Auswahl der wissenschaftlichen Literatur zum Thema „Aggregation induced“

Acutin was isolated from Agkistrodon acutus venom and batroxobin and thrombocytin were isolated from Bothrops atrox venom. These three thrombin-like enzymes had different specificity for platelet activation and fibrinogen clotting. The clotting activities were 700, 170 and 7 μ/mg for batroxobin, acutin and thrombocytin, respectively. They induced aggregation and ATP release of washed rabbit platelets. The aggregating activities were 102, 104 and 105 times less than that of thrombin for thrombocytin, acutin and batroxobin, respectively basing on the clotting unit. The platelet -activating potency was correlated with their effectiveness on the retractility and elasticity of the clots. Platelet aggregation induced by thrombin or thrombocytin could be inhibited by heparin with antithrombin III while that by acutin or batroxobin could not. The thrombin-like enzymes did not induce aggregation of thrombin-degranulated platelets even fibrinogen was added. Indomethacin showed weak inhibition on the aggregation while the ADP - scavenging system, creatine phosphate/creatine phosphokinase, or apyrase inhibited the aggregation induced by the three thrombin-like enzymes but not that by thrombin. In the presence of EGTA, only thrombin could induce ATP release from platelets. It is concluded that the aggregation induced by thrombin-like enzymes is different from that of thrombin and mainly due to ADP released from platelets.

Eight monoclonal antibodies were obtained which recognized platelet surface antigens of these, 5 (NNKYl-32, NNKY2-5, NNKY2-6, NNKY2-11, NNKY2-18 ) recognized GP IIb-IIIa complex, 2 (NNKY5-4, NNKY5-5 ) recognized GP lb and 1 (NNKYl-19) recognized CD 9 antigen. They were used to research the platelet membrane antigens.Monoclonal antibodies that recognize CD 9 antigen, which exists on the surface of platelets, acute lymphoblastic leukemia cells, eosinophils and other tissue, are known to act as an aggregating agent to platelets and NNKYl-19 was fond to induce platelet aggregation accompanied by ATP release. NNKY5-4 had no effect on platelet functions. NNKY5-5 inhibited aggregation induced by ristocetin but had no effect on aggregation induced by ADP, collagen, thrombin, and NNKYl-19. NNKYl-32, 2-5, 2-6, 2-11, and 2-18 inhibited aggregation induced by ADP, collagen, thrombin, and NNKYl-19, although slight release of ATP was recognized when NNKYl-19-induced aggregation was completely inhibited by NNKYl-32. Mutual inhibition of binding to platelet membranes between the 3 groups of monoclonal antibodies was not recognizedNNKYl-19-induced aggregation was associated with a lag time that was plo-longed in inverse proportion to antibody concentration. Aspirin had almost no effect on NNKYl-19-induced aggregation. A TXA2 receptor antagonist, a calci-um-channel blocking drug and EDTA inhibited NNKYl-19-induced aggregation. These results indicate that GP I b, GP IIb-IIIa complex and the cyclooxygenase pathway are not involved in NNKYl-19-induced platelet activation, that the target of NNKYl-19 on the platelet membrane is same as that of TXA2, and that the mechanism of activation by NNKYl-19 is related to calcium flux.

Many drugs and other agents have been reported to induce platelet dysfunction and clinical bleedability; however, tetrahydrocannabinol (marijuana) has thus far not been reported. The patient herein described is a 28-year-old Caucasian female who wasreferred for evaluation of easy and spontaneous bruising. On history, the patient related that for a three-month period she had been developing spontaneous ecchymoses of the extremities and torso. She denied any medication other than heavy marijuana use. Hemostasis evaluation revealed her to have a normal prothrombin time, partial thromboplastin time (PTT), Factor VIII coagulant activity (Factor VIII:C), Factor VIII related antigen (Factor VIII:RAg), and ristocetincofactor activity. Platelet aggregation was performed which revealed abnormal aggregation to epinephrine, adenosine diphosphate (ADP) and abnormal release but normal aggregation toristocetin. She was asked to refrainfrom marijuana and was reaggregated revealing normal aggregation and release to epinephrine, ADP, collagen and arachidonic acid; however, ADP release induced by ristocetin remainedmoderately abnormal, even though aggregation was normal. In addition, with cessation of marijuana use, her clinical bruising abated.Following this, she again indulged in marijuana and she was reaggregated, revealing delayed aggregation and release to epinephrine with abnormal aggregation to ADP. Additionally, ristocetin release and adenosine triphosphate (ATP) release remained abnormal but aggregation remained normal and arachidonic acid aggregationremained normal.In summary, we herein describe a young female who demonstrated aggregation abnormalities and clinically significant spontaneous bruising during periods of using marijuana; the defect disappeared upon cessation of marijuana and reappeared upon resumption of marijuana use. The defect atpresent appears to be that of a membrane-type defect with no evidence that marijuana interferes with the prostaglandin pathway.

A receptor for fibrinogen on the platelet GP Ila/lIIb complex is induced by ADP, thrombin and other agonists. To study functional domains on GP Ilb/IIIa, the effects of anti-GP Ilb/IIIa monoclonal antibodies (Mab’s) on platelet function were determined. One of these Mab’s, 6C9, induced platelet aggregation. The antibody binds to the intact GP Ilb/IIIa complex only, not to free GP lib or free GP Ilia. Its epitope is different from that of C17, a Mab that inhibits ADP-induced fibrinogen binding and platelet aggregation. 6C9 induces fibrinogen-mediated aggregation rather than agglutination since 6C9-induced platelet interactions were blocked by treatments that also inhibited the effects of ADP etc., without inhibiting binding of 6C9 itself. 6C9 induces binding of 125I-fibrinogen (35.000 ± 7.300 molecules/platelet, Kd = 1.3 ± 0.4 µM) to unstirred platelets. Binding of fibrinogen was 60 to 80% inhibited by apyrase, which indicates that 6C9-induced fibrinogen binding is largely mediated via ADP released from platelets. In addition, 6C9 induced aggregation of platelets in the absence of extracellular fibrinogen. Mediation of this process by platelet fibrinogen or other a-granule proteins, released upon activation by 6C9, was implicated by the finding that aggregation of washed platelets, but not of platelets to which fibrinogen was added, could be blocked by PGI2. Platelet release was also assessed directly by measuring β-thromboglobulin (α-granules) and (14C) serotonin (dense granules) in the medium of unstirred platelets incubated with 6C9. F(ab')2 fragments of 6C9 only aggregated platelets in the presence of fibrinogen and did not release (14C) serotonin. Moreover, release induced by intact 6C9 was inhibited by anti-GP Ilb/IIIa Mab C17 but not by C17 F(ab’)2, although the latter inhibited ADP-induced platelet aggregation. These data indicate that binding of antibodies to specific sites on GP Ilb/IIIa may induce Fc-dependent platelet activation.This study was supported by the Foundation for Medical Research MEDIGON (grant no. 900-526-057.

Epinephrine or UK 14304 (a specific (α2-adrenoceptor agonist) synergizes with phorbol esters (phorbol 12,13-dibutyrate, PdBu) or bioactive diacylglycerols (sn-1,2-dioctanoylglycerol, DiC8) to induce aggregation and ATP-secretion of platelets. The effect on aggregation is more pronounced than on secretion, and it is observed in aspirinized platelet-rich plasma or suspensions of washed platelets containing ADP-scavengers. No prior shape change is found. In the presence of epinephrine, DiCg induces reversible aggregation and PdBu evokes irreversible aggregation that correlates with the effects, on protein phosphorylation. Epinephrine and UK 14304 neither induce nor enhance the phosphorylation of myosin light chain (20kDa), the substrate of protein kinase C (47kDa), or a 38kDa protein evoked by DiCg) or PdBu. Epinephrine does not cause, stimulation of phospholipase C as reflected by the production of inositol mono-, bis- and tris-phosphate or phosphatidic acid. Even under conditions of maximal aggregation induced by epinephrine plus PdBu, formation of 32p-phOSphatidic acid is not observed. The synergistic action of epinephrine and PdBu does not depend on extracellular Ca2+. Primary aggregation induced by epinephrine, but not platelet aggregation induced by PdBu plus epinephrine, is inhibited by high intracellular concentrations of the calcium chelator quin2. Prostacyclin prevents platelet aggregation but does not affect protein phosphorylation induced by PdBu plus epinephrine.The experiments indicate that α2-adrenoceptor agonists may induce primary aggregation by a mechanism involving release of membrane-bound Ca2+. The synergism with protein kinase C is, however, caused by a mechanism that occurs distally to protein phosphorylation and is not related to Phospholipase C activation and Ca2+-fluxes across the Dlasma membrane or in the cvtosol. Evidence is presented suoportina the view that this mechanism miqht be related to the dissociation of Gi caused by α2-adrenoceptor activation.

The overall goal of this project was to elucidate the role of dissolved organic matter (DOM) in soil retention, bioavailability and plant uptake of silver and cerium oxide NPs. The environmental risks of manufactured nanoparticles (NPs) are attracting increasing attention from both industrial and scientific communities. These NPs have shown to be taken-up, translocated and bio- accumulated in plant edible parts. However, very little is known about the behavior of NPs in soil-plant system as affected by dissolved organic matter (DOM). Thus DOM effect on NPs behavior is critical to assessing the environmental fate and risks related to NP exposure. Carbon-based nanomaterials embedded with metal NPs demonstrate a great potential to serve as catalyst and disinfectors. Hence, synthesis of novel carbon-based nanocomposites and testing them in the environmentally relevant conditions (particularly in the DOM presence) is important for their implementation in water purification. Sorption of DOM on Ag-Ag₂S NPs, CeO₂ NPs and synthesized Ag-Fe₃O₄-carbon nanotubebifunctional composite has been studied. High DOM concentration (50mg/L) decreased the adsorptive and catalytic efficiencies of all synthesized NPs. Recyclable Ag-Fe₃O₄-carbon nanotube composite exhibited excellent catalytic and anti-bacterial action, providing complete reduction of common pollutants and inactivating gram-negative and gram-positive bacteria at environmentally relevant DOM concentrations (5-10 mg/L). Our composite material may be suitable for water purification ranging from natural to the industrial waste effluents. We also examined the role of maize (Zeamays L.)-derived root exudates (a form of DOM) and their components on the aggregation and dissolution of CuONPs in the rhizosphere. Root exudates (RE) significantly inhibited the aggregation of CuONPs regardless of ionic strength and electrolyte type. With RE, the critical coagulation concentration of CuONPs in NaCl shifted from 30 to 125 mM and the value in CaCl₂ shifted from 4 to 20 mM. This inhibition was correlated with molecular weight (MW) of RE fractions. Higher MW fraction (> 10 kDa) reduced the aggregation most. RE also significantly promoted the dissolution of CuONPs and lower MW fraction (< 3 kDa) RE mainly contributed to this process. Also, Cu accumulation in plant root tissues was significantly enhanced by RE. This study provides useful insights into the interactions between RE and CuONPs, which is of significance for the safe use of CuONPs-based antimicrobial products in agricultural production. Wheat root exudates (RE) had high reducing ability to convert Ag+ to nAg under light exposure. Photo-induced reduction of Ag+ to nAg in pristine RE was mainly attributed to the 0-3 kDa fraction. Quantification of the silver species change over time suggested that Cl⁻ played an important role in photoconversion of Ag+ to nAg through the formation and redox cycling of photoreactiveAgCl. Potential electron donors for the photoreduction of Ag+ were identified to be reducing sugars and organic acids of low MW. Meanwhile, the stabilization of the formed particles was controlled by both low (0-3 kDa) and high (>3 kDa) MW molecules. This work provides new information for the formation mechanism of metal nanoparticles mediated by RE, which may further our understanding of the biogeochemical cycling and toxicity of heavy metal ions in agricultural and environmental systems. Copper sulfide nanoparticles (CuSNPs) at 1:1 and 1:4 ratios of Cu and S were synthesized, and their respective antifungal efficacy was evaluated against the pathogenic activity of Gibberellafujikuroi(Bakanae disease) in rice (Oryza sativa). In a 2-d in vitro study, CuS decreased G. fujikuroiColony- Forming Units (CFU) compared to controls. In a greenhouse study, treating with CuSNPs at 50 mg/L at the seed stage significantly decreased disease incidence on rice while the commercial Cu-based pesticide Kocide 3000 had no impact on disease. Foliar-applied CuONPs and CuS (1:1) NPs decreased disease incidence by 30.0 and 32.5%, respectively, which outperformed CuS (1:4) NPs (15%) and Kocide 3000 (12.5%). CuS (1:4) NPs also modulated the shoot salicylic acid (SA) and Jasmonic acid (JA) production to enhance the plant defense mechanisms against G. fujikuroiinfection. These results are useful for improving the delivery efficiency of agrichemicals via nano-enabled strategies while minimizing their environmental impact, and advance our understanding of the defense mechanisms triggered by the NPs presence in plants.

Historically, the aversive response of humans and other mammals to bitter-taste substances has been useful for survival, since many toxic constituents taste bitter. Today, the range of foods available is more diverse. Many bitter foods are not only safe for consumption but contain bitter constituents that provide nutritional benefits. Despite this, these foods are often eliminated from our current diets because of their unacceptable bitterness. Extensive technology has been developed to remove or mask bitterness in foods, but a lack of understanding of the mechanisms of bitterness perception at the taste receptor level has prevented the development of inhibitors or efficient methods for reducing bitterness. In our original application we proposed to: (a) investigate the time course and effect of selected bitter tastants relevant to agricultural products on the formation of intracellular signal molecules (cAMP, IP3, Ca2+) in intact taste cells, in model cells and in membranes derived therefrom; (b) study the effect of specific bitter taste inhibitors on messenger formation and identify G-proteins that may be involved in tastant-induced bitter sensation; (c) investigate interactions and self-aggregation of bitter tastants within membranes; (d) study human sensory responses over time to these bitter-taste stimuli and inhibitors in order to validate the biochemical data. Quench-flow module (QFM) and fast pipetting system (FPS) allowed us to monitor fast release of the aforementioned signal molecules (cGMP, as a putative initial signal was substituted for Ca2+ ions) - using taste membranes and intact taste cells in a time range below 500 ms (real time of taste sensation) - in response to bitter-taste stimulation. Limonin (citrus) and catechin (wine) were found to reduce cellular cAMP and increase IP3 contents. Naringin (citrus) stimulated an IP3 increase whereas the cheese-derived bitter peptide cyclo(leu-Trp) reduced IP3 but significantly increased cAMP levels. Thus, specific transduction pathways were identified, the results support the notion of multiple transduction pathways for bitter taste and cross-talk between a few of those transduction pathways. Furthermore, amphipathic tastants permeate rapidly (within seconds) into liposomes and taste cells suggesting their availability for direct activation of signal transduction components by means of receptor-independent mechanisms within the time course of taste sensation. The activation of pigment movement and transduction pathways in frog melanophores by these tastants supports such mechanisms. Some bitter tastants, due to their amphipathic properties, permeated (or interacted with) into a bitter tastant inhibitor (specific phospholipid mixture) which apparently forms micelles. Thus, a mechanism via which this bitter taste inhibitor acts is proposed. Human sensory evaluation experiments humans performed according to their 6-n-propyl thiouracil (PROP) status (non-tasters, tasters, super-tasters), indicated differential perception of bitterness threshold and intensity of these bitter compounds by different individuals independent of PROP status. This suggests that natural products containing bitter compounds (e.g., naringin and limonin in citrus), are perceived very differently, and are in line with multiple transduction pathways suggested in the biochemical experiments. This project provides the first comprehensive effort to explore the molecular basis of bitter taste at the taste-cell level induced by economically important and agriculturally relevant food products. The findings, proposing a mechanism for bitter-taste inhibition by a bitter taste inhibitor (made up of food components) pave the way for the development of new, and perhaps more potent bitter-taste inhibitors which may eventually become economically relevant.

For accurate stock assessment, survey design must consider fish behavior and ecology. Yearlings and older individuals of the commercially exploited cold-water species vendace (Coregonus albula) are found below the metalimnion through periods of thermal stratification. These stratification periods generally last for 3-4 months, from the middle of summer to early autumn. In lakes with heterogeneous distribution of depths, the habitat volume for vendace vary drastically within and across years, which affects the distribution and population densities. Variable thermal habitat volumes, with food and oxygen depletion in the hypolimnion through the period of stratification, may act as a population size-regulating factor. Using hydroacoustics in combination with trawl data and temperature profiles, we examined the distribution of vendace through annual periods of thermal stratification. We found that yearling and older vendace these periods were confined to cold-water habitat volumes representing less than 10 % of the total water volume of Lake Mälaren, the third largest lake in Sweden. By introducing stratification to the design of hydroacoustic surveys supported by midwater trawling, seasonal aggregations of fish in temporally restricted thermal habitat volumes can be used to lower survey effort and improve the precision in estimates of population size. Temporally restricted habitat volumes may induce risks for the populations to over-fishing and sensitivity to environmental changes that potentially may call for directed management.

With the proliferation of Free Trade Agreements (FTAs) over the past decade, demand for quantitative analysis of their likely impacts has surged. The main quantitative tool for performing such analysis is Computable General Equilibrium (CGE) modeling. Yet these models have been widely criticized for performing poorly (Kehoe, 2002) and having weak econometric foundations (McKitrick, 1998; Jorgenson, 1984). FTA results have been shown to be particularly sensitive to the trade elasticities, with small trade elasticities generating large terms of trade effects and relatively modest efficiency gains, whereas large trade elasticities lead to the opposite result. Critics are understandably wary of results being determined largely by the authors’ choice of trade elasticities. Where do these trade elasticities come from? CGE modelers typically draw these elasticities from econometric work that uses time series price variation to identify an elasticity of substitution between domestic goods and composite imports (Alaouze, 1977; Alaouze, et al., 1977; Stern et al., 1976; Gallaway, McDaniel and Rivera, 2003). This approach has three problems: the use of point estimates as “truth”, the magnitude of the point estimates, and estimating the relevant elasticity. First, modelers take point estimates drawn from the econometric literature, while ignoring the precision of these estimates. As we will make clear below, the confidence one has in various CGE conclusions depends critically on the size of the confidence interval around parameter estimates. Standard “robustness checks” such as systematically raising or lowering the substitution parameters does not properly address this problem because it ignores information about which parameters we know with some precision and which we do not. A second problem with most existing studies derives from the use of import price series to identify home vs. foreign substitution, for example, tends to systematically understate the true elasticity. This is because these estimates take price variation as exogenous when estimating the import demand functions, and ignore quality variation. When quality is high, import demand and prices will be jointly high. This biases estimated elasticities toward zero. A related point is that the fixed-weight import price series used by most authors are theoretically inappropriate for estimating the elasticities of interest. CGE modelers generally examine a nested utility structure, with domestic production substitution for a CES composite import bundle. The appropriate price series is then the corresponding CES price index among foreign varieties. Constructing such an index requires knowledge of the elasticity of substitution among foreign varieties (see below). By using a fixed-weight import price series, previous estimates place too much weight on high foreign prices, and too small a weight on low foreign prices. In other words, they overstate the degree of price variation that exists, relative to a CES price index. Reconciling small trade volume movements with large import price series movements requires a small elasticity of substitution. This problem, and that of unmeasured quality variation, helps explain why typical estimated elasticities are very small. The third problem with the existing literature is that estimates taken from other researchers’ studies typically employ different levels of aggregation, and exploit different sources of price variation, from what policy modelers have in mind. Employment of elasticities in experiments ill-matched to their original estimation can be problematic. For example, estimates may be calculated at a higher or lower level of aggregation than the level of analysis than the modeler wants to examine. Estimating substitutability across sources for paddy rice gives one a quite different answer than estimates that look at agriculture as a whole. When analyzing Free Trade Agreements, the principle policy experiment is a change in relative prices among foreign suppliers caused by lowering tariffs within the FTA. Understanding the substitution this will induce across those suppliers is critical to gauging the FTA’s real effects. Using home v. foreign elasticities rather than elasticities of substitution among imports supplied from different countries may be quite misleading. Moreover, these “sourcing” elasticities are critical for constructing composite import price series to appropriate estimate home v. foreign substitutability. In summary, the history of estimating the substitution elasticities governing trade flows in CGE models has been checkered at best. Clearly there is a need for improved econometric estimation of these trade elasticities that is well-integrated into the CGE modeling framework. This paper provides such estimation and integration, and has several significant merits. First, we choose our experiment carefully. Our CGE analysis focuses on the prospective Free Trade Agreement of the Americas (FTAA) currently under negotiation. This is one of the most important FTAs currently “in play” in international negotiations. It also fits nicely with the source data used to estimate the trade elasticities, which is largely based on imports into North and South America. Our assessment is done in a perfectly competitive, comparative static setting in order to emphasize the role of the trade elasticities in determining the conventional gains/losses from such an FTA. This type of model is still widely used by government agencies for the evaluation of such agreements. Extensions to incorporate imperfect competition are straightforward, but involve the introduction of additional parameters (markups, extent of unexploited scale economies) as well as structural assumptions (entry/no-entry, nature of inter-firm rivalry) that introduce further uncertainty. Since our focus is on the effects of a PTA we estimate elasticities of substitution across multiple foreign supply sources. We do not use cross-exporter variation in prices or tariffs alone. Exporter price series exhibit a high degree of multicolinearity, and in any case, would be subject to unmeasured quality variation as described previously. Similarly, tariff variation by itself is typically unhelpful because by their very nature, Most Favored Nation (MFN) tariffs are non-discriminatory in nature, affecting all suppliers in the same way. Tariff preferences, where they exist, are often difficult to measure – sometimes being confounded by quantitative barriers, restrictive rules of origin, and other restrictions. Instead we employ a unique methodology and data set drawing on not only tariffs, but also bilateral transportation costs for goods traded internationally (Hummels, 1999). Transportation costs vary much more widely than do tariffs, allowing much more precise estimation of the trade elasticities that are central to CGE analysis of FTAs. We have highly disaggregated commodity trade flow data, and are therefore able to provide estimates that precisely match the commodity aggregation scheme employed in the subsequent CGE model. We follow the GTAP Version 5.0 aggregation scheme which includes 42 merchandise trade commodities covering food products, natural resources and manufactured goods. With the exception of two primary commodities that are not traded, we are able to estimate trade elasticities for all merchandise commodities that are significantly different form zero at the 95% confidence level. Rather than producing point estimates of the resulting welfare, export and employment effects, we report confidence intervals instead. These are based on repeated solution of the model, drawing from a distribution of trade elasticity estimates constructed based on the econometrically estimated standard errors. There is now a long history of CGE studies based on SSA: Systematic Sensitivity Analysis (Harrison and Vinod, 1992; Wigle, 1991; Pagon and Shannon, 1987) Ho