasitoids of Spodoptera litura (Fabricious) (Lepidoptera: Noctuidae) in tobacco, Nicotiana tabacum L. (Solanales: Solanaceae) at Nanxiong, Guangdong Province, South China. The niches and interspecific competition relationships of the two species were studied. The results show that the competition between the two species for spatial and food resources was very intense, and C. chlorideae was always dominant when the two species compete for spatial and food resources in different periods. Thus C. chlorideae may drive M. prodeniae away when they occupy the same spatial or food resource. The adaptability of C. chlorideae to the environment in the tobacco fields may be greater than that of M. prodeniae, so C. chlorideae can maintain a higher population compared to that of M. prodeniae. PMID:20575741

Predicted structure of MIF/CD74 and RTL1000/CD74 complexes.

PubMed

Meza-Romero, Roberto; Benedek, Gil; Leng, Lin; Bucala, Richard; Vandenbark, Arthur A

2016-04-01

Macrophage migration inhibitory factor (MIF) is a key cytokine in autoimmune and inflammatory diseases that attracts and then retains activated immune cells from the periphery to the tissues. MIF exists as a homotrimer and its effects are mediated through its primary receptor, CD74 (the class II invariant chain that exhibits a highly structured trimerization domain), present on class II expressing cells. Although a number of binding residues have been identified between MIF and CD74 trimers, their spatial orientation has not been established. Using a docking program in silico, we have modeled binding interactions between CD74 and MIF as well as CD74 and a competitive MIF inhibitor, RTL1000, a partial MHC class II construct that is currently in clinical trials for multiple sclerosis. These analyses revealed 3 binding sites on the MIF trimer that each were predicted to bind one CD74 trimer through interactions with two distinct 5 amino acid determinants. Surprisingly, predicted binding of one CD74 trimer to a single RTL1000 antagonist utilized the same two 5 residue determinants, providing strong suggestive evidence in support of the MIF binding regions on CD74. Taken together, our structural modeling predicts a new MIF(CD74)3 dodecamer that may provide the basis for increased MIF potency and the requirement for ~3-fold excess RTL1000 to achieve full antagonism.

Competition between stink bug and heliothine caterpillar pests on cotton at within-plant spatial scales

USDA-ARS?s Scientific Manuscript database

We investigated competition between Heliothine larvae and the secondary pests, southern green and brown stink bugs at the single boll and multiple boll scales; if competition does not occur with this very close association, it might be unlikely at larger scales with less close association. In both ...

Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor.

PubMed

Armour, S L; Foord, S; Kenakin, T; Chen, W J

1999-12-01

Receptor-activity-modifying proteins (RAMPs) are a family of single transmembrane domain proteins shown to be important for the transport and ligand specificity of the calcitonin gene-related peptide (CGRP) receptor. In this report, we describe the analysis of pharmacological properties of the human calcitonin receptor (hCTR) coexpressed with different RAMPs with the use of the Xenopus laevis melanophore expression system. We show that coexpression of RAMP3 with human calcitonin receptor changed the relative potency of hCTR to human calcitonin (hCAL) and rat amylin. RAMP1 and RAMP2, in contrast, had little effect on the change of hCTR potency to hCAL or rat amylin. When coexpressed with RAMP3, hCTR reversed the relative potency by a 3.5-fold loss in sensitivity to hCAL and a 19-fold increase in sensitivity to rat amylin. AC66, an inverse agonist, produced apparent simple competitive antagonism of hCAL and rat amylin, as indicated by linear Schild regressions. The potency of AC66 was changed in the blockade of rat amylin but not hCAL responses with RAMP3 coexpression. The mean pK(B) for AC66 to hCAL was 9.4 +/- 0.3 without RAMP3 and 9.45 +/- 0.07 with RAMP3. For the antagonism of AC66 to rat amylin, the pK(B) was 9.25 +/- 0.15 without RAMP3 and 8.2 +/- 0.35 with RAMP3. The finding suggests that RAMP3 might modify the active states of calcitonin receptor in such a way as to create a new receptor phenotype that is "amylin-like." Irrespective of the physiological association of the new receptor species, the finding that a coexpressed membrane protein can completely change agonist and antagonist affinities for a receptor raises implications for screening in recombinant receptor systems.

Interference competition and invasion: spatial structure, novel weapons and resistance zones.

PubMed

Allstadt, Andrew; Caraco, Thomas; Molnár, F; Korniss, G

2012-08-07

Certain invasive plants may rely on interference mechanisms (e.g., allelopathy) to gain competitive superiority over native species. But expending resources on interference presumably exacts a cost in another life-history trait, so that the significance of interference competition for invasion ecology remains uncertain. We model ecological invasion when combined effects of preemptive and interference competition govern interactions at the neighborhood scale. We consider three cases. Under "novel weapons," only the initially rare invader exercises interference. For "resistance zones" only the resident species interferes, and finally we take both species as interference competitors. Interference increases the other species' mortality, opening space for colonization. However, a species exercising greater interference has reduced propagation, which can hinder its colonization of open sites. Interference never enhances a rare invader's growth in the homogeneously mixing approximation to our model. But interference can significantly increase an invader's competitiveness, and its growth when rare, if interactions are structured spatially. That is, interference can increase an invader's success when colonization of open sites depends on local, rather than global, species densities. In contrast, interference enhances the common, resident species' resistance to invasion independently of spatial structure, unless the propagation-cost is too great. The particular combination of propagation and interference producing the strongest biotic resistance in a resident species depends on the shape of the tradeoff between the two traits. Increases in background mortality (i.e., mortality not due to interference) always reduce the effectiveness of interference competition. Copyright © 2012 Elsevier Ltd. All rights reserved.

Elucidating the interaction between light competition and herbivore feeding patterns using functional-structural plant modelling.

PubMed

de Vries, Jorad; Poelman, Erik H; Anten, Niels; Evers, Jochem B

2018-01-24

Plants usually compete with neighbouring plants for resources such as light as well as defend themselves against herbivorous insects. This requires investment of limiting resources, resulting in optimal resource distribution patterns and trade-offs between growth- and defence-related traits. A plant's competitive success is determined by the spatial distribution of its resources in the canopy. The spatial distribution of herbivory in the canopy in turn differs between herbivore species as the level of herbivore specialization determines their response to the distribution of resources and defences in the canopy. Here, we investigated to what extent competition for light affects plant susceptibility to herbivores with different feeding preferences. To quantify interactions between herbivory and competition, we developed and evaluated a 3-D spatially explicit functional-structural plant model for Brassica nigra that mechanistically simulates competition in a dynamic light environment, and also explicitly models leaf area removal by herbivores with different feeding preferences. With this novel approach, we can quantitatively explore the extent to which herbivore feeding location and light competition interact in their effect on plant performance. Our results indicate that there is indeed a strong interaction between levels of plant-plant competition and herbivore feeding preference. When plants did not compete, herbivory had relatively small effects irrespective of feeding preference. Conversely, when plants competed, herbivores with a preference for young leaves had a strong negative effect on the competitiveness and subsequent performance of the plant, whereas herbivores with a preference for old leaves did not. Our study predicts how plant susceptibility to herbivory depends on the composition of the herbivore community and the level of plant competition, and highlights the importance of considering the full range of dynamics in plant-plant-herbivore interactions. © The Author(s) 2018. Published by Oxford University Press on behalf of the Annals of Botany Company.

Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library.

PubMed

Cuozzo, John W; Centrella, Paolo A; Gikunju, Diana; Habeshian, Sevan; Hupp, Christopher D; Keefe, Anthony D; Sigel, Eric A; Soutter, Holly H; Thomson, Heather A; Zhang, Ying; Clark, Matthew A

2017-05-04

We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA-encoded library of over 110 million compounds by using multiple parallel selection conditions, including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP, and another enriched at both high and low concentrations of BTK and was not competitive with ATP. A compound representing the latter profile showed low nanomolar potency in biochemical and cellular BTK assays. Results from kinetic mechanism of action studies were consistent with the selection profiles. Analysis of the co-crystal structure of the most potent compound demonstrated a novel binding mode that revealed a new pocket in BTK. Our results demonstrate that profile-based selection strategies using DNA-encoded libraries form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Implementation of a Fluorescence-Based Screening Assay Identifies Histamine H3 Receptor Antagonists Clobenpropit and Iodophenpropit as Subunit-Selective N-Methyl-d-Aspartate Receptor Antagonists

PubMed Central

Hansen, Kasper B.; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L.; Yuan, Hongjie; Vance, Katie M.; Orr, Anna G.; Kvist, Trine; Ogden, Kevin K.; Le, Phuong; Vellano, Kimberly M.; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T. J.; Snyder, James P.; Bräuner-Osborne, Hans

2010-01-01

N-Methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism. PMID:20197375

Effect of polygodial and its direct derivatives on the mammalian Na+/K+-ATPase activity.

PubMed

Garcia, Diogo Gomes; Gonçalves-de-Albuquerque, Cassiano Felippe; da Silva, Camila Ignácio; Kiss, Robert; Dasari, Ramesh; Chandra, Sunena; Kornienko, Alexander; Burth, Patricia

2018-07-15

The sesquiterpene polygodial is an agonist of the transient receptor potential vanilloid 1 (TRPV1). Our group recently reported the synthesis and anticancer effects of polygodial and its derivatives, and showed that these compounds retain activity against apoptosis- and multidrug-resistant cancer cells. Herein, we tested the inhibitory effect of these compounds on the activity of the enzyme Na + /K + -ATPase (NKA) from kidney (α 1 isoform) and brain (α 2 and α 3 isoforms) guinea pig extracts. Polygodial (1) displayed a dose-dependent inhibition of both kidney and brain purified NKA preparations, with higher sensitivity for the cerebral isoforms. Polygo-11,12-diol (2) and C11,C12-pyridazine derivative (3) proved to be poor inhibitors. Unsaturated ester (4) and 9-epipolygodial (5) inhibited NKA preparations from brain and kidney, with the same inhibitory potency. Nevertheless, they did not achieve maximum inhibition even at higher concentration. Comparing the inhibitory potency in crude homogenates and purified preparations of NKA, compounds 4 and 5 revealed a degree of selectivity toward the renal enzyme. Kinetic studies showed a non-competitive inhibition for Na + and K + by compounds 1, 4 and 5 and for ATP by 1 and 4. However, compound 5 presented a competitive inhibition type. Furthermore, K + -activated p-nitrophenylphosphatase activity of these purified preparations was not inhibited by 1, 4 and 5, suggesting that these compounds acted in the initial phase of the enzyme's catalytic cycle. These findings suggest that the antitumor action of polygodial and its analogues may be linked to their NKA inhibitory properties and reinforce that NKA may be an important target for cancer therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Spatial arrangements affect suppression of invasive Alternanthera philoxeroides by native Hemarthria compressa

NASA Astrophysics Data System (ADS)

Liao, Jianxiong; Tao, Min; Jiang, Mingxi

2014-08-01

It has been hypothesized that differences in spatial arrangements change the relative frequency of intra- and interspecific encounters between plant species. Manipulating spatial arrangement may play a role in invasive plant suppression when native species are used as competitors against introduced species. In this study, a replacement series experiment was performed to investigate the effects of intraspecifically random and aggregated spatial arrangements on interactions between the native plant Hemarthria compressa and the invasive plant Alternanthera philoxeroides, to test the possibility and effectiveness of H. compressa in suppressing A. philoxeroides. When both species were planted in intraspecifically random spatial patterns, H. compressa had a competitive advantage over A. philoxeroides at relative densities of 2:2 and 3:1. However, aggregation increased the strength, and therefore the cost, of intraspecific competition in H. compressa, resulting in lower biomass production, which reduced its effectiveness as an interspecific competitor. As the relative density of H. compressa in mixtures decreased, plants allocated more biomass to belowground parts, but fewer interspecific encounters lowered its inhibitory effects on A. philoxeroides. The results not only confirm that the frequency of conspecific and heterospecific encounters can influence competitive outcomes, but also suggest that a reduction in the degree of spatial aggregation in H. compressa and an increase in its relative densities may be essential to increase the suppression of A. philoxeroides.

Andrographolide sodium bisulphite-induced inactivation of urease: inhibitory potency, kinetics and mechanism.

PubMed

Mo, Zhi-Zhun; Wang, Xiu-Fen; Zhang, Xie; Su, Ji-Yan; Chen, Hai-Ming; Liu, Yu-Hong; Zhang, Zhen-Biao; Xie, Jian-Hui; Su, Zi-Ren

2015-07-16

The inhibitory effect of andrographolide sodium bisulphite (ASB) on jack bean urease (JBU) and Helicobacter pylori urease (HPU) was performed to elucidate the inhibitory potency, kinetics and mechanism of inhibition in 20 mM phosphate buffer, pH 7.0, 2 mM EDTA, 25 °C. The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of ASB was characterized with IC50 values. Lineweaver-Burk and Dixon plots for JBU inhibition of ASB was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni2+ binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode. The IC50 of ASB against JBU and HPU was 3.28±0.13 mM and 3.17±0.34 mM, respectively. The inhibition proved to be competitive and concentration- dependent in a slow-binding progress. The rapid formation of initial ASB-JBU complex with an inhibition constant of Ki=2.86×10(-3) mM was followed by a slow isomerization into the final complex with an overall inhibition constant of Ki*=1.33×10(-4) mM. The protective experiment proved that the urease active site is involved in the binding of ASB. Thiol reagents (L-cysteine and dithiothreithol) strongly protect the enzyme from the loss of enzymatic activity, while boric acid and fluoride show weaker protection, indicating that the active-site sulfhydryl group of JBU was potentially involved in the blocking process. Moreover, inhibition of ASB proved to be reversible since ASB-inactivated JBU could be reactivated by dithiothreitol application. Molecular docking assay suggested that ASB made contacts with the important sulfhydryl group Cys-592 residue and restricted the mobility of the active-site flap. ASB was a competitive inhibitor targeting thiol groups of urease in a slow-binding manner both reversibly and concentration-dependently, serving as a promising urease inhibitor for the treatment of urease-related diseases.

Interspecific Competition for Shelters in Territorial and Gregarious Intertidal Grazers: Consequences for Individual Behaviour

PubMed Central

Aguilera, Moisés A.; Navarrete, Sergio A.

2012-01-01

Experiments have shown that interspecific interactions within consumer guilds can alter patterns of distribution, abundance and size of species. Plastic behavioural responses can be modulated by agonistic interactions. In many cases, consumers compete for space and shelters, and these interactions change the manner in which they exploit food. This study investigates the consequences of competition in the spatial and temporal organization of behaviour of intertidal grazers, which share algal resources and the use of rock crevices while resting, but exhibit different body sizes, spatial behaviour and foraging modes. We evaluate interaction strength between small gregarious Siphonaria lessoni and the larger territorial keyhole limpet Fissurella crassa and between S. lessoni and the medium-size gregarious chiton Chiton granosus. Using field manipulations and artificial arenas in the laboratory, we tested whether the use of crevices, micro-spatial distribution and activity are modified by the density of conspecifics and the presence of heterospecifics. Our results show that small-scale spatial segregation observed in the field between S. lessoni and C. granosus result from species-specific differences in habitat use. In turn, we found evidence that spatial segregation between F. crassa and S. lessoni results from highly asymmetric interference competition in the use of shelters. The presence of F. crassa reduced the use of crevices and growth rates of S. lessoni. Effects on growth rates are assumed to result from exposure to harsh environmental conditions rather than food limitation. Thus, neither gregarious behaviour nor differences in activity were sufficient to prevent competition with the larger grazer. Our study illustrates the importance of competition for shelters, which results in behavioural changes of the smaller-sized species, and how these plastic responses can translate into differences in growth rates. Use of shelters can thus be modulated by environmental conditions in a species-specific as well as an interactive manner within consumers’ guilds. PMID:23049980

The interaction between the spatial distribution of resource patches and population density: consequences for intraspecific growth and morphology.

PubMed

Jacobson, Bailey; Grant, James W A; Peres-Neto, Pedro R

2015-07-01

How individuals within a population distribute themselves across resource patches of varying quality has been an important focus of ecological theory. The ideal free distribution predicts equal fitness amongst individuals in a 1 : 1 ratio with resources, whereas resource defence theory predicts different degrees of monopolization (fitness variance) as a function of temporal and spatial resource clumping and population density. One overlooked landscape characteristic is the spatial distribution of resource patches, altering the equitability of resource accessibility and thereby the effective number of competitors. While much work has investigated the influence of morphology on competitive ability for different resource types, less is known regarding the phenotypic characteristics conferring relative ability for a single resource type, particularly when exploitative competition predominates. Here we used young-of-the-year rainbow trout (Oncorhynchus mykiss) to test whether and how the spatial distribution of resource patches and population density interact to influence the level and variance of individual growth, as well as if functional morphology relates to competitive ability. Feeding trials were conducted within stream channels under three spatial distributions of nine resource patches (distributed, semi-clumped and clumped) at two density levels (9 and 27 individuals). Average trial growth was greater in high-density treatments with no effect of resource distribution. Within-trial growth variance had opposite patterns across resource distributions. Here, variance decreased at low-population, but increased at high-population densities as patches became increasingly clumped as the result of changes in the levels of interference vs. exploitative competition. Within-trial growth was related to both pre- and post-trial morphology where competitive individuals were those with traits associated with swimming capacity and efficiency: larger heads/bodies/caudal fins and less angled pectoral fins. The different degrees of within-population growth variance at the same density level found here, as a function of spatial resource distribution, provide an explanation for the inconsistencies in within-site growth variance and population regulation often noted with regard to density dependence in natural landscapes. © 2015 The Authors. Journal of Animal Ecology © 2015 British Ecological Society.

Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors.

PubMed

Acuña-Castillo, Claudio; Villalobos, Claudio; Moya, Pablo R; Sáez, Patricio; Cassels, Bruce K; Huidobro-Toro, J Pablo

2002-06-01

The pharmacological profile of a series of (+/-)-2,5-dimethoxy-4-(X)-phenylisopropylamines (X=I, Br, NO(2), CH(3), or H) and corresponding phenylethylamines, was determined in Xenopus laevis oocytes injected with cRNA coding for rat 5-HT(2A) or 5-HT(2C) receptors. The efficacy and relative potency of these drugs were determined and compared to classical 5-HT(2) receptor agonists and antagonists. The rank order of agonist potency at the 5-HT(2A) receptor was: alpha-methyl-5-HT=5-HT>m-CPP>MK-212; at the 5-HT(2C) receptor the order was: 5-HT>alpha-methyl-5-HT>MK-212>m-CPP. All these compounds were full agonists at the 5-HT(2C) receptor, but alpha-methyl-5-HT and m-CPP showed lower efficacy at the 5-HT(2A) receptor. 4-(4-Fluorobenzoyl)-1-(4-phenylbutyl)piperidine (4F 4PP) was 200 times more potent as a 5-HT(2A) antagonist than at 5-HT(2C) receptors. Conversely, RS 102221 was 100 times more potent as a 5-HT(2C) antagonist, confirming their relative receptor selectivities. The phenylisopropylamines were partial agonists at the 5-HT(2A) receptor, with I(max) relative to 5-HT in the 22+/-7 to 58+/-15% range; the corresponding phenylethylamines had lower or undetectable efficacies. All these drugs had higher efficacies at 5-HT(2C) receptors; DOI was a full 5-HT(2C) agonist. 2C-I and the other phenylethylamines examined showed relative efficacies at the 5-HT(2C) receptor ranging from 44+/-10% to 76+/-16%. 2C-N was a 5-HT(2) receptor antagonist; the mechanism was competitive at the 5-HT(2A), but non-competitive at the 5-HT(2C) receptor. The antagonism was time-dependent at the 5-HT(2C) receptor but independent of pre-incubation time at the 5-HT(2A) receptor subtype. The alpha-methyl group determines the efficacy of these phenylalkylamines at the 5-HT(2A) and 5-HT(2C) receptors.

The role of spatial and temporal heterogeneity and competition in structuring trematode communities in the great pond snail, Lymnaea stagnalis (L.)

USGS Publications Warehouse

Soldánová, Miroslava; Kuris, Armand M.; Scholz, Tomáš; Lafferty, Kevin D.

2012-01-01

We assessed how spatial and temporal heterogeneity and competition structure larval trematode communities in the pulmonate snail Lymnaea stagnalis. To postulate a dominance hierarchy, mark-release-recapture was used to monitor replacements of trematode species within snails over time. In addition, we sampled the trematode community in snails in different ponds in 3 consecutive years. A total of 7,623 snails (10,382 capture events) was sampled in 7 fishponds in the Jindřichův Hradec and Třeboň areas in South Bohemia (Czech Republic) from August 2006 to October 2008. Overall, 39% of snails were infected by a community of 14 trematode species; 7% of snails were infected with more than 1 trematode species (constituting 16 double- and 4 triple-species combinations). Results of the null-model analyses suggested that spatial heterogeneity in recruitment among ponds isolated trematode species from each other, whereas seasonal pulses in recruitment increased species interactions in some ponds. Competitive exclusion among trematodes led to a rarity of multiple infections compared to null-model expectations. Competitive relationships among trematode species were hypothesized as a dominance hierarchy based on direct evidence of replacement and invasion and on indirect evidence. Seven top dominant species with putatively similar competitive abilities (6 rediae and 1 sporocyst species) reduced the prevalence of the other trematode species developing in sporocysts only.

Turbulent dispersal promotes species coexistence

PubMed Central

Berkley, Heather A; Kendall, Bruce E; Mitarai, Satoshi; Siegel, David A

2010-01-01

Several recent advances in coexistence theory emphasize the importance of space and dispersal, but focus on average dispersal rates and require spatial heterogeneity, spatio-temporal variability or dispersal-competition tradeoffs to allow coexistence. We analyse a model with stochastic juvenile dispersal (driven by turbulent flow in the coastal ocean) and show that a low-productivity species can coexist with a high-productivity species by having dispersal patterns sufficiently uncorrelated from those of its competitor, even though, on average, dispersal statistics are identical and subsequent demography and competition is spatially homogeneous. This produces a spatial storage effect, with an ephemeral partitioning of a ‘spatial niche’, and is the first demonstration of a physical mechanism for a pure spatiotemporal environmental response. ‘Turbulent coexistence’ is widely applicable to marine species with pelagic larval dispersal and relatively sessile adult life stages (and perhaps some wind-dispersed species) and complements other spatial and temporal storage effects previously documented for such species. PMID:20455921

Male urine signals social rank in the Mozambique tilapia (Oreochromis mossambicus)

PubMed Central

Barata, Eduardo N; Hubbard, Peter C; Almeida, Olinda G; Miranda, António; Canário, Adelino VM

2007-01-01

Background The urine of freshwater fish species investigated so far acts as a vehicle for reproductive pheromones affecting the behaviour and physiology of the opposite sex. However, the role of urinary pheromones in intra-sexual competition has received less attention. This is particularly relevant in lek-breeding species, such as the Mozambique tilapia (Oreochromis mossambicus), where males establish dominance hierarchies and there is the possibility for chemical communication in the modulation of aggression among males. To investigate whether males use urine during aggressive interactions, we measured urination frequency of dye-injected males during paired interactions between size-matched males. Furthermore, we assessed urinary volume stored in the bladder of males in a stable social hierarchy and the olfactory potency of their urine by recording of the electro-olfactogram. Results Males released urine in pulses of short duration (about one second) and markedly increased urination frequency during aggressive behaviour, but did not release urine whilst submissive. In the stable hierarchy, subordinate males stored less urine than males of higher social rank; the olfactory potency of the urine was positively correlated with the rank of the male donor. Conclusion Dominant males store urine and use it as a vehicle for odorants actively released during aggressive disputes. The olfactory potency of the urine is positively correlated with the social status of the male. We suggest that males actively advertise their dominant status through urinary odorants which may act as a 'dominance' pheromone to modulate aggression in rivals, thereby contributing to social stability within the lek. PMID:18076759

Propagation dynamics for a spatially periodic integrodifference competition model

NASA Astrophysics Data System (ADS)

Wu, Ruiwen; Zhao, Xiao-Qiang

2018-05-01

In this paper, we study the propagation dynamics for a class of integrodifference competition models in a periodic habitat. An interesting feature of such a system is that multiple spreading speeds can be observed, which biologically means different species may have different spreading speeds. We show that the model system admits a single spreading speed, and it coincides with the minimal wave speed of the spatially periodic traveling waves. A set of sufficient conditions for linear determinacy of the spreading speed is also given.

Evaluating apparent competition in limiting the recovery of an endangered ungulate.

PubMed

Johnson, Heather E; Hebblewhite, Mark; Stephenson, Thomas R; German, David W; Pierce, Becky M; Bleich, Vernon C

2013-01-01

Predation can disproportionately affect endangered prey populations when generalist predators are numerically linked to more abundant primary prey. Apparent competition, the term for this phenomenon, has been increasingly implicated in the declines of endangered prey populations. We examined the potential for apparent competition to limit the recovery of Sierra Nevada bighorn sheep (Ovis canadensis sierrae), an endangered subspecies under the US Endangered Species Act. Using a combination of location, demographic, and habitat data, we assessed whether cougar (Puma concolor) predation on endangered bighorn sheep was a consequence of their winter range overlap with abundant mule deer (Odocoileus hemionus). Consistent with the apparent competition hypothesis, bighorn sheep populations with higher spatial overlap with deer exhibited higher rates of cougar predation which had additive effects on adult survival. Bighorn sheep killed by cougars were primarily located within deer winter ranges, even though those areas constituted only a portion of the bighorn sheep winter ranges. We suspect that variation in sympatry between bighorn sheep and deer populations was largely driven by differences in habitat selection among bighorn sheep herds. Indeed, bighorn sheep herds that experienced the highest rates of predation and the greatest spatial overlap with deer also exhibited the strongest selection for low elevation habitat. Although predator-mediated apparent competition may limit some populations of bighorn sheep, it is not the primary factor limiting all populations, suggesting that the dynamics of different herds are highly idiosyncratic. Management plans for endangered species should consider the spatial distributions of key competitors and predators to reduce the potential for apparent competition to hijack conservation success.

Temporal Analysis of Market Competition and Density in Renal Transplantation Volume and Outcome.

PubMed

Adler, Joel T; Yeh, Heidi; Markmann, James F; Nguyen, Louis L

2016-03-01

Kidney transplant centers are distributed unevenly throughout 58 donor service areas (DSAs) in the United States. Market competition and transplant center density may affect transplantation access and outcomes. We evaluated the role of spatial organization of transplant centers in conjunction with market competition in the conduct of kidney transplantation. The Scientific Registry of Transplant Recipients was queried for market characteristics associated with kidney transplantation between 2003 and 2012. Market competition was calculated using the Herfindahl Hirschman Index. Kidney transplant centers were geocoded to measure spatial organization by the average nearest neighbor (ANN) method. Kidney quality was assessed by kidney donor risk index. A hierarchical negative binomial mixed effects model tested the relationship between market characteristics and annual kidney transplants by DSA. About 152,071 kidney transplants were performed at 229 adult kidney transplant centers in 58 DSAs. Greater market competition was associated with kidney transplant center spatial clustering (P < 0.001). In multivariable analysis, more kidney transplant centers (incidence rate ratio [IRR], 1.04; P = 0.005), 100 more new listings (IRR, 1.02; P = 0.003), 100 more deceased donors (IRR, 1.23; P < 0.001), 100 more new dialysis registrants (IRR, 1.01; P < 0.001), and higher kidney donor risk index (IRR, 1.98; P < 0.001) were associated with increased kidney transplants. After controlling for market characteristics, larger numbers of kidney transplant centers were associated with more kidney transplants and increased utilization of deceased donor kidneys. This underlines the importance of understanding geography as well as competition in improving access to kidney transplantation.

Benzodiazepine antagonism by harmane and other beta-carbolines in vitro and in vivo.

PubMed

Rommelspacher, H; Nanz, C; Borbe, H O; Fehske, K J; Müller, W E; Wollert, U

1981-03-26

Harmane and other related beta-carbolines are putative endogenous ligands of the benzodiazepine receptor. Since the compounds are potent convulsants they may have agonist activities at the benzodiazepine receptor while the benzodiazepines may be antagonists. This hypothesis was proved by comparing the in vivo and in vitro antagonism of benzodiazepines by harmane and other beta-carbolines. Harmane is clearly a competitive inhibitor of benzodiazepine receptor binding in vitro. Moreover, harmane-induced convulsions can be inhibited reversibly by diazepam in a manner which is consistent with the assumption of competitive antagonism in vivo. For some beta-carboline derivatives a correlation was found between the affinity for the benzodiazepine receptor in vitro and the convulsive potency in vivo. Thus, the data reported suggest that harmane or other related beta-carbolines are putative endogenous agonists of the benzodiazepine receptor. This suggestion is further supported by the observation that diazepam is equally potent in inhibiting harmane- or picrotoxin-induced convulsions, indicating a convulsive mechanism within the GABA receptor-benzodiazepine receptor system.

Neonicotinoids and Other Insect Nicotinic Receptor Competitive Modulators: Progress and Prospects.

PubMed

Casida, John E

2018-01-07

Neonicotinoids (neonics) are remarkably effective as plant systemics to control sucking insects and for flea control on dogs and cats. The nitroimines imidacloprid, clothianidin, thiamethoxam, and dinotefuran are the leaders among the seven commercial neonics that also include the nitromethylene nitenpyram, the nitromethylene-derived cycloxaprid, and the cyanoimines acetamiprid and thiacloprid. Honey bees are highly sensitive to the nitroimines and nitromethylenes, but the cyanoimines are less toxic. All neonics are nicotinic acetylcholine receptor (nAChR) agonists with a common mode of action, target-site cross-resistance, and much higher potency on insect than mammalian nAChRs at defined binding sites. The structurally related sulfoximine sulfoxaflor and butenolide flupyradifurone are also nAChR agonists, and the mesoionic triflumezopyrim is a nAChR competitive modulator with little or no target-site cross-resistance. Some neonics induce stress tolerance in plants via salicylate-associated systems. The neonics in general are readily metabolized and, except for pollinators, have favorable toxicological profiles.

Spatial pattern affects diversity-productivity relationships in experimental meadow communities

NASA Astrophysics Data System (ADS)

Lamošová, Tereza; Doležal, Jiří; Lanta, Vojtěch; Lepš, Jan

2010-05-01

Plant species create aggregations of conspecifics as a consequence of limited seed dispersal, clonal growth and heterogeneous environment. Such intraspecific aggregation increases the importance of intraspecific competition relative to interspecific competition which may slow down competitive exclusion and promote species coexistence. To examine how spatial aggregation impacts the functioning of experimental assemblages of varying species richness, eight perennial grassland species of different growth form were grown in random and aggregated patterns in monocultures, two-, four-, and eight-species mixtures. In mixtures with an aggregated pattern, monospecific clumps were interspecifically segregated. Mixed model ANOVA was used to test (i) how the total productivity and productivity of individual species is affected by the number of species in a mixture, and (ii) how these relationships are affected by spatial pattern of sown plants. The main patterns of productivity response to species richness conform to other studies: non-transgressive overyielding is omnipresent (the productivity of mixtures is higher than the average of its constituent species so that the net diversity, selection and complementarity effects are positive), whereas transgressive overyielding is found only in a minority of cases (average of log(overyielding) being close to zero or negative). The theoretical prediction that plants in a random pattern should produce more than in an aggregated pattern (the distances to neighbours are smaller and consequently the competition among neighbours stronger) was confirmed in monocultures of all the eight species. The situation is more complicated in mixtures, probably as a consequence of complicated interplay between interspecific and intraspecific competition. The most productive species ( Achillea, Holcus, Plantago) were competitively superior and increased their relative productivity with mixture richness. The intraspecific competition of these species is stronger than that of most other species. The aggregated pattern in the full mixture increased the survival of subordinate species, and consequently, we conclude that an aggregated pattern can promote species coexistence (or at least postpone competitive exclusion), particularly in comparison with homogeneously sown mixtures.

The advantage of being slow: The quasi-neutral contact process.

PubMed

de Oliveira, Marcelo Martins; Dickman, Ronald

2017-01-01

According to the competitive exclusion principle, in a finite ecosystem, extinction occurs naturally when two or more species compete for the same resources. An important question that arises is: when coexistence is not possible, which mechanisms confer an advantage to a given species against the other(s)? In general, it is expected that the species with the higher reproductive/death ratio will win the competition, but other mechanisms, such as asymmetry in interspecific competition or unequal diffusion rates, have been found to change this scenario dramatically. In this work, we examine competitive advantage in the context of quasi-neutral population models, including stochastic models with spatial structure as well as macroscopic (mean-field) descriptions. We employ a two-species contact process in which the "biological clock" of one species is a factor of α slower than that of the other species. Our results provide new insights into how stochasticity and competition interact to determine extinction in finite spatial systems. We find that a species with a slower biological clock has an advantage if resources are limited, winning the competition against a species with a faster clock, in relatively small systems. Periodic or stochastic environmental variations also favor the slower species, even in much larger systems.

Interspecific interactions through 2 million years: are competitive outcomes predictable?

PubMed Central

Di Martino, Emanuela; Rust, Seabourne

2016-01-01

Ecological interactions affect the survival and reproduction of individuals. However, ecological interactions are notoriously difficult to measure in extinct populations, hindering our understanding of how the outcomes of interactions such as competition vary in time and influence long-term evolutionary changes. Here, the outcomes of spatial competition in a temporally continuous community over evolutionary timescales are presented for the first time. Our research domain is encrusting cheilostome bryozoans from the Wanganui Basin of New Zealand over a ca 2 Myr time period (Pleistocene to Recent). We find that a subset of species can be identified as consistent winners, and others as consistent losers, in the sense that they win or lose interspecific competitive encounters statistically more often than the null hypothesis of 50%. Most species do not improve or worsen in their competitive abilities through the 2 Myr period, but a minority of species are winners in some intervals and losers in others. We found that conspecifics tend to cluster spatially and interact more often than expected under a null hypothesis: most of these are stand-off interactions where the two colonies involved stopped growing at edges of encounter. Counterintuitively, competitive ability has no bearing on ecological dominance. PMID:27581885

Asymmetric competition causes multimodal size distributions in spatially structured populations

PubMed Central

Velázquez, Jorge; Allen, Robert B.; Coomes, David A.; Eichhorn, Markus P.

2016-01-01

Plant sizes within populations often exhibit multimodal distributions, even when all individuals are the same age and have experienced identical conditions. To establish the causes of this, we created an individual-based model simulating the growth of trees in a spatially explicit framework, which was parametrized using data from a long-term study of forest stands in New Zealand. First, we demonstrate that asymmetric resource competition is a necessary condition for the formation of multimodal size distributions within cohorts. By contrast, the legacy of small-scale clustering during recruitment is transient and quickly overwhelmed by density-dependent mortality. Complex multi-layered size distributions are generated when established individuals are restricted in the spatial domain within which they can capture resources. The number of modes reveals the effective number of direct competitors, while the separation and spread of modes are influenced by distances among established individuals. Asymmetric competition within local neighbourhoods can therefore generate a range of complex size distributions within even-aged cohorts. PMID:26817778

Nonlocal birth-death competitive dynamics with volume exclusion

NASA Astrophysics Data System (ADS)

Khalil, Nagi; López, Cristóbal; Hernández-García, Emilio

2017-06-01

A stochastic birth-death competition model for particles with excluded volume is proposed. The particles move, reproduce, and die on a regular lattice. While the death rate is constant, the birth rate is spatially nonlocal and implements inter-particle competition by a dependence on the number of particles within a finite distance. The finite volume of particles is accounted for by fixing an upper value to the number of particles that can occupy a lattice node, compromising births and movements. We derive closed macroscopic equations for the density of particles and spatial correlation at two adjacent sites. Under different conditions, the description is further reduced to a single equation for the particle density that contains three terms: diffusion, a linear death, and a highly nonlinear and nonlocal birth term. Steady-state homogeneous solutions, their stability which reveals spatial pattern formation, and the dynamics of time-dependent homogeneous solutions are discussed and compared, in the one-dimensional case, with numerical simulations of the particle system.

Variable allelopathy among phytoplankton reflected in red tide metabolome.

PubMed

Poulin, Remington X; Poulson-Ellestad, Kelsey L; Roy, Jessie S; Kubanek, Julia

2018-01-01

Harmful algae are known to utilize allelopathy, the release of compounds that inhibit competitors, as a form of interference competition. Competitor responses to allelopathy are species-specific and allelopathic potency of producing algae is variable. In the current study, the biological variability in allelopathic potency was mapped to the underlying chemical variation in the exuded metabolomes of five genetic strains of the red tide dinoflagellate Karenia brevis using 1 H nuclear magnetic resonance (NMR) spectroscopy. The impacts of K. brevis allelopathy on growth of a model competitor, Asterionellopsis glacialis, ranged from strongly inhibitory to negligible to strongly stimulatory. Unique metabolomes of K. brevis were visualized as chemical fingerprints, suggesting three distinct metabolic modalities - allelopathic, non-allelopathic, and stimulatory - with each modality distinguished from the others by different concentrations of several metabolites. Allelopathic K. brevis was characterized by enhanced concentrations of fatty acid-derived lipids and aromatic or other polyunsaturated compounds, relative to less allelopathic K. brevis. These findings point to a previously untapped source of information in the study of allelopathy: the chemical variability of phytoplankton, which has been underutilized in the study of bloom dynamics and plankton chemical ecology. Copyright © 2017 Elsevier B.V. All rights reserved.

Indanones as high-potency reversible inhibitors of monoamine oxidase.

PubMed

Mostert, Samantha; Petzer, Anél; Petzer, Jacobus P

2015-05-01

Recent reports document that α-tetralone (3,4-dihydro-2H-naphthalen-1-one) is an appropriate scaffold for the design of high-potency monoamine oxidase (MAO) inhibitors. Based on the structural similarity between α-tetralone and 1-indanone, the present study involved synthesis of 34 1-indanone and related indane derivatives as potential inhibitors of recombinant human MAO-A and MAO-B. The results show that C6-substituted indanones are particularly potent and selective MAO-B inhibitors, with IC50 values ranging from 0.001 to 0.030 μM. C5-Substituted indanone and indane derivatives are comparatively weaker MAO-B inhibitors. Although the 1-indanone and indane derivatives are selective inhibitors of the MAO-B isoform, a number of homologues are also potent MAO-A inhibitors, with three homologues possessing IC50 values <0.1 μM. Dialysis of enzyme-inhibitor mixtures further established a selected 1-indanone as a reversible MAO inhibitor with a competitive mode of inhibition. It may be concluded that 1-indanones are promising leads for the design of therapies for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The impact of resource dependence of the mechanisms of life on the spatial population dynamics of an in silico microbial community

NASA Astrophysics Data System (ADS)

Daly, Aisling J.; Baetens, Jan M.; De Baets, Bernard

2016-12-01

Biodiversity has a critical impact on ecosystem functionality and stability, and thus the current biodiversity crisis has motivated many studies of the mechanisms that sustain biodiversity, a notable example being non-transitive or cyclic competition. We therefore extend existing microscopic models of communities with cyclic competition by incorporating resource dependence in demographic processes, characteristics of natural systems often oversimplified or overlooked by modellers. The spatially explicit nature of our individual-based model of three interacting species results in the formation of stable spatial structures, which have significant effects on community functioning, in agreement with experimental observations of pattern formation in microbial communities.

Spatio-temporal interactions facilitate large carnivore sympatry across a resource gradient

PubMed Central

Karanth, K. Ullas; Srivathsa, Arjun; Puri, Mahi; Parameshwaran, Ravishankar; Kumar, N. Samba

2017-01-01

Species within a guild vary their use of time, space and resources, thereby enabling sympatry. As intra-guild competition intensifies, such behavioural adaptations may become prominent. We assessed mechanisms of facilitating sympatry among dhole (Cuon alpinus), leopard (Panthera pardus) and tiger (Panthera tigris) in tropical forests of India using camera-trap surveys. We examined population-level temporal, spatial and spatio-temporal segregation among them across four reserves representing a gradient of carnivore and prey densities. Temporal and spatial overlaps were higher at lower prey densities. Combined spatio-temporal overlap was minimal, possibly due to chance. We found fine-scale avoidance behaviours at one high-density reserve. Our results suggest that: (i) patterns of spatial, temporal and spatio-temporal segregation in sympatric carnivores do not necessarily mirror each other; (ii) carnivores are likely to adopt temporal, spatial, and spatio-temporal segregation as alternative mechanisms to facilitate sympatry; and (iii) carnivores show adaptability across a gradient of resource availability, a driver of inter-species competition. We discuss behavioural mechanisms that permit carnivores to co-occupy rather than dominate functional niches, and adaptations to varying intensities of competition that are likely to shape structure and dynamics of carnivore guilds. PMID:28179511

Spatio-temporal interactions facilitate large carnivore sympatry across a resource gradient.

PubMed

Karanth, K Ullas; Srivathsa, Arjun; Vasudev, Divya; Puri, Mahi; Parameshwaran, Ravishankar; Kumar, N Samba

2017-02-08

Species within a guild vary their use of time, space and resources, thereby enabling sympatry. As intra-guild competition intensifies, such behavioural adaptations may become prominent. We assessed mechanisms of facilitating sympatry among dhole ( Cuon alpinus ), leopard ( Panthera pardus ) and tiger ( Panthera tigris ) in tropical forests of India using camera-trap surveys. We examined population-level temporal, spatial and spatio-temporal segregation among them across four reserves representing a gradient of carnivore and prey densities. Temporal and spatial overlaps were higher at lower prey densities. Combined spatio-temporal overlap was minimal, possibly due to chance. We found fine-scale avoidance behaviours at one high-density reserve. Our results suggest that: (i) patterns of spatial, temporal and spatio-temporal segregation in sympatric carnivores do not necessarily mirror each other; (ii) carnivores are likely to adopt temporal, spatial, and spatio-temporal segregation as alternative mechanisms to facilitate sympatry; and (iii) carnivores show adaptability across a gradient of resource availability, a driver of inter-species competition. We discuss behavioural mechanisms that permit carnivores to co-occupy rather than dominate functional niches, and adaptations to varying intensities of competition that are likely to shape structure and dynamics of carnivore guilds. © 2017 The Author(s).

Structural implications of hERG K+ channel block by a high-affinity minimally structured blocker

PubMed Central

Helliwell, Matthew V.; Zhang, Yihong; El Harchi, Aziza; Du, Chunyun; Hancox, Jules C.; Dempsey, Christopher E.

2018-01-01

Cardiac potassium channels encoded by human ether-à-go-go–related gene (hERG) are major targets for structurally diverse drugs associated with acquired long QT syndrome. This study characterized hERG channel inhibition by a minimally structured high-affinity hERG inhibitor, Cavalli-2, composed of three phenyl groups linked by polymethylene spacers around a central amino group, chosen to probe the spatial arrangement of side chain groups in the high-affinity drug-binding site of the hERG pore. hERG current (IhERG) recorded at physiological temperature from HEK293 cells was inhibited with an IC50 of 35.6 nm with time and voltage dependence characteristic of blockade contingent upon channel gating. Potency of Cavalli-2 action was markedly reduced for attenuated inactivation mutants located near (S620T; 54-fold) and remote from (N588K; 15-fold) the channel pore. The S6 Y652A and F656A mutations decreased inhibitory potency 17- and 75-fold, respectively, whereas T623A and S624A at the base of the selectivity filter also decreased potency (16- and 7-fold, respectively). The S5 helix F557L mutation decreased potency 10-fold, and both F557L and Y652A mutations eliminated voltage dependence of inhibition. Computational docking using the recent cryo-EM structure of an open channel hERG construct could only partially recapitulate experimental data, and the high dependence of Cavalli-2 block on Phe-656 is not readily explainable in that structure. A small clockwise rotation of the inner (S6) helix of the hERG pore from its configuration in the cryo-EM structure may be required to optimize Phe-656 side chain orientations compatible with high-affinity block. PMID:29545312

The roles of competition and habitat in the dynamics of populations and species distributions Ecology

Treesearch

Charles B. Yackulic; Janice Reid; James D. Nichols; James E. Hines; Raymond Davis; Eric Forsman

2014-01-01

The role of competition in structuring biotic communities at fine spatial scales is well known from detailed process-based studies. Our understanding of competition’s importance at broader scales is less resolved and mainly based on static species distribution maps. Here, we bridge this gap by examining the joint occupancy dynamics of an invading species (Barred Owl,...

Application of GIS in exploring spatial dimensions of Efficiency in Competitiveness of Regions

NASA Astrophysics Data System (ADS)

Rahmat, Shahid; Sen, Joy

2017-04-01

Infrastructure is an important component in building competitiveness of a region. Present global scenario of economic slowdown that is led by slump in demand of goods and services and decreasing capacity of government institutions in investing public infrastructure. Strategy of augmenting competitiveness of a region can be built around improving efficient distribution of public infrastructure in the region. This efficiency in the distribution of infrastructure will reduce the burden of government institution and improve the relative output of the region in relative lesser investment. A rigorous literature study followed by an expert opinion survey (RIDIT scores) reveals that Railway, Road, ICTs and Electricity infrastructure is very crucial for better competitiveness of a region. Discussion with Experts in ICTs, Railways and Electricity sectors were conducted to find the issues, hurdles and possible solution for the development of these sectors. In an underdeveloped country like India, there is a large constrain of financial resources, for investment in infrastructure sector. Judicious planning for allocation of resources for infrastructure provisions becomes very important for efficient and sustainable development. Data Envelopment Analysis (DEA) is the mathematical programming optimization tool that measure technical efficiency of the multiple-input and/or multiple-output case by constructing a relative technical efficiency score. This paper tries to utilize DEA to identify the efficiency at which present level of selected components of Infrastructure (Railway, Road, ICTs and Electricity) is utilized in order to build competitiveness of the region. This paper tries to identify a spatial pattern of efficiency of Infrastructure with the help of spatial auto-correlation and Hot-spot analysis in Arc GIS. This analysis leads to policy implications for efficient allocation of financial resources for the provision of infrastructure in the region and building a prerequisite to boost an efficient Regional Competitiveness.

Spatial firm competition in two dimensions with linear transportation costs: simulations and analytical results

NASA Astrophysics Data System (ADS)

Roncoroni, Alan; Medo, Matus

2016-12-01

Models of spatial firm competition assume that customers are distributed in space and transportation costs are associated with their purchases of products from a small number of firms that are also placed at definite locations. It has been long known that the competition equilibrium is not guaranteed to exist if the most straightforward linear transportation costs are assumed. We show by simulations and also analytically that if periodic boundary conditions in a plane are assumed, the equilibrium exists for a pair of firms at any distance. When a larger number of firms is considered, we find that their total equilibrium profit is inversely proportional to the square root of the number of firms. We end with a numerical investigation of the system's behavior for a general transportation cost exponent.

Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

PubMed Central

Feldman, D; Couropmitree, C

1976-01-01

Because some nonsteroidal anti-inflammatory drugs (NSAID) induce salt and water retention and exhibit other steroid-like actions, studies were performed to ascertain whether these drugs possess intrinsic mineralocorticoid agonist activity. In vitro competitive binding assays utilizing tissue from adrenalectomized rats demonstrated that some NSAID can displace [3H]-aldosterone from renal cytoplasmic mineralocorticoid receptors. Displacement potency for these sites was in the sequence: aldosterone greater than spironolactone greater than phenylbutazone (PBZ) greater than aspirin (ASA) greater than indomethacin (IDM). Concentration ratios required to obtain significant displacement of [3H]aldosterone were high but clearly within the therapeutic range for PBZ and ASA but not IDM. The analogues oxyphenbutazone (OBZ) and sodium salicylate (SS) were similar in binding activity to PBZ and ASA, respectively. Lineweaver-Burk analysis revealed that the inhibition of [3H]aldosterone binding was competitive in nature. In addition, PBZ was shown to prevent the nuclear binding of [3H]aldosterone. In vivo injection of PBZ and ASA resulted in competition for [3H]aldosterone renal binding comparable to the in vitro studies. Administration of PBZ and OBZ to adrenalectomized rats resulted in significant salt retention whereas ASA and SS did not differ significantly from controls. Salt retention elicited by PBZ and OBZ was inhibited by spironolactone, a competitive mineralocorticoid antagonist. These data suggest that, despite nonsteroidal structures, PBZ and OBZ induce salt retention via a receptor-mediated mineralocorticoid pathway analogous to aldosterone action. PMID:173739

Modeling spatial competition for light in plant populations with the porous medium equation.

PubMed

Beyer, Robert; Etard, Octave; Cournède, Paul-Henry; Laurent-Gengoux, Pascal

2015-02-01

We consider a plant's local leaf area index as a spatially continuous variable, subject to particular reaction-diffusion dynamics of allocation, senescence and spatial propagation. The latter notably incorporates the plant's tendency to form new leaves in bright rather than shaded locations. Applying a generalized Beer-Lambert law allows to link existing foliage to production dynamics. The approach allows for inter-individual variability and competition for light while maintaining robustness-a key weakness of comparable existing models. The analysis of the single plant case leads to a significant simplification of the system's key equation when transforming it into the well studied porous medium equation. Confronting the theoretical model to experimental data of sugar beet populations, differing in configuration density, demonstrates its accuracy.

Preliminary Assessment of Spatial Competition in the Market for E85

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clinton, Bentley

Anecdotal evidence suggests retail E85 prices may track retail gasoline prices rather than wholesale costs. This indicates E85 prices may be higher than they would be if priced on a cost basis hence limiting adoption by some price-sensitive consumers. Using publicly available and proprietary E83 and regular gasoline price data, we examine pricing behavior in the market for E85. Specifically, we assess the extent to which local retail competition in E85 markets decreases E85 retail prices. Results of econometric analysis suggest that higher levels of retail competition (measured in terms of station density) are associated with lower E85 prices atmore » the pump. While more precise causal estimates may be produced from more comprehensive data, this study is the first to our knowledge that estimates the spatial competition dimension of E85 pricing behavior by firms. This is an initial presentation; a related technical report is also available.« less

Preliminary Assessment of Spatial Competition in the Market for E85: Presentation Supplement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clinton, Bentley; Johnson, Caley; Moriarty, Kristi

Anecdotal evidence suggests retail E85 prices may track retail gasoline prices rather than wholesale costs. This indicates E85 prices may be higher than they would be if priced on a cost basis hence limiting adoption by some price-sensitive consumers. Using publicly available and proprietary E85 and regular gasoline price data, we examine pricing behavior in the market for E85. Specifically, we assess the extent to which local retail competition in E85 markets decreases E85 retail prices. Results of econometric analysis suggest that higher levels of retail competition (measured in terms of station density) are associated with lower E85 prices atmore » the pump. While more precise causal estimates may be produced from more comprehensive data, this study is the first to our knowledge that estimates the spatial competition dimension of E85 pricing behavior by firms. This technical report elaborates on a related presentation.« less

The Implementation of Spatial Technologies in Australian Schools: 1996-2005

ERIC Educational Resources Information Center

McInerney, Malcolm

2006-01-01

The story of Geographic Information Systems (GIS) in schools in Australia started in 1996 with the limited involvement of schools in the Australasian Urban and Regional Information Systems Association (AURISA) "GIS in schools" competition. AURISA is now known as the Spatial Science Institute (SSI) and is conducting the Spatial Technology…

Isolation and characterization of iron chelators from turmeric (Curcuma longa): selective metal binding by curcuminoids.

PubMed

Messner, Donald J; Surrago, Christine; Fiordalisi, Celia; Chung, Wing Yin; Kowdley, Kris V

2017-10-01

Iron overload disorders may be treated by chelation therapy. This study describes a novel method for isolating iron chelators from complex mixtures including plant extracts. We demonstrate the one-step isolation of curcuminoids from turmeric, the medicinal food spice derived from Curcuma longa. The method uses iron-nitrilotriacetic acid (NTA)-agarose, to which curcumin binds rapidly, specifically, and reversibly. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin each bound iron-NTA-agarose with comparable affinities and a stoichiometry near 1. Analyses of binding efficiencies and purity demonstrated that curcuminoids comprise the primary iron binding compounds recovered from a crude turmeric extract. Competition of curcuminoid binding to the iron resin was used to characterize the metal binding site on curcumin and to detect iron binding by added chelators. Curcumin-Iron-NTA-agarose binding was inhibited by other metals with relative potency: (>90% inhibition) Cu 2+  ~ Al 3+  > Zn 2+  ≥ Ca 2+  ~ Mg 2+  ~ Mn 2+ (<20% inhibition). Binding was also inhibited by pharmaceutical iron chelators (desferoxamine or EDTA) or by higher concentrations of weak iron chelators (citrate or silibinin). Investigation of the physiological effects of iron binding by curcumin revealed that curcumin uptake by cultured cells was reduced >80% by addition of iron to the media; uptake was completely restored by desferoxamine. Ranking of metals by relative potencies for blocking curcumin uptake agreed with their relative potencies in blocking curcumin binding to iron-NTA-agarose. We conclude that curcumin can selectively bind toxic metals including iron in a physiological setting, and propose inhibition of curcumin binding to iron-NTA-agarose for iron chelator screening.

Generation of cell lines for drug discovery through random activation of gene expression: application to the human histamine H3 receptor.

PubMed

Song, J; Doucette, C; Hanniford, D; Hunady, K; Wang, N; Sherf, B; Harrington, J J; Brunden, K R; Stricker-Krongrad, A

2005-06-01

Target-based high-throughput screening (HTS) plays an integral role in drug discovery. The implementation of HTS assays generally requires high expression levels of the target protein, and this is typically accomplished using recombinant cDNA methodologies. However, the isolated gene sequences to many drug targets have intellectual property claims that restrict the ability to implement drug discovery programs. The present study describes the pharmacological characterization of the human histamine H3 receptor that was expressed using random activation of gene expression (RAGE), a technology that over-expresses proteins by up-regulating endogenous genes rather than introducing cDNA expression vectors into the cell. Saturation binding analysis using [125I]iodoproxyfan and RAGE-H3 membranes revealed a single class of binding sites with a K(D) value of 0.77 nM and a B(max) equal to 756 fmol/mg of protein. Competition binding studies showed that the rank order of potency for H3 agonists was N(alpha)-methylhistamine approximately (R)-alpha- methylhistamine > histamine and that the rank order of potency for H3 antagonists was clobenpropit > iodophenpropit > thioperamide. The same rank order of potency for H3 agonists and antagonists was observed in the functional assays as in the binding assays. The Fluorometic Imaging Plate Reader assays in RAGE-H3 cells gave high Z' values for agonist and antagonist screening, respectively. These results reveal that the human H3 receptor expressed with the RAGE technology is pharmacologically comparable to that expressed through recombinant methods. Moreover, the level of expression of the H3 receptor in the RAGE-H3 cells is suitable for HTS and secondary assays.

The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro.

PubMed Central

Horton, R. W.; Lowther, S.; Chivers, J.; Jenner, P.; Marsden, C. D.; Testa, B.

1988-01-01

1. The interaction of substituted benzamides with brain benzodiazepine (BDZ) binding sites was examined by their ability to displace [3H]-flunitrazepam ([3H]-FNM) from specific binding sites in bovine cortical membranes in vitro. 2. Clebopride, Delagrange 2674, Delagrange 2335 and BRL 20627 displayed concentration-dependent displacement of [3H]-FNM with IC50 values of 73 nM, 132 nM, 7.7 microM and 5.9 microM, respectively. Other substituted benzamides including metoclopramide, sulpiride, tiapride, sultopride and cisapride were inactive at 10(-5) M. 3. Inhibition by clebopride and Delagrange 2674 of [3H]-FNM binding was apparently competitive and readily reversible. 4. In the presence of gamma-aminobutyric acid (GABA), the ability of diazepam and Delagrange 2674 to displace [3H]-Ro 15-1788 binding was increased 3.6 and 1.6 fold respectively, compared to the absence of GABA, while ethyl beta-carboline-3-carboxylate (beta CCE) and clebopride were less potent in the presence of GABA. 5. Diazepam was 30 fold less potent at displacing [3H]-Ro 15-1788 in membranes that had been photoaffinity labelled with FNM than in control membranes, whereas the potency of beta CCE did not differ. Clebopride and Delagrange 2674 showed a less than two fold loss of potency in photoaffinity labelled membranes. 6. The pattern of binding of clebopride and Delagrange 2674 in these in vitro tests is similar to that found previously with partial agonists or antagonists at BDZ binding sites. 7. Clebopride and Delagrange 2674 inhibited [3H]-FNM binding with similar potency in rat cerebellar and hippocampal membranes, suggesting they have no selectivity for BDZ1 and BDZ2 binding sites.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2850059

The guinea pig ileum lacks the direct, high-potency, M(2)-muscarinic, contractile mechanism characteristic of the mouse ileum.

PubMed

Griffin, Michael T; Matsui, Minoru; Ostrom, Rennolds S; Ehlert, Frederick J

2009-10-01

We explored whether the M(2) muscarinic receptor in the guinea pig ileum elicits a highly potent, direct-contractile response, like that from the M(3) muscarinic receptor knockout mouse. First, we characterized the irreversible receptor-blocking activity of 4-DAMP mustard in ileum from muscarinic receptor knockout mice to verify its M(3) selectivity. Then, we used 4-DAMP mustard to inactivate M(3) responses in the guinea pig ileum to attempt to reveal direct, M(2) receptor-mediated contractions. The muscarinic agonist, oxotremorine-M, elicited potent contractions in ileum from wild-type, M(2) receptor knockout, and M(3) receptor knockout mice characterized by negative log EC(50) (pEC (50)) values +/- SEM of 6.75 +/- 0.03, 6.26 +/- 0.05, and 6.99 +/- 0.08, respectively. The corresponding E (max) values in wild-type and M(2) receptor knockout mice were approximately the same, but that in the M(3) receptor knockout mouse was only 36% of wild type. Following 4-DAMP mustard treatment, the concentration-response curve of oxotremorine-M in wild-type ileum resembled that of the M(3) knockout mouse in terms of its pEC (50), E (max), and inhibition by selective muscarinic antagonists. Thus, 4-DAMP mustard treatment appears to inactivate M(3) responses selectively and renders the muscarinic contractile behavior of the wild-type ileum similar to that of the M(3) knockout mouse. Following 4-DAMP mustard treatment, the contractile response of the guinea pig ileum to oxotremorine-M exhibited low potency and a competitive-antagonism profile consistent with an M(3) response. The guinea pig ileum, therefore, lacks a direct, highly potent, M(2)-contractile component but may have a direct, lower potency M(2) component.

Bisphenol A alternatives bisphenol S and bisphenol F interfere with thyroid hormone signaling pathway in vitro and in vivo.

PubMed

Zhang, Yin-Feng; Ren, Xiao-Min; Li, Yuan-Yuan; Yao, Xiao-Fang; Li, Chuan-Hai; Qin, Zhan-Fen; Guo, Liang-Hong

2018-06-01

The wide use of the alternatives to bisphenol A (BPA) has raised concerns about their potential toxicities. Considering the disrupting activity of BPA on thyroid hormone (TH) signaling, we investigated whether bisphenol S (BPS) and bisphenol F (BPF), two leading alternatives, could interfere with TH signaling pathway using a series of assays in vitro and in vivo. In the fluorescence competitive binding assay, we found BPS and BPF, like BPA, bound to TH receptors (TRα and TRβ), with the binding potencies an order of magnitude lower than BPA (BPA > BPF > BPS). Molecular docking data also show their binding potencies to TRs. In the coactivator recruitment assay, BPS and BPF recruited coactivator to TRβ but not TRα, with weaker potencies than BPA. Correspondingly, agonistic actions of the three bisphenols in the absence or presence of T3 were observed in the TR-mediated reporter gene transcription assay. Also, all the three bisphenols induced TH-dependent GH3 cell proliferation, whereas BPA and BPF inhibited T3 induction in the presence of T3. As for in vivo assay, the three bisphenols like T3 induced TH-response gene transcription in Pelophylax nigromaculatus tadpoles, but in the presence of T3 altered T3-induced gene transcription in a biphasic concentration-response manner. These results for the first time demonstrate that BPS and BPF, like BPA, have potential to interfere with TH signaling pathway, i.e., they generally activate TH signaling in the absence of T3, but in the presence of TH, display agonistic or/and antagonistic actions under certain condition. Our study highlights the potential risks of BPS and BPF as BPA alternatives. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spatial complementarity and the coexistence of species.

PubMed

Velázquez, Jorge; Garrahan, Juan P; Eichhorn, Markus P

2014-01-01

Coexistence of apparently similar species remains an enduring paradox in ecology. Spatial structure has been predicted to enable coexistence even when population-level models predict competitive exclusion if it causes each species to limit its own population more than that of its competitor. Nevertheless, existing hypotheses conflict with regard to whether clustering favours or precludes coexistence. The spatial segregation hypothesis predicts that in clustered populations the frequency of intra-specific interactions will be increased, causing each species to be self-limiting. Alternatively, individuals of the same species might compete over greater distances, known as heteromyopia, breaking down clusters and opening space for a second species to invade. In this study we create an individual-based model in homogeneous two-dimensional space for two putative sessile species differing only in their demographic rates and the range and strength of their competitive interactions. We fully characterise the parameter space within which coexistence occurs beyond population-level predictions, thereby revealing a region of coexistence generated by a previously-unrecognised process which we term the triadic mechanism. Here coexistence occurs due to the ability of a second generation of offspring of the rarer species to escape competition from their ancestors. We diagnose the conditions under which each of three spatial coexistence mechanisms operates and their characteristic spatial signatures. Deriving insights from a novel metric - ecological pressure - we demonstrate that coexistence is not solely determined by features of the numerically-dominant species. This results in a common framework for predicting, given any pair of species and knowledge of the relevant parameters, whether they will coexist, the mechanism by which they will do so, and the resultant spatial pattern of the community. Spatial coexistence arises from complementary combinations of traits in each species rather than solely through self-limitation.

Spatial Complementarity and the Coexistence of Species

PubMed Central

Velázquez, Jorge; Garrahan, Juan P.; Eichhorn, Markus P.

2014-01-01

Coexistence of apparently similar species remains an enduring paradox in ecology. Spatial structure has been predicted to enable coexistence even when population-level models predict competitive exclusion if it causes each species to limit its own population more than that of its competitor. Nevertheless, existing hypotheses conflict with regard to whether clustering favours or precludes coexistence. The spatial segregation hypothesis predicts that in clustered populations the frequency of intra-specific interactions will be increased, causing each species to be self-limiting. Alternatively, individuals of the same species might compete over greater distances, known as heteromyopia, breaking down clusters and opening space for a second species to invade. In this study we create an individual-based model in homogeneous two-dimensional space for two putative sessile species differing only in their demographic rates and the range and strength of their competitive interactions. We fully characterise the parameter space within which coexistence occurs beyond population-level predictions, thereby revealing a region of coexistence generated by a previously-unrecognised process which we term the triadic mechanism. Here coexistence occurs due to the ability of a second generation of offspring of the rarer species to escape competition from their ancestors. We diagnose the conditions under which each of three spatial coexistence mechanisms operates and their characteristic spatial signatures. Deriving insights from a novel metric — ecological pressure — we demonstrate that coexistence is not solely determined by features of the numerically-dominant species. This results in a common framework for predicting, given any pair of species and knowledge of the relevant parameters, whether they will coexist, the mechanism by which they will do so, and the resultant spatial pattern of the community. Spatial coexistence arises from complementary combinations of traits in each species rather than solely through self-limitation. PMID:25532018

Examining spatial patterns of selection and use for an altered predator guild

USGS Publications Warehouse

Organ, John F.; Mumma, Matthew; Holbrook, Joseph D.; Rayl, Nathaniel D.; Zieminski, Christopher J.; Fuller, Todd K.; Mahoney, Shane P.; Waits, Lisette P.

2017-01-01

Anthropogenic disturbances have altered species’ distributions potentially impacting interspecific interactions. Interference competition is when one species denies a competing species access to a resource. One mechanism of interference competition is aggression, which can result in altered space-use of a subordinate species due to the threat of harm, otherwise known as a ‘landscape of fear’. Alternatively, subordinates might outcompete dominant species in resource-poor environments via a superior ability to extract resources. Our goal was to evaluate spatial predictions of the ‘landscape of fear’ hypothesis for a carnivore guild in Newfoundland, Canada, where coyotes recently immigrated. Native Newfoundland carnivores include red foxes, Canada lynx, and black bears. We predicted foxes and lynx would avoid coyotes because of their larger size and similar dietary niches. We used scat-detecting dogs and genetic techniques to locate and identify predator scats. We then built resource selection functions and tested for avoidance by incorporating predicted values of selection for the alternative species into the best supported models of each species. We found multiple negative relationships, but notably did not find avoidance by foxes of areas selected by coyotes. While we did find that lynx avoided coyotes, we also found a reciprocal relationship. The observed patterns suggest spatial partitioning and not coyote avoidance, although avoidance could still be occurring at different spatial or temporal scales. Furthermore, Newfoundland’s harsh climate and poor soils may swing the pendulum of interspecific interactions from interference competition to exploitative competition, where subordinates outcompete dominant competitors through a superior ability to extract resources.

Examining spatial patterns of selection and use for an altered predator guild.

PubMed

Mumma, Matthew A; Holbrook, Joseph D; Rayl, Nathaniel D; Zieminski, Christopher J; Fuller, Todd K; Organ, John F; Mahoney, Shane P; Waits, Lisette P

2017-12-01

Anthropogenic disturbances have altered species' distributions potentially impacting interspecific interactions. Interference competition is when one species denies a competing species access to a resource. One mechanism of interference competition is aggression, which can result in altered space-use of a subordinate species due to the threat of harm, otherwise known as a 'landscape of fear'. Alternatively, subordinates might outcompete dominant species in resource-poor environments via a superior ability to extract resources. Our goal was to evaluate spatial predictions of the 'landscape of fear' hypothesis for a carnivore guild in Newfoundland, Canada, where coyotes recently immigrated. Native Newfoundland carnivores include red foxes, Canada lynx, and black bears. We predicted foxes and lynx would avoid coyotes because of their larger size and similar dietary niches. We used scat-detecting dogs and genetic techniques to locate and identify predator scats. We then built resource selection functions and tested for avoidance by incorporating predicted values of selection for the alternative species into the best supported models of each species. We found multiple negative relationships, but notably did not find avoidance by foxes of areas selected by coyotes. While we did find that lynx avoided coyotes, we also found a reciprocal relationship. The observed patterns suggest spatial partitioning and not coyote avoidance, although avoidance could still be occurring at different spatial or temporal scales. Furthermore, Newfoundland's harsh climate and poor soils may swing the pendulum of interspecific interactions from interference competition to exploitative competition, where subordinates outcompete dominant competitors through a superior ability to extract resources.

Competitive intransitivity promotes species coexistence.

PubMed

Laird, Robert A; Schamp, Brandon S

2006-08-01

Using a spatially explicit cellular automaton model with local competition, we investigate the potential for varied levels of competitive intransitivity (i.e., nonhierarchical competition) to promote species coexistence. As predicted, on average, increased levels of intransitivity result in more sustained coexistence within simulated communities, although the outcome of competition also becomes increasingly unpredictable. Interestingly, even a moderate degree of intransitivity within a community can promote coexistence, in terms of both the length of time until the first competitive exclusion and the number of species remaining in the community after 500 simulated generations. These results suggest that modest levels of intransitivity in nature, such as those that are thought to be characteristic of plant communities, can contribute to coexistence and, therefore, community-scale biodiversity. We explore a potential connection between competitive intransitivity and neutral theory, whereby competitive intransitivity may represent an important mechanism for "ecological equivalence."

Predicting spatial distribution of privet (liguestrum spp.) in South Carolina from MODIS and forest inventory plot data

Treesearch

Dumitru Salajanu; Dennis M. Jacobs

2009-01-01

Privet's aggressive competitive behavior causes environmental harm to the ecosystem by degrading species diversity and wildlife habitat. Effective control of its spread requires high-quality spatial distribution information. Our...

Inhibitors of acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 1: Hit to lead evaluation of a novel arylsulfonamide series.

PubMed

Green, Oluyinka M; McKenzie, Andrew R; Shapiro, Adam B; Otterbein, Ludovic; Ni, Haihong; Patten, Arthur; Stokes, Suzanne; Albert, Robert; Kawatkar, Sameer; Breed, Jason

2012-02-15

A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40. Copyright © 2012 Elsevier Ltd. All rights reserved.

On factors structuring the flatfish assemblage in the southern North Sea

NASA Astrophysics Data System (ADS)

Piet, G. J.; Pfisterer, A. B.; Rijnsdorp, A. D.

1998-09-01

Ten species of flatfish were studied to see to what extent interspecific competition influences their diet or spatial distribution and whether the potential of these flatfish species to avoid interspecific competition through resource partitioning is constrained by specific morphological characteristics. For this, seven morphological characteristics were measured, diet composition was determined from gut content analyses and overlap in distribution was determined from the co-occurrence in trawl hauls. Canonical correspondence analysis revealed the morphological characteristics that were most strongly correlated with the diet composition. Based on these findings the mouth gape was considered to be the most important morphological constraint affecting the choice of food. Two resource dimensions were distinguished along which interspecific competition can act on the flatfish assemblage: the trophic dimension (diet composition) and the spatial dimension (distribution). Resource partitioning was observed along both dimensions separately and, more importantly, the degree of resource partitioning along the two dimensions was negatively correlated. Especially the latter was considered strong circumstantial evidence that interspecific competition is a major factor structuring the flatfish assemblage. Resource partitioning along the two resource dimensions increased with decreasing mouth gape, suggesting that interspecific competition mainly acts on the small-mouthed fish, i.e. juveniles.

Spatial patterns, ecological niches, and interspecific competition of avian brood parasites: inferring from a case study of Korea.

PubMed

Lee, Jin-Won; Noh, Hee-Jin; Lee, Yunkyoung; Kwon, Young-Soo; Kim, Chang-Hoe; Yoo, Jeong-Chil

2014-09-01

Since obligate avian brood parasites depend completely on the effort of other host species for rearing their progeny, the availability of hosts will be a critical resource for their life history. Circumstantial evidence suggests that intense competition for host species may exist not only within but also between species. So far, however, few studies have demonstrated whether the interspecific competition really occurs in the system of avian brood parasitism and how the nature of brood parasitism is related to their niche evolution. Using the occurrence data of five avian brood parasites from two sources of nationwide bird surveys in South Korea and publically available environmental/climatic data, we identified their distribution patterns and ecological niches, and applied species distribution modeling to infer the effect of interspecific competition on their spatial distribution. We found that the distribution patterns of five avian brood parasites could be characterized by altitude and climatic conditions, but overall their spatial ranges and ecological niches extensively overlapped with each other. We also found that the predicted distribution areas of each species were generally comparable to the realized distribution areas, and the numbers of individuals in areas where multiple species were predicted to coexist showed positive relationships among species. In conclusion, despite following different coevolutionary trajectories to adapt to their respect host species, five species of avian brood parasites breeding in South Korea occupied broadly similar ecological niches, implying that they tend to conserve ancestral preferences for ecological conditions. Furthermore, our results indicated that contrary to expectation interspecific competition for host availability between avian brood parasites seemed to be trivial, and thus, play little role in shaping their spatial distributions and ecological niches. Future studies, including the complete ranges of avian brood parasites and ecological niches of host species, will be worthwhile to further elucidate these issues.

Interaction and coexistence with self-regulating species

NASA Astrophysics Data System (ADS)

Zhu, Haoqi; Wang, Maoxiang; Hu, Fenglan

2018-07-01

Based on Lotka-Volterra (LV) system with spatial diffusion we study a self-regulating species, whose interactions can change with the other's population size. These interactions can be divided into four types described by the interaction portrait. The activity of self-regulation in population also depends on the opposite species, when the opposite species is strong competitive, the self-regulating species cannot adjust its population actively until the roles reverse. Furthermore the way of coexistence with self-regulating system, including competition-coexistence and parasitism-coexistence is discussed; it suggests that proper competition is better to acquire larger total population than a single sacrifice as a host. Moreover both self-regulation and spatial diffusion may be opportunities to switch the final surviving species, but self-regulation can result into stable situation and promote the diversity, in accordance with Darwin's theory of evolution.

Spatial cross-correlation of undisturbed, natural shortleaf pine stands in northern Georgia

Treesearch

Robin M. Reich; Raymond L. Czaplewski; William A. Bechtold

1994-01-01

In this study a cross-correlation statistic is used to analyse the spatial relationship among stand characteristics of natural, undisturbed shortleaf pine stands sampled during 1961-72 and 1972-82 in northern Georgia. Stand characteristics included stand age, site index, tree density, hardwood competition, and mortality. In each time period, the spatial cross-...

Have Sex Differences in Spatial Ability Evolved from Male Competition for Mating and Female Concern for Survival?

ERIC Educational Resources Information Center

Ecuyer-Dab, Isabelle; Robert, Michele

2004-01-01

Drawing on the theoretical and empirical foundations of two evolutionary models, we argue that, among humans and other mammals, a twofold selection process would parsimoniously account for sex-linked advantages in spatial contexts. In males, a superiority for both solving navigation-related spatial problems and understanding physical principles…

Spatiotemporal model of barley and cereal yellow dwarf virus transmission dynamics with seasonality and plant competition

Treesearch

S.M. Moore; C.A. Manore; V.A. Bokil; E.T. Borer; P.R. Hosseini

2011-01-01

Many generalist pathogens are influenced by the spatial distributions and relative abundances of susceptible host species. The spatial structure of host populations can influence patterns of infection incidence (or disease outbreaks), and the effects of a generalist pathogen on host community dynamics in a spatially heterogeneous community may differ from predictions...

Similarity in Spatial Origin of Information Facilitates Cue Competition and Interference

ERIC Educational Resources Information Center

Amundson, Jeffrey C.; Miller, Ralph R.

2007-01-01

Two lick suppression studies were conducted with water-deprived rats to investigate the influence of spatial similarity in cue interaction. Experiment 1 assessed the influence of similarity of the spatial origin of competing cues in a blocking procedure. Greater blocking was observed in the condition in which the auditory blocking cue and the…

Spatial aspects of tree mortality strongly differ between young and old-growth forests.

PubMed

Larson, Andrew J; Lutz, James A; Donato, Daniel C; Freund, James A; Swanson, Mark E; HilleRisLambers, Janneke; Sprugel, Douglas G; Franklin, Jerry F

2015-11-01

Rates and spatial patterns of tree mortality are predicted to change during forest structural development. In young forests, mortality should be primarily density dependent due to competition for light, leading to an increasingly spatially uniform pattern of surviving trees. In contrast, mortality in old-growth forests should be primarily caused by contagious and spatially autocorrelated agents (e.g., insects, wind), causing spatial aggregation of surviving trees to increase through time. We tested these predictions by contrasting a three-decade record of tree mortality from replicated mapped permanent plots located in young (< 60-year-old) and old-growth (> 300-year-old) Abies amabilis forests. Trees in young forests died at a rate of 4.42% per year, whereas trees in old-growth forests died at 0.60% per year. Tree mortality in young forests was significantly aggregated, strongly density dependent, and caused live tree patterns to become more uniform through time. Mortality in old-growth forests was spatially aggregated, but was density independent and did not change the spatial pattern of surviving trees. These results extend current theory by demonstrating that density-dependent competitive mortality leading to increasingly uniform tree spacing in young forests ultimately transitions late in succession to a more diverse tree mortality regime that maintains spatial heterogeneity through time.

Spatial competition and price formation

NASA Astrophysics Data System (ADS)

Nagel, Kai; Shubik, Martin; Paczuski, Maya; Bak, Per

2000-12-01

We look at price formation in a retail setting, that is, companies set prices, and consumers either accept prices or go someplace else. In contrast to most other models in this context, we use a two-dimensional spatial structure for information transmission, that is, consumers can only learn from nearest neighbors. Many aspects of this can be understood in terms of generalized evolutionary dynamics. In consequence, we first look at spatial competition and cluster formation without price. This leads to establishement size distributions, which we compare to reality. After some theoretical considerations, which at least heuristically explain our simulation results, we finally return to price formation, where we demonstrate that our simple model with nearly no organized planning or rationality on the part of any of the agents indeed leads to an economically plausible price.

Targeting Phosphatidylserine with a 64Cu-Labeled Peptide for Molecular Imaging of Apoptosis.

PubMed

Perreault, Amanda; Richter, Susan; Bergman, Cody; Wuest, Melinda; Wuest, Frank

2016-10-03

Molecular imaging of programmed cell death (apoptosis) in vivo is an innovative strategy for early assessment of treatment response and treatment efficacy in cancer patients. Externalization of phosphatidylserine (PS) to the cell membrane surface of dying cells makes this phospholipid an attractive molecular target for the development of apoptosis imaging probes. In this study, we have radiolabeled PS-binding 14-mer peptide FNFRLKAGAKIRFG (PSBP-6) with positron-emitter copper-64 ( 64 Cu) for PET imaging of apoptosis. Peptide PSBP-6 was conjugated with radiometal chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) through an aminovaleric acid (Ava) linker for subsequent radiolabeling with 64 Cu to prepare radiotracer 64 Cu-NOTA-Ava-PSBP-6. PS-binding potencies of PSBP-6, NOTA-Ava-PSBP-6, and nat Cu-NOTA-Ava-PSBP-6 were determined in a competitive radiometric PS-binding assay. Radiotracer 64 Cu-NOTA-Ava-PSBP-6 was studied in camptothecin-induced apoptotic EL4 mouse lymphoma cells and in a murine EL4 tumor model of apoptosis using dynamic PET imaging. Peptide PSBP-6 was also conjugated via an Ava linker with fluorescein isothiocyanate (FITC). FITC-Ava-PSBP-6 was evaluated in flow cytometry and fluorescence confocal microscopy experiments. Radiopeptide 64 Cu-NOTA-Ava-PSBP-6 was synthesized in high radiochemical yields of >95%. The IC 50 values for PS-binding potency of PSBP-6, NOTA-Ava-PSBP-6, and nat Cu-NOTA-PSBP-6 were 600 μM, 30 μM, and 23 μM, respectively. A competitive radiometric cell binding assay confirmed binding of 64 Cu-NOTA-Ava-PSBP-6 to camptothecin-induced apoptotic EL4 cells in a Ca 2+ -independent manner. PET imaging studies demonstrated significantly higher uptake of 64 Cu-NOTA-Ava-PSBP-6 in apoptotic EL4 tumors (SUV 5min 0.95 ± 0.04) compared to control tumors (SUV 5min 0.74 ± 0.03). Flow cytometry studies showed significantly higher binding of FITC-Ava-PSBP-6 to EL4 cells treated with camptothecin compared to untreated cells. Fluorescence microscopy studies revealed that FITC-Ava-PSBP-6 was binding to cell membranes of early apoptotic cells, but was internalized in late apoptotic and necrotic cells. The present study showed that radiotracer 64 Cu-NOTA-Ava-PSBP-6 holds promise as a first peptide-based PET imaging agent for molecular imaging of apoptosis. However, additional "fine-tuning" of 64 Cu-NOTA-Ava-PSBP-6 is required to enhance PS-binding potency and in vivo stability to improve tumor uptake and retention.

Inferring local competition intensity from patch size distributions: a test using biological soil crusts

USGS Publications Warehouse

Bowker, Matthew A.; Maestre, Fernando T.

2012-01-01

Dryland vegetation is inherently patchy. This patchiness goes on to impact ecology, hydrology, and biogeochemistry. Recently, researchers have proposed that dryland vegetation patch sizes follow a power law which is due to local plant facilitation. It is unknown what patch size distribution prevails when competition predominates over facilitation, or if such a pattern could be used to detect competition. We investigated this question in an alternative vegetation type, mosses and lichens of biological soil crusts, which exhibit a smaller scale patch-interpatch configuration. This micro-vegetation is characterized by competition for space. We proposed that multiplicative effects of genetics, environment and competition should result in a log-normal patch size distribution. When testing the prevalence of log-normal versus power law patch size distributions, we found that the log-normal was the better distribution in 53% of cases and a reasonable fit in 83%. In contrast, the power law was better in 39% of cases, and in 8% of instances both distributions fit equally well. We further hypothesized that the log-normal distribution parameters would be predictably influenced by competition strength. There was qualitative agreement between one of the distribution's parameters (μ) and a novel intransitive (lacking a 'best' competitor) competition index, suggesting that as intransitivity increases, patch sizes decrease. The correlation of μ with other competition indicators based on spatial segregation of species (the C-score) depended on aridity. In less arid sites, μ was negatively correlated with the C-score (suggesting smaller patches under stronger competition), while positive correlations (suggesting larger patches under stronger competition) were observed at more arid sites. We propose that this is due to an increasing prevalence of competition transitivity as aridity increases. These findings broaden the emerging theory surrounding dryland patch size distributions and, with refinement, may help us infer cryptic ecological processes from easily observed spatial patterns in the field.

Novel propanamides as fatty acid amide hydrolase inhibitors.

PubMed

Deplano, Alessandro; Morgillo, Carmine Marco; Demurtas, Monica; Björklund, Emmelie; Cipriano, Mariateresa; Svensson, Mona; Hashemian, Sanaz; Smaldone, Giovanni; Pedone, Emilia; Luque, F Javier; Cabiddu, Maria G; Novellino, Ettore; Fowler, Christopher J; Catalanotti, Bruno; Onnis, Valentina

2017-08-18

Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroaryl)-2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or non-competitive (TPA14) inhibition modes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The Stoichiometry of Isoquercitrin Complex with Iron or Copper Is Highly Dependent on Experimental Conditions

PubMed Central

Tvrdý, Václav; Karlíčková, Jana; Migkos, Thomas; Mladěnka, Přemysl

2017-01-01

Interaction of flavonoids with transition metals can be partially responsible for their impact on humans. Stoichiometry of the iron/copper complex with a flavonoid glycoside isoquercitrin, a frequent component of food supplements, was assessed using competitive and non-competitive methods in four (patho)physiologically-relevant pH values (4.5. 5.5, 6.8, and 7.5). Isoquercitrin chelated all tested ions (Fe2+, Fe3+, Cu2+, and Cu+) but its affinity for Cu+ ions proved to be very low. In general, the chelation potency dropped with pH lowering. Metal complexes of 1:1 stoichiometry were mostly formed, however, they were not stable and the stoichiometry changed depending on conditions. Isoquercitrin was able to reduce both Cu2+ and Fe3+ ions at low ratios, but its reducing potential was diminished at higher ratios (isoquercitrin to metal) due to the metal chelation. In conclusion, this study emphasizes the need of using multiple different methods for the assessment of chelation potential in moderately-active metal chelators, like flavonoids. PMID:29084179

Comparison of the effects of the K(+)-channel openers cromakalim and minoxidil sulphate on vascular smooth muscle.

PubMed Central

Wickenden, A. D.; Grimwood, S.; Grant, T. L.; Todd, M. H.

1991-01-01

1 The actions of the potassium channel openers, cromakalim and minoxidil sulphate, were compared in a range of isolated blood vessel preparations. 2 Cromakalim and minoxidil sulphate inhibited spontaneous mechanical activity of the guinea-pig portal vein and relaxed the noradrenaline precontracted rat aorta with similar potency. In contrast, minoxidil sulphate was less potent than cromakalim in inhibiting spontaneous activity in the rat portal vein and was essentially inactive in the noradrenaline precontracted rat mesenteric artery and rabbit aorta. 3 Minoxidil sulphate did not antagonize the effects of cromakalim in the rabbit aorta indicating it was not acting as a partial 'agonist'. 4 Charybdotoxin, noxiustoxin and rubidium failed to discriminate between cromakalim and minoxidil sulphate indicating that the apparently selective effects of minoxidil sulphate were not mediated by either Ca(2+)-activated potassium channels, delayed rectifiers or rubidium impermeable potassium channels. 5 Glibenclamide antagonized the effects of cromakalim in an apparently competitive manner whereas the effects of minoxidil sulphate were antagonized in a non-competitive manner. The involvement of subtypes of ATP-sensitive potassium channels is discussed. PMID:1878752

Discovery of Selective, Substrate-Competitive, and Passive Membrane Permeable Glycogen Synthase Kinase-3β Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling of New C-Glycosylflavones.

PubMed

Liang, Zhibin; Li, Qing X

2018-05-16

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme responsible for tau hyperphosphorylation and is a viable therapeutic target of Alzheimer's disease (AD). We developed a new class of GSK-3β inhibitors based on the 6- C-glycosylflavone isoorientin (1). The new inhibitors are passive membrane permeable and constitutively attenuate GSK-3β mediated tau hyperphosphorylation and amyloid neurotoxicity in an AD cellular model. Enzymatic assays and kinetic studies demonstrated that compound 30 is a GSK-3β substrate-competitive inhibitor with distinct kinase selectivity, isoform-selectivity and over 310-fold increased potency as compared to 1. Structure-activity relationship analyses and in silico modeling suggest the mechanism of actions by which the hydrophobic, π-cation, and orthogonal multipolar interactions of 30 with the substrate site are critical for the GSK-3β inhibition and selectivity. The results provide new insights into GSK-3β drug discovery. The new inhibitors are valuable chemical probes and drug leads with therapeutic potential to tackle AD and other GSK-3β relevant diseases.

Interspecific interference competition at the resource patch scale: do large herbivores spatially avoid elephants while accessing water?

PubMed

Ferry, Nicolas; Dray, Stéphane; Fritz, Hervé; Valeix, Marion

2016-11-01

Animals may anticipate and try to avoid, at some costs, physical encounters with other competitors. This may ultimately impact their foraging distribution and intake rates. Such cryptic interference competition is difficult to measure in the field, and extremely little is known at the interspecific level. We tested the hypothesis that smaller species avoid larger ones because of potential costs of interference competition and hence expected them to segregate from larger competitors at the scale of a resource patch. We assessed fine-scale spatial segregation patterns between three African herbivore species (zebra Equus quagga, kudu Tragelaphus strepsiceros and giraffe Giraffa camelopardalis) and a megaherbivore, the African elephant Loxodonta africana, at the scale of water resource patches in the semi-arid ecosystem of Hwange National Park, Zimbabwe. Nine waterholes were monitored every two weeks during the dry season of a drought year, and observational scans of the spatial distribution of all herbivores were performed every 15 min. We developed a methodological approach to analyse such fine-scale spatial data. Elephants increasingly used waterholes as the dry season progressed, as did the probability of co-occurrence and agonistic interaction with elephants for the three study species. All three species segregated from elephants at the beginning of the dry season, suggesting a spatial avoidance of elephants and the existence of costs of being close to them. However, contrarily to our expectations, herbivores did not segregate from elephants the rest of the dry season but tended to increasingly aggregate with elephants as the dry season progressed. We discuss these surprising results and the existence of a trade-off between avoidance of interspecific interference competition and other potential factors such as access to quality water, which may have relative associated costs that change with the time of the year. © 2016 The Authors. Journal of Animal Ecology © 2016 British Ecological Society.

Neural dynamics of object-based multifocal visual spatial attention and priming: Object cueing, useful-field-of-view, and crowding

PubMed Central

Foley, Nicholas C.; Grossberg, Stephen; Mingolla, Ennio

2015-01-01

How are spatial and object attention coordinated to achieve rapid object learning and recognition during eye movement search? How do prefrontal priming and parietal spatial mechanisms interact to determine the reaction time costs of intra-object attention shifts, inter-object attention shifts, and shifts between visible objects and covertly cued locations? What factors underlie individual differences in the timing and frequency of such attentional shifts? How do transient and sustained spatial attentional mechanisms work and interact? How can volition, mediated via the basal ganglia, influence the span of spatial attention? A neural model is developed of how spatial attention in the where cortical stream coordinates view-invariant object category learning in the what cortical stream under free viewing conditions. The model simulates psychological data about the dynamics of covert attention priming and switching requiring multifocal attention without eye movements. The model predicts how “attentional shrouds” are formed when surface representations in cortical area V4 resonate with spatial attention in posterior parietal cortex (PPC) and prefrontal cortex (PFC), while shrouds compete among themselves for dominance. Winning shrouds support invariant object category learning, and active surface-shroud resonances support conscious surface perception and recognition. Attentive competition between multiple objects and cues simulates reaction-time data from the two-object cueing paradigm. The relative strength of sustained surface-driven and fast-transient motion-driven spatial attention controls individual differences in reaction time for invalid cues. Competition between surface-driven attentional shrouds controls individual differences in detection rate of peripheral targets in useful-field-of-view tasks. The model proposes how the strength of competition can be mediated, though learning or momentary changes in volition, by the basal ganglia. A new explanation of crowding shows how the cortical magnification factor, among other variables, can cause multiple object surfaces to share a single surface-shroud resonance, thereby preventing recognition of the individual objects. PMID:22425615

Neural dynamics of object-based multifocal visual spatial attention and priming: object cueing, useful-field-of-view, and crowding.

PubMed

Foley, Nicholas C; Grossberg, Stephen; Mingolla, Ennio

2012-08-01

How are spatial and object attention coordinated to achieve rapid object learning and recognition during eye movement search? How do prefrontal priming and parietal spatial mechanisms interact to determine the reaction time costs of intra-object attention shifts, inter-object attention shifts, and shifts between visible objects and covertly cued locations? What factors underlie individual differences in the timing and frequency of such attentional shifts? How do transient and sustained spatial attentional mechanisms work and interact? How can volition, mediated via the basal ganglia, influence the span of spatial attention? A neural model is developed of how spatial attention in the where cortical stream coordinates view-invariant object category learning in the what cortical stream under free viewing conditions. The model simulates psychological data about the dynamics of covert attention priming and switching requiring multifocal attention without eye movements. The model predicts how "attentional shrouds" are formed when surface representations in cortical area V4 resonate with spatial attention in posterior parietal cortex (PPC) and prefrontal cortex (PFC), while shrouds compete among themselves for dominance. Winning shrouds support invariant object category learning, and active surface-shroud resonances support conscious surface perception and recognition. Attentive competition between multiple objects and cues simulates reaction-time data from the two-object cueing paradigm. The relative strength of sustained surface-driven and fast-transient motion-driven spatial attention controls individual differences in reaction time for invalid cues. Competition between surface-driven attentional shrouds controls individual differences in detection rate of peripheral targets in useful-field-of-view tasks. The model proposes how the strength of competition can be mediated, though learning or momentary changes in volition, by the basal ganglia. A new explanation of crowding shows how the cortical magnification factor, among other variables, can cause multiple object surfaces to share a single surface-shroud resonance, thereby preventing recognition of the individual objects. Copyright © 2012 Elsevier Inc. All rights reserved.

Evolution of phenotypic clusters through competition and local adaptation along an environmental gradient.

PubMed

Leimar, Olof; Doebeli, Michael; Dieckmann, Ulf

2008-04-01

We have analyzed the evolution of a quantitative trait in populations that are spatially extended along an environmental gradient, with gene flow between nearby locations. In the absence of competition, there is stabilizing selection toward a locally best-adapted trait that changes gradually along the gradient. According to traditional ideas, gradual spatial variation in environmental conditions is expected to lead to gradual variation in the evolved trait. A contrasting possibility is that the trait distribution instead breaks up into discrete clusters. Doebeli and Dieckmann (2003) argued that competition acting locally in trait space and geographical space can promote such clustering. We have investigated this possibility using deterministic population dynamics for asexual populations, analyzing our model numerically and through an analytical approximation. We examined how the evolution of clusters is affected by the shape of competition kernels, by the presence of Allee effects, and by the strength of gene flow along the gradient. For certain parameter ranges clustering was a robust outcome, and for other ranges there was no clustering. Our analysis shows that the shape of competition kernels is important for clustering: the sign structure of the Fourier transform of a competition kernel determines whether the kernel promotes clustering. Also, we found that Allee effects promote clustering, whereas gene flow can have a counteracting influence. In line with earlier findings, we could demonstrate that phenotypic clustering was favored by gradients of intermediate slope.

Strategies of offspring investment and dispersal in a spatially structured environment: a theoretical study using ants.

PubMed

Cronin, Adam L; Loeuille, Nicolas; Monnin, Thibaud

2016-02-05

Offspring investment strategies vary markedly between and within taxa, and much of this variation is thought to stem from the trade-off between offspring size and number. While producing larger offspring can increase their competitive ability, this often comes at a cost to their colonization ability. This competition-colonization trade-off (CCTO) is thought to be an important mechanism supporting coexistence of alternative strategies in a wide range of taxa. However, the relative importance of an alternative and possibly synergistic mechanism-spatial structuring of the environment-remains the topic of some debate. In this study, we explore the influence of these mechanisms on metacommunity structure using an agent-based model built around variable life-history traits. Our model combines explicit resource competition and spatial dynamics, allowing us to tease-apart the influence of, and explore the interaction between, the CCTO and the spatial structure of the environment. We test our model using two reproductive strategies which represent extremes of the CCTO and are common in ants. Our simulations show that colonisers outperform competitors in environments subject to higher temporal and spatial heterogeneity and are favoured when agents mature late and invest heavily in reproduction, whereas competitors dominate in low-disturbance, high resource environments and when maintenance costs are low. Varying life-history parameters has a marked influence on coexistence conditions and yields evolutionary stable strategies for both modes of reproduction. Nonetheless, we show that these strategies can coexist over a wide range of life-history and environmental parameter values, and that coexistence can in most cases be explained by a CCTO. By explicitly considering space, we are also able to demonstrate the importance of the interaction between dispersal and landscape structure. The CCTO permits species employing different reproductive strategies to coexist over a wide range of life-history and environmental parameters, and is likely to be an important factor in structuring ant communities. Our consideration of space highlights the importance of dispersal, which can limit the success of low-dispersers through kin competition, and enhance coexistence conditions for different strategies in spatially structured environments.

An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1

PubMed Central

Konze, Kyle D.; Ma, Anqi; Li, Fengling; Barsyte-Lovejoy, Dalia; Parton, Trevor; MacNevin°, Christopher J.; Liu, Feng; Gao, Cen; Huang, Xi-Ping; Kuznetsova, Ekaterina; Rougie°, Marie; Jiang, Alice; Pattenden, Samantha G.; Norris, Jacqueline L.; James, Lindsey I.; Roth, Bryan L.; Brown, Peter J.; Frye, Stephen V.; Arrowsmith, Cheryl H.; Hahn°, Klaus M.; Wang, Gang Greg; Vedadi, Masoud; Jin, Jian

2013-01-01

EZH2 or EZH1 is the catalytic subunit of the polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). The trimethylation of H3K27 (H3K27me3) is a transcriptionally repressive post-translational modification. Overexpression of EZH2 and hypertrimethylation of H3K27 have been implicated in a number of cancers. Several selective inhibitors of EZH2 have been reported recently. Herein we disclose UNC1999, the first orally bioavailable inhibitor that has high in vitro potency for wild-type and mutant EZH2 as well as EZH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZH2 in their respective catalytic domains. UNC1999 was highly selective for EZH2 and EZH1 over a broad range of epigenetic and non-epigenetic targets, competitive with the cofactor SAM, and non-competitive with the peptide substrate. This inhibitor potently reduced H3K27me3 levels in cells and selectively killed diffused large B cell lymphoma cell lines harboring the EZH2Y641N mutant. Importantly, UNC1999 was orally bioavailable in mice, making this inhibitor a valuable tool for investigating the role of EZH2 and EZH1 in chronic animal studies. We also designed and synthesized UNC2400, a close analog of UNC1999 with >1,000-fold lower potency than UNC1999 as a negative control for cell-based studies. Finally, we created a biotin-tagged UNC1999 (UNC2399) which enriched EZH2 in pull-down studies, and a UNC1999 – dye conjugate (UNC2239) for co-localization studies with EZH2 in live cells. Taken together, these compounds represent a set of useful tools for the biomedical community to investigate the role of EZH2 and EZH1 in health and disease. PMID:23614352

Direct determination of GSK-3β activity and inhibition by UHPLC-UV-vis diode arrays detector (DAD).

PubMed

D'Urzo, Annalisa; De Simone, Angela; Fiori, Jessica; Naldi, Marina; Milelli, Andrea; Andrisano, Vincenza

2016-05-30

Altered GSK-3β activity can contribute to a number of pathological processes including Alzheimer's disease (AD). Indeed, GSK-3β catalyzes the hyperphosphorylation of tau protein by transferring a phosphate moiety from ATP to the protein substrate serine residue causing the formation of the toxic insoluble neurofibrillary tangles; for this reason it represents a key target for the development of new therapeutic agents for AD treatment. Herein we describe a new selective UHPLC methodology developed for the direct characterization of GSK-3β kinase activity and for the determination of its inhibition, which could be crucial in AD drug discovery. The UHPLC-UV (DAD) based method was validated for the very fast determination of ATP as reactant and ADP as product, and applied for the analysis of the enzymatic reaction between a phosphate primed peptide substrate (GSM), resembling tau protein sequence, ATP and GSK-3β, with/without inhibitors. Analysis time was ten times improved, when compared with previously published chromatographic methods. The method was also validated by determining enzyme reaction kinetic constants (KM and vmax) for GSM and ATP and by analyzing well known GSK-3β inhibitors. Inhibition potency (IC50) values for SB-415286 (81 ± 6 nM) and for Tideglusib (251 ± 17 nM), found by the newly developed UHPLC method, were in good agreement with the luminescence method taken as independent reference method. Further on, the UHPLC method was applied to the elucidation of Tideglusib mechanism of action by determining its inhibition constants (Ki). In agreement with literature data, Tideglusib resulted a GSM competitive inhibitor, whereas SB-415286 was found inhibiting GSK-3β in an ATP competitive manner. This method was applied to the determination of the potency of a new lead compound and was found potentially scalable to inhibitor screening of large compounds collections. Copyright © 2016 Elsevier B.V. All rights reserved.

Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels

PubMed Central

Ihara, Makoto; Ling, Yun; Yang, Xinling; Kai, Kenji; Hayashi, Hideo; Matsuda, Kazuhiko

2015-01-01

Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori) larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA)-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR) RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs. PMID:25902139

Llama Antibody Fragments Recognizing Various Epitopes of the CD4bs Neutralize a Broad Range of HIV-1 Subtypes A, B and C

PubMed Central

Aasa-Chapman, Marlèn; Gorlani, Andrea; Forsman Quigley, Anna; Hulsik, David Lutje; Chen, Lei; Weiss, Robin; de Haard, Hans; Verrips, Theo

2012-01-01

Many of the neutralising antibodies, isolated to date, display limited activities against the globally most prevalent HIV-1 subtypes A and C. Therefore, those subtypes are considered to be an important target for antibody-based therapy. Variable domains of llama heavy chain antibodies (VHH) have some superior properties compared with classical antibodies. Therefore we describe the application of trimeric forms of envelope proteins (Env), derived from HIV-1 of subtype A and B/C, for a prolonged immunization of two llamas. A panel of VHH, which interfere with CD4 binding to HIV-1 Env were selected with use of panning. The results of binding and competition assays to various Env, including a variant with a stabilized CD4-binding state (gp120Ds2), cross-competition experiments, maturation analysis and neutralisation assays, enabled us to classify the selected VHH into three groups. The VHH of group I were efficient mainly against viruses of subtype A, C and B′/C. The VHH of group II resemble the broadly neutralising antibody (bnmAb) b12, neutralizing mainly subtype B and C viruses, however some had a broader neutralisation profile. A representative of the third group, 2E7, had an even higher neutralization breadth, neutralizing 21 out of the 26 tested strains belonging to the A, A/G, B, B/C and C subtypes. To evaluate the contribution of certain amino acids to the potency of the VHH a small set of the mutants were constructed. Surprisingly this yielded one mutant with slightly improved neutralisation potency against 92UG37.A9 (subtype A) and 96ZM651.02 (subtype C). These findings and the well-known stability of VHH indicate the potential application of these VHH as anti-HIV-1 microbicides. PMID:22438910

Antispasmodic effects and composition of the essential oils from two South American chemotypes of Lippia alba.

PubMed

Blanco, Marcos A; Colareda, Germán A; van Baren, Catalina; Bandoni, Arnaldo L; Ringuelet, Jorge; Consolini, Alicia E

2013-10-07

Lippia alba (Mill.) N. E. Brown (Verbenaceae) is an aromatic species used in Central and South America as eupeptic for indigestion. In Argentina, it is used by the "criollos" from the Chaco province. There are several chemotypes which differ in the chemical composition of the essential oils. Nowadays, it is experimentally cultivated in some countries of the region, including Argentina. To compare the chemical composition and pharmacology of the essential oils from two chemotypes: "citral" (CEO) and "linalool" (LEO), in isolated rat duodenum and ileum. Contractile concentration-response curves (CRC) of acetylcholine (ACh) and calcium in 40mM K(+)-medium (Ca(2+)-CRC) were done in isolated intestine portions, in the absence and presence of CEO or LEO at different concentrations. Likewise verapamil, CEO and LEO induced a non-competitive inhibition of the ACh-CRC, with IC50 of 7.0±0.3mg CEO/mL and 37.2±4.2mg LEO/mL. l-NAME, a NO-synthase blocker, increased the IC50 of CEO to 26.1±8.7mg CEO/mL. Likewise verapamil, CEO and LEO non-competitively inhibited the Ca(2+)-CRC, with IC50 of 6.3±1.7mg CEO/mL, 7.0±2.5mg LEO/mL and 0.24±0.04mg verapamil/mL (pIC50: 6.28). CEO was proved to possess limonene, neral, geranial and (-)-carvone as the major components, while LEO was rich in linalool. Results suggest that CEO has five times more potency than LEO to inhibit muscarinic contractions. The essential oils of both chemotypes interfered with the Ca(2+)-influx, but with an IC50 about 28 times higher than that of verapamil. Moreover, CEO partially stimulated the NO production. These results show the medicinal usefulness of both Lippia alba chemotypes, thus validating its traditional use, potency and mechanism of action. © 2013 Published by Elsevier Ireland Ltd.

Spatial Competition: Roughening of an Experimental Interface.

PubMed

Allstadt, Andrew J; Newman, Jonathan A; Walter, Jonathan A; Korniss, G; Caraco, Thomas

2016-07-28

Limited dispersal distance generates spatial aggregation. Intraspecific interactions are then concentrated within clusters, and between-species interactions occur near cluster boundaries. Spread of a locally dispersing invader can become motion of an interface between the invading and resident species, and spatial competition will produce variation in the extent of invasive advance along the interface. Kinetic roughening theory offers a framework for quantifying the development of these fluctuations, which may structure the interface as a self-affine fractal, and so induce a series of temporal and spatial scaling relationships. For most clonal plants, advance should become spatially correlated along the interface, and width of the interface (where invader and resident compete directly) should increase as a power function of time. Once roughening equilibrates, interface width and the relative location of the most advanced invader should each scale with interface length. We tested these predictions by letting white clover (Trifolium repens) invade ryegrass (Lolium perenne). The spatial correlation of clover growth developed as anticipated by kinetic roughening theory, and both interface width and the most advanced invader's lead scaled with front length. However, the scaling exponents differed from those predicted by recent simulation studies, likely due to clover's growth morphology.

Spatial Competition: Roughening of an Experimental Interface

PubMed Central

Allstadt, Andrew J.; Newman, Jonathan A.; Walter, Jonathan A.; Korniss, G.; Caraco, Thomas

2016-01-01

Limited dispersal distance generates spatial aggregation. Intraspecific interactions are then concentrated within clusters, and between-species interactions occur near cluster boundaries. Spread of a locally dispersing invader can become motion of an interface between the invading and resident species, and spatial competition will produce variation in the extent of invasive advance along the interface. Kinetic roughening theory offers a framework for quantifying the development of these fluctuations, which may structure the interface as a self-affine fractal, and so induce a series of temporal and spatial scaling relationships. For most clonal plants, advance should become spatially correlated along the interface, and width of the interface (where invader and resident compete directly) should increase as a power function of time. Once roughening equilibrates, interface width and the relative location of the most advanced invader should each scale with interface length. We tested these predictions by letting white clover (Trifolium repens) invade ryegrass (Lolium perenne). The spatial correlation of clover growth developed as anticipated by kinetic roughening theory, and both interface width and the most advanced invader’s lead scaled with front length. However, the scaling exponents differed from those predicted by recent simulation studies, likely due to clover’s growth morphology. PMID:27465518

Are Distal and Proximal Visual Cues Equally Important during Spatial Learning in Mice? A Pilot Study of Overshadowing in the Spatial Domain

PubMed Central

Hébert, Marie; Bulla, Jan; Vivien, Denis; Agin, Véronique

2017-01-01

Animals use distal and proximal visual cues to accurately navigate in their environment, with the possibility of the occurrence of associative mechanisms such as cue competition as previously reported in honey-bees, rats, birds and humans. In this pilot study, we investigated one of the most common forms of cue competition, namely the overshadowing effect, between visual landmarks during spatial learning in mice. To this end, C57BL/6J × Sv129 mice were given a two-trial place recognition task in a T-maze, based on a novelty free-choice exploration paradigm previously developed to study spatial memory in rodents. As this procedure implies the use of different aspects of the environment to navigate (i.e., mice can perceive from each arm of the maze), we manipulated the distal and proximal visual landmarks during both the acquisition and retrieval phases. Our prospective findings provide a first set of clues in favor of the occurrence of an overshadowing between visual cues during a spatial learning task in mice when both types of cues are of the same modality but at varying distances from the goal. In addition, the observed overshadowing seems to be non-reciprocal, as distal visual cues tend to overshadow the proximal ones when competition occurs, but not vice versa. The results of the present study offer a first insight about the occurrence of associative mechanisms during spatial learning in mice, and may open the way to promising new investigations in this area of research. Furthermore, the methodology used in this study brings a new, useful and easy-to-use tool for the investigation of perceptive, cognitive and/or attentional deficits in rodents. PMID:28634446

Competitive release and outbreaks of non-target pests associated with transgenic Bt cotton

USDA-ARS?s Scientific Manuscript database

This study tests a competitive release hypothesis that Helicoverpa zea larval herbivory will 1) deter oviposition and increase leaving rates of the stink bugs, Euchistus servus and Nezara viridula and that 2) that these effects will be stronger for E. servus than for N. viridula. By spatially separa...

Spatial constraints govern competition of mutant clones in human epidermis.

PubMed

Lynch, M D; Lynch, C N S; Craythorne, E; Liakath-Ali, K; Mallipeddi, R; Barker, J N; Watt, F M

2017-10-24

Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.

Flow environment and matrix structure interact to determine spatial competition in Pseudomonas aeruginosa biofilms.

PubMed

Nadell, Carey D; Ricaurte, Deirdre; Yan, Jing; Drescher, Knut; Bassler, Bonnie L

2017-01-13

Bacteria often live in biofilms, which are microbial communities surrounded by a secreted extracellular matrix. Here, we demonstrate that hydrodynamic flow and matrix organization interact to shape competitive dynamics in Pseudomonas aeruginosa biofilms. Irrespective of initial frequency, in competition with matrix mutants, wild-type cells always increase in relative abundance in planar microfluidic devices under simple flow regimes. By contrast, in microenvironments with complex, irregular flow profiles - which are common in natural environments - wild-type matrix-producing and isogenic non-producing strains can coexist. This result stems from local obstruction of flow by wild-type matrix producers, which generates regions of near-zero shear that allow matrix mutants to locally accumulate. Our findings connect the evolutionary stability of matrix production with the hydrodynamics and spatial structure of the surrounding environment, providing a potential explanation for the variation in biofilm matrix secretion observed among bacteria in natural environments.

Comprehensive analysis of sexual function outcome in prostate cancer patients after robot-assisted radical prostatectomy.

PubMed

Woo, Seung Hyo; Kang, Dong Il; Ha, Yun-Sok; Salmasi, Amirali Hassanzadeh; Kim, Jeong Hyun; Lee, Dong-Hyeon; Kim, Wun-Jae; Kim, Isaac Yi

2014-02-01

The recovery of potency following radical prostatectomy is complex and has a very wide range. In this study, we analyzed in detail the precise pattern of recovery of potency following robot-assisted radical prostatectomy (RARP). Prospectively collected database of patients with a minimum follow-up of 1 year after RARP were evaluated retrospectively. Of 503 patients identified, 483 patients completed the sexual health inventory for men (SHIM) preoperatively and postoperatively every 3 months for the first 12 months. Overall potency, usage of phosphodiesterase type-5 (PDE-5) inhibitors, and return to baseline erectile function were evaluated. Potency was defined as having erection that is sufficient for sexual intercourse more than 50% of attempts, while quality potency was defined as being potent without the use of PDE-5 inhibitors. Preoperatively, the overall potency and quality potency rate were 67.1% and 48.1%, respectively. Postoperatively, the overall potency rate was 61.4%, while the quality potency rate was 37.2%. In multivariate regression analysis, independent predictors of potency recovery were young age (<60), preoperative potency status, and bilateral preservation of neurovascular bundles (NVBs). In men with SHIM>21, the overall potency and quality potency rate were 79.7% and 41.2%, respectively. More importantly, only 21.4% of the men with normal erection preoperatively (SHIM>21) returned to baseline erectile function (SHIM>21) 12 months after surgery. This study indicates that young age (<60), preoperative potency, and bilateral preservation of NVBs were positive predictors of potency recovery following RARP. However, an overwhelming majority of men experience a deterioration in the overall quality of erection after RARP.

Spatially structured superinfection and the evolution of disease virulence.

PubMed

Caraco, Thomas; Glavanakov, Stephan; Li, Shengua; Maniatty, William; Szymanski, Boleslaw K

2006-06-01

When pathogen strains differing in virulence compete for hosts, spatial structuring of disease transmission can govern both evolved levels of virulence and patterns in strain coexistence. We develop a spatially detailed model of superinfection, a form of contest competition between pathogen strains; the probability of superinfection depends explicitly on the difference in levels of virulence. We apply methods of adaptive dynamics to address the interplay of spatial dynamics and evolution. The mean-field approximation predicts evolution to criticality; any small increase in virulence capable of dynamical persistence is favored. Both pair approximation and simulation of the detailed model indicate that spatial structure constrains disease virulence. Increased spatial clustering reduces the maximal virulence capable of single-strain persistence and, more importantly, reduces the convergent-stable virulence level under strain competition. The spatially detailed model predicts that increasing the probability of superinfection, for given difference in virulence, increases the likelihood of between-strain coexistence. When strains differing in virulence can coexist ecologically, our results may suggest policies for managing diseases with localized transmission. Comparing equilibrium densities from the pair approximation, we find that introducing a more virulent strain into a host population infected by a less virulent strain can sometimes reduce total host mortality and increase global host density.

Does livestock grazing influence spatial patterns of woody plant proliferation?

USDA-ARS?s Scientific Manuscript database

Patterns of woody plant proliferation in grasslands and savannas influence rates of erosion, spread of disturbance, and nutrient pools.  Spatial pattern is the outcome of plant dispersal, recruitment, competition/facilitation, and disturbance. We quantified effects of livestock grazing, a widely cit...

Examining reference frame interaction in spatial memory using a distribution analysis.

PubMed

Street, Whitney N; Wang, Ranxiao Frances

2016-02-01

Previous research showed competition among reference frames in spatial attention and language. The present studies developed a new distribution analysis to examine reference frame interactions in spatial memory. Participants viewed virtual arrays of colored pegs and were instructed to remember them either from their own perspective or from the perspective aligned with the rectangular floor. Then they made judgments of relative directions from their respective encoding orientation. Those taking the floor-axis perspective showed systematic bias in the signed errors toward their egocentric perspective, while those taking their own perspective showed no systematic bias, both for random and symmetrical object arrays. The bias toward the egocentric perspective was observed when learning a real symmetric regular object array with strong environmental cues for the aligned axis. These results indicate automatic processing of the self reference while taking the floor-axis perspective but not vice versa, and suggest that research on spatial memory needs to consider the implications of competition effects in reference frame use.

Interaction of H+ and Zn2+ on recombinant and native rat neuronal GABAA receptors

PubMed Central

Krishek, Belinda J; Moss, Stephen J; Smart, Trevor G

1998-01-01

The interaction of Zn2+ and H+ ions with GABAA receptors was examined using Xenopus laevis oocytes expressing recombinant GABAA receptors composed of subunits selected from α1, β1, γ2S and δ types, and by using cultured rat cerebellar granule neurones. The potency of Zn2+ as a non-competitive antagonist of GABA-activated responses on α1β1 receptors was reduced by lowering the external pH from 7.4 to 5.4, increasing the Zn2+ IC50 value from 1.2 to 58.3 μm. Zinc-induced inhibition was largely unaffected by alkaline pH up to pH 9.4. For α1β1δ subunits, concentration-response curves for GABA were displaced laterally by Zn2+ in accordance with a novel mixed/competitive-type inhibition. The Zn2+ IC50 at pH 7.4 was 16.3 μm. Acidification of Ringer solution resulted in a reduced antagonism by Zn2+ (IC50, 49.0 μm) without affecting the type of inhibition. At pH 9.4, Zn2+ inhibition remained unaffected. The addition of the γ2S subunit to the α1β1δ construct caused a marked reduction in the potency of Zn2+ (IC50, 615 μm), comparable to that observed with α1β1γ2S receptors (IC50 639 μm). GABA concentration-response curves were depressed in a mixed/non-competitive fashion. In cultured cerebellar granule neurones, Zn2+ inhibited responses to GABA in a concentration-dependent manner. Lowering external pH from 7.4 to 6.4 increased the IC50 from 139 to 253 μm. The type of inhibition exhibited by Zn2+ on cerebellar granule neurones, previously grown in high K+-containing culture media, was complex, with the GABA concentration-response curves shifting laterally with reduced slopes and similar maxima. The Zn2+-induced shift in the GABA EC50 values was reduced by lowering the external pH from 7.4 to 6.4. The interaction of H+ and Zn2+ ions on GABAA receptors suggests that they share either a common regulatory pathway or coincident binding sites on the receptor protein. The apparent competitive mode of block induced by Zn2+ on α1β1δ receptors is shared by GABAA receptors on cerebellar granule neurones, which are known to express δ-subunit-containing receptors. This novel mechanism is masked when a γ2 subunit is incorporated into the receptor complex, revealing further diversity in the response of native GABAA receptors to endogenous cations. PMID:9508826

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein

PubMed Central

Min, Hongping; Niu, Miaomiao; Zhang, Weilin; Yan, Jia; Li, Jiachang; Tan, Xiying; Li, Bo; Su, Mengxiang; Di, Bin; Yan, Fang

2017-01-01

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression. PMID:29121121

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein.

PubMed

Min, Hongping; Niu, Miaomiao; Zhang, Weilin; Yan, Jia; Li, Jiachang; Tan, Xiying; Li, Bo; Su, Mengxiang; Di, Bin; Yan, Fang

2017-01-01

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression.

Increased competition does not lead to increased phylogenetic overdispersion in a native grassland.

PubMed

Bennett, Jonathan A; Lamb, Eric G; Hall, Jocelyn C; Cardinal-McTeague, Warren M; Cahill, James F

2013-09-01

That competition is stronger among closely related species and leads to phylogenetic overdispersion is a common assumption in community ecology. However, tests of this assumption are rare and field-based experiments lacking. We tested the relationship between competition, the degree of relatedness, and overdispersion among plants experimentally and using a field survey in a native grassland. Relatedness did not affect competition, nor was competition associated with phylogenetic overdispersion. Further, there was only weak evidence for increased overdispersion at spatial scales where plants are likely to compete. These results challenge traditional theory, but are consistent with recent theories regarding the mechanisms of plant competition and its potential effect on phylogenetic structure. We suggest that specific conditions related to the form of competition and trait conservatism must be met for competition to cause phylogenetic overdispersion. Consequently, overdispersion as a result of competition is likely to be rare in natural communities. © 2013 John Wiley & Sons Ltd/CNRS.

Geographically differentiated pay in the labour market for nurses.

PubMed

Elliott, Robert F; Ma, Ada H Y; Scott, Anthony; Bell, David; Roberts, Elizabeth

2007-01-01

This novel application of spatial wage theory to health service labour markets analyses the competitiveness of nurse's pay and how this differs between local labour markets in Britain. A switching regression model is estimated to derive standardised spatial wage differentials (SSWDs) for nurses and their comparators. An SSWD gap is constructed and its relationship to vacancies estimated. A reduction in the gap in a local area is shown to result in an increase in the long-term vacancy rate for National Health Service (NHS) nurses. The competitiveness of nursing pay is shown to have a strong effect on the ability of the NHS to attract and retain nurses.

Spatial attention during saccade decisions.

PubMed

Jonikaitis, Donatas; Klapetek, Anna; Deubel, Heiner

2017-07-01

Behavioral measures of decision making are usually limited to observations of decision outcomes. In the present study, we made use of the fact that oculomotor and sensory selection are closely linked to track oculomotor decision making before oculomotor responses are made. We asked participants to make a saccadic eye movement to one of two memorized target locations and observed that visual sensitivity increased at both the chosen and the nonchosen saccade target locations, with a clear bias toward the chosen target. The time course of changes in visual sensitivity was related to saccadic latency, with the competition between the chosen and nonchosen targets resolved faster before short-latency saccades. On error trials, we observed an increased competition between the chosen and nonchosen targets. Moreover, oculomotor selection and visual sensitivity were influenced by top-down and bottom-up factors as well as by selection history and predicted the direction of saccades. Our findings demonstrate that saccade decisions have direct visual consequences and show that decision making can be traced in the human oculomotor system well before choices are made. Our results also indicate a strong association between decision making, saccade target selection, and visual sensitivity. NEW & NOTEWORTHY We show that saccadic decisions can be tracked by measuring spatial attention. Spatial attention is allocated in parallel to the two competing saccade targets, and the time course of spatial attention differs for fast-slow and for correct-erroneous decisions. Saccade decisions take the form of a competition between potential saccade goals, which is associated with spatial attention allocation to those locations. Copyright © 2017 the American Physiological Society.

Spatial variation in the ecological relationships among the components of Beijing's carbon metabolic system.

PubMed

Xia, Linlin; Fath, Brian D; Scharler, Ursula M; Zhang, Yan

2016-02-15

In this paper, we construct a spatially explicit model of carbon metabolism for the flows of carbon among the components of an urban area. We used the model to identify spatial heterogeneity in the ecological relationships within a carbon metabolic network. We combined land-use and cover type maps for Beijing from 1990 to 2010 with empirical coefficients and socioeconomic data to quantify the flows. We used utility analysis to determine the ecological relationships between the components of the system and analyzed their changes during urban development. We used ArcGIS to analyze their spatial variation. We found that the positive utilities in Beijing decreased over time and that negative relationships mostly outweighed positive relationships after 2000. The main ecological relationships were distributed throughout the entire urban area before 2000; subsequently, exploitation, control, and mutualism relationships became concentrated in the southeast, leaving competition relationships to dominate the northwest. Mutualism relationships were most common for natural components, but were not stable because they were easily disturbed by urban expansion. Transportation and industrial land and urban land were the most important contributors to exploitation and control relationships and may be important indicators of spatial adjustment. Increasing competition relationships unbalanced the carbon metabolism, and limitations on the area of land available for development and on the water resources led to increasingly serious competition. The results provide an objective basis for planning adjustments to Beijing's land-use patterns to improve its carbon metabolism and reduce carbon emission. Copyright © 2015 Elsevier B.V. All rights reserved.

Altering spatial priority maps via reward-based learning.

PubMed

Chelazzi, Leonardo; Eštočinová, Jana; Calletti, Riccardo; Lo Gerfo, Emanuele; Sani, Ilaria; Della Libera, Chiara; Santandrea, Elisa

2014-06-18

Spatial priority maps are real-time representations of the behavioral salience of locations in the visual field, resulting from the combined influence of stimulus driven activity and top-down signals related to the current goals of the individual. They arbitrate which of a number of (potential) targets in the visual scene will win the competition for attentional resources. As a result, deployment of visual attention to a specific spatial location is determined by the current peak of activation (corresponding to the highest behavioral salience) across the map. Here we report a behavioral study performed on healthy human volunteers, where we demonstrate that spatial priority maps can be shaped via reward-based learning, reflecting long-lasting alterations (biases) in the behavioral salience of specific spatial locations. These biases exert an especially strong influence on performance under conditions where multiple potential targets compete for selection, conferring competitive advantage to targets presented in spatial locations associated with greater reward during learning relative to targets presented in locations associated with lesser reward. Such acquired biases of spatial attention are persistent, are nonstrategic in nature, and generalize across stimuli and task contexts. These results suggest that reward-based attentional learning can induce plastic changes in spatial priority maps, endowing these representations with the "intelligent" capacity to learn from experience. Copyright © 2014 the authors 0270-6474/14/348594-11$15.00/0.

Ontogenetic shifts in plant-plant interactions in a rare cycad within angiosperm communities.

PubMed

Álvarez-Yépiz, Juan C; Búrquez, Alberto; Dovčiak, Martin

2014-06-01

Gymnosperms and angiosperms can co-occur within the same habitats but key plant traits are thought to give angiosperms an evolutionary competitive advantage in many ecological settings. We studied ontogenetic changes in competitive and facilitative interactions between a rare gymnosperm (Dioon sonorense, our target species) and different plant and abiotic neighbours (conspecific-cycads, heterospecific-angiosperms, or abiotic-rocks) from 2007 to 2010 in an arid environment of northwestern Mexico. We monitored survival and growth of seedlings, juveniles, and adults of the cycad Dioon sonorense to evaluate how cycad survival and relative height growth rate (RHGR) responded to intra- and interspecific competition, canopy openness, and nearest neighbour. We tested spatial associations among D. sonorense life stages and angiosperm species and measured ontogenetic shifts in cycad shade tolerance. Canopy openness decreased cycad survival while intraspecific competition decreased survival and RHGR during early ontogeny. Seedling survival was higher in association with rocks and heterospecific neighbours where intraspecific competition was lower. Shade tolerance decreased with cycad ontogeny reflecting the spatial association of advanced stages with more open canopies. Interspecific facilitation during early ontogeny of our target species may promote its persistence in spite of increasing interspecific competition in later stages. We provide empirical support to the long-standing assumption that marginal rocky habitats serve as refugia from angiosperm competition for slow-growing gymnosperms such as cycads. The lack of knowledge of plant-plant interactions in rare or endangered species may hinder developing efficient conservation strategies (e.g. managing for sustained canopy cover), especially under the ongoing land use and climatic changes.

beta-Endorphin-induced analgesia is inhibited by synthetic analogs of beta-endorphin.

PubMed

Nicolas, P; Hammonds, R G; Li, C H

1984-05-01

Competitive antagonism of human beta-endorphin (beta h-EP)-induced analgesia by synthetic beta h-EP analogs with high in vitro opiate receptor binding to in vivo analgesic potency ratio has been demonstrated. A parallel shift of the dose-response curve for analgesia to the right was observed when either beta h-EP or [ Trp27 ] -beta h-EP was coinjected with various doses of [Gln8, Gly31 ]-beta h-EP-Gly-Gly-NH2, [Arg9,19,24,28,29]-beta h-EP, or [ Cys11 ,26, Phe27 , Gly31 ]-beta h-EP. It was estimated that the most potent antagonist, [Gln8, Gly31 ]-beta h-EP-Gly-NH2, is at least 200 times more potent than naloxone.

Quantitation of cytokine mRNA expression as an endpoint for prediction and diagnosis of xenobiotic-induced hypersensitivity reactions.

PubMed

Gaspard, I; Kerdine, S; Pallardy, M; Lebrec, H

1999-09-01

Xenobiotic-induced hypersensitivity reactions are immune-mediated effects that involve specific antibodies and/or effector and regulatory T lymphocytes. Cytokines are key mediators of such responses and must be considered as possible endpoints for predicting sensitizing potency of drugs and chemicals, as well as for helping diagnosis of allergy. Detecting cytokine production at the protein level has been shown to not be always sensitive enough. This paper describes three examples of the utilization of semiquantitative or competitive reverse transcription polymerase chain reaction analysis of interleukin-4, interferon gamma, and interleukin-1beta mRNAs as endpoints for assessing T-cell or dendritic cell responses to sensitizing drugs (beta-lactam antibiotics) or chemicals (dinitrochlorobenzene). Copyright 1999 Academic Press.

Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.

PubMed

Freund, Yvonne R; Akama, Tsutomu; Alley, M R K; Antunes, Joana; Dong, Chen; Jarnagin, Kurt; Kimura, Richard; Nieman, James A; Maples, Kirk R; Plattner, Jacob J; Rock, Fernando; Sharma, Rashmi; Singh, Rajeshwar; Sanders, Virginia; Zhou, Yasheen

2012-09-21

We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Synthesis and biological evaluation of cyclopropyl analogues of 2-amino-5-phosphonopentanoic acid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dappen, M.S.; Pellicciari, R.; Natalini, B.

1991-01-01

A series of cyclopropyl analogues related to 2-amino-5-phosphonopentanoic acid (AP5) were synthesized and their biological activity was assessed as competitive antagonists for the N-methyl-D-aspartate (NMDA) receptor. In vitro receptor binding using (3H)-L-glutamate as the radioligand provided affinity data, while modulation of (3H)MK-801 binding was used as a functional assay. The analogues were also evaluated in (3H)kainate binding to assess selectivity over non-NMDA glutamate receptors. Of the compounds tested, 4,5-methano-AP5 analogue 26 was the most potent selective NMDA antagonist; however, potency was lower than that for (((+/-)-2-carboxypiperidin-4-yl)methyl)phosphonic acid (CGS 19755, 5).

Spatiotemporal Proximity Effects in Visual Short-Term Memory Examined by Target-Nontarget Analysis

ERIC Educational Resources Information Center

Sapkota, Raju P.; Pardhan, Shahina; van der Linde, Ian

2016-01-01

Visual short-term memory (VSTM) is a limited-capacity system that holds a small number of objects online simultaneously, implying that competition for limited storage resources occurs (Phillips, 1974). How the spatial and temporal proximity of stimuli affects this competition is unclear. In this 2-experiment study, we examined the effect of the…

Stochastic population dynamics in spatially extended predator-prey systems

NASA Astrophysics Data System (ADS)

Dobramysl, Ulrich; Mobilia, Mauro; Pleimling, Michel; Täuber, Uwe C.

2018-02-01

Spatially extended population dynamics models that incorporate demographic noise serve as case studies for the crucial role of fluctuations and correlations in biological systems. Numerical and analytic tools from non-equilibrium statistical physics capture the stochastic kinetics of these complex interacting many-particle systems beyond rate equation approximations. Including spatial structure and stochastic noise in models for predator-prey competition invalidates the neutral Lotka-Volterra population cycles. Stochastic models yield long-lived erratic oscillations stemming from a resonant amplification mechanism. Spatially extended predator-prey systems display noise-stabilized activity fronts that generate persistent correlations. Fluctuation-induced renormalizations of the oscillation parameters can be analyzed perturbatively via a Doi-Peliti field theory mapping of the master equation; related tools allow detailed characterization of extinction pathways. The critical steady-state and non-equilibrium relaxation dynamics at the predator extinction threshold are governed by the directed percolation universality class. Spatial predation rate variability results in more localized clusters, enhancing both competing species’ population densities. Affixing variable interaction rates to individual particles and allowing for trait inheritance subject to mutations induces fast evolutionary dynamics for the rate distributions. Stochastic spatial variants of three-species competition with ‘rock-paper-scissors’ interactions metaphorically describe cyclic dominance. These models illustrate intimate connections between population dynamics and evolutionary game theory, underscore the role of fluctuations to drive populations toward extinction, and demonstrate how space can support species diversity. Two-dimensional cyclic three-species May-Leonard models are characterized by the emergence of spiraling patterns whose properties are elucidated by a mapping onto a complex Ginzburg-Landau equation. Multiple-species extensions to general ‘food networks’ can be classified on the mean-field level, providing both fundamental understanding of ensuing cooperativity and profound insight into the rich spatio-temporal features and coarsening kinetics in the corresponding spatially extended systems. Novel space-time patterns emerge as a result of the formation of competing alliances; e.g. coarsening domains that each incorporate rock-paper-scissors competition games.

Spatial structure and nest demography reveal the influence of competition, parasitism and habitat quality on slavemaking ants and their hosts

PubMed Central

2011-01-01

Background Natural communities are structured by intra-guild competition, predation or parasitism and the abiotic environment. We studied the relative importance of these factors in two host-social parasite ecosystems in three ant communities in Europe (Bavaria) and North America (New York, West Virginia). We tested how these factors affect colony demography, life-history and the spatial pattern of colonies, using a large sample size of more than 1000 colonies. The strength of competition was measured by the distance to the nearest competitor. Distance to the closest social parasite colony was used as a measure of parasitism risk. Nest sites (i.e., sticks or acorns) are limited in these forest ecosystems and we therefore included nest site quality as an abiotic factor in the analysis. In contrast to previous studies based on local densities, we focus here on the positioning and spatial patterns and we use models to compare our predictions to random expectations. Results Colony demography was universally affected by the size of the nest site with larger and more productive colonies residing in larger nest sites of higher quality. Distance to the nearest competitor negatively influenced host demography and brood production in the Bavarian community, pointing to an important role of competition, while social parasitism was less influential in this community. The New York community was characterized by the highest habitat variability, and productive colonies were clustered in sites of higher quality. Colonies were clumped on finer spatial scales, when we considered only the nearest neighbors, but more regularly distributed on coarser scales. The analysis of spatial positioning within plots often produced different results compared to those based on colony densities. For example, while host and slavemaker densities are often positively correlated, slavemakers do not nest closer to potential host colonies than expected by random. Conclusions The three communities are differently affected by biotic and abiotic factors. Some of the differences can be attributed to habitat differences and some to differences between the two slavemaking-host ecosystems. The strong effect of competition in the Bavarian community points to the scarcity of resources in this uniform habitat compared to the other more diverse sites. The decrease in colony aggregation with scale indicates fine-scale resource hotspots: colonies are locally aggregated in small groups. Our study demonstrates that species relationships vary across scales and spatial patterns can provide important insights into species interactions. These results could not have been obtained with analyses based on local densities alone. Previous studies focused on social parasitism and its effect on host colonies. The broader approach taken here, considering several possible factors affecting colony demography and not testing each one in isolation, shows that competition and environmental variability can have a similar strong impact on demography and life-history of hosts. We conclude that the effects of parasites or predators should be studied in parallel to other ecological influences. PMID:21443778

Spatial structure and nest demography reveal the influence of competition, parasitism and habitat quality on slavemaking ants and their hosts.

PubMed

Scharf, Inon; Fischer-Blass, Birgit; Foitzik, Susanne

2011-03-28

Natural communities are structured by intra-guild competition, predation or parasitism and the abiotic environment. We studied the relative importance of these factors in two host-social parasite ecosystems in three ant communities in Europe (Bavaria) and North America (New York, West Virginia). We tested how these factors affect colony demography, life-history and the spatial pattern of colonies, using a large sample size of more than 1000 colonies. The strength of competition was measured by the distance to the nearest competitor. Distance to the closest social parasite colony was used as a measure of parasitism risk. Nest sites (i.e., sticks or acorns) are limited in these forest ecosystems and we therefore included nest site quality as an abiotic factor in the analysis. In contrast to previous studies based on local densities, we focus here on the positioning and spatial patterns and we use models to compare our predictions to random expectations. Colony demography was universally affected by the size of the nest site with larger and more productive colonies residing in larger nest sites of higher quality. Distance to the nearest competitor negatively influenced host demography and brood production in the Bavarian community, pointing to an important role of competition, while social parasitism was less influential in this community. The New York community was characterized by the highest habitat variability, and productive colonies were clustered in sites of higher quality. Colonies were clumped on finer spatial scales, when we considered only the nearest neighbors, but more regularly distributed on coarser scales. The analysis of spatial positioning within plots often produced different results compared to those based on colony densities. For example, while host and slavemaker densities are often positively correlated, slavemakers do not nest closer to potential host colonies than expected by random. The three communities are differently affected by biotic and abiotic factors. Some of the differences can be attributed to habitat differences and some to differences between the two slavemaking-host ecosystems. The strong effect of competition in the Bavarian community points to the scarcity of resources in this uniform habitat compared to the other more diverse sites. The decrease in colony aggregation with scale indicates fine-scale resource hotspots: colonies are locally aggregated in small groups. Our study demonstrates that species relationships vary across scales and spatial patterns can provide important insights into species interactions. These results could not have been obtained with analyses based on local densities alone. Previous studies focused on social parasitism and its effect on host colonies. The broader approach taken here, considering several possible factors affecting colony demography and not testing each one in isolation, shows that competition and environmental variability can have a similar strong impact on demography and life-history of hosts. We conclude that the effects of parasites or predators should be studied in parallel to other ecological influences.

Rational design of small molecules as vaccine adjuvants.

PubMed

Wu, Tom Y-H; Singh, Manmohan; Miller, Andrew T; De Gregorio, Ennio; Doro, Francesco; D'Oro, Ugo; Skibinski, David A G; Mbow, M Lamine; Bufali, Simone; Herman, Ann E; Cortez, Alex; Li, Yongkai; Nayak, Bishnu P; Tritto, Elaine; Filippi, Christophe M; Otten, Gillis R; Brito, Luis A; Monaci, Elisabetta; Li, Chun; Aprea, Susanna; Valentini, Sara; Calabrό, Samuele; Laera, Donatello; Brunelli, Brunella; Caproni, Elena; Malyala, Padma; Panchal, Rekha G; Warren, Travis K; Bavari, Sina; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M

2014-11-19

Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants. Copyright © 2014, American Association for the Advancement of Science.

Spatial vegetation patterns and neighborhood competition among woody plants in an East African savanna

USDA-ARS?s Scientific Manuscript database

The majority of research on savanna vegetation dynamics has focused on the coexistence of woody and herbaceous vegetation; interactions among woody plants in savannas are relatively poorly understood. We present data from a 10-year longitudinal study of spatially explicit growth patterns of woody ve...

Optimizing spatial patterns with sparse filter bands for motor-imagery based brain-computer interface.

PubMed

Zhang, Yu; Zhou, Guoxu; Jin, Jing; Wang, Xingyu; Cichocki, Andrzej

2015-11-30

Common spatial pattern (CSP) has been most popularly applied to motor-imagery (MI) feature extraction for classification in brain-computer interface (BCI) application. Successful application of CSP depends on the filter band selection to a large degree. However, the most proper band is typically subject-specific and can hardly be determined manually. This study proposes a sparse filter band common spatial pattern (SFBCSP) for optimizing the spatial patterns. SFBCSP estimates CSP features on multiple signals that are filtered from raw EEG data at a set of overlapping bands. The filter bands that result in significant CSP features are then selected in a supervised way by exploiting sparse regression. A support vector machine (SVM) is implemented on the selected features for MI classification. Two public EEG datasets (BCI Competition III dataset IVa and BCI Competition IV IIb) are used to validate the proposed SFBCSP method. Experimental results demonstrate that SFBCSP help improve the classification performance of MI. The optimized spatial patterns by SFBCSP give overall better MI classification accuracy in comparison with several competing methods. The proposed SFBCSP is a potential method for improving the performance of MI-based BCI. Copyright © 2015 Elsevier B.V. All rights reserved.

Degree of Response to Homeopathic Potencies Correlates with Dipole Moment Size in Molecular Detectors: Implications for Understanding the Fundamental Nature of Serially Diluted and Succussed Solutions.

PubMed

Cartwright, Steven J

2018-02-01

 The use of solvatochromic dyes to investigate homeopathic potencies holds out the promise of understanding the nature of serially succussed and diluted solutions at a fundamental physicochemical level. Recent studies have shown that a range of different dyes interact with potencies and, moreover, the nature of the interaction is beginning to allow certain specific characteristics of potencies to be delineated.  The study reported in this article takes previous investigations further and aims to understand more about the nature of the interaction between potencies and solvatochromic dyes. To this end, the UV-visible spectra of a wide range of potential detectors of potencies have been examined using methodologies previously described.  Results presented demonstrate that solvatochromic dyes are a sub-group of a larger class of compounds capable of demonstrating interactions with potencies. In particular, amino acids containing an aromatic bridge also show marked optical changes in the presence of potencies. Several specific features of molecular detectors can now be shown to be necessary for significant interactions with homeopathic potencies. These include systems with a large dipole moment, electron delocalisation, polarizability and molecular rigidity.  Analysis of the optical changes occurring on interaction with potencies suggests that in all cases potencies increase the polarity of molecular detectors to a degree that correlates with the size of the compound's permanent or ground dipole moment. These results can be explained by inferring that potencies themselves have polarity. Possible candidates for the identity of potencies, based on these and previously reported results, are discussed. The Faculty of Homeopathy.

Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk.

PubMed

Maxwell, G L; Schildkraut, J M; Calingaert, B; Risinger, J I; Dainty, L; Marchbanks, P A; Berchuck, A; Barrett, J C; Rodriguez, G C

2006-11-01

Using data from a case-control study of endometrial cancer, we investigated the relationship between the progestin and estrogen potency in combination oral contraceptives (OCs) and the risk of developing endometrial cancer. Subjects included 434 endometrial cancer cases and 2,557 controls identified from the Cancer and Steroid Hormone (CASH) study. OCs were classified into four categories according to the individual potencies of each hormonal constituent (high versus low estrogen or progestin potency). Logistic regression was used to evaluate associations between endometrial cancer risk and combination OC formulations. With non-users as the referent group, use of OCs with either high potency progestin [odds ratio for endometrial cancer (OR)=0.21, 95% confidence interval (CI)=0.10 to 0.43] or with low potency progestin (OR=0.39, 95% CI=0.25 to 0.60) were both associated with a decreased risk of endometrial cancer. Overall high progestin potency OCs did not confer significantly more protection than low progestin potency OCs (OR=0.52, 95% CI=0.24 to 1.14). However, among women with a body mass index of 22.1 kg/m2 or higher, those who used high progestin potency oral contraceptives had a lower risk of endometrial cancer than those who used low progestin potency oral contraceptives (OR=0.31, 95% CI=0.11 to 0.92) while those with a BMI below 22.1 kg/m2 did not (OR=1.36, 95% CI=0.39 to 4.70). The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus.

Elevated CO2 changes interspecific competition among three species of wheat aphids: Sitobion avenae, Rhopalosiphum padi, and Schizaphis graminum.

PubMed

Sun, Yu Cheng; Chen, Fa Jun; Ge, Feng

2009-02-01

Effects of elevated CO2 (twice ambient) on the interspecific competition among three species of wheat aphids (Sitobion avenae, Rhopalosiphum padi, and Schizaphis graminum) and on wheat-aphid interactions were studied. Wheat plants had higher biomass and yield and lower water and nitrogen content of grain when grown under elevated CO2 than under ambient CO2; levels of condensed tannins, total phenols, and total nonstructural carbohydrates were also higher in wheat ears under elevated CO2. Compared with ambient CO2, elevated CO2 increased the abundance of R. padi when introduced solely but reduced its abundance when S. avenae was also present. The spatial distribution of wheat aphids was apparently influenced by CO2 levels, with significantly more S. avenae on ears and a more even distribution of R. padi on wheat plants under elevated CO2 versus ambient CO2. Elevated CO2 did not affect the abundance and spatial distribution of S. graminus when inoculated solely. Moreover, when S. avenae was present with either R. padi or S. graminum, spatial niche overlap was significantly decreased with elevated CO2. When three species co-occurred, elevated CO2 reduced spatial niche overlap between S. avenae and S. graminum and between R. padi and S. graminum. Our results suggest that increases in atmospheric CO2 would alleviate interspecific competition for these cases, which would accentuate the abundance of and the damage caused by these wheat aphids.

The Curious Case of the Camelthorn: Competition, Coexistence, and Nest-Site Limitation in a Multispecies Mutualism.

PubMed

Campbell, Heather; Fellowes, Mark D E; Cook, James M

2015-12-01

Myrmecophyte plants house ants within domatia in exchange for protection against herbivores. Ant-myrmecophyte mutualisms exhibit two general patterns due to competition between ants for plant occupancy: (i) domatia nest sites are a limiting resource and (ii) each individual plant hosts one ant species at a time. However, individual camelthorn trees (Vachellia erioloba) typically host two to four ant species simultaneously, often coexisting in adjacent domatia on the same branch. Such fine-grain spatial coexistence brings into question the conventional wisdom on ant-myrmecophyte mutualisms. Camelthorn ants appear not to be nest-site limited, despite low abundance of suitable domatia, and have random distributions of nest sites within and across trees. These patterns suggest a lack of competition between ants for domatia and contrast strongly with other ant-myrmecophyte systems. Comparison of this unusual case with others suggests that spatial scale is crucial to coexistence or competitive exclusion involving multiple ant species. Furthermore, coexistence may be facilitated when co-occurring ant species diverge strongly on at least one niche axis. Our conclusions provide recommendations for future ant-myrmecophyte research, particularly in utilizing multispecies systems to further our understanding of mutualism biology.

Preliminary Assessment of Spatial Competition in the Market for E85

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bentley Clinton

The Preliminary Assessment of Spatial Competition in the Market for E85 presentation and supplementary report from the U.S. Department of Energy’s National Renewable Energy Laboratory examine how the spacing of E85 fueling stations impacts E85 retail pricing. The analysis finds an inverse correlation between station density and E85 prices, with local competition putting downward pressure on E85 prices. A gas station with E85 whose nearest competitor is within a 0.5 mile radius is associated with a lower E85 price per gallon than an otherwise identical station with E85 whose nearest competitor is farther away. The analysis also finds a highermore » level of correlation between E85 and both E10 and wholesale gasoline prices than with ethanol costs. This indicates that E85 may, in fact, be priced with respect to its substitute fuel, and not based on the cost of its inputs. These findings help identify key trends and barriers in E85 markets and highlight data gaps that, if addressed, could help enable competitive E85 markets. The analysis was released in February 2017 and uses national and Minnesota-specific price data.« less

Preliminary Assessment of Spatial Competition in the Market for E85: Presentation Supplement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clinton, Bentley; Johnson, Caley; Moriarty, Kristi

The Preliminary Assessment of Spatial Competition in the Market for E85 presentation and supplementary report from the U.S. Department of Energy’s National Renewable Energy Laboratory examine how the spacing of E85 fueling stations impacts E85 retail pricing. The analysis finds an inverse correlation between station density and E85 prices, with local competition putting downward pressure on E85 prices. A gas station with E85 whose nearest competitor is within a 0.5 mile radius is associated with a lower E85 price per gallon than an otherwise identical station with E85 whose nearest competitor is farther away. The analysis also finds a highermore » level of correlation between E85 and both E10 and wholesale gasoline prices than with ethanol costs. This indicates that E85 may, in fact, be priced with respect to its substitute fuel, and not based on the cost of its inputs. These findings help identify key trends and barriers in E85 markets and highlight data gaps that, if addressed, could help enable competitive E85 markets. The analysis was released in February 2017 and uses national and Minnesota-specific price data.« less

Tropical forests are non-equilibrium ecosystems governed by interspecific competition based on universal 1/6 niche width.

PubMed

Fort, Hugo; Inchausti, Pablo

2013-01-01

Tropical forests are mega-diverse ecosystems that display complex and non-equilibrium dynamics. However, theoretical approaches have largely focused on explaining steady-state behaviour and fitting snapshots of data. Here we show that local and niche interspecific competition can realistically and parsimoniously explain the observed non-equilibrium regime of permanent plots of nine tropical forests, in eight different countries. Our spatially-explicit model, besides predicting with accuracy the main biodiversity metrics for these plots, can also reproduce their dynamics. A central finding is that tropical tree species have a universal niche width of approximately 1/6 of the niche axis that echoes the observed widespread convergence in their functional traits enabling them to exploit similar resources and to coexist despite of having large niche overlap. This niche width yields an average ratio of 0.25 between interspecific and intraspecific competition that corresponds to an intermediate value between the extreme claims of the neutral model and the classical niche-based model of community assembly (where interspecific competition is dominant). In addition, our model can explain and yield observed spatial patterns that classical niche-based and neutral theories cannot.

Chemical applicability domain of the local lymph node assay (LLNA) for skin sensitisation potency. Part 4. Quantitative correlation of LLNA potency with human potency.

PubMed

Roberts, David W; Api, Anne Marie

2018-07-01

Prediction of skin sensitisation potential and potency by non-animal methods is the target of many active research programmes. Although the aim is to predict sensitisation potential and potency in humans, data from the murine local lymph node assay (LLNA) constitute much the largest source of quantitative data on in vivo skin sensitisation. The LLNA has been the preferred in vivo method for identification of skin sensitising chemicals and as such is potentially valuable as a benchmark for assessment of non-animal approaches. However, in common with all predictive test methods, the LLNA is subject to false positives and false negatives with an overall level of accuracy said variously to be approximately 80% or 90%. It is also necessary to consider the extent to which, for true positives, LLNA potency correlates with human potency. In this paper LLNA potency and human potency are compared so as to express quantitatively the correlation between them, and reasons for non-agreement between LLNA and human potency are analysed. This leads to a better definition of the applicability domain of the LLNA, within which LLNA data can be used confidently to predict human potency and as a benchmark to assess the performance of non-animal approaches. Copyright © 2018. Published by Elsevier Inc.

Space sequestration below ground in old-growth spruce-beech forests-signs for facilitation?

PubMed

Bolte, Andreas; Kampf, Friederike; Hilbrig, Lutz

2013-01-01

Scientists are currently debating the effects of mixing tree species for the complementary resource acquisition in forest ecosystems. In four unmanaged old-growth spruce-beech forests in strict nature reserves in southern Sweden and northern Germany we assessed forest structure and fine rooting profiles and traits (≤2 mm) by fine root sampling and the analysis of fine root morphology and biomass. These studies were conducted in selected tree groups with four different interspecific competition perspectives: (1) spruce as a central tree, (2) spruce as competitor, (3) beech as a central tree, and (4) beech as competitor. Mean values of life fine root attributes like biomass (FRB), length (FRL), and root area index (RAI) were significantly lower for spruce than for beech in mixed stands. Vertical profiles of fine root attributes adjusted to one unit of basal area (BA) exhibited partial root system stratification when central beech is growing with spruce competitors. In this constellation, beech was able to raise its specific root length (SRL) and therefore soil exploration efficiency in the subsoil, while increasing root biomass partitioning into deeper soil layers. According to relative values of fine root attributes (rFRA), asymmetric below-ground competition was observed favoring beech over spruce, in particular when central beech trees are admixed with spruce competitors. We conclude that beech fine rooting is facilitated in the presence of spruce by lowering competitive pressure compared to intraspecific competition whereas the competitive pressure for spruce is increased by beech admixture. Our findings underline the need of spatially differentiated approaches to assess interspecific competition below ground. Single-tree approaches and simulations of below-ground competition are required to focus rather on microsites populated by tree specimens as the basic spatial study area.

Space sequestration below ground in old-growth spruce-beech forests—signs for facilitation?

PubMed Central

Bolte, Andreas; Kampf, Friederike; Hilbrig, Lutz

2013-01-01

Scientists are currently debating the effects of mixing tree species for the complementary resource acquisition in forest ecosystems. In four unmanaged old-growth spruce-beech forests in strict nature reserves in southern Sweden and northern Germany we assessed forest structure and fine rooting profiles and traits (≤2 mm) by fine root sampling and the analysis of fine root morphology and biomass. These studies were conducted in selected tree groups with four different interspecific competition perspectives: (1) spruce as a central tree, (2) spruce as competitor, (3) beech as a central tree, and (4) beech as competitor. Mean values of life fine root attributes like biomass (FRB), length (FRL), and root area index (RAI) were significantly lower for spruce than for beech in mixed stands. Vertical profiles of fine root attributes adjusted to one unit of basal area (BA) exhibited partial root system stratification when central beech is growing with spruce competitors. In this constellation, beech was able to raise its specific root length (SRL) and therefore soil exploration efficiency in the subsoil, while increasing root biomass partitioning into deeper soil layers. According to relative values of fine root attributes (rFRA), asymmetric below-ground competition was observed favoring beech over spruce, in particular when central beech trees are admixed with spruce competitors. We conclude that beech fine rooting is facilitated in the presence of spruce by lowering competitive pressure compared to intraspecific competition whereas the competitive pressure for spruce is increased by beech admixture. Our findings underline the need of spatially differentiated approaches to assess interspecific competition below ground. Single-tree approaches and simulations of below-ground competition are required to focus rather on microsites populated by tree specimens as the basic spatial study area. PMID:24009616

Spatial and Temporal Habitat Segregation of Mosquitoes in Urban Florida

PubMed Central

Juliano, Steven A.

2014-01-01

Understanding mechanisms fostering coexistence between invasive and resident species is important in predicting ecological, economic, or health impacts of invasive species. The non-native mosquitoes Aedes aegypti and Culex quinquefasciatus have been resident in the southeastern United States for over a century. They coexist at some urban sites with the more recent invasive Aedes albopictus, which is usually superior in interspecific competition. We tested predictions of temporal and spatial habitat segregation that foster coexistence of these resident species with the superior invasive competitor. We measured spatial and temporal patterns of site occupancy and abundance for all three species among standard oviposition traps in metropolitan Tampa, Florida. Consistent with the condition-specific competition hypothesis, A. albopictus and A. aegypti abundances were greater and C. quinquefasciatus abundance was lower late (September) versus early (June) in the rainy season, and the proportional increase of A. albopictus abundance was greater than that of A. aegypti. These results are postulated to result from greater dry-season egg mortality and associated greater rainy-season competitive superiority of larvae of A. albopictus, followed by A. aegypti, and C. quinquefasciatus. Spatial partitioning among landscape variables was also evident among species, with A. albopictus more likely to oviposit across a range of open grass landscapes whereas A. aegypti were mostly restricted to cemeteries. Culex quinquefasciatus showed a shift in abundance from cemeteries early in the rainy season to developed areas characterized by built environments with large proportions of impervious surfaces late in the rainy season, where A. albopictus was not in its highest abundance. These results suggest that both temporal and spatial variation, and their interaction, may contribute to local coexistence between Aedes and Culex mosquito species in urban areas. PMID:24621592

Spatial and temporal habitat segregation of mosquitoes in urban Florida.

PubMed

Leisnham, Paul T; LaDeau, Shannon L; Juliano, Steven A

2014-01-01

Understanding mechanisms fostering coexistence between invasive and resident species is important in predicting ecological, economic, or health impacts of invasive species. The non-native mosquitoes Aedes aegypti and Culex quinquefasciatus have been resident in the southeastern United States for over a century. They coexist at some urban sites with the more recent invasive Aedes albopictus, which is usually superior in interspecific competition. We tested predictions of temporal and spatial habitat segregation that foster coexistence of these resident species with the superior invasive competitor. We measured spatial and temporal patterns of site occupancy and abundance for all three species among standard oviposition traps in metropolitan Tampa, Florida. Consistent with the condition-specific competition hypothesis, A. albopictus and A. aegypti abundances were greater and C. quinquefasciatus abundance was lower late (September) versus early (June) in the rainy season, and the proportional increase of A. albopictus abundance was greater than that of A. aegypti. These results are postulated to result from greater dry-season egg mortality and associated greater rainy-season competitive superiority of larvae of A. albopictus, followed by A. aegypti, and C. quinquefasciatus. Spatial partitioning among landscape variables was also evident among species, with A. albopictus more likely to oviposit across a range of open grass landscapes whereas A. aegypti were mostly restricted to cemeteries. Culex quinquefasciatus showed a shift in abundance from cemeteries early in the rainy season to developed areas characterized by built environments with large proportions of impervious surfaces late in the rainy season, where A. albopictus was not in its highest abundance. These results suggest that both temporal and spatial variation, and their interaction, may contribute to local coexistence between Aedes and Culex mosquito species in urban areas.

Free radical scavenging and COX-2 inhibition by simple colon metabolites of polyphenols: A theoretical approach.

PubMed

Amić, Ana; Marković, Zoran; Marković, Jasmina M Dimitrić; Jeremić, Svetlana; Lučić, Bono; Amić, Dragan

2016-12-01

Free radical scavenging and inhibitory potency against cyclooxygenase-2 (COX-2) by two abundant colon metabolites of polyphenols, i.e., 3-hydroxyphenylacetic acid (3-HPAA) and 4-hydroxyphenylpropionic acid (4-HPPA) were theoretically studied. Different free radical scavenging mechanisms are investigated in water and pentyl ethanoate as a solvent. By considering electronic properties of scavenged free radicals, hydrogen atom transfer (HAT) and sequential proton loss electron transfer (SPLET) mechanisms are found to be thermodynamically probable and competitive processes in both media. The Gibbs free energy change for reaction of inactivation of free radicals indicates 3-HPAA and 4-HPPA as potent scavengers. Their reactivity toward free radicals was predicted to decrease as follows: hydroxyl>alkoxyls>phenoxyl≈peroxyls>superoxide. Shown free radical scavenging potency of 3-HPAA and 4-HPPA along with their high μM concentration produced by microbial colon degradation of polyphenols could enable at least in situ inactivation of free radicals. Docking analysis with structural forms of 3-HPAA and 4-HPPA indicates dianionic ligands as potent inhibitors of COX-2, an inducible enzyme involved in colon carcinogenesis. Obtained results suggest that suppressing levels of free radicals and COX-2 could be achieved by 3-HPAA and 4-HPPA indicating that these compounds may contribute to reduced risk of colon cancer development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibition of Mammalian 15-Lipoxygenase by Three Ebselen-like Drugs. A QM/MM and MM/PBSA Comparative Study.

PubMed

Cebrián-Prats, Anna; Rovira, Tiffani; Saura, Patricia; González-Lafont, Àngels; Lluch, José M

2017-12-28

Ebselen is a potent competitive inhibitor of the active form of rabbit 15-lipoxygenase, an enzyme involved in many inflammatory diseases. Light-induced Z-to-E isomerization of the ebselen-like 2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester (BODTCM) molecule was used to convert the weak (Z)-BOTDCM inhibitor into the (E)-isomer with much higher inhibitory capacity. In this study, the binding modes of ebselen, (E)-BOTDCM and (Z)-BOTDCM, have been analyzed to provide molecular insights on the inhibitory potency of ebselen and on the geometric-isomer specificity of (E)- and (Z)-BOTDCM inhibitors. The inhibitor-enzyme structures obtained from docking and molecular dynamics simulations as well as from QM/MM calculations show that the inhibitor molecules are not coordinated to the nonheme iron in the active site. Thermal motion allows ebselen and (E)-BOTDCM to visit a wide range of the configurational space competing with the polyunsaturated fatty acid for binding at the active site. Both molecules present similar MM/PBSA binding free energies. The energy penalty for the bigger geometric deformation undergone by (E)-BODTCM would explain its lower inhibitor potency. The (Z)-isomer is the weakest inhibitor because thermal motion moves it to a region very far from the first coordination sphere of Fe, where it could not compete with the fatty acid substrate.

A conserved mechanism for gating in an ionotropic glutamate receptor.

PubMed

Moore, Bryn S; Mirshahi, Uyenlinh L; Ebersole, Tonya L; Mirshahi, Tooraj

2013-06-28

Ionotropic glutamate receptor (iGluR) channels control synaptic activity. The crystallographic structure of GluA2, the prototypical iGluR, reveals a clamshell-like ligand-binding domain (LBD) that closes in the presence of glutamate to open a gate on the pore lining α-helix. How LBD closure leads to gate opening remains unclear. Here, we show that bending the pore helix at a highly conserved alanine residue (Ala-621) below the gate is responsible for channel opening. Substituting Ala-621 with the smaller more flexible glycine resulted in a basally active, nondesensitizing channel with ∼39-fold increase in glutamate potency without affecting surface expression or binding. On GluA2(A621G), the partial agonist kainate showed efficacy similar to a full agonist, and competitive antagonists CNQX and DNQX acted as a partial agonists. Met-629 in GluA2 sits above the gate and is critical in transmitting LBD closure to the gate. Substituting Met-629 with the flexible glycine resulted in reduced channel activity and glutamate potency. The pore regions in potassium channels are structurally similar to iGluRs. Whereas potassium channels typically use glycines as a hinge for gating, iGluRs use the less flexible alanine as a hinge at a similar position to maintain low basal activity allowing for ligand-mediated gating.

Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

PubMed Central

Alder, J Tracy; Hacksell, Uli; Strange, Philip G

2003-01-01

Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). Ligand binding studies were used to determine dissociation constants for agonist binding to the 5-HT1A receptor: Ki values for agonists were determined in competition versus the binding of the agonist [3H]-8-OH DPAT. Competition data were all fitted best by a one-binding site model.Ki values for agonists were also determined in competition versus the binding of the antagonist [3H]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (Kh) and lower affinity (Kl) sites were determined. The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [35S]-GTPγS binding. Maximal effects of agonists (Emax) and their potencies (EC50) were determined from concentration/response curves for stimulation of [35S]-GTPγS binding. Kl/Kh determined from ligand binding assays correlated with the relative efficacy (relative Emax) of agonists determined in [35S]-GTPγS binding assays. There was also a correlation between Kl/Kh and Kl/EC50 for agonists determined from ligand binding and [35S]-GTPγS binding assays. Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of Kl/Kh for predicting the relative efficacy of agonists. PMID:12684269

PA1 Protein, a New Competitive Decelerator Acting at More than One Step to Impede Glucocorticoid Receptor-mediated Transactivation*

PubMed Central

Zhang, Zhenhuan; Sun, Yunguang; Cho, Young-Wook; Chow, Carson C.; Simons, S. Stoney

2013-01-01

Numerous cofactors modulate the gene regulatory activity of glucocorticoid receptors (GRs) by affecting one or more of the following three major transcriptional properties: the maximal activity of agonists (Amax), the potency of agonists (EC50), and the partial agonist activity of antisteroids (PAA). Here, we report that the recently described nuclear protein, Pax2 transactivation domain interaction protein (PTIP)-associated protein 1 (PA1), is a new inhibitor of GR transactivation. PA1 suppresses Amax, increases the EC50, and reduces the PAA of an exogenous reporter gene in a manner that is independent of associated PTIP. PA1 is fully active with, and strongly binds to, the C-terminal half of GR. PA1 reverses the effects of the coactivator TIF2 on GR-mediated gene induction but is unable to augment the actions of the corepressor SMRT. Analysis of competition assays between PA1 and TIF2 with an exogenous reporter indicates that the kinetic definition of PA1 action is a competitive decelerator at two sites upstream from where TIF2 acts. With the endogenous genes IGFBP1 and IP6K3, PA1 also represses GR induction, increases the EC50, and decreases the PAA. ChIP and re-ChIP experiments indicate that PA1 accomplishes this inhibition of the two genes via different mechanisms as follows: PA1 appears to increase GR dissociation from and reduce GR transactivation at the IGFBP1 promoter regions but blocks GR binding to the IP6K3 promoter. We conclude that PA1 is a new competitive decelerator of GR transactivation and can act at more than one molecularly defined step in a manner that depends upon the specific gene. PMID:23161582

PA1 protein, a new competitive decelerator acting at more than one step to impede glucocorticoid receptor-mediated transactivation.

PubMed

Zhang, Zhenhuan; Sun, Yunguang; Cho, Young-Wook; Chow, Carson C; Simons, S Stoney

2013-01-04

Numerous cofactors modulate the gene regulatory activity of glucocorticoid receptors (GRs) by affecting one or more of the following three major transcriptional properties: the maximal activity of agonists (A(max)), the potency of agonists (EC(50)), and the partial agonist activity of antisteroids (PAA). Here, we report that the recently described nuclear protein, Pax2 transactivation domain interaction protein (PTIP)-associated protein 1 (PA1), is a new inhibitor of GR transactivation. PA1 suppresses A(max), increases the EC(50), and reduces the PAA of an exogenous reporter gene in a manner that is independent of associated PTIP. PA1 is fully active with, and strongly binds to, the C-terminal half of GR. PA1 reverses the effects of the coactivator TIF2 on GR-mediated gene induction but is unable to augment the actions of the corepressor SMRT. Analysis of competition assays between PA1 and TIF2 with an exogenous reporter indicates that the kinetic definition of PA1 action is a competitive decelerator at two sites upstream from where TIF2 acts. With the endogenous genes IGFBP1 and IP6K3, PA1 also represses GR induction, increases the EC(50), and decreases the PAA. ChIP and re-ChIP experiments indicate that PA1 accomplishes this inhibition of the two genes via different mechanisms as follows: PA1 appears to increase GR dissociation from and reduce GR transactivation at the IGFBP1 promoter regions but blocks GR binding to the IP6K3 promoter. We conclude that PA1 is a new competitive decelerator of GR transactivation and can act at more than one molecularly defined step in a manner that depends upon the specific gene.

Investigation of the Binding Interaction of Fatty Acids with Human G Protein-Coupled Receptor 40 Using a Site-Specific Fluorescence Probe by Flow Cytometry.

PubMed

Ren, Xiao-Min; Cao, Lin-Ying; Zhang, Jing; Qin, Wei-Ping; Yang, Yu; Wan, Bin; Guo, Liang-Hong

2016-04-05

Human G protein-coupled receptor 40 (hGPR40), with medium- and long-chain free fatty acids (FFAs) as its natural ligands, plays an important role in the enhancement of glucose-dependent insulin secretion. To date, information about the direct binding of FFAs to hGPR40 is very limited, and how carbon-chain length affects the activities of FFAs on hGPR40 is not yet understood. In this study, a fluorescein-fasiglifam analogue (F-TAK-875A) conjugate was designed and synthesized as a site-specific fluorescence probe to study the interaction of FFAs with hGPR40. hGPR40 was expressed in human embryonic kidney 293 cells and labeled with F-TAK-875A. By using flow cytometry, competitive binding of FFA and F-TAK-875A to hGPR40-expressed cells was measured. Binding affinities of 18 saturated FFAs, with carbon-chain lengths ranging from C6 to C23, were analyzed. The results showed that the binding potencies of FFAs to hGPR40 were dependent on carbon length. There was a positive correlation between length and binding potency for seven FFAs (C9-C15), with myristic acid (C15) showing the highest potency, 0.2% relative to TAK-875. For FFAs with a length of fewer than C9 or more than C15, they had very weak or no binding. Molecular docking results showed that the binding pocket of TAK-875 in hGPR40 could enclose FFAs with lengths of C15 or fewer. However, for FFAs with lengths longer than C15, part of the alkyl chain extended out of the binding pocket. This study provided insights into the structural dependence of FFAs binding to and activation of hGPR40.

New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis

PubMed Central

Korhonen, L E; Turpeinen, M; Rahnasto, M; Wittekindt, C; Poso, A; Pelkonen, O; Raunio, H; Juvonen, R O

2007-01-01

Background and purpose: The cytochrome P450 2B6 (CYP2B6) enzyme metabolises a number of clinically important drugs. Drug-drug interactions resulting from inhibition or induction of CYP2B6 activity may cause serious adverse effects. The aims of this study were to construct a three-dimensional structure-activity relationship (3D-QSAR) model of the CYP2B6 protein and to identify novel potent and selective inhibitors of CYP2B6 for in vitro research purposes. Experimental approach: The inhibition potencies (IC50 values) of structurally diverse chemicals were determined with recombinant human CYP2B6 enzyme. Two successive models were constructed using Comparative Molecular Field Analysis (CoMFA). Key results: Three compounds proved to be very potent and selective competitive inhibitors of CYP2B6 in vitro (IC50<1 μM): 4-(4-chlorobenzyl)pyridine (CBP), 4-(4-nitrobenzyl)pyridine (NBP), and 4-benzylpyridine (BP). A complete inhibition of CYP2B6 activity was achieved with 0.1 μM CBP, whereas other CYP-related activities were not affected. Forty-one compounds were selected for further testing and construction of the final CoMFA model. The created CoMFA model was of high quality and predicted accurately the inhibition potency of a test set (n=7) of structurally diverse compounds. Conclusions and implications: Two CoMFA models were created which revealed the key molecular characteristics of inhibitors of the CYP2B6 enzyme. The final model accurately predicted the inhibitory potencies of several structurally unrelated compounds. CBP, BP and NBP were identified as novel potent and selective inhibitors of CYP2B6 and CBP especially is a suitable inhibitor for in vitro screening studies. PMID:17325652

The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro.

PubMed

Horton, R W; Lowther, S; Chivers, J; Jenner, P; Marsden, C D; Testa, B

1988-08-01

1. The interaction of substituted benzamides with brain benzodiazepine (BDZ) binding sites was examined by their ability to displace [3H]-flunitrazepam ([3H]-FNM) from specific binding sites in bovine cortical membranes in vitro. 2. Clebopride, Delagrange 2674, Delagrange 2335 and BRL 20627 displayed concentration-dependent displacement of [3H]-FNM with IC50 values of 73 nM, 132 nM, 7.7 microM and 5.9 microM, respectively. Other substituted benzamides including metoclopramide, sulpiride, tiapride, sultopride and cisapride were inactive at 10(-5) M. 3. Inhibition by clebopride and Delagrange 2674 of [3H]-FNM binding was apparently competitive and readily reversible. 4. In the presence of gamma-aminobutyric acid (GABA), the ability of diazepam and Delagrange 2674 to displace [3H]-Ro 15-1788 binding was increased 3.6 and 1.6 fold respectively, compared to the absence of GABA, while ethyl beta-carboline-3-carboxylate (beta CCE) and clebopride were less potent in the presence of GABA. 5. Diazepam was 30 fold less potent at displacing [3H]-Ro 15-1788 in membranes that had been photoaffinity labelled with FNM than in control membranes, whereas the potency of beta CCE did not differ. Clebopride and Delagrange 2674 showed a less than two fold loss of potency in photoaffinity labelled membranes. 6. The pattern of binding of clebopride and Delagrange 2674 in these in vitro tests is similar to that found previously with partial agonists or antagonists at BDZ binding sites. 7. Clebopride and Delagrange 2674 inhibited [3H]-FNM binding with similar potency in rat cerebellar and hippocampal membranes, suggesting they have no selectivity for BDZ1 and BDZ2 binding sites. 8. Clebopride and Delagrange 2674 are structurally dissimilar to other BDZ ligands and represent another chemical structure to probe brain BDZ binding sites.

Bipartite electronic superstructures in the vortex core of Bi2Sr2CaCu2O8+δ

PubMed Central

Machida, T.; Kohsaka, Y.; Matsuoka, K.; Iwaya, K.; Hanaguri, T.; Tamegai, T.

2016-01-01

The central issue in the physics of cuprate superconductivity is the mutual relationship among superconductivity, pseudogap and broken-spatial-symmetry states. A magnetic field B suppresses superconductivity, providing an opportunity to investigate the competition among these states. Although various B-induced electronic superstructures have been reported, their energy, spatial and momentum-space structures are unclear. Here, we show using spectroscopic-imaging scanning tunnelling microscopy on Bi2Sr2CaCu2O8+δ that there are two distinct B-induced electronic superstructures, both being localized in the vortex core but appearing at different energies. In the low-energy range where the nodal Bogoliubov quasiparticles are well-defined, we observe the so-called vortex checkerboard that we identify as the B-enhanced quasiparticle interference pattern. By contrast, in the high-energy region where the pseudogap develops, the broken-spatial-symmetry patterns that pre-exist at B=0 T is locally enhanced in the vortex core. This evidences the competition between superconductivity and the broken-spatial-symmetry state that is associated with the pseudogap. PMID:27230420

Tumor evolution in space: the effects of competition colonization tradeoffs on tumor invasion dynamics.

PubMed

Orlando, Paul A; Gatenby, Robert A; Brown, Joel S

2013-01-01

We apply competition colonization tradeoff models to tumor growth and invasion dynamics to explore the hypothesis that varying selection forces will result in predictable phenotypic differences in cells at the tumor invasive front compared to those in the core. Spatially, ecologically, and evolutionarily explicit partial differential equation models of tumor growth confirm that spatial invasion produces selection pressure for motile phenotypes. The effects of the invasive phenotype on normal adjacent tissue determine the patterns of growth and phenotype distribution. If tumor cells do not destroy their environment, colonizer and competitive phenotypes coexist with the former localized at the invasion front and the latter, to the tumor interior. If tumors cells do destroy their environment, then cell motility is strongly selected resulting in accelerated invasion speed with time. Our results suggest that the widely observed genetic heterogeneity within cancers may not be the stochastic effect of random mutations. Rather, it may be the consequence of predictable variations in environmental selection forces and corresponding phenotypic adaptations.

Characterization of spiraling patterns in spatial rock-paper-scissors games.

PubMed

Szczesny, Bartosz; Mobilia, Mauro; Rucklidge, Alastair M

2014-09-01

The spatiotemporal arrangement of interacting populations often influences the maintenance of species diversity and is a subject of intense research. Here, we study the spatiotemporal patterns arising from the cyclic competition between three species in two dimensions. Inspired by recent experiments, we consider a generic metapopulation model comprising "rock-paper-scissors" interactions via dominance removal and replacement, reproduction, mutations, pair exchange, and hopping of individuals. By combining analytical and numerical methods, we obtain the model's phase diagram near its Hopf bifurcation and quantitatively characterize the properties of the spiraling patterns arising in each phase. The phases characterizing the cyclic competition away from the Hopf bifurcation (at low mutation rate) are also investigated. Our analytical approach relies on the careful analysis of the properties of the complex Ginzburg-Landau equation derived through a controlled (perturbative) multiscale expansion around the model's Hopf bifurcation. Our results allow us to clarify when spatial "rock-paper-scissors" competition leads to stable spiral waves and under which circumstances they are influenced by nonlinear mobility.

Interaction dynamics between grouping principles in touch: phenomenological and psychophysical evidence.

PubMed

Prieto, Antonio; Mayas, Julia; Ballesteros, Soledad

2018-05-24

In two experiments, we investigated the interactions between the grouping principles of spatial proximity and texture similarity in touch. For that purpose, we adapted to touch two paradigms widely employed in vision. In Experiment 1, we used an experimental phenomenological task consisting of rating the strength of grouping in both acting alone and conjoined cooperative and competitive conditions. In Experiment 2, participants performed a psychophysical task in which an objective (in)correct response was defined by selectively attending to one grouping cue in different blocks of trials. The results showed that spatial proximity dominated over texture similarity when the two principles were conjoined in competition. In addition, the present results are compatible with an additive model of grouping effects as indicated by the greater grouping effect in the cooperative condition and the smaller grouping effect in the competitive condition relative to a.0cting alone grouping principles. The similarities and differences between vision and touch are discussed.

Tumor Evolution in Space: The Effects of Competition Colonization Tradeoffs on Tumor Invasion Dynamics

PubMed Central

Orlando, Paul A.; Gatenby, Robert A.; Brown, Joel S.

2013-01-01

We apply competition colonization tradeoff models to tumor growth and invasion dynamics to explore the hypothesis that varying selection forces will result in predictable phenotypic differences in cells at the tumor invasive front compared to those in the core. Spatially, ecologically, and evolutionarily explicit partial differential equation models of tumor growth confirm that spatial invasion produces selection pressure for motile phenotypes. The effects of the invasive phenotype on normal adjacent tissue determine the patterns of growth and phenotype distribution. If tumor cells do not destroy their environment, colonizer and competitive phenotypes coexist with the former localized at the invasion front and the latter, to the tumor interior. If tumors cells do destroy their environment, then cell motility is strongly selected resulting in accelerated invasion speed with time. Our results suggest that the widely observed genetic heterogeneity within cancers may not be the stochastic effect of random mutations. Rather, it may be the consequence of predictable variations in environmental selection forces and corresponding phenotypic adaptations. PMID:23508890

Masking potency and whiteness of noise at various noise check sizes.

PubMed

Kukkonen, H; Rovamo, J; Näsänen, R

1995-02-01

The masking effect of spatial noise can be increased by increasing either the rms contrast or check size of noise. In this study, the authors investigated the largest noise check size that still mimics the effect of white noise in grating detection and how it depends on the bandwidth and spatial frequency of a grating. The authors measured contrast energy thresholds, E, for vertical cosine gratings at various spatial frequencies and bandwidths. Gratings were embedded in two-dimensional spatial noise. The side length of the square noise checks was varied in the experiments. The spectral density, N(0,0), of white spatial noise at zero frequency was calculated by multiplying the noise check area by the rms contrast of noise squared. The physical signal-to-noise ratio at threshold [E/N(0,0)]0.5 was initially constant but then started to decrease. The largest noise check that still produced a constant physical signal-to-noise ratio at threshold was directly proportional to the spatial frequency. When expressed as a fraction of grating cycle, the largest noise check size depended only on stimulus bandwidth. The smallest number of noise checks per grating cycle needed to mimic the effect of white noise decreased from 4.2 to 2.6 when the number of grating cycles increased from 1 to 64. Spatial noise can be regarded as white in grating detection if there are at least four square noise checks per grating cycle at all spatial frequencies.

Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase.

PubMed

Huff, Sarah E; Mohammed, Faiz Ahmad; Yang, Mu; Agrawal, Prashansa; Pink, John; Harris, Michael E; Dealwis, Chris G; Viswanathan, Rajesh

2018-02-08

Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR reversibly. We herein report the synthesis and biochemical characterization of 25 distinct analogs. We designed each analog through docking to the C-site of hRR based on our 2.7 Å X-ray crystal structure (PDB ID: 5TUS). Broad tolerance to minor structural variations preserving inhibitory potency is observed. E-3f (82% yield) displayed an in vitro IC 50 of 5.3 ± 1.8 μM against hRR, making it the most potent in this series. Kinetic assays reveal that E-3a, E-3c, E-3t, and E-3w bind and inhibit hRR through a reversible and competitive mode. Target selectivity toward the R1 subunit of hRR is established, providing a novel way of inhibition of this crucial enzyme.

Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry.

PubMed

Bravery, Christopher A; Carmen, Jessica; Fong, Timothy; Oprea, Wanda; Hoogendoorn, Karin H; Woda, Juliana; Burger, Scott R; Rowley, Jon A; Bonyhadi, Mark L; Van't Hof, Wouter

2013-01-01

The evaluation of potency plays a key role in defining the quality of cellular therapy products (CTPs). Potency can be defined as a quantitative measure of relevant biologic function based on the attributes that are linked to relevant biologic properties. To achieve an adequate assessment of CTP potency, appropriate in vitro or in vivo laboratory assays and properly controlled clinical data need to be created. The primary objective of a potency assay is to provide a mechanism by which the manufacturing process and the final product for batch release are scrutinized for quality, consistency and stability. A potency assay also provides the basis for comparability assessment after process changes, such as scale-up, site transfer and new starting materials (e.g., a new donor). Potency assays should be in place for early clinical development, and validated assays are required for pivotal clinical trials. Potency is based on the individual characteristics of each individual CTP, and the adequacy of potency assays will be evaluated on a case-by-case basis by regulatory agencies. We provide an overview of the expectations and challenges in development of potency assays specific for CTPs; several real-life experiences from the cellular therapy industry are presented as illustrations. The key observation and message is that aggressive early investment in a solid potency evaluation strategy can greatly enhance eventual CTP deployment because it can mitigate the risk of costly product failure in late-stage development. Copyright © 2013. Published by Elsevier Inc.

Influence of Interspecific Competition and Landscape Structure on Spatial Homogenization of Avian Assemblages

PubMed Central

Robertson, Oliver J.; McAlpine, Clive; House, Alan; Maron, Martine

2013-01-01

Human-induced biotic homogenization resulting from landscape change and increased competition from widespread generalists or ‘winners’, is widely recognized as a global threat to biodiversity. However, it remains unclear what aspects of landscape structure influence homogenization. This paper tests the importance of interspecific competition and landscape structure, for the spatial homogeneity of avian assemblages within a fragmented agricultural landscape of eastern Australia. We used field observations of the density of 128 diurnal bird species to calculate taxonomic and functional similarity among assemblages. We then examined whether taxonomic and functional similarity varied with patch type, the extent of woodland habitat, land-use intensity, habitat subdivision, and the presence of Manorina colonies (a competitive genus of honeyeaters). We found the presence of a Manorina colony was the most significant factor positively influencing both taxonomic and functional similarity of bird assemblages. Competition from members of this widespread genus of native honeyeater, rather than landscape structure, was the main cause of both taxonomic and functional homogenization. These species have not recently expanded their range, but rather have increased in density in response to agricultural landscape change. The negative impacts of Manorina honeyeaters on assemblage similarity were most pronounced in landscapes of moderate land-use intensity. We conclude that in these human-modified landscapes, increased competition from dominant native species, or ‘winners’, can result in homogeneous avian assemblages and the loss of specialist species. These interacting processes make biotic homogenization resulting from land-use change a global threat to biodiversity in modified agro-ecosystems. PMID:23724136

Development of Special Biological Products

DTIC Science & Technology

1981-01-01

Rocky Mountain Spotted Fever (RMSF) 20. Continued B. Tissue Culture / ?Two production lots of FRhL-2 dnd three of MRC-5 were stabilized...104) was potency tested. J. Q Fever Vaccine Storage Stability Potency Testing Q fever vaccine (NDBR 105) was put on potency test. K. Rocky Mountain Spotted Fever (RMSF...Fever Vaccine Storage Stability Potency Testing Two lots of Q fever vaccine (NDBR 105) were put on potency test. K. Rocky Mountain Spotted Fever

Clade perseverance from Mesozoic to present: a multidisciplinary approach to interpretation of pattern and process.

PubMed

Barnes, David K A

2002-10-01

Two clades of marine bryozoans, cyclostomes and cheilostomes, exemplify the benefits of applying a multidisciplinary approach to the interpretation of long-term evolutionary patterns. The cyclostome bryozoans were dominant in the Mesozoic; since that era, they have decreased in absolute terms and the cheilostomes have come to exceed them in both abundance and diversity. Many studies of living assemblages of the encrusting members of these two clades indicate that cheilostomes are superior space competitors, but paleontological studies suggest that competition between the two taxa has not been escalating over geological time. Both clades occur throughout the world's oceans and seas, and recent work in the geographical extremes has shown that the relative success of the clades varies markedly from place to place. In this study, the importance of differential patterns of recruitment and cumulative space occupation in the two clades was evaluated over four years and in two environments, one temperate and one polar. In both of these environments, peaks of recruitment and space occupation by the two clades were out of phase. The different strategies and outcomes of spatial competition are examined, largely using data from the literature. Only recently has it been realized that tied outcomes of competition are stable alternative results and not simply transitory phases. Many competitive encounters involving cyclostomes result in ties, implying that their strategy is based on persistence rather than dominance. When different indices and models are used to analyze competition data from the two clades, the interpretation varies markedly with methodology. The differences in patterns of recruitment, space occupation, and spatial competition have influenced both our understanding of how the two clades have persisted alongside each other and our perception of cheilostome superiority. Analysis of fluid dynamics has shown that small differences in the mechanical structure of typical members of each clade lead to fundamental differences in water movement. For animals that rely on water motion for transport of nutritional and excretory elements (suspension feeders), small changes in current velocity and direction can have a major impact. Preliminary chemical analysis of the excurrent stream leaving cheilostome colonies has shown it to be laden with excretory products, which can interfere and mix with a neighbor's feeding currents. Clearly, spatial competition involves more than a simple mechanical "showdown."

beta-Endorphin-induced analgesia is inhibited by synthetic analogs of beta-endorphin.

PubMed Central

Nicolas, P; Hammonds, R G; Li, C H

1984-01-01

Competitive antagonism of human beta-endorphin (beta h-EP)-induced analgesia by synthetic beta h-EP analogs with high in vitro opiate receptor binding to in vivo analgesic potency ratio has been demonstrated. A parallel shift of the dose-response curve for analgesia to the right was observed when either beta h-EP or [ Trp27 ] -beta h-EP was coinjected with various doses of [Gln8, Gly31 ]-beta h-EP-Gly-Gly-NH2, [Arg9,19,24,28,29]-beta h-EP, or [ Cys11 ,26, Phe27 , Gly31 ]-beta h-EP. It was estimated that the most potent antagonist, [Gln8, Gly31 ]-beta h-EP-Gly-NH2, is at least 200 times more potent than naloxone. PMID:6328494

3-(2-Benzofuranyl)quinuclidin-2-ene derivatives: novel muscarinic antagonists.

PubMed

Nordvall, G; Sundquist, S; Johansson, G; Glas, G; Nilvebrant, L; Hacksell, U

1996-08-16

A series of 26 derivatives of the novel muscarinic antagonist 3-(2-benzofuranyl)quinuclidin-2-ene (1) has been synthesized and evaluated for muscarinic and antimuscarinic properties. The affinity of the compounds was determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic-potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. The 5-fluorobenzofuranyl derivative was slightly more potent than 1. The 7-bromo-substituted 8 displayed a 14-fold tissue selectivity ratio for muscarinic receptors in the cortex versus the parotid gland. Comparative molecular field analysis and quantitative structure-activity relationship models were developed for this series of substituted benzofuranyl derivatives.

Synthesis and characterization of time-resolved fluorescence probes for evaluation of competitive binding to melanocortin receptors.

PubMed

Alleti, Ramesh; Vagner, Josef; Dehigaspitiya, Dilani Chathurika; Moberg, Valerie E; Elshan, N G R D; Tafreshi, Narges K; Brabez, Nabila; Weber, Craig S; Lynch, Ronald M; Hruby, Victor J; Gillies, Robert J; Morse, David L; Mash, Eugene A

2013-09-01

Probes for use in time-resolved fluorescence competitive binding assays at melanocortin receptors based on the parental ligands MSH(4), MSH(7), and NDP-α-MSH were prepared by solid phase synthesis methods, purified, and characterized. The saturation binding of these probes was studied using HEK-293 cells engineered to overexpress the human melanocortin 4 receptor (hMC4R) as well as the human cholecystokinin 2 receptor (hCCK2R). The ratios of non-specific binding to total binding approached unity at high concentrations for each probe. At low probe concentrations, receptor-mediated binding and uptake was discernable, and so probe concentrations were kept as low as possible in determining Kd values. The Eu-DTPA-PEGO-MSH(4) probe exhibited low specific binding relative to non-specific binding, even at low nanomolar concentrations, and was deemed unsuitable for use in competition binding assays. The Eu-DTPA-PEGO probes based on MSH(7) and NDP-α-MSH exhibited Kd values of 27±3.9nM and 4.2±0.48nM, respectively, for binding with hMC4R. These probes were employed in competitive binding assays to characterize the interactions of hMC4R with monovalent and divalent MSH(4), MSH(7), and NDP-α-MSH constructs derived from squalene. Results from assays with both probes reflected only statistical enhancements, suggesting improper ligand spacing on the squalene scaffold for the divalent constructs. The Ki values from competitive binding assays that employed the MSH(7)-based probe were generally lower than the Ki values obtained when the probe based on NDP-α-MSH was employed, which is consistent with the greater potency of the latter probe. The probe based on MSH(7) was also competed with monovalent, divalent, and trivalent MSH(4) constructs that previously demonstrated multivalent binding in competitive binding assays against a variant of the probe based on NDP-α-MSH. Results from these assays confirm multivalent binding, but suggest a more modest increase in avidity for these MSH(4) constructs than was previously reported. Copyright © 2013 Elsevier Ltd. All rights reserved.

Spatial continuity of tree attributes in bottomland hardwood forests in the Southeastern United States

Treesearch

Luben D. Dimov; Jim L. Chambers; Brian Roy Lockhart

2005-01-01

Sustainable forest management and conservation require understanding of underlying basic structural and competitive relationships. To gain insight into these relationships, we analyzed spatial continuity of tree basal area (BA) and crown projection area (CPA) on twelve 0.64-ha plots in four mixed bottomland hardwood stands in Louisiana, Arkansas, and Mississippi....

Market power in electric power markets: Indications of competitiveness in spatial prices for wholesale electricity

NASA Astrophysics Data System (ADS)

Denton, Michael John

The issue of market delineation and power in the wholesale electric energy market is explored using three separate approaches: two of these are analyses of spatial pricing data to explore the functional size of the markets, and the third is a series of experimental tests of the effects of different cost structures and market mechanisms on oligopoly strength in those markets. An equilibrium model of spatial network competition is shown to yield linear relationships between spatial prices. A data set comprising two years of spatial weekly peak and off-peak prices and weather for 6 locations in the Western States Coordinating Council and the Southwest Power Pool is subjected to a pairwise cointegration analysis. The use of dummy variables to account the the flow directions is found to significantly improve model performance. The second analytical technique utilizes the extraction of principal components from a spatial price correlation matrix to identify the extent of natural markets. One year of daily price observations for eleven locations within the WSCC is compiled and eigenvectors are extracted and subjected to oblique rotation, each of which is then interpreted as representing a separate geographic market. The results show that two distinct natural markets, correlated at 84%, account for over 96% of the variation in the spatial prices in the WSSC. Together, the findings support the assertion that the wholesale electricity market in the Western U.S. is large and highly competitive. The experimental analysis utilizes a radial three node network in which suppliers located at the outer nodes sell to buyers located at the central node. The parameterization captures the salient characteristics of the existing bulk power markets, and includes cyclical demand, transmission losses, as well as fixed and avoidable fixed costs for all agents. Treatments varied the number of sellers, the avoidable fixed cost structures, and the trading mechanism. Results indicated that sealed bid markets greatly reduced the ability of sellers to exert market power. Overall the existence of higher avoidable fixed costs tended to ameliorate market power effects.

Stimulus competition mediates the joint effects of spatial and feature-based attention

PubMed Central

White, Alex L.; Rolfs, Martin; Carrasco, Marisa

2015-01-01

Distinct attentional mechanisms enhance the sensory processing of visual stimuli that appear at task-relevant locations and have task-relevant features. We used a combination of psychophysics and computational modeling to investigate how these two types of attention—spatial and feature based—interact to modulate sensitivity when combined in one task. Observers monitored overlapping groups of dots for a target change in color saturation, which they had to localize as being in the upper or lower visual hemifield. Pre-cues indicated the target's most likely location (left/right), color (red/green), or both location and color. We measured sensitivity (d′) for every combination of the location cue and the color cue, each of which could be valid, neutral, or invalid. When three competing saturation changes occurred simultaneously with the target change, there was a clear interaction: The spatial cueing effect was strongest for the cued color, and the color cueing effect was strongest at the cued location. In a second experiment, only the target dot group changed saturation, such that stimulus competition was low. The resulting cueing effects were statistically independent and additive: The color cueing effect was equally strong at attended and unattended locations. We account for these data with a computational model in which spatial and feature-based attention independently modulate the gain of sensory responses, consistent with measurements of cortical activity. Multiple responses then compete via divisive normalization. Sufficient competition creates interactions between the two cueing effects, although the attentional systems are themselves independent. This model helps reconcile seemingly disparate behavioral and physiological findings. PMID:26473316

Affective learning modulates spatial competition during low-load attentional conditions.

PubMed

Lim, Seung-Lark; Padmala, Srikanth; Pessoa, Luiz

2008-04-01

It has been hypothesized that the amygdala mediates the processing advantage of emotional items. In the present study, we employed functional magnetic resonance imaging (fMRI) to investigate how fear conditioning affected the visual processing of task-irrelevant faces. We hypothesized that faces previously paired with shock (threat faces) would more effectively vie for processing resources during conditions involving spatial competition. To investigate this question, following conditioning, participants performed a letter-detection task on an array of letters that was superimposed on task-irrelevant faces. Attentional resources were manipulated by having participants perform an easy or a difficult search task. Our findings revealed that threat fearful faces evoked stronger responses in the amygdala and fusiform gyrus relative to safe fearful faces during low-load attentional conditions, but not during high-load conditions. Consistent with the increased processing of shock-paired stimuli during the low-load condition, such stimuli exhibited increased behavioral priming and fMRI repetition effects relative to unpaired faces during a subsequent implicit-memory task. Overall, our results suggest a competition model in which affective significance signals from the amygdala may constitute a key modulatory factor determining the neural fate of visual stimuli. In addition, it appears that such competitive advantage is only evident when sufficient processing resources are available to process the affective stimulus.

9 CFR 113.9 - New potency test.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false New potency test. 113.9 Section 113.9 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES... New potency test. A potency test written into the filed Outline of Production for a product shall be...

Niche segregation between wild and domestic herbivores in Chilean Patagonia.

PubMed

Iranzo, Esperanza C; Traba, Juan; Acebes, Pablo; González, Benito A; Mata, Cristina; Estades, Cristián F; Malo, Juan E

2013-01-01

Competition arises when two co-occuring species share a limiting resource. Potential for competition is higher when species have coexisted for a short time, as it is the case for herbivores and livestock introduced in natural systems. Sheep, introduced in the late 19(th) century in Patagonia, bear a great resemblance in size and diet to the guanaco, the main native herbivore in Patagonia. In such circumstances, it could be expected that the two species compete and one of them could be displaced. We investigated spatial overlap and habitat selection by coexisting sheep and guanaco in winter and in summer. Additionally, we studied habitat selection of the guanaco in a control situation free from sheep, both in summer and winter. We also determined overlap between species in areas with different intensity of use (named preferred and marginal areas) in order to further detect the potential level of competition in the case of overlapping. Guanaco and sheep showed significantly different habitat preferences through all seasons, in spite of their spatial overlap at landscape scale. Additionally, the habitat used by guanaco was similar regardless of the presence or absence of livestock, which further indicates that sheep is not displacing guanaco where they coexist. These results suggest that habitat segregation between guanaco and sheep is due to a differential habitat selection and not to a competitive displacement process. Therefore, the potential for competition is considered low, contrary to what has been previously observed, although this could be a density-dependent result.

Vasoconstriction Potency Induced by Aminoamide Local Anesthetics Correlates with Lipid Solubility

PubMed Central

Sung, Hui-Jin; Ok, Seong-Ho; Sohn, Jin-Young; Son, Yong Hyeok; Kim, Jun Kyu; Lee, Soo Hee; Han, Jeong Yeol; Lim, Dong Hoon; Shin, Il-Woo; Lee, Heon-Keun; Chung, Young-Kyun; Choi, Mun-Jeoung; Sohn, Ju-Tae

2012-01-01

Aminoamide local anesthetics induce vasoconstriction in vivo and in vitro. The goals of this in vitro study were to investigate the potency of local anesthetic-induced vasoconstriction and to identify the physicochemical property (octanol/buffer partition coefficient, pKa, molecular weight, or potency) of local anesthetics that determines their potency in inducing isolated rat aortic ring contraction. Cumulative concentration-response curves to local anesthetics (levobupivacaine, ropivacaine, lidocaine, and mepivacaine) were obtained from isolated rat aorta. Regression analyses were performed to determine the relationship between the reported physicochemical properties of local anesthetics and the local anesthetic concentration that produced 50% (ED50) of the local anesthetic-induced maximum vasoconstriction. We determined the order of potency (ED50) of vasoconstriction among local anesthetics to be levobupivacaine > ropivacaine > lidocaine > mepivacaine. The relative importance of the independent variables that affect the vasoconstriction potency is octanol/buffer partition coefficient > potency > pKa > molecular weight. The ED50 in endothelium-denuded aorta negatively correlated with the octanol/buffer partition coefficient of local anesthetics (r2 = 0.9563; P < 0.001). The potency of the vasoconstriction in the endothelium-denuded aorta induced by local anesthetics is determined primarily by lipid solubility and, in part, by other physicochemical properties including potency and pKa. PMID:22778542

Effect of high-potency cannabis on corpus callosum microstructure.

PubMed

Rigucci, S; Marques, T R; Di Forti, M; Taylor, H; Dell'Acqua, F; Mondelli, V; Bonaccorso, S; Simmons, A; David, A S; Girardi, P; Pariante, C M; Murray, R M; Dazzan, P

2016-03-01

The use of cannabis with higher Δ9-tetrahydrocannabinol content has been associated with greater risk, and earlier onset, of psychosis. However, the effect of cannabis potency on brain morphology has never been explored. Here, we investigated whether cannabis potency and pattern of use are associated with changes in corpus callosum (CC) microstructural organization, in patients with first-episode psychosis (FEP) and individuals without psychosis, cannabis users and non-users. The CC of 56 FEP (37 cannabis users) and 43 individuals without psychosis (22 cannabis users) was virtually dissected and segmented using diffusion tensor imaging tractography. The diffusion index of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity was calculated for each segment. Across the whole sample, users of high-potency cannabis had higher total CC MD and higher total CC AD than both low-potency users and those who never used (p = 0.005 and p = 0.004, respectively). Daily users also had higher total CC MD and higher total CC AD than both occasional users and those who never used (p = 0.001 and p < 0.001, respectively). However, there was no effect of group (patient/individuals without psychosis) or group x potency interaction for either potency or frequency of use. The within-group analysis showed in fact that the effects of potency and frequency were similar in FEP users and in users without psychosis. Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.

Sexual Function and the use of Medical Devices or Drugs to Optimize Potency after Prostate Brachytherapy

PubMed Central

Whaley, J. Taylor; Levy, Lawrence B.; Swanson, David A.; Pugh, Thomas J.; Kudchadker, Rajat J.; Bruno, Teresa L.; Frank, Steven J.

2013-01-01

Purpose Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center. Methods and Materials Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile-volume receiving 100% of the prescribed dose (V100) were calculated. Results At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p=0.04) and age (p=0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients over 70 maintained optimal potency (p=0.02). Diabetes was related to a decline in potency (p=0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p<0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested. Conclusions Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry. PMID:22300559

Sexual function and the use of medical devices or drugs to optimize potency after prostate brachytherapy.

PubMed

Whaley, J Taylor; Levy, Lawrence B; Swanson, David A; Pugh, Thomas J; Kudchadker, Rajat J; Bruno, Teresa L; Frank, Steven J

2012-04-01

Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center. Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile volume receiving 100% of the prescribed dose (V100) were calculated. At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p = 0.04) and age (p = 0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients older than 70 maintained optimal potency (p = 0.02). Diabetes was related to a decline in potency (p = 0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p < 0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested. Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry. Copyright © 2012 Elsevier Inc. All rights reserved.

Sexual Function and the Use of Medical Devices or Drugs to Optimize Potency After Prostate Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whaley, J. Taylor; Levy, Lawrence B.; Swanson, David A.

Purpose: Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center. Methods and Materials: Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile volume receiving 100% of the prescribed dose (V100) were calculated. Results: Atmore » baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p = 0.04) and age (p = 0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients older than 70 maintained optimal potency (p = 0.02). Diabetes was related to a decline in potency (p = 0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p < 0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested. Conclusions: Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry.« less

Present status of grouper fisheries at waters of Kotania Bay, Western Seram District Maluku Province

NASA Astrophysics Data System (ADS)

Huliselan, N. V.; Wawo, M.; Tuapattinaja, M. A.; Sahetapy, D.

2017-10-01

Study on present status of groupers fishes at waters of Kotania Bay was conducted from 2016 to 2017. Survey and Participatory Rural Appraisal (PRA) method were used to collect and examine data and information concerning species potential and utilization of these species. The result shows that there are 35 species of grouper fishes inhabit Kotania Bay waters. From six genera recorded, Epinephelus found to have more varieties species richness compared to other five genera. In general, main habitat of adult grouper is coral reef, whilst mangrove and seagrass are habitat for nursery and grow out. The potency of the Epinephelus, Cephalopholis and Plectropomus genus tend to decrease started in 2000 up to 2017. At the same period, the production of these genera was also declined. Species potency and production declined was attributable to habitat (coral reef) degradation and high fishing intensity as a result of high market demand. Hand line, bottom long line and trap net are general fishing gear used in harvesting of theses fishes. Fishing activities took place all year round except for bottom long line which only lasted from June to October (East monsoon). Spatial fishing ground distribution is predominantly at coral reef ecosystem of Kotania Bay.

Morphological response to competition for light in the clonal Trifolium repens (Fabaceae).

PubMed

Bittebiere, Anne-Kristel; Renaud, Nolwenn; Clément, Bernard; Mony, Cendrine

2012-04-01

Plant communities in temperate zones are dominated by clonal plants that can plastically modify their growth characteristics in response to competition. Given that plants compete with one another, and the implications this has for species coexistence, we conducted a study to assess how clonal species morphologically respond to competition for light depending on its intensity and heterogeneity, which are determined by the competitor species. We assessed the morphological response to competition for light of the clonal species Trifolium repens L. by measuring its growth performance, and vertical and horizontal growth traits. We used five competitive environments, i.e., one without competitor and four differing by their competitor species creating different conditions of competition intensity and heterogeneity. The morphological response of Trifolium repens to competition for light depended on the competitor identity. Competition intensity and heterogeneity, determined by competitor identity, had an interactive effect on most traits. The increase in petiole elongation and specific leaf area due to increased competition intensity was observed only at low to intermediate competition heterogeneity. Competition heterogeneity promoted the elongation of clone connections allowing space exploration. Our results demonstrated that the intensity and heterogeneity of competition, which depended on competitor identity, are of primary importance in determining the plastic response of Trifolium repens. This emphasizes that it is important to consider the fine-scale spatial distribution of individuals when studying their interactions within plant communities.

Effects of soil nutrient heterogeneity on intraspecific competition in the invasive, clonal plant Alternanthera philoxeroides.

PubMed

Zhou, Jian; Dong, Bi-Cheng; Alpert, Peter; Li, Hong-Li; Zhang, Ming-Xiang; Lei, Guang-Chun; Yu, Fei-Hai

2012-03-01

Fine-scale, spatial heterogeneity in soil nutrient availability can increase the growth of individual plants, the productivity of plant communities and interspecific competition. If this is due to the ability of plants to concentrate their roots where nutrient levels are high, then nutrient heterogeneity should have little effect on intraspecific competition, especially when there are no genotypic differences between individuals in root plasticity. We tested this hypothesis in a widespread, clonal species in which individual plants are known to respond to nutrient heterogeneity. Plants derived from a single clone of Alternanthera philoxeroides were grown in the greenhouse at low or high density (four or 16 plants per 27·5 × 27·5-cm container) with homogeneous or heterogeneous availability of soil nutrients, keeping total nutrient availability per container constant. After 9 weeks, measurements of size, dry mass and morphology were taken. Plants grew more in the heterogeneous than in the homogeneous treatment, showing that heterogeneity promoted performance; they grew less in the high- than in the low-density treatment, showing that plants competed. There was no interactive effect of nutrient heterogeneity and plant density, supporting the hypothesis that heterogeneity does not affect intraspecific competition in the absence of genotypic differences in plasticity. Treatments did not affect morphological characteristics such as specific leaf area or root/shoot ratio. Results indicate that fine-scale, spatial heterogeneity in the availability of soil nutrients does not increase competition when plants are genetically identical, consistent with the suggestion that effects of heterogeneity on competition depend upon differences in plasticity between individuals. Heterogeneity is only likely to increase the spread of monoclonal, invasive populations such as that of A. philoxeroides in China.

Competitive interactions affect working memory performance for both simultaneous and sequential stimulus presentation.

PubMed

Ahmad, Jumana; Swan, Garrett; Bowman, Howard; Wyble, Brad; Nobre, Anna C; Shapiro, Kimron L; McNab, Fiona

2017-07-06

Competition between simultaneously presented visual stimuli lengthens reaction time and reduces both the BOLD response and neural firing. In contrast, conditions of sequential presentation have been assumed to be free from competition. Here we manipulated the spatial proximity of stimuli (Near versus Far conditions) to examine the effects of simultaneous and sequential competition on different measures of working memory (WM) for colour. With simultaneous presentation, the measure of WM precision was significantly lower for Near items, and participants reported the colour of the wrong item more often. These effects were preserved when the second stimulus immediately followed the first, disappeared when they were separated by 500 ms, and were partly recovered (evident for our measure of mis-binding but not WM precision) when the task was altered to encourage participants to maintain the sequentially presented items together in WM. Our results show, for the first time, that competition affects the measure of WM precision, and challenge the assumption that sequential presentation removes competition.

Quantifying and mapping spatial variability in simulated forest plots

Treesearch

Gavin R. Corral; Harold E. Burkhart

2016-01-01

We used computer simulations to test the efficacy of multivariate statistical methods to detect, quantify, and map spatial variability of forest stands. Simulated stands were developed of regularly-spaced plantations of loblolly pine (Pinus taeda L.). We assumed no affects of competition or mortality, but random variability was added to individual tree characteristics...

Bacteria and game theory: the rise and fall of cooperation in spatially heterogeneous environments.

PubMed

Lambert, Guillaume; Vyawahare, Saurabh; Austin, Robert H

2014-08-06

One of the predictions of game theory is that cooperative behaviours are vulnerable to exploitation by selfish individuals, but this result seemingly contradicts the survival of cooperation observed in nature. In this review, we will introduce game theoretical concepts that lead to this conclusion and show how the spatial competition dynamics between microorganisms can be used to model the survival and maintenance of cooperation. In particular, we focus on how Escherichia coli bacteria with a growth advantage in stationary phase (GASP) phenotype maintain a proliferative phenotype when faced with overcrowding to gain a fitness advantage over wild-type populations. We review recent experimental approaches studying the growth dynamics of competing GASP and wild-type strains of E. coli inside interconnected microfabricated habitats and use a game theoretical approach to analyse the observed inter-species interactions. We describe how the use of evolutionary game theory and the ideal free distribution accurately models the spatial distribution of cooperative and selfish individuals in spatially heterogeneous environments. Using bacteria as a model system of cooperative and selfish behaviours may lead to a better understanding of the competition dynamics of other organisms-including tumour-host interactions during cancer development and metastasis.

Modelling individual tree height to crown base of Norway spruce (Picea abies (L.) Karst.) and European beech (Fagus sylvatica L.)

PubMed Central

Jansa, Václav

2017-01-01

Height to crown base (HCB) of a tree is an important variable often included as a predictor in various forest models that serve as the fundamental tools for decision-making in forestry. We developed spatially explicit and spatially inexplicit mixed-effects HCB models using measurements from a total 19,404 trees of Norway spruce (Picea abies (L.) Karst.) and European beech (Fagus sylvatica L.) on the permanent sample plots that are located across the Czech Republic. Variables describing site quality, stand density or competition, and species mixing effects were included into the HCB model with use of dominant height (HDOM), basal area of trees larger in diameters than a subject tree (BAL- spatially inexplicit measure) or Hegyi’s competition index (HCI—spatially explicit measure), and basal area proportion of a species of interest (BAPOR), respectively. The parameters describing sample plot-level random effects were included into the HCB model by applying the mixed-effects modelling approach. Among several functional forms evaluated, the logistic function was found most suited to our data. The HCB model for Norway spruce was tested against the data originated from different inventory designs, but model for European beech was tested using partitioned dataset (a part of the main dataset). The variance heteroscedasticity in the residuals was substantially reduced through inclusion of a power variance function into the HCB model. The results showed that spatially explicit model described significantly a larger part of the HCB variations [R2adj = 0.86 (spruce), 0.85 (beech)] than its spatially inexplicit counterpart [R2adj = 0.84 (spruce), 0.83 (beech)]. The HCB increased with increasing competitive interactions described by tree-centered competition measure: BAL or HCI, and species mixing effects described by BAPOR. A test of the mixed-effects HCB model with the random effects estimated using at least four trees per sample plot in the validation data confirmed that the model was precise enough for the prediction of HCB for a range of site quality, tree size, stand density, and stand structure. We therefore recommend measuring of HCB on four randomly selected trees of a species of interest on each sample plot for localizing the mixed-effects model and predicting HCB of the remaining trees on the plot. Growth simulations can be made from the data that lack the values for either crown ratio or HCB using the HCB models. PMID:29049391

Noise frame duration, masking potency and whiteness of temporal noise.

PubMed

Kukkonen, Heljä; Rovamo, Jyrki; Donner, Kristian; Tammikallio, Marja; Raninen, Antti

2002-09-01

Because of the limited contrast range, increasing the duration of the noise frame is often the only option for increasing the masking potency of external, white temporal noise. This, however, reduces the high-frequency cutoff beyond which noise is no longer white. This study was conducted to determine the longest noise frame duration that produces the strongest masking effect and still mimics white noise on the detection of sinusoidal flicker. Contrast energy thresholds (E(th)) were measured for flicker at 1.25 to 20 Hz in strong, purely temporal (spatially uniform), additive, external noise. The masking power of white external noise, characterized by its spectral density at zero frequency N0, increases with the duration of the noise frame. For short noise frame durations, E(th) increased in direct proportion to N0, keeping the nominal signal-to-noise ratio [SNR = (E(th)/N0)(0.5)] constant at threshold. The masking effect thus increased with the duration of the noise frame and the noise mimicked white noise. When noise frame duration and N0 increased further, the nominal SNR at threshold started to decrease, indicating that noise no longer mimicked white noise. The minimum number of noise frames per flicker cycle needed to mimic white noise decreased with increasing flicker frequency from 8.3 at 1.25 Hz to 1.6 at 20 Hz. The critical high-frequency cutoff of detection-limiting temporal noise in terms of noise frames per signal cycle depends on the temporal frequency of the signal. This is opposite to the situation in the spatial domain and must be taken into consideration when temporal signals are masked with temporal noise.

Rapid Diversity Loss of Competing Animal Species in Well-Connected Landscapes

PubMed Central

Schippers, Peter; Hemerik, Lia; Baveco, Johannes M.; Verboom, Jana

2015-01-01

Population viability of a single species, when evaluated with metapopulation based landscape evaluation tools, always increases when the connectivity of the landscape increases. However, when interactions between species are taken into account, results can differ. We explore this issue using a stochastic spatially explicit meta-community model with 21 competing species in five different competitive settings: (1) weak, coexisting competition, (2) neutral competition, (3) strong, excluding competition, (4) hierarchical competition and (5) random species competition. The species compete in randomly generated landscapes with various fragmentation levels. With this model we study species loss over time. Simulation results show that overall diversity, the species richness in the entire landscape, decreases slowly in fragmented landscapes whereas in well-connected landscapes rapid species losses occur. These results are robust with respect to changing competitive settings, species parameters and spatial configurations. They indicate that optimal landscape configuration for species conservation differs between metapopulation approaches, modelling species separately and meta-community approaches allowing species interactions. The mechanism behind this is that species in well-connected landscapes rapidly outcompete each other. Species that become abundant, by chance or by their completive strength, send out large amounts of dispersers that colonize and take over other patches that are occupied by species that are less abundant. This mechanism causes rapid species loss. In fragmented landscapes the colonization rate is lower, and it is difficult for a new species to establish in an already occupied patch. So, here dominant species cannot easily take over patches occupied by other species and higher diversity is maintained for a longer time. These results suggest that fragmented landscapes have benefits for species conservation previously unrecognized by the landscape ecology and policy community. When species interactions are important, landscapes with a low fragmentation level can be better for species conservation than well-connected landscapes. Moreover, our results indicate that metapopulation based landscape evaluation tools may overestimate the value of connectivity and should be replaced by more realistic meta-community based tools. PMID:26218682

The carry-over effect of competition in task-sharing: evidence from the joint Simon task.

PubMed

Iani, Cristina; Anelli, Filomena; Nicoletti, Roberto; Rubichi, Sandro

2014-01-01

The Simon effect, that is the advantage of the spatial correspondence between stimulus and response locations when stimulus location is a task-irrelevant dimension, occurs even when the task is performed together by two participants, each performing a go/no-go task. Previous studies showed that this joint Simon effect, considered by some authors as a measure of self-other integration, does not emerge when during task performance co-actors are required to compete. The present study investigated whether and for how long competition experienced during joint performance of one task can affect performance in a following joint Simon task. In two experiments, we required pairs of participants to perform together a joint Simon task, before and after jointly performing together an unrelated non-spatial task (the Eriksen flanker task). In Experiment 1, participants always performed the joint Simon task under neutral instructions, before and after performing the joint flanker task in which they were explicitly required either to cooperate with (i.e., cooperative condition) or to compete against a co-actor (i.e., competitive condition). In Experiment 2, they were required to compete during the joint flanker task and to cooperate during the subsequent joint Simon task. Competition experienced in one task affected the way the subsequent joint task was performed, as revealed by the lack of the joint Simon effect, even though, during the Simon task participants were not required to compete (Experiment 1). However, prior competition no longer affected subsequent performance if a new goal that created positive interdependence between the two agents was introduced (Experiment 2). These results suggest that the emergence of the joint Simon effect is significantly influenced by how the goals of the co-acting individuals are related, with the effect of competition extending beyond the specific competitive setting and affecting subsequent interactions.

Sexual competition affects biomass partitioning, carbon-nutrient balance, Cd allocation and ultrastructure of Populus cathayana females and males exposed to Cd stress.

PubMed

Chen, Juan; Duan, Baoli; Xu, Gang; Korpelainen, Helena; Niinemets, Ülo; Li, Chunyang

2016-11-01

Although increasing attention has been paid to plant adaptation to soil heavy metal contamination, competition and neighbor effects have been largely overlooked, especially in dioecious plants. In this study, we investigated growth as well as biochemical and ultrastructural responses of Populus cathayana Rehder females and males to cadmium (Cd) stress under different sexual competition patterns. The results showed that competition significantly affects biomass partitioning, photosynthetic capacity, leaf and root ultrastructure, Cd accumulation, the contents of polyphenols, and structural and nonstructural carbohydrates. Compared with single-sex cultivation, plants of opposite sexes exposed to sexual competition accumulated more Cd in tissues and their growth was more strongly inhibited, indicating enhanced Cd toxicity under sexual competition. Under intrasexual competition, females showed greater Cd accumulation, more serious damage at the ultrastructural level and greater reduction in physiological activity than under intersexual competition, while males performed better under intrasexual competition than under intersexual competition. Males improved the female microenvironment by greater Cd uptake and lower resource consumption under intersexual competition. These results demonstrate that the sex of neighbor plants and competition affect sexual differences in growth and in key physiological processes under Cd stress. The asymmetry of sexual competition highlighted here might regulate population structure, and spatial segregation and phytoremediation potential of both sexes in P. cathayana growing in heavy metal-contaminated soils. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor

PubMed Central

Lountos, George T; Tropea, Joseph E; Zhang, Di; Jobson, Andrew G; Pommier, Yves; Shoemaker, Robert H; Waugh, David S

2009-01-01

Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNA-damaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC50 = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATP-binding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity. PMID:19177354

In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2

PubMed Central

Jamil, Khurram; Pappas, Stephen Chris; Devarakonda, Krishna R

2018-01-01

Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V1) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys8]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg8]-vasopressin (AVP) at V1 and vasopressin-2 (V2) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V1 and V2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [3H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V1) and cyclic adenosine monophosphate (V2). Binding potency at V1 and V2 was AVP>LVP>>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V1 than for V2. Cellular activity potency was also AVP>LVP>>terlipressin. Terlipressin was a partial agonist at V1 and a full agonist at V2; LVP was a full agonist at both V1 and V2. The in vivo response to terlipressin is likely due to the partial V1 agonist activity of terlipressin and full V1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors. PMID:29302194

In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2.

PubMed

Jamil, Khurram; Pappas, Stephen Chris; Devarakonda, Krishna R

2018-01-01

Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V 1 ) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys 8 ]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg 8 ]-vasopressin (AVP) at V 1 and vasopressin-2 (V 2 ) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V 1 and V 2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [ 3 H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V 1 ) and cyclic adenosine monophosphate (V 2 ). Binding potency at V 1 and V 2 was AVP>LVP>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V 1 than for V 2 . Cellular activity potency was also AVP>LVP>terlipressin. Terlipressin was a partial agonist at V 1 and a full agonist at V 2 ; LVP was a full agonist at both V 1 and V 2 . The in vivo response to terlipressin is likely due to the partial V 1 agonist activity of terlipressin and full V 1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.

Assessing competition in hospital care markets: the importance of accounting for quality differentiation.

PubMed

Tay, Abigail

2003-01-01

Quality differentiation is especially important in the hospital industry, where the choices of Medicare patients are unaffected by prices. Unlike previous studies that use geographic market concentration to estimate hospital competitiveness, this article emphasizes the importance of quality differentiation in this spatially differentiated market. I estimate a random-coefficients discrete-choice model that predicts patient flow to different hospitals and find that demand responses to both distance and quality are substantial. The estimates suggest that patients do not substitute toward alternative hospitals in proportion to current market shares, implying that geographic market concentration is an inappropriate measure of hospital competitiveness.

Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ

DOE PAGES

Somoza, John R.; Koditek, David; Villaseñor, Armando G.; ...

2015-01-28

Idelalisib (also known as GS-1101, CAL-101, IC489666, and Zydelig) is a PI3Kδ inhibitor that has recently been approved for the treatment of several hematological malignancies. Given its use in human diseases, we needed a clear picture of how idelalisib binds to and inhibits PI3Kδ. Here, our data show that idelalisib is a potent and selective inhibitor of the kinase activity of PI3Kδ. A kinetic characterization clearly demonstrated ATP-competitive inhibition, and several additional biochemical and biophysical assays showed that the compound binds reversibly and noncovalently to the kinase. Lastly, a crystal structure of idelalisib bound to the p110δ subunit of PI3Kδmore » furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib.« less

Natural products as zinc-dependent histone deacetylase inhibitors.

PubMed

Tan, Shuai; Liu, Zhao-Peng

2015-03-01

Zinc-dependent histone deacetylases (HDACs), a family of hydrolases that remove acetyl groups from lysine residues, play an important role in the regulation of multiple processes, from gene expression to protein activity. The dysregulation of HDACs is associated with many diseases including cancer, neurological disorders, cellular metabolism disorders, and inflammation. Molecules that act as HDAC inhibitors (HDACi) exhibit a variety of related bioactivities. In particular, HDACi have been applied clinically for the treatment of cancers. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small-molecule chemotypes, including a number of natural products. This review provides a systematic introduction of natural HDACi, with an emphasis on their enzyme inhibitory potency, selectivity, and biological activities, highlighting their various binding modes with HDACs. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Peptides as modifiers of Na+-induced pinocytosis in starved Amoeba proteus.

PubMed

Josefsson, J O; Johansson, P

1985-01-01

Low concentrations of six peptide hormones; glucagon, vasoactive intestinal peptide, substance P, angiotensin II, lysine-vasopressin, arginine-vasopressin, and the chemotactic peptide fMet-Leu-Phe, activated the capacity for pinocytosis in starved Amoeba proteus. Competitive inhibitors of the chemotactic peptide in leucocytes inhibited activation by fMet-Leu-Phe, suggesting that its action in the amoeba is mediated by specific receptors. The opioid peptides, beta-endorphin, dynorphin (1-13) and leu-enkephalin abolished through a naloxone-sensitive mechanism activation by hormones and several other activating agents. Also, low concentrations of beef and pork insulin inhibited activation by peptide hormones. An insulin analogue of low potency in mammalian cells was inactive in the amoeba. These results support the hypothesis that besides opioid receptors, there may be insulin receptors and possibly receptors for several other peptide hormones in Amoeba proteus.

Spatial analysis of agri-environmental policy uptake and expenditure in Scotland.

PubMed

Yang, Anastasia L; Rounsevell, Mark D A; Wilson, Ronald M; Haggett, Claire

2014-01-15

Agri-environment is one of the most widely supported rural development policy measures in Scotland in terms of number of participants and expenditure. It comprises 69 management options and sub-options that are delivered primarily through the competitive 'Rural Priorities scheme'. Understanding the spatial determinants of uptake and expenditure would assist policy-makers in guiding future policy targeting efforts for the rural environment. This study is unique in examining the spatial dependency and determinants of Scotland's agri-environmental measures and categorised options uptake and payments at the parish level. Spatial econometrics is applied to test the influence of 40 explanatory variables on farming characteristics, land capability, designated sites, accessibility and population. Results identified spatial dependency for each of the dependent variables, which supported the use of spatially-explicit models. The goodness of fit of the spatial models was better than for the aspatial regression models. There was also notable improvement in the models for participation compared with the models for expenditure. Furthermore a range of expected explanatory variables were found to be significant and varied according to the dependent variable used. The majority of models for both payment and uptake showed a significant positive relationship with SSSI (Sites of Special Scientific Interest), which are designated sites prioritised in Scottish policy. These results indicate that environmental targeting efforts by the government for AEP uptake in designated sites can be effective. However habitats outside of SSSI, termed here the 'wider countryside' may not be sufficiently competitive to receive funding in the current policy system. Copyright © 2013 Elsevier Ltd. All rights reserved.

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.

PubMed

Boerner, Thomas; Bygrave, Alexei M; Chen, Jingkai; Fernando, Anushka; Jackson, Stephanie; Barkus, Chris; Sprengel, Rolf; Seeburg, Peter H; Harrison, Paul J; Gilmour, Gary; Bannerman, David M; Sanderson, David J

2017-04-01

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1 -/- mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1 -/- mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function. © 2017 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The Premotor theory of attention: time to move on?

PubMed

Smith, Daniel T; Schenk, Thomas

2012-05-01

Spatial attention and eye-movements are tightly coupled, but the precise nature of this coupling is controversial. The influential but controversial Premotor theory of attention makes four specific predictions about the relationship between motor preparation and spatial attention. Firstly, spatial attention and motor preparation use the same neural substrates. Secondly, spatial attention is functionally equivalent to planning goal directed actions such as eye-movements (i.e. planning an action is both necessary and sufficient for a shift of spatial attention). Thirdly, planning a goal directed action with any effector system is sufficient to trigger a shift of spatial attention. Fourthly, the eye-movement system has a privileged role in orienting visual spatial attention. This article reviews empirical studies that have tested these predictions. Contrary to predictions one and two there is evidence of anatomical and functional dissociations between endogenous spatial attention and motor preparation. However, there is compelling evidence that exogenous attention is reliant on activation of the oculomotor system. With respect to the third prediction, there is correlational evidence that spatial attention is directed to the endpoint of goal-directed actions but no direct evidence that this attention shift is dependent on motor preparation. The few studies to have directly tested the fourth prediction have produced conflicting results, so the extent to which the oculomotor system has a privileged role in spatial attention remains unclear. Overall, the evidence is not consistent with the view that spatial attention is functionally equivalent to motor preparation so the Premotor theory should be rejected, although a limited version of the Premotor theory in which only exogenous attention is dependent on motor preparation may still be tenable. A plausible alternative account is that activity in the motor system contributes to biased competition between different sensory representations with the winner of the competition becoming the attended item. Copyright © 2012 Elsevier Ltd. All rights reserved.

Potency control of modified live viral vaccines for veterinary use.

PubMed

Terpstra, C; Kroese, A H

1996-04-01

This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of vaccination, are exemplified. Recommendations are presented for designing potency assays on master virus seeds and vaccine batches.

Potency control of modified live viral vaccines for veterinary use.

PubMed

Terpstra, C; Kroese, A H

1996-01-01

This paper reviews various aspects of efficacy, and methods for assaying the potency of modified live viral vaccines. The pros and cons of parametric versus non-parametric methods for analysis of potency assays are discussed and critical levels of protection, as determined by the target(s) of vaccination, are exemplified. Recommendations are presented for designing potency assays on master virus seeds and vaccine batches.

CSP-TSM: Optimizing the performance of Riemannian tangent space mapping using common spatial pattern for MI-BCI.

PubMed

Kumar, Shiu; Mamun, Kabir; Sharma, Alok

2017-12-01

Classification of electroencephalography (EEG) signals for motor imagery based brain computer interface (MI-BCI) is an exigent task and common spatial pattern (CSP) has been extensively explored for this purpose. In this work, we focused on developing a new framework for classification of EEG signals for MI-BCI. We propose a single band CSP framework for MI-BCI that utilizes the concept of tangent space mapping (TSM) in the manifold of covariance matrices. The proposed method is named CSP-TSM. Spatial filtering is performed on the bandpass filtered MI EEG signal. Riemannian tangent space is utilized for extracting features from the spatial filtered signal. The TSM features are then fused with the CSP variance based features and feature selection is performed using Lasso. Linear discriminant analysis (LDA) is then applied to the selected features and finally classification is done using support vector machine (SVM) classifier. The proposed framework gives improved performance for MI EEG signal classification in comparison with several competing methods. Experiments conducted shows that the proposed framework reduces the overall classification error rate for MI-BCI by 3.16%, 5.10% and 1.70% (for BCI Competition III dataset IVa, BCI Competition IV Dataset I and BCI Competition IV Dataset IIb, respectively) compared to the conventional CSP method under the same experimental settings. The proposed CSP-TSM method produces promising results when compared with several competing methods in this paper. In addition, the computational complexity is less compared to that of TSM method. Our proposed CSP-TSM framework can be potentially used for developing improved MI-BCI systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Potency under pressure: the impact of hydrostatic pressure on antigenic properties of influenza virus hemagglutinin.

PubMed

Eichelberger, Schafer L; Sultana, Ishrat; Gao, Jin; Getie-Kebtie, Melkamu; Alterman, Michail; Eichelberger, Maryna C

2013-11-01

Influenza vaccines are effective in protecting against illness and death caused by this seasonal pathogen. The potency of influenza vaccines is measured by single radial immunodiffusion (SRID) assay that quantifies antigenic forms of hemagglutinin (HA). Hydrostatic pressure results in loss of binding of influenza virus to red blood cells, but it is not known whether this infers loss of potency. Our goal was to determine the impact of pressure on HA antigenic structure. Viruses included in the 2010-2011 trivalent influenza vaccine were subjected to increasing number of cycles at 35,000 psi in a barocycler, and the impact of this treatment measured by determining hemagglutination units (HAU) and potency. Potency was assessed by SRID and immunogenicity in mice. After 25 cycles of pressure, the potency measured by SRID assay was below the limit of quantification for the H1N1 and B viruses used in our study, while the H3N2 component retained some potency that was lost after 50 pressure cycles. Pressure treatment also resulted in loss of HAU, but this did not strictly correlate with the potency value. Curiously, loss of potency was abrogated when influenza A, but not B, antigens were exposed to pressure in chicken egg allantoic fluid. Protection against pressure appeared to be mediated by specific interactions because addition of bovine serum albumin did not have the same effect. Our results show that pressure-induced loss of potency is strain dependent and suggests that pressure treatment may be useful for identifying vaccine formulations that improve HA stability. Published 2013. This article is U.S. Government work and in the public domain in the USA.

The role of the mother-child relationship for anxiety disorders and depression: results from a prospective-longitudinal study in adolescents and their mothers.

PubMed

Asselmann, Eva; Wittchen, Hans-Ulrich; Lieb, Roselind; Beesdo-Baum, Katja

2015-04-01

This study aims to examine whether (a) low child valence (emotional connectedness) within the mother-child relationship increases the risk for offspring depression, (b) low child potency (individual autonomy) increases the risk for offspring anxiety, and (c) maternal psychopathology pronounces these associations. We used data from a prospective-longitudinal study of adolescents (aged 14-17 at baseline) and their mothers (N = 1,015 mother-child dyads). Anxiety disorders and depression were assessed repeatedly over 10 years in adolescents (T0, T1, T2, T3) and their mothers (T1, T3) using the DSM-IV/M-CIDI. Valence and potency were assessed in mothers (T1) with the Subjective Family Image Questionnaire. Odds ratios (OR) from logistic regression were used to estimate associations between low child valence/potency and offspring psychopathology (cumulated lifetime incidences; adjusted for sex and age). In separate models (low valence or low potency as predictor), low child valence predicted offspring depression only (OR = 1.26 per SD), while low child potency predicted offspring anxiety (OR = 1.24) and depression (OR = 1.24). In multiple models (low valence and low potency as predictors), low child valence predicted offspring depression only (OR = 1.19), while low child potency predicted offspring anxiety only (OR = 1.22). Low child potency interacted with maternal anxiety on predicting offspring depression (OR = 1.49), i.e. low child potency predicted offspring depression only in the presence of maternal anxiety (OR = 1.33). These findings suggest that low child valence increases the risk for offspring depression, while low child potency increases the risk for offspring anxiety and depression and interacts with maternal psychopathology on predicting offspring depression.

Examining the profile of high-potency cannabis and its association with severity of cannabis dependence.

PubMed

Freeman, T P; Winstock, A R

2015-11-01

Cannabis use is decreasing in England and Wales, while demand for cannabis treatment in addiction services continues to rise. This could be partly due to an increased availability of high-potency cannabis. Adults residing in the UK were questioned about their drug use, including three types of cannabis (high potency: skunk; low potency: other grass, resin). Cannabis types were profiled and examined for possible associations between frequency of use and (i) cannabis dependence, (ii) cannabis-related concerns. Frequent use of high-potency cannabis predicted a greater severity of dependence [days of skunk use per month: b = 0.254, 95% confidence interval (CI) 0.161-0.357, p < 0.001] and this effect became stronger as age decreased (b = -0.006, 95% CI -0.010 to -0.002, p = 0.004). By contrast, use of low-potency cannabis was not associated with dependence (days of other grass use per month: b = 0.020, 95% CI -0.029 to 0.070, p = 0.436; days of resin use per month: b = 0.025, 95% CI -0.019 to 0.067, p = 0.245). Frequency of cannabis use (all types) did not predict severity of cannabis-related concerns. High-potency cannabis was clearly distinct from low-potency varieties by its marked effects on memory and paranoia. It also produced the best high, was preferred, and most available. High-potency cannabis use is associated with an increased severity of dependence, especially in young people. Its profile is strongly defined by negative effects (memory, paranoia), but also positive characteristics (best high, preferred type), which may be important when considering clinical or public health interventions focusing on cannabis potency.

The comparative performance of the single intradermal test and the single intradermal comparative tuberculin test in Irish cattle, using tuberculin PPD combinations of differing potencies.

PubMed

Good, M; Clegg, T A; Costello, E; More, S J

2011-11-01

In national bovine tuberculosis (BTB) control programmes, testing is generally conducted using a single source of bovine purified protein derivative (PPD) tuberculin. Alternative tuberculin sources should be identified as part of a broad risk management strategy as problems of supply or quality cannot be discounted. This study was conducted to compare the impact of different potencies of a single bovine PPD tuberculin on the field performance of the single intradermal comparative tuberculin test (SICTT) and single intradermal test (SIT). Three trial potencies of bovine PPD tuberculin, as assayed in naturally infected bovines, namely, low (1192IU/dose), normal (6184IU/dose) and high (12,554IU/dose) were used. Three SICTTs (using) were conducted on 2102 animals. Test results were compared based on reactor-status and changes in skin-thickness at the bovine tuberculin injection site. There was a significant difference in the number of reactors detected using the high and low potency tuberculins. In the SICTT, high and low potency tuberculin detected 40% more and 50% fewer reactors, respectively, than normal potency tuberculin. Furthermore, use of the low potency tuberculin in the SICTT failed to detect 20% of 35 animals with visible lesions, and in the SIT 11% of the visible lesion animals would have been classified as negative. Tuberculin potency is critical to the performance of both the SICTT and SIT. Tuberculin of different potencies will affect reactor disclosure rates, confounding between-year or between-country comparisons. Independent checks of tuberculin potency are an important aspect of quality control in national BTB control programmes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Correlation of liquid chromatographic and biological assay for potency assessment of filgrastim and related impurities.

PubMed

Skrlin, Ana; Kosor Krnic, Ela; Gosak, Darko; Prester, Berislav; Mrsa, Vladimir; Vuletic, Marko; Runac, Domagoj

2010-11-02

In vivo and in vitro potency assays have always been a critical tool for confirmation of protein activity. However, due to their complexity and time consuming procedures, it remains a challenge to find an alternative analytical approach that would enable their replacement with no impact on the quality of provided information. The goal of this research was to determine if a correlation between liquid chromatography assays and in vitro biological assay could be established for filgrastim (recombinant human granulocyte-colony stimulating factor, rhG-CSF) samples containing various amounts of related impurities. For that purpose, relevant filgrastim related impurities were purified to homogeneity and characterized by liquid chromatography and mass spectrometry. A significant correlation (R(2)>0.90) between the two types of assays was revealed. Potency of oxidized filgrastim was determined to be approximately 25% of filgrastim stated potency (1 x 10(8)IU/mg of protein). Formyl-methionine filgrastim had potency of 89% of the filgrastim stated potency, while filgrastim dimer had 67% of filgrastim stated potency. A mathematical model for the estimation of biological activity of filgrastim samples from chromatography data was established and a significant correlation between experimental potency values and potency values estimated by the mathematical model was obtained (R(2)=0.92). Based on these results a conclusion was made that reversed phase high performance liquid chromatography could be used as an alternative for the in vitro biological assay for potency assessment of filgrastim samples. Such an alternative model would enable substitution of a complex and time consuming biological assay with a robust and precise instrumental method in many practical cases. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Structure-based design of competitive ligands to target Spon2 in gastric cancer: An integration of molecular modeling and in vitro assay.

PubMed

Xu, Zhenglei; Yu, Zhichao; Nai, Shumei; Shi, Ruiyue; Tang, Qinhong; Zhang, Haiyang; Ye, Lijuan; Wang, Lisheng; Hong, Yincai

2017-10-01

Spon2 is a proto-oncogene matrix protein that plays an essential role in the tumorigenesis and metastasis of gastric cancer. The protein has recently been found to function as a guanine nucleotide exchange factor through the activation of RhoGTPase. Here, computational modeling and bioinformatics analysis were employed to investigate the molecular mechanism and biological implication underlying Spon2 autoinhibition. It is revealed that the binding of PxxP motif to SH domain can stabilize the intramolecular interaction between the N-terminal helix and DH domain of Spon2, thus shifting the protein into an autoinhibitory state. Here, we proposed releasing Spon2 autoinhibition by targeting SH domain with competitive peptide ligands. To verify this notion, the PxxP sequence was adopted as the start to derive an array of efficient SH binders by using a structure-based rational design strategy, which were then substantiated with fluorescence spectroscopy analysis and guanine nucleotide exchange test. Consequently, the obtained peptide ligands were determined to have a moderate or high affinity for SH domain; they can also enhance Spon2 exchange activity by 1.2-6.1 folds, exhibiting a significant correlation with their SH-binding affinity (Pearson's coefficient=0.92). In addition, neutral substitution of conserved residues in a high-affinity peptide ligand can largely reduce its Spon2-activating potency, confirming that the designed peptide activates Spon2 by competitively disrupting SH-PxxP interaction. Copyright © 2017 Elsevier Inc. All rights reserved.

Disturbance and density-dependent processes (competition and facilitation) influence the fine-scale genetic structure of a tree species' population.

PubMed

Fajardo, Alex; Torres-Díaz, Cristian; Till-Bottraud, Irène

2016-01-01

Disturbances, dispersal and biotic interactions are three major drivers of the spatial distribution of genotypes within populations, the last of which has been less studied than the other two. This study aimed to determine the role of competition and facilitation in the degree of conspecific genetic relatedness of nearby individuals of tree populations. It was expected that competition among conspecifics will lead to low relatedness, while facilitation will lead to high relatedness (selection for high relatedness within clusters). The stand structure and spatial genetic structure (SGS) of trees were examined within old-growth and second-growth forests (including multi-stemmed trees at the edge of forests) of Nothofagus pumilio following large-scale fires in Patagonia, Chile. Genetic spatial autocorrelations were computed on a spatially explicit sampling of the forests using five microsatellite loci. As biotic plant interactions occur among immediate neighbours, mean nearest neighbour distance (MNND) among trees was computed as a threshold for distinguishing the effects of disturbances and biotic interactions. All forests exhibited a significant SGS for distances greater than the MNND. The old-growth forest genetic and stand structure indicated gap recolonization from nearby trees (significantly related trees at distances between 4 and 10 m). At distances smaller than the MNND, trees of the second-growth interior forest showed significantly lower relatedness, suggesting a fading of the recolonization structure by competition, whereas the second-growth edge forest showed a positive and highly significant relatedness among trees (higher among stems of a cluster than among stems of different clusters), resulting from facilitation. Biotic interactions are shown to influence the genetic composition of a tree population. However, facilitation can only persist if individuals are related. Thus, the genetic composition in turn influences what type of biotic interactions will take place among immediate neighbours in post-disturbance forests. © The Author 2015. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Local Competition-Based Superpixel Segmentation Algorithm in Remote Sensing

PubMed Central

Liu, Jiayin; Tang, Zhenmin; Cui, Ying; Wu, Guoxing

2017-01-01

Remote sensing technologies have been widely applied in urban environments’ monitoring, synthesis and modeling. Incorporating spatial information in perceptually coherent regions, superpixel-based approaches can effectively eliminate the “salt and pepper” phenomenon which is common in pixel-wise approaches. Compared with fixed-size windows, superpixels have adaptive sizes and shapes for different spatial structures. Moreover, superpixel-based algorithms can significantly improve computational efficiency owing to the greatly reduced number of image primitives. Hence, the superpixel algorithm, as a preprocessing technique, is more and more popularly used in remote sensing and many other fields. In this paper, we propose a superpixel segmentation algorithm called Superpixel Segmentation with Local Competition (SSLC), which utilizes a local competition mechanism to construct energy terms and label pixels. The local competition mechanism leads to energy terms locality and relativity, and thus, the proposed algorithm is less sensitive to the diversity of image content and scene layout. Consequently, SSLC could achieve consistent performance in different image regions. In addition, the Probability Density Function (PDF), which is estimated by Kernel Density Estimation (KDE) with the Gaussian kernel, is introduced to describe the color distribution of superpixels as a more sophisticated and accurate measure. To reduce computational complexity, a boundary optimization framework is introduced to only handle boundary pixels instead of the whole image. We conduct experiments to benchmark the proposed algorithm with the other state-of-the-art ones on the Berkeley Segmentation Dataset (BSD) and remote sensing images. Results demonstrate that the SSLC algorithm yields the best overall performance, while the computation time-efficiency is still competitive. PMID:28604641

Local Competition-Based Superpixel Segmentation Algorithm in Remote Sensing.

PubMed

Liu, Jiayin; Tang, Zhenmin; Cui, Ying; Wu, Guoxing

2017-06-12

Remote sensing technologies have been widely applied in urban environments' monitoring, synthesis and modeling. Incorporating spatial information in perceptually coherent regions, superpixel-based approaches can effectively eliminate the "salt and pepper" phenomenon which is common in pixel-wise approaches. Compared with fixed-size windows, superpixels have adaptive sizes and shapes for different spatial structures. Moreover, superpixel-based algorithms can significantly improve computational efficiency owing to the greatly reduced number of image primitives. Hence, the superpixel algorithm, as a preprocessing technique, is more and more popularly used in remote sensing and many other fields. In this paper, we propose a superpixel segmentation algorithm called Superpixel Segmentation with Local Competition (SSLC), which utilizes a local competition mechanism to construct energy terms and label pixels. The local competition mechanism leads to energy terms locality and relativity, and thus, the proposed algorithm is less sensitive to the diversity of image content and scene layout. Consequently, SSLC could achieve consistent performance in different image regions. In addition, the Probability Density Function (PDF), which is estimated by Kernel Density Estimation (KDE) with the Gaussian kernel, is introduced to describe the color distribution of superpixels as a more sophisticated and accurate measure. To reduce computational complexity, a boundary optimization framework is introduced to only handle boundary pixels instead of the whole image. We conduct experiments to benchmark the proposed algorithm with the other state-of-the-art ones on the Berkeley Segmentation Dataset (BSD) and remote sensing images. Results demonstrate that the SSLC algorithm yields the best overall performance, while the computation time-efficiency is still competitive.

Methods for the Quality Control of Inactivated Poliovirus Vaccines.

PubMed

Wilton, Thomas

2016-01-01

Inactivated poliovirus vaccine (IPV) plays an instrumental role in the Global Poliovirus Eradication Initiative (GPEI). The quality of IPV is controlled by assessment of the potency of vaccine batches. The potency of IPV can be assessed by both in vivo and in vitro methods. In vitro potency assessment is based upon the assessment of the quantity of the D-Antigen (D-Ag) units in an IPV. The D-Ag unit is used as a measure of potency as it is largely expressed on native infectious virions and is the protective immunogen. The most commonly used in vitro test is the indirect ELISA which is used to ensure consistency throughout production.A range of in vivo assays have been developed in monkeys, chicks, guinea pigs, mice, and rats to assess the potency of IPV. All are based on assessment of the neutralizing antibody titer within the sera of the respective animal model. The rat potency test has become the favored in vivo potency test as it shows minimal variation between laboratories and the antibody patterns of rats and humans are similar. With the development of transgenic mice expressing the human poliovirus receptor, immunization-challenge tests have been developed to assess the potency of IPVs. This chapter describes in detail the methodology of these three laboratory tests to assess the quality of IPVs.

A Sphingosine 1-phosphate receptor 2 selective allosteric agonist

PubMed Central

Satsu, Hideo; Schaeffer, Marie-Therese; Guerrero, Miguel; Saldana, Adrian; Eberhart, Christina; Hodder, Peter; Cayanan, Charmagne; Schürer, Stephan; Bhhatarai, Barun; Roberts, Ed; Rosen, Hugh; Brown, Steven J.

2013-01-01

Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. PMID:23849205

Increased stem density and competition may diminish the positive effects of warming at alpine treeline.

PubMed

Wang, Yafeng; Pederson, Neil; Ellison, Aaron M; Buckley, Hannah L; Case, Bradley S; Liang, Eryuan; Julio Camarero, J

2016-07-01

The most widespread response to global warming among alpine treeline ecotones is not an upward shift, but an increase in tree density. However, the impact of increasing density on interactions among trees at treeline is not well understood. Here, we test if treeline densification induced by climatic warming leads to increasing intraspecific competition. We mapped and measured the size and age of Smith fir trees growing in two treelines located in the southeastern Tibetan Plateau. We used spatial point-pattern and codispersion analyses to describe the spatial association and covariation among seedlings, juveniles, and adults grouped in 30-yr age classes from the 1860s to the present. Effects of competition on tree height and regeneration were inferred from bivariate mark-correlations. Since the 1950s, a rapid densification occurred at both sites in response to climatic warming. Competition between adults and juveniles or seedlings at small scales intensified as density increased. Encroachment negatively affected height growth and further reduced recruitment around mature trees. We infer that tree recruitment at the studied treelines was more cold-limited prior to 1950 and shifted to a less temperature-constrained regime in response to climatic warming. Therefore, the ongoing densification and encroachment of alpine treelines could alter the way climate drives their transitions toward subalpine forests. © 2016 by the Ecological Society of America.

The implications of spatially variable pre‐emergence herbicide efficacy for weed management

PubMed Central

Milne, Alice E; Hull, Richard; Murdoch, Alistair J; Storkey, Jonathan

2017-01-01

Abstract BACKGROUND The efficacy of pre‐emergence herbicides within fields is spatially variable as a consequence of soil heterogeneity. We quantified the effect of soil organic matter on the efficacy of two pre‐emergence herbicides, flufenacet and pendimethalin, against Alopecurus myosuroides and investigated the implications of variation in organic matter for weed management using a crop–weed competition model. RESULTS Soil organic matter played a critical role in determining the level of control achieved. The high organic matter soil had more surviving weeds with higher biomass than the low organic matter soil. In the absence of competition, surviving plants recovered to produce the same amount of seed as if no herbicide had been applied. The competition model predicted that weeds surviving pre‐emergence herbicides could compensate for sublethal effects even when competing with the crop. The ED50 (median effective dose) was higher for weed seed production than seedling mortality or biomass. This difference was greatest on high organic matter soil. CONCLUSION These results show that the application rate of herbicides should be adjusted to account for within‐field variation in soil organic matter. The results from the modelling emphasised the importance of crop competition in limiting the capacity of weeds surviving pre‐emergence herbicides to compensate and replenish the seedbank. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID:29095563

Body size mediated coexistence of consumers competing for resources in space

USGS Publications Warehouse

Basset, A.; Angelis, D.L.

2007-01-01

Body size is a major phenotypic trait of individuals that commonly differentiates co-occurring species. We analyzed inter-specific competitive interactions between a large consumer and smaller competitors, whose energetics, selection and giving-up behaviour on identical resource patches scaled with individual body size. The aim was to investigate whether pure metabolic constraints on patch behaviour of vagile species can determine coexistence conditions consistent with existing theoretical and experimental evidence. We used an individual-based spatially explicit simulation model at a spatial scale defined by the home range of the large consumer, which was assumed to be parthenogenic and semelparous. Under exploitative conditions, competitive coexistence occurred in a range of body size ratios between 2 and 10. Asymmetrical competition and the mechanism underlying asymmetry, determined by the scaling of energetics and patch behaviour with consumer body size, were the proximate determinant of inter-specific coexistence. The small consumer exploited patches more efficiently, but searched for profitable patches less effectively than the larger competitor. Therefore, body-size related constraints induced niche partitioning, allowing competitive coexistence within a set of conditions where the large consumer maintained control over the small consumer and resource dynamics. The model summarises and extends the existing evidence of species coexistence on a limiting resource, and provides a mechanistic explanation for decoding the size-abundance distribution patterns commonly observed at guild and community levels. ?? Oikos.

Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents.

PubMed

Zheng, Suqing; Santosh Laxmi, Y R; David, Emilie; Dinkova-Kostova, Albena T; Shiavoni, Katherine H; Ren, Yanqing; Zheng, Ying; Trevino, Isaac; Bumeister, Ronald; Ojima, Iwao; Wigley, W Christian; Bliska, James B; Mierke, Dale F; Honda, Tadashi

2012-05-24

Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-α and IL-1β with potencies that are higher than those of bardoxolone methyl and TBE-31.

In vitro versus in vivo concordance: a case study of the replacement of an animal potency test with an immunochemical assay.

PubMed

Schofield, T

2002-01-01

Early in its development, the potency of Merck's recombinant hepatitis B vaccine, RECOMBIVAX HB, was monitored using an assay performed in mice. A specification was determined to be the lowest potency which induced acceptable response in clinical trials. As a post-licensing commitment, Merck was asked to replace its mouse potency assay with an in vitro procedure for product release in the US market. Early studies with a commercial enzyme immunoassay (EIA) yielded highly variable results. That assay, combined with a sample pretreatment step, proved more dependable and predictive of potency in the mouse assay. Based on measurements made on manufactured materials, combined with experiments contrived to yield a wide range of reactivity in the two assays, concordance was established between the EIA and the mouse potency assay. This concordance was used to calibrate a specification for the in vitro assay that is predictive of a satisfactory response in vivo. Data from clinical trials established a correspondence between human immunogenicity and these potency markers.

Does interference competition with wolves limit the distribution and abundance of coyotes?

PubMed

Berger, Kim Murray; Gese, Eric M

2007-11-01

Interference competition with wolves Canis lupus is hypothesized to limit the distribution and abundance of coyotes Canis latrans, and the extirpation of wolves is often invoked to explain the expansion in coyote range throughout much of North America. We used spatial, seasonal and temporal heterogeneity in wolf distribution and abundance to test the hypothesis that interference competition with wolves limits the distribution and abundance of coyotes. From August 2001 to August 2004, we gathered data on cause-specific mortality and survival rates of coyotes captured at wolf-free and wolf-abundant sites in Grand Teton National Park (GTNP), Wyoming, USA, to determine whether mortality due to wolves is sufficient to reduce coyote densities. We examined whether spatial segregation limits the local distribution of coyotes by evaluating home-range overlap between resident coyotes and wolves, and by contrasting dispersal rates of transient coyotes captured in wolf-free and wolf-abundant areas. Finally, we analysed data on population densities of both species at three study areas across the Greater Yellowstone Ecosystem (GYE) to determine whether an inverse relationship exists between coyote and wolf densities. Although coyotes were the numerically dominant predator, across the GYE, densities varied spatially and temporally in accordance with wolf abundance. Mean coyote densities were 33% lower at wolf-abundant sites in GTNP, and densities declined 39% in Yellowstone National Park following wolf reintroduction. A strong negative relationship between coyote and wolf densities (beta = -3.988, P < 0.005, r(2) = 0.54, n = 16), both within and across study sites, supports the hypothesis that competition with wolves limits coyote populations. Overall mortality of coyotes resulting from wolf predation was low, but wolves were responsible for 56% of transient coyote deaths (n = 5). In addition, dispersal rates of transient coyotes captured at wolf-abundant sites were 117% higher than for transients captured in wolf-free areas. Our results support the hypothesis that coyote abundance is limited by competition with wolves, and suggest that differential effects on survival and dispersal rates of transient coyotes are important mechanisms by which wolves reduce coyote densities.

Sex differences on the competitive place task in the water maze: The influence of peripheral pool time on spatial navigation performance in rats.

PubMed

Devan, Bryan D; Tobin, Elizabeth L; Dunn, Emily N; Magalis, Christopher

2016-11-01

This study investigated sex differences on the competitive place version of the Morris water maze task to determine whether potential strategy differences would emerge during any phase of the study but in particular on the competitive place phase. Previous findings indicate that this version of the task is highly sensitive to measures that disrupt NMDA-dependent synaptic plasticity within the hippocampus during memory consolidation (McDonald et al., 2005). The present findings revealed significant sex differences during all phases of the study, including Phase I with standard place training to located a hidden platform/goal, Phase II mass training to a new place with the platform/goal relocated to the diagonally opposite quadrant and Phase III, competitive place probe test with the platform removed to measure spatial behaviour directed at either location. The findings showed no sex difference in escape latency and other standard performance measures during the first two phases, initial place acquisition and mass training to a new location. A very subtle male advantage in visiting both Old and New place locations during the third phase place competition test was observed, however, in the time spent swimming in the periphery of the pool, the pool wall (Zone C - outer third radial distance) was increased for females during all phases of the study, suggesting a general effect may have influenced place location search behaviour of the females. Increased peripheral pool time may represent a female preference for approaching the wall, a local cue. Alternatively, the possibility that increased peripheral swimming/thigmotaxis may represent hormonal influences interacting with strategic preferences were discussed, though no definitive conclusions about sex differences in cognitive-spatial performance or memory consolidation were inferred from the present findings. The findings suggest that mixed results reported in the literature by others may be due in part to an interaction with a persistent peripheral pool swimming response demonstrated in female rats. Copyright © 2016 Elsevier B.V. All rights reserved.

The shift from plant-plant facilitation to competition under severe water deficit is spatially explicit.

PubMed

O'Brien, Michael J; Pugnaire, Francisco I; Armas, Cristina; Rodríguez-Echeverría, Susana; Schöb, Christian

2017-04-01

The stress-gradient hypothesis predicts a higher frequency of facilitative interactions as resource limitation increases. Under severe resource limitation, it has been suggested that facilitation may revert to competition, and identifying the presence as well as determining the magnitude of this shift is important for predicting the effect of climate change on biodiversity and plant community dynamics. In this study, we perform a meta-analysis to compare temporal differences of species diversity and productivity under a nurse plant ( Retama sphaerocarpa ) with varying annual rainfall quantity to test the effect of water limitation on facilitation. Furthermore, we assess spatial differences in the herbaceous community under nurse plants in situ during a year with below-average rainfall. We found evidence that severe rainfall deficit reduced species diversity and plant productivity under nurse plants relative to open areas. Our results indicate that the switch from facilitation to competition in response to rainfall quantity is nonlinear. The magnitude of this switch depended on the aspect around the nurse plant. Hotter south aspects under nurse plants resulted in negative effects on beneficiary species, while the north aspect still showed facilitation. Combined, these results emphasize the importance of spatial heterogeneity under nurse plants for mediating species loss under reduced precipitation, as predicted by future climate change scenarios. However, the decreased water availability expected under climate change will likely reduce overall facilitation and limit the role of nurse plants as refugia, amplifying biodiversity loss.

Spatial and Dietary Overlap Creates Potential for Competition between Red Snapper (Lutjanus campechanus) and Vermilion snapper (Rhomboplites aurorubens)

PubMed Central

Davis, William T.; Drymon, J. Marcus; Powers, Sean P.

2015-01-01

Understanding the complex nature of direct and indirect species interactions is a critical precursor to successful resource management. In the northern Gulf of Mexico fisheries ecosystem, red snapper (Lutjanus campechanus) and vermilion snapper (Rhomboplites aurorubens) are two commercially harvested species within a larger reef fish complex. These two species share similar habitats and diets; however, little is known about how these species partition habitat and dietary resources. In this study we examined the extent of spatial and dietary overlap between red snapper and vermilion snapper, and experimentally compared their feeding behavior. Field data from multiple gear types demonstrates that red snapper and vermilion snapper frequently cohabited reefs in the northern Gulf of Mexico, and Pianka’s niche overlap indices suggest significantly overlapping diets. Experimental manipulations show that red snapper are the dominant forager of the two species, as red snapper foraging alone ate more shrimp per fish than vermilion snapper in both the single species (p = 0.003) and mixed species (p = 0.02) treatments. In addition, red snapper ate significantly more shrimp per fish in the mixed species treatment than in the single species treatment (p = 0.04). Vermilion snapper shrimp consumption per fish did not differ significantly between mixed and single species treatments. Cumulatively, our results suggest that spatial and dietary overlap could lead to competition between red and vermilion snapper in the study area; however, conclusively determining the existence of such competition would require further research. PMID:26630481

Spatial and Dietary Overlap Creates Potential for Competition between Red Snapper (Lutjanus campechanus) and Vermilion snapper (Rhomboplites aurorubens).

PubMed

Davis, William T; Drymon, J Marcus; Powers, Sean P

2015-01-01

Understanding the complex nature of direct and indirect species interactions is a critical precursor to successful resource management. In the northern Gulf of Mexico fisheries ecosystem, red snapper (Lutjanus campechanus) and vermilion snapper (Rhomboplites aurorubens) are two commercially harvested species within a larger reef fish complex. These two species share similar habitats and diets; however, little is known about how these species partition habitat and dietary resources. In this study we examined the extent of spatial and dietary overlap between red snapper and vermilion snapper, and experimentally compared their feeding behavior. Field data from multiple gear types demonstrates that red snapper and vermilion snapper frequently cohabited reefs in the northern Gulf of Mexico, and Pianka's niche overlap indices suggest significantly overlapping diets. Experimental manipulations show that red snapper are the dominant forager of the two species, as red snapper foraging alone ate more shrimp per fish than vermilion snapper in both the single species (p = 0.003) and mixed species (p = 0.02) treatments. In addition, red snapper ate significantly more shrimp per fish in the mixed species treatment than in the single species treatment (p = 0.04). Vermilion snapper shrimp consumption per fish did not differ significantly between mixed and single species treatments. Cumulatively, our results suggest that spatial and dietary overlap could lead to competition between red and vermilion snapper in the study area; however, conclusively determining the existence of such competition would require further research.

An empirical investigation of spatial differentiation and price floor regulations in retail markets for gasoline

NASA Astrophysics Data System (ADS)

Houde, Jean-Francois

In the first essay of this dissertation, I study an empirical model of spatial competition. The main feature of my approach is to formally specify commuting paths as the "locations" of consumers in a Hotelling-type model of spatial competition. The main consequence of this location assumption is that the substitution patterns between stations depend in an intuitive way on the structure of the road network and the direction of traffic flows. The demand-side of the model is estimated by combining a model of traffic allocation with econometric techniques used to estimate models of demand for differentiated products (Berry, Levinsohn and Pakes (1995)). The estimated parameters are then used to evaluate the importance of commuting patterns in explaining the distribution of gasoline sales, and compare the economic predictions of the model with the standard home-location model. In the second and third essays, I examine empirically the effect of a price floor regulation on the dynamic and static equilibrium outcomes of the gasoline retail industry. In particular, in the second essay I study empirically the dynamic entry and exit decisions of gasoline stations, and measure the impact of a price floor on the continuation values of staying in the industry. In the third essay, I develop and estimate a static model of quantity competition subject to a price floor regulation. Both models are estimated using a rich panel dataset on the Quebec gasoline retail market before and after the implementation of a price floor regulation.

The pilosebaceous unit—a phthalate-induced pathway to skin sensitization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simonsson, Carl, E-mail: carl.simonsson@chem.gu.se; Stenfeldt, Anna-Lena; Karlberg, Ann-Therese

2012-10-01

Allergic contact dermatitis (ACD) is caused by low-molecular weight compounds called haptens. It has been shown that the potency of haptens can depend on the formulation in which they are applied on the skin. Specifically the sensitization potency of isothiocyanates, a group of haptens which can be released from e.g. adhesive tapes and neoprene materials, increases with the presence of phthalates; however, the underlying mechanisms are not clear. A better understanding of the mechanisms governing the potency of haptens is important, e.g. to improve the risk assessment and the formulation of chemicals in consumer products. In this study we havemore » explored phthalate-induced effects on the sensitization potency, skin distribution, and reactivity of fluorescent model isothiocyanate haptens using non-invasive two-photon microscopy to provide new insights regarding vehicle effects in ACD. The data presented in this paper indicate that the sensitization potency of isothiocyanates increases when applied in combination with dibutylphthalate due to a specific uptake via the pilosebaceous units. The results highlight the importance of shunt pathways when evaluating the bioavailability of skin sensitizers. The findings also indicate that vehicle-dependent hapten reactivity towards stratum corneum proteins regulates the bioavailability, and thus the potency, of skin sensitizers. -- Highlights: ► Vehicle effects on sensitization potency were investigated in the LLNA. ► In vivo cutaneous absorption of contact sensitizers was visualized using TPM. ► Sensitizing potency of isothiocyanates depends on the presence of a phthalate. ► Phthalate induced cutaneous absorption via the pilosebaceous units. ► Vehicle-dependent reactivity regulates sensitization potency.« less

The Effects of Medical Marijuana Laws on Potency

PubMed Central

Pacula, Rosalie Liccardo; Heaton, Paul

2014-01-01

Background Marijuana potency has risen dramatically over the past two decades. In the United States, it is unclear whether state medical marijuana policies have contributed to this increase. Methods Employing a differences-in-differences model within a mediation framework, we analyzed data on n = 39,157 marijuana samples seized by law enforcement in 51 U.S. jurisdictions between 1990-2010, producing estimates of the direct and indirect effects of state medical marijuana laws on potency, as measured by Δ9-tetrahydrocannabinol content. Results We found evidence that potency increased by a half percentage point on average after legalization of medical marijuana, although this result was not significant. When we examined specific medical marijuana supply provisions, results suggest that legal allowances for retail dispensaries had the strongest influence, significantly increasing potency by about one percentage point on average. Our mediation analyses examining the mechanisms through which medical marijuana laws influence potency found no evidence of direct regulatory impact. Rather, the results suggest that the impact of these laws occurs predominantly through a compositional shift in the share of the market captured by high-potency sinsemilla. Conclusion Our findings have important implications for policymakers and those in the scientific community trying to understand the extent to which greater availability of higher potency marijuana increases the risk of negative public health outcomes, such as drugged driving and drug-induced psychoses. Future work should reconsider the impact of medical marijuana laws on health outcomes in light of dramatic and ongoing shifts in both marijuana potency and the medical marijuana policy environment. PMID:24502887

Radioligand binding, autoradiographic and functional studies demonstrate tachykinin NK-2 receptors in dog urinary bladder.

PubMed

Mussap, C J; Stamatakos, C; Burcher, E

1996-10-01

Tachykinin receptors in the dog bladder were characterized using radioligand binding, functional and autoradiographic techniques. In detrusor muscle homogenates, specific binding of [125l]iodohistidyl neurokinin A (INKA) and [125l]Bolton Hunter eledoisin was reversible, saturable and, to a single class of sites of Kd, 3,6 and 27 nM, respectively. No specific binding of [125l]Bolton Hunter[Sar9, Met (O2)11] substance P occurred. INKA binding was reduced by the peptidase inhibitor bacitracin. The rank potency order of agonists competing for binding of both radioligands indicated interaction at NK-2 sites. NK-2-selective antagonists also competed for INKA binding, with SR 48968, GR 94800, MDL 29913 and the selective agonist [Lys5, MeLeu9, Nle10]-NKA(4-10) showing biphasic binding profiles. Autoradiographic studies revealed specific binding of INKA and [125l]Bolton Hunter eledoisin over detrusor muscle and small arteries. [125l]Bolton Hunter [Sar9, Met (O2)11] SP labeled the intima of arteries and arterioles, but not the detrusor muscle. Tachykinins contracted detrusor muscle strips, with potency order at the carbachol EC15 NKA = kassinin > [Lys5, MeLeu9, Nle10]-NKA(4-10) = neuropeptide gamma = neuropeptide K = NKB > > MDL 28564, with [Sar9, Met(O2)11]-SP ineffective. Shallow concentration-response curves, variable efficacies and inhibition by atropine and mepyramine suggest that other mechanisms may influence contractile responses. Responses to [Lys5, MeLeu9, Nle10]-NKA(4-10) were inhibited competitively by MDL 29913 and MEN 10207 (pA2 values: 6.4 and 5.3, respectively). Antagonism by SR 48968 and GR 94800 was noncompetitive (both pK8 values 8.9). In summary, NK-2-preferring ligands showed superior potency as both binding competitors and contractile agonists, demonstrating that NK-2 receptors mediate detrusor muscle contraction, similar to the human detrusor. Tachykinins may play important roles in the micturition reflex and in regulating detrusor muscle blood flow in the dog.

Hedonic valuation of the spatial competition for urban circumstance utilities: case Wuhan, China

NASA Astrophysics Data System (ADS)

Zheng, Bin; Liu, Yaolin; Huang, Lina

2008-10-01

It has generally accepted Alonso's [1] theory about the allocation of different land uses of commerce, resident and industry in urban area. A bunch of researches have provided their aspects of the theme of the relationships between urban circumstances and urban land uses in either the influence of one or several designate circumstance factors on different land uses, or the comprehensive analysis of the influence of all kinds of circumstance on one selected land usage (e.g. residential use). There is still not a wholly analysis about the influence of all kinds of spatial characteristics, available for the location selection of different land uses. That's why this research selects to engage in a study on the difference among "consumer preferences" to the location amenities in the city. Here we regard the behavior as "spatial competition of the locations". Hedonic regression model (HRM) analysis is employed as the basic framework of the research. Tabular comparison of HRM parameters performed with principal components analysis (PCA) and Geographic Information Science (GIS) provides all necessary numerical investigation and spatial analysis until to the finally results. The research can be helpful for putting forward to a further integrated investigation on the relationship between urban circumstance and real land use values.

Opioid analgesics: does potency matter?

PubMed

Passik, Steven D; Webster, Lynn

2014-01-01

Prescription opioid analgesics with a wide range of potencies are currently used for the treatment of chronic pain. Yet understanding the clinical relevance and therapeutic consequences of opioid potency remains ill defined. Both patients and clinicians alike have misperceptions about opioid potency, expecting that less-potent opioids will be less effective or fearing that more-potent opioids are more dangerous or more likely to be abused. In this review, common myths about the potency of opioid analgesics will be discussed. Clinicians should understand that pharmacologic potency per se does not necessarily imply more effective analgesia or higher abuse liability. Published dose conversion tables may not accurately calculate the dose for effective and safe rotation from one opioid to another in patients receiving long-term opioid therapy because they are based on limited data that may not apply to chronic pain. Differences in pharmacologic potency are largely accounted for by the actual doses prescribed, according to individualized patient need. Factors for achieving effective analgesia and reducing the risks involved with opioid use include careful medication selection based on patient characteristics, appropriate dosing titration and opioid rotation practices, knowledge of product formulation characteristics (eg, extended release, immediate release, and tamper-resistant features), and an awareness of differences in opioid pharmacokinetics and metabolism. Clinicians should remain vigilant in monitoring patients on any opioid medication, regardless of classification along the opioid potency continuum.

Using a mass balance to determine the potency loss during the production of a pharmaceutical blend.

PubMed

Mackaplow, Michael B

2010-09-01

The manufacture of a blend containing the active pharmaceutical ingredient (API) and inert excipients is a precursor for the production of most pharmaceutical capsules and tablets. However, if there is a net water gain or preferential loss of API during production, the potency of the final drug product may be less than the target value. We use a mass balance to predict the mean potency loss during the production of a blend via wet granulation and fluidized bed drying. The result is an explicit analytical equation for the change in blend potency a function of net water gain, solids losses (both regular and high-potency), and the fraction of excipients added extragranularly. This model predicts that each 1% gain in moisture content (as determined by a loss on drying test) will decrease the API concentration of the final blend at least 1% LC. The effect of pre-blend solid losses increases with their degree of superpotency. This work supports Quality by Design by providing a rational method to set the process design space to minimize blend potency losses. When an overage is necessary, the model can help justify it by providing a quantitative, first-principles understanding of the sources of potency loss. The analysis is applicable to other manufacturing processes where the primary sources of potency loss are net water gain and/or mass losses.

21 CFR 610.10 - Potency.

Code of Federal Regulations, 2010 CFR

2010-04-01

... in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter. ...

21 CFR 610.10 - Potency.

Code of Federal Regulations, 2011 CFR

2011-04-01

... in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter. ...

Building a Pre-Competitive Knowledge Base to Support Australia's Wave Energy Industry

NASA Astrophysics Data System (ADS)

Hoeke, R. K.; Hemer, M. A.; Symonds, G.; Rosebrock, U.; Kenyon, R.; Zieger, S.; Durrant, T.; Contardo, S.; O'Grady, J.; Mcinnes, K. L.

2016-02-01

A pre-competitive, query-able and openly available spatio-temporal atlas of Australia's wind-wave energy resource and marine management uses is being delivered. To provide the best representation of wave energy resource information, accounting for both spatial and temporal characteristics of the resource, a 34+yr numerical hindcast of wave conditions in the Australian region has been developed. Considerable in situ and remotely sensed data have been collected to support calibration and validation of the hindcast, resulting in a high-quality characterisation of the available wave resource in the Australian domain. Planning for wave energy projects is also subject to other spatial constraints. Spatial information on alternative uses of the marine domain including, for example, fisheries and aquaculture, oil and gas, shipping, navigation and ports, marine parks and reserves, sub-sea cables and infrastructure, shipwrecks and sites of cultural significance, have been compiled to complement the spatial characterisation of resource and support spatial planning of future wave energy projects. Both resource and spatial constraint information are being disseminated via a state-of-the-art portal, designed to meet the needs of all industry stakeholders. Another aspect currently impeding the industry in Australia is the limited evidence-base of impacts of wave energy extraction on adjacent marine and coastal environments. To build this evidence base, a network of in situ wave measurement devices have been deployed surrounding the 3 wave energy converters of Carnegie Wave Energy Limited's Perth Wave Energy Project. This data is being used to calibrate and validate numerical simulations of the project site. Early stage results will be presented.

Context-specific energy strategies: coupling energy system visions with feasible implementation scenarios.

PubMed

Trutnevyte, Evelina; Stauffacher, Michael; Schlegel, Matthias; Scholz, Roland W

2012-09-04

Conventional energy strategy defines an energy system vision (the goal), energy scenarios with technical choices and an implementation mechanism (such as economic incentives). Due to the lead of a generic vision, when applied in a specific regional context, such a strategy can deviate from the optimal one with, for instance, the lowest environmental impacts. This paper proposes an approach for developing energy strategies by simultaneously, rather than sequentially, combining multiple energy system visions and technically feasible, cost-effective energy scenarios that meet environmental constraints at a given place. The approach is illustrated by developing a residential heat supply strategy for a Swiss region. In the analyzed case, urban municipalities should focus on reducing heat demand, and rural municipalities should focus on harvesting local energy sources, primarily wood. Solar thermal units are cost-competitive in all municipalities, and their deployment should be fostered by information campaigns. Heat pumps and building refurbishment are not competitive; thus, economic incentives are essential, especially for urban municipalities. In rural municipalities, wood is cost-competitive, and community-based initiatives are likely to be most successful. Thus, the paper shows that energy strategies should be spatially differentiated. The suggested approach can be transferred to other regions and spatial scales.

A Game of Hide and Seek: Expectations of Clumpy Resources Influence Hiding and Searching Patterns

PubMed Central

Wilke, Andreas; Minich, Steven; Panis, Megane; Langen, Tom A.; Skufca, Joseph D.; Todd, Peter M.

2015-01-01

Resources are often distributed in clumps or patches in space, unless an agent is trying to protect them from discovery and theft using a dispersed distribution. We uncover human expectations of such spatial resource patterns in collaborative and competitive settings via a sequential multi-person game in which participants hid resources for the next participant to seek. When collaborating, resources were mostly hidden in clumpy distributions, but when competing, resources were hidden in more dispersed (random or hyperdispersed) patterns to increase the searching difficulty for the other player. More dispersed resource distributions came at the cost of higher overall hiding (as well as searching) times, decreased payoffs, and an increased difficulty when the hider had to recall earlier hiding locations at the end of the experiment. Participants’ search strategies were also affected by their underlying expectations, using a win-stay lose-shift strategy appropriate for clumpy resources when searching for collaboratively-hidden items, but moving equally far after finding or not finding an item in competitive settings, as appropriate for dispersed resources. Thus participants showed expectations for clumpy versus dispersed spatial resources that matched the distributions commonly found in collaborative versus competitive foraging settings. PMID:26154661

Competition and cooperation among different punishing strategies in the spatial public goods game

NASA Astrophysics Data System (ADS)

Chen, Xiaojie; Szolnoki, Attila; Perc, Matjaž

2015-07-01

Inspired by the fact that people have diverse propensities to punish wrongdoers, we study a spatial public goods game with defectors and different types of punishing cooperators. During the game, cooperators punish defectors with class-specific probabilities and subsequently share the associated costs of sanctioning. We show that in the presence of different punishing cooperators the highest level of public cooperation is always attainable through a selection mechanism. Interestingly, the selection does not necessarily favor the evolution of punishers who would be able to prevail on their own against the defectors, nor does it always hinder the evolution of punishers who would be unable to prevail on their own. Instead, the evolutionary success of punishing strategies depends sensitively on their invasion velocities, which in turn reveals fascinating examples of both competition and cooperation among them. Furthermore, we show that under favorable conditions, when punishment is not strictly necessary for the maintenance of public cooperation, the less aggressive, mild form of sanctioning is the sole victor of the selection process. Our work reveals that natural strategy selection cannot only promote, but sometimes also hinders competition among prosocial strategies.

Comparative carcinogenic potencies of particulates from diesel engine exhausts, coke oven emissions, roofing tar aerosols and cigarette smoke.

PubMed Central

Albert, R E

1983-01-01

Mammalian cell mutagenesis, transformation and skin tumorigenesis assays show similar results in comparing the potencies of diesel, coke oven, roofing tar and cigarette smoke particulates. These assay results are reasonably consistent with the comparative carcinogenic potencies of coke oven and roofing tar emissions as determined by epidemiological studies. The bacterial mutagenesis assay tends to show disproportionately high potencies, particularly with diesel particulates. Results to date encourage the approach to the assessment for carcinogenic risks from diesel emissions based on the use of epidemiological data on cancer induced by coke oven emissions, roofing tar particulates and cigarette smoke with the comparative potencies of these materials determined by in vivo and in vitro bioassays. PMID:6186481

Synthesis and study of thiocarbonate derivatives of choline as potential inhibitors of acetylcholinesterase.

PubMed

Boyle, N A; Talesa, V; Giovannini, E; Rosi, G; Norton, S J

1997-09-12

Fourteen alkyl and aryl thiocarbonate derivatives of choline were synthesized and studied as potential inhibitors of acetylcholinesterase (AChE). Twelve of the compounds inhibited AChEs derived from calf forebrain, human red blood cells, and octopus brain ranging from low to moderately high inhibition potency. The concentration of each inhibitory compound giving 50% inhibition of enzyme activity (IC50 values, which ranged from 1 x 10(-2) to 8 x 10(-7) M) was determined and is reported; inhibitor constants (Ki values) for the most inhibitory compounds, (1-pentylthiocarbonyl)choline chloride and (1-heptylthiocarbonyl)choline chloride, were calculated from kinetic data and are also reported. The inhibitors are competitive with substrate, and they are not hydrolyzed by the AChE activities. Certain of these new compounds may provide direction for the development of new drugs that have anticholinesterase activity and may be used for the treatment of Alzheimer's disease.

Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration.

PubMed

Tzvetkov, Nikolay T; Antonov, Liudmil

2017-12-01

Pharmacological and physicochemical studies of N-unsubstituted indazole-5-carboxamides (subclass I) and their structurally optimised N1-methylated analogues (subclass II), initially developed as drug and radioligand candidates for the treatment and diagnosis of Parkinson's disease (PD), are presented. The compounds are highly brain permeable, selective, reversible, and competitive monoamine oxidase B (MAO-B) inhibitors with improved water-solubility and subnanomolar potency (pIC 50  >8.8). Using a well-validated, combined X-ray/modelling technology platform, we performed a semi-quantitative analysis of the binding modes of all compounds and investigated the role of the indazole N1 position for their MAO-B inhibitory activity. Moreover, compounds NTZ-1006, 1032, and 1441 were investigated for their ability to bind Fe 2+ and Fe 3+ ions using UV-visible spectroscopy.

In Vitro Binding of [³H]PSB-0413 to P2Y₁₂ Receptors.

PubMed

Dupuis, Arnaud; Heim, Véronique; Ohlmann, Philippe; Gachet, Christian

2015-12-08

The P2Y₁₂/ADP receptor plays a central role in platelet activation. Characterization of this receptor is mandatory for studying disorders associated with a P2Y₁₂ receptor defect and for evaluating P2Y₁₂ receptor agonists and antagonists. In the absence of suitable anti-P2Y₁₂ antibodies, radioligand binding assays are the only way to conduct such studies. While various radioligands were employed in the past for this purpose, none were found to be suitable for routine use. Described in this unit are protocols for quantitatively and qualitatively assessing P2Y₁₂ receptors with [³H]PSB-0413, a selective antagonist for this site. The saturation and competition assays described herein make possible the determination of P2Y₁₂ receptor density on cells, as well as the potencies and affinities of test agents at this site. Copyright © 2015 John Wiley & Sons, Inc.

RECEPTOR AFFINITY AND PHOSPHODIESTERASES 4B AND 10A ACTIVITY OF OCTAHYDRO- AND 6,7-DIMETHOXY-3,4-DIHYDRO- ISOQUINOLIN-2(1H)-YL-ALKYL DERIVATIVES OF IMIDAZO- AND PYRIMIDINO[2,1-f]PURINES.

PubMed

Zagórska, Agnieszka; Gryzło, Beata; Satała, Grzegorz; Bojarski, Andrzej J; Głuch-Lutwin, Monika; Mordyl, Barbara; Kazek, Grzegorz; Pawłowski, Maciej

2016-01-01

A series of octahydro- and 6,7-dimethoxy-3,4-dihydro- isoquinolin-2(1H)-yl-alkyl derivatives of imidazo- and pyrimidino[2,1-f]purines were synthesized and biologically evaluated in in vitro competition binding experiments for serotonin 5-HT(1A), 5-HT(6), 5-HT(7), and dopamine D2 receptors and inhibitory potencies for phosphodiesterases - PDE4B1 and PDE10A. The structure-activity relationships allowed to determine the structural features responsible for receptor and enzyme activity. Compound 5 (8-(4-(6,7-dimethoxy-3,4-dihydroiso- quinolin-2(1H)butyl)1,3-dimethyl-H-imidazo[2,1-f]purine-2,4(3H,8H)-dione) could be regarded as promising structure for further modification and detailed mechanistic study for obtained hybrid ligands.

Broad spectrum antiviral agent ribavirin inhibits capping of mRNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goswami, B.B.; Borek, E.; Sharma, O.K.

1979-08-13

Ribavirin (1-..beta..-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a broad spectrum antiviral substance active against a wide range of both DNA and RNA viruses. It is, however, virtually inactive against polio virus. Its pharmacological mechanism of action was obscure. A possible common target for a chemotherapeutic agent in both DNA and RNA viruses is the capping reaction of mRNAs which inter alia involves the formation of a guanine pyrophosphate structure at the 5' terminus by mRNA guanylyl transferase. We have observed that Ribavirin triphosphate is a potent competitive inhibitor of the capping guanylation of viral mRNA. This finding could account for the antiviral potency ofmore » the drug against both DNA and RNA viruses and its ineffectiveness against a virus in which the mRNAs derived from them are not capped.« less

Interaction of berberine with human platelet. alpha. sub 2 adrenoceptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hui, Ka Kit; Yu, Jun Liang; Chan, Wai Fong A.

1991-01-01

Berberine was found to inhibit competitively the specific binding of ({sup 3}H)-yohimbine. The displacement curve was parallel to those of clonidine, epinephrine, norepinephrine, with the rank order of potency (IC{sub 50}) being clonidine {gt} epinephrine {gt} norepinephrine (14.5 {mu}M) = berberine. Increasing concentrations of berberine from 0.1 {mu}M to 10 {mu}M inhibited ({sup 3}H)-yohimbine binding, shifting the saturation binding curve to the right without decreasing the maximum binding capacity. In platelet cyclic AMP accumulation experiments, berberine at concentrations of 0.1 {mu}M to 0.1 mM inhibited the cAMP accumulation induced by 10 {mu}M prostaglandin E{sub 1} in a dose dependent manner,more » acting as an {alpha}{sub 2} adrenoceptor agonist. In the presence of L-epinephrine, berberine blocked the inhibitory effect of L-epinephrine behaving as an {alpha}{sub 2} adrenoceptor antagonist.« less

Hepatic progenitor cells of biliary origin with liver repopulation capacity

PubMed Central

Boulter, Luke; Tsuchiya, Atsunori; Cole, Alicia M; Hay, Trevor; Guest, Rachel V; Wojtacha, Davina; Man, Tak Yung; Mackinnon, Alison; Ridgway, Rachel A; Kendall, Timothy; Williams, Michael J; Jamieson, Thomas; Raven, Alex; Hay, David C; Iredale, John P; Clarke, Alan R; Sansom, Owen J; Forbes, Stuart J

2015-01-01

Summary Hepatocytes and cholangiocytes self renew following liver injury. Following severe injury hepatocytes are increasingly senescent, whether Hepatic Progenitor Cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where Mdm2 is inducibly deleted in over 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease. PMID:26192438

(/sup 3/H)Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNeal, E.T.; Lewandowski, G.A.; Daly, J.W.

1985-03-01

(/sup 3/H)Batrachotoxinin A benzoate ((/sup 3/H)BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of (/sup 3/H)BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of (/sup 3/H)BTX-B binding provides a rapid,more » quantitative, and facile method for the screening and investigation of local anesthetic activity.« less

Potency Determination of Antidandruff Shampoos in Nystatin International Unit Equivalents

PubMed Central

Anusha Hewage, D. B. G.; Pathirana, W.; Pinnawela, Amara

2008-01-01

A convenient standard microbiological potency determination test for the antidandruff shampoos was developed by adopting the pharmacopoeial microbiological assay procedure of the drug nystatin. A standard curve was drawn consisting of the inhibition zone diameters vs. logarithm of nystatin concentrations in international units using the fungus Saccharomyces cerevisiae (yeast) strain National Collection of Type Culture (NCTC) 1071606 as the test organism. From the standard curve the yeast inhibitory potencies of the shampoos in nystatin international unit equivalents were determined from the respective inhibition zones of the test samples of the shampoos. Under test conditions four shampoo samples showed remarkable fungal inhibitory potencies of 10227, 10731, 12396 and 18211 nystatin international unit equivalents/ml while two shampoo samples had extremely feeble inhibitory potencies 4.07 and 4.37 nystatin international unit equivalents/ml although the latter two products claimed antifungal activity. The potency determination method could be applied to any antidandruff shampoo with any one or a combination of active ingredients. PMID:21394271

Measuring the potency labelling of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin (®)) in an LD50 assay.

PubMed

Dressler, Dirk; Mander, Gerd; Fink, Klaus

2012-01-01

The biological potency of botulinum toxin (BT) drugs is determined by a standardised LD50 assay. However, the potency labelling varies vary amongst different BT drugs. One reason for this may be differences in the LD50 assays applied. When five unexpired batches of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin(®)) are compared in the Xeomin(®) batch release assay, the potency variability of both BT drugs fell within the range allowed by the European Pharmacopoiea. Statistical analyses failed to detect differences in the potency labelling of both products. Although the existence of a conversion ratio has been questioned recently, our experimental data are in line with previous clinical experience showing that Botox(®) and Xeomin(®) can be compared using a 1:1 conversion ratio. Identical potency labelling allows easy exchange of both BT drugs in a therapeutic setting, and direct comparison of efficacy, adverse effects and costs.

[Territory and decentralization in the agenda for productive transformation with equity].

PubMed

Sojo, A

1991-08-01

The regional perspective and the decentralization in Latin American and Caribbean countries was examined in light of technological changes and transformation of economic production to boost productivity. National population policies were not the major cause of redistribution of the population, rather such transformation significantly changed the comparative regional and urban advantages in the use of territory affecting the spatial distribution of the population. Hypotheses were advanced using the transformation of production, regional development, and decentralization on the retention, attraction, and migration of population in different areas with varying economic conditions. Spurious competitiveness means global strategies of enterprises that establish foreign operations by means of factor sourcing. Flexible specialization is a company strategy of permanent innovation based on flexible equipment and a qualified work force. The increasing transnationalization of capital is the source of skills and technology that sustain competitive advantages. Decentralization can resolve local demand, facilitate access to information, mobilize resources, and exercise control over local operations. In Japan, Germany, and Italy vs. the US and France there is a social contract among companies, trade unions, universities, and regional administrations in the interest of capital and the work force. There is no direct relationship between technology and region, the industrial cluster exhibits systemic competitiveness in developed countries (the Emilian model in Italy affirms the ability of small enterprises to develop new products), the regional impact is diverse relative to new technologies (some deprived rural economic areas have potential as in central and northern Italy), and population and region are linked (regional and rural-urban differences in the growth of population and migratory flows account for spatial distribution of the population). Decentralization and systemic competitiveness concern productivity and regional policies (spatial diversity for increased productivity) and technology and human resources are interdependent (technical progress is determined by the level of qualification of the population).

Density of founder cells affects spatial pattern formation and cooperation in Bacillus subtilis biofilms

PubMed Central

van Gestel, Jordi; Weissing, Franz J; Kuipers, Oscar P; Kovács, Ákos T

2014-01-01

In nature, most bacteria live in surface-attached sedentary communities known as biofilms. Biofilms are often studied with respect to bacterial interactions. Many cells inhabiting biofilms are assumed to express ‘cooperative traits', like the secretion of extracellular polysaccharides (EPS). These traits can enhance biofilm-related properties, such as stress resilience or colony expansion, while being costly to the cells that express them. In well-mixed populations cooperation is difficult to achieve, because non-cooperative individuals can reap the benefits of cooperation without having to pay the costs. The physical process of biofilm growth can, however, result in the spatial segregation of cooperative from non-cooperative individuals. This segregation can prevent non-cooperative cells from exploiting cooperative neighbors. Here we examine the interaction between spatial pattern formation and cooperation in Bacillus subtilis biofilms. We show, experimentally and by mathematical modeling, that the density of cells at the onset of biofilm growth affects pattern formation during biofilm growth. At low initial cell densities, co-cultured strains strongly segregate in space, whereas spatial segregation does not occur at high initial cell densities. As a consequence, EPS-producing cells have a competitive advantage over non-cooperative mutants when biofilms are initiated at a low density of founder cells, whereas EPS-deficient cells have an advantage at high cell densities. These results underline the importance of spatial pattern formation for competition among bacterial strains and the evolution of microbial cooperation. PMID:24694715

Density of founder cells affects spatial pattern formation and cooperation in Bacillus subtilis biofilms.

PubMed

van Gestel, Jordi; Weissing, Franz J; Kuipers, Oscar P; Kovács, Akos T

2014-10-01

In nature, most bacteria live in surface-attached sedentary communities known as biofilms. Biofilms are often studied with respect to bacterial interactions. Many cells inhabiting biofilms are assumed to express 'cooperative traits', like the secretion of extracellular polysaccharides (EPS). These traits can enhance biofilm-related properties, such as stress resilience or colony expansion, while being costly to the cells that express them. In well-mixed populations cooperation is difficult to achieve, because non-cooperative individuals can reap the benefits of cooperation without having to pay the costs. The physical process of biofilm growth can, however, result in the spatial segregation of cooperative from non-cooperative individuals. This segregation can prevent non-cooperative cells from exploiting cooperative neighbors. Here we examine the interaction between spatial pattern formation and cooperation in Bacillus subtilis biofilms. We show, experimentally and by mathematical modeling, that the density of cells at the onset of biofilm growth affects pattern formation during biofilm growth. At low initial cell densities, co-cultured strains strongly segregate in space, whereas spatial segregation does not occur at high initial cell densities. As a consequence, EPS-producing cells have a competitive advantage over non-cooperative mutants when biofilms are initiated at a low density of founder cells, whereas EPS-deficient cells have an advantage at high cell densities. These results underline the importance of spatial pattern formation for competition among bacterial strains and the evolution of microbial cooperation.

Cutoff in Potency Implicates Alcohol Inhibition of N-Methyl-D-Aspartate Receptors in Alcohol Intoxication

NASA Astrophysics Data System (ADS)

Peoples, Robert W.; Weight, Forrest F.

1995-03-01

As the number of carbon atoms in an aliphatic n-alcohol is increased from one to five, intoxicating potency, lipid solubility, and membrane lipid disordering potency all increase in a similar exponential manner. However, the potency of aliphatic n-alcohols for producing intoxication reaches a maximum at six to eight carbon atoms and then decreases. The molecular basis of this "cutoff" effect is not understood, as it is not correlated with either the lipid solubility or the membrane disordering potency of the alcohols, which continue to increase exponentially. Since it has been suggested that inhibition of N-methyl-D-aspartate (NMDA) receptors by alcohols may play a role in alcohol intoxication, we investigated whether a series of aliphatic n-alcohols would exhibit a cutoff in potency for inhibition of NMDA receptors. We found that although potency for inhibition of NMDA receptors increased exponentially for alcohols with one to five carbon atoms, potency for inhibition of NMDA receptors reached a maximum at six to eight carbon atoms and then abruptly disappeared. This cutoff for alcohol inhibition of NMDA receptors is consistent with an interaction of the alcohols with a hydrophobic pocket on the receptor protein. In addition, the similarity of the cutoffs for alcohol inhibition of NMDA receptors and alcohol intoxication suggests that the cutoff for NMDA receptor inhibition may contribute to the cutoff for alcohol intoxication, which is consistent with an important role of NMDA receptors in alcohol intoxication.

Competitiveness of Romanian Regions in the Spatial Structure of the EU

NASA Astrophysics Data System (ADS)

Török, Ibolya

2017-12-01

In the last years, in order to enhance the competitiveness of the regions, researchers and decision makers alike attribute a special role to supporting entrepreneurial activity, strengthening the SME sector, attracting foreign working capital into the local economy, but also to the territorial concentration of R&D centres. Within the present study, I have considered all relevant economic factors, which might influence competitiveness, having at the same time an impact on the position of the Romanian regions within in the economic structure of the European Union. In the study have managed to prove that Romania is in a rather disadvantaged situation in the case of the three main elements, with a significant impact on the competitiveness of regions: the GDP per capita, the employment rate and labour productivity. Only the Bucharest-Ilfov region is in a more favourable position, but its development level remains far behind the central regions of the EU.

Differential phytosociological interactions involving male and female atriplex bonnevillensis

USGS Publications Warehouse

Sinclair, J.; Emlen, J.M.; Rinella, M.; Snelgrove, J.; Freeman, D.C.

2009-01-01

Wind-pollinated dioecious plants often exhibit spatial segregation of the sexes. This partial niche separation has most often been explored using abiotic niche axes. However, if the sexes are truly separated in space, then they are apt to encounter different plant species that may heavily affect growth and reproduction. Also, to the extent that their niches differ, the sexes may respond differently to the same co-occurring species. Here we examine interspecific interactions that influence male and female reproductive potential in Atriplex bonnevillensis. Using Emlen's interaction assessment, a technique which assesses species interactions based on cover classes, we show that Salsola species compete significantly with females but not males, while Halogeton glomeratus competes with males but not females. The effect of competition only became apparent when we corrected for site-specific fertility. These results imply that differential competition must be considered when studying dioecious plants that display spatial segregation of the sexes.

Discriminating the effects of spatial extent and population size in cyclic competition among species

NASA Astrophysics Data System (ADS)

Lamouroux, D.; Eule, S.; Geisel, T.; Nagler, J.

2012-08-01

We introduce a population model for species under cyclic competition. This model allows individuals to coexist and interact on single cells while migration takes place between adjacent cells. In contrast to the model introduced by Reichenbach, Mobilia, and Frey [Reichenbach, Mobilia, and Frey, Nature (London)NATUAS0028-083610.1038/nature06095 448, 1046 (2007)], we find that the emergence of spirals results in an ambiguous behavior regarding the stability of coexistence. The typical time until extinction exhibits, however, a qualitatively opposite dependence on the newly introduced nonunit carrying capacity in the spiraling and the nonspiraling regimes. This allows us to determine a critical mobility that marks the onset of this spiraling state sharply. In contrast, we demonstrate that the conventional finite size stability analysis with respect to spatial size is of limited use for identifying the onset of the spiraling regime.

A Model for Aryl Hydrocarbon Receptor-Activated Gene Expression Shows Potency and Efficacy Changes and Predicts Squelching Due to Competition for Transcription Co-Activators

PubMed Central

Simon, Ted W.; Budinsky, Robert A.; Rowlands, J. Craig

2015-01-01

A stochastic model of nuclear receptor-mediated transcription was developed based on activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and subsequent binding the activated AHR to xenobiotic response elements (XREs) on DNA. The model was based on effects observed in cells lines commonly used as in vitro experimental systems. Following ligand binding, the AHR moves into the cell nucleus and forms a heterodimer with the aryl hydrocarbon nuclear translocator (ARNT). In the model, a requirement for binding to DNA is that a generic coregulatory protein is subsequently bound to the AHR-ARNT dimer. Varying the amount of coregulator available within the nucleus altered both the potency and efficacy of TCDD for inducing for transcription of CYP1A1 mRNA, a commonly used marker for activation of the AHR. Lowering the amount of available cofactor slightly increased the EC50 for the transcriptional response without changing the efficacy or maximal response. Further reduction in the amount of cofactor reduced the efficacy and produced non-monotonic dose-response curves (NMDRCs) at higher ligand concentrations. The shapes of these NMDRCs were reminiscent of the phenomenon of squelching. Resource limitations for transcriptional machinery are becoming apparent in eukaryotic cells. Within single cells, nuclear receptor-mediated gene expression appears to be a stochastic process; however, intercellular communication and other aspects of tissue coordination may represent a compensatory process to maintain an organism’s ability to respond on a phenotypic level to various stimuli within an inconstant environment. PMID:26039703

Quantitative structure-activity relationship modeling on in vitro endocrine effects and metabolic stability involving 26 selected brominated flame retardants.

PubMed

Harju, Mikael; Hamers, Timo; Kamstra, Jorke H; Sonneveld, Edwin; Boon, Jan P; Tysklind, Mats; Andersson, Patrik L

2007-04-01

In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A, and hexabromocyclododecane, have been identified as potential endocrine disruptors. Quantitative structure-activity relationship models were built based on the in vitro potencies of 26 selected BFRs. The in vitro assays included interactions with, for example, androgen, progesterone, estrogen, and dioxin (aryl hydrocarbon) receptor, plus competition with thyroxine for its plasma carrier protein (transthyretin), inhibition of estradiol sulfation via sulfotransferase, and finally, rate of metabolization. The QSAR modeling, a number of physicochemical parameters were calculated describing the electronic, lipophilic, and structural characteristics of the molecules. These include frontier molecular orbitals, molecular charges, polarities, log octanol/water partitioning coefficient, and two- and three-dimensional molecularproperties. Experimental properties were included and measured for PBDEs, such as their individual ultraviolet spectra (200-320 nm) and retention times on three different high-performance liquid chromatography columns and one nonpolar gas chromatography column. Quantitative structure-activity relationship models based on androgen antagonism and metabolic degradation rates generally gave similar results, suggesting that lower-brominated PBDEs with bromine substitutions in ortho positions and bromine-free meta- and para positions had the highest potencies and metabolic degradation rates. Predictions made for the constituents of the technical flame retardant Bromkal 70-5DE found BDE 17 to be a potent androgen antagonist and BDE 66, which is a relevant PBDE in environmental samples, to be only a weak antagonist.

Activation and inhibition of adenylyl cyclase isoforms by forskolin analogs.

PubMed

Pinto, Cibele; Papa, Dan; Hübner, Melanie; Mou, Tung-Chung; Lushington, Gerald H; Seifert, Roland

2008-04-01

Adenylyl cyclase (AC) isoforms 1 to 9 are differentially expressed in tissues and constitute an interesting drug target. ACs 1 to 8 are activated by the diterpene, forskolin (FS). It is unfortunate that there is a paucity of AC isoform-selective activators. To develop such compounds, an understanding of the structure/activity relationships of diterpenes is necessary. Therefore, we examined the effects of FS and nine FS analogs on ACs 1, 2, and 5 expressed in Spodoptera frugiperda insect cells. Diterpenes showed the highest potencies at AC1 and the lowest potencies at AC2. We identified full agonists, partial agonists, antagonists, and inverse agonists, i.e., diterpenes that reduced basal AC activity. Each AC isoform exhibited a distinct pharmacological profile. AC2 showed the highest basal activity of all AC isoforms and highest sensitivity to inverse agonistic effects of 1-deoxy-forskolin, 7-deacetyl-1,9-dideoxy-forskolin, and, particularly, BODIPY-forskolin. In contrast, BODIPY-forskolin acted as partial agonist at the other ACs. 1-Deoxy-forskolin analogs were devoid of agonistic activity at ACs but antagonized the effects of FS in a mixed competitive/noncompetitive manner. At purified catalytic AC subunits, BODIPY-forskolin acted as weak partial agonist/strong partial antagonist. Molecular modeling revealed that the BODIPY group rotates promiscuously outside of the FS-binding site. Collectively, ACs are not uniformly activated and inhibited by FS and FS analogs, demonstrating the feasibility to design isoform-selective FS analogs. The two- and multiple-state models, originally developed to conceptualize ligand effects at G-protein-coupled receptors, can be applied to ACs to explain certain experimental data.

Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice.

PubMed

Vignisse, Julie; Steinbusch, Harry W M; Grigoriev, Vladimir; Bolkunov, Alexei; Proshin, Alexey; Bettendorff, Lucien; Bachurin, Sergey; Strekalova, Tatyana

2014-02-01

Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6J at 1 or 5mg/kg, ip) with new derivatives of isothiourea (0.5-1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC₅₀ values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Choice and competition between adult congenital heart disease centers: evidence of considerable geographical disparities and association with clinical or academic results.

PubMed

Diller, Gerhard-Paul; Kempny, Aleksander; Piorkowski, Adam; Grübler, Martin; Swan, Lorna; Baumgartner, Helmut; Dimopoulos, Konstantinos; Gatzoulis, Michael A

2014-03-01

Although concentrating adult congenital heart disease services at high-volume centers has been widely advocated, the potential beneficial effects of competition and patient choice have received relatively little attention. We aimed to assess the degree of patient choice and competition between adult congenital heart disease units and to investigate whether competition indices correlate with clinical quality or research output. Competition between the 10 major adult congenital heart disease units in England was evaluated based on the Herfindahl-Hirschman Index, representing the sum of squared market shares of individual units. In addition, to account for geography and feasible access, we calculated spatial indices of competition based on travel time by road. These indices were correlated with 30-day mortality postpulmonary valve replacement in adult patients (as obtained from the National Central Cardiac Audit Database) and the aggregate research impact factors of individual centers. On a national level, a high level of competition without obvious dominant players was found (Herfindahl-Hirschman Index between 0.107 and 0.013). When accounting for geography, however, important disparities in patient choice and competition faced by individual centers emerged. The degree of local competition was correlated significantly with clinical outcomes and research output. In contrast, no association between center volume and outcome could be established. Beyond the usual focus on concentrating services at high-volume centers, the potentially beneficial effects of competition should not be ignored. Therefore, policymakers should consider fostering a competitive environment for adult congenital heart disease centers or at least avoiding creating government-granted monopolies in the field.

RELATIVE POTENCY OF FUNGAL EXTRACTS IN INDUCING ALLERGIC ASTHMA-LIKE RESPONSES IN BALB/C MICE

EPA Science Inventory

Indoor mold has been associated with the development of allergic asthma. However, relative potency of molds in the induction of allergic asthma is not clear. In this study, we tested the relative potency of fungal extracts (Metarizium anisophilae [MACA], Stachybotrys ...