974 resultados para Monitoraggio Livellazione Due-Torri-Bologna
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The interaction of tunneling with groundwater is a problem both from an environmental and an engineering point of view. In fact, tunnel drilling may cause a drawdown of piezometric levels and water inflows into tunnels that may cause problems during excavation of the tunnel. While the influence of tunneling on the regional groundwater systems may be adequately predicted in porous media using analytical solutions, such an approach is difficult to apply in fractured rocks. Numerical solutions are preferable and various conceptual approaches have been proposed to describe and model groundwater flow through fractured rock masses, ranging from equivalent continuum models to discrete fracture network simulation models. However, their application needs many preliminary investigations on the behavior of the groundwater system based on hydrochemical and structural data. To study large scale flow systems in fractured rocks of mountainous terrains, a comprehensive study was conducted in southern Switzerland, using as case studies two infrastructures actually under construction: (i) the Monte Ceneri base railway tunnel (Ticino), and the (ii) San Fedele highway tunnel (Roveredo, Graubiinden). The chosen approach in this study combines the temporal and spatial variation of geochemical and geophysical measurements. About 60 localities from both surface and underlying tunnels were temporarily and spatially monitored during more than one year. At first, the project was focused on the collection of hydrochemical and structural data. A number of springs, selected in the area surrounding the infrastructures, were monitored for discharge, electric conductivity, pH, and temperature. Water samples (springs, tunnel inflows and rains) were taken for isotopic analysis; in particular the stable isotope composition (δ2Η, δ180 values) can reflect the origin of the water, because of spatial (recharge altitude, topography, etc.) and temporal (seasonal) effects on precipitation which in turn strongly influence the isotopic composition of groundwater. Tunnel inflows in the accessible parts of the tunnels were also sampled and, if possible, monitored with time. Noble-gas concentrations and their isotope ratios were used in selected locations to better understand the origin and the circulation of the groundwater. In addition, electrical resistivity and VLF-type electromagnetic surveys were performed to identify water bearing fractures and/or weathered areas that could be intersected at depth during tunnel construction. The main goal of this work was to demonstrate that these hydrogeological data and geophysical methods, combined with structural and hydrogeological information, can be successfully used in order to develop hydrogeological conceptual models of the groundwater flow in regions to be exploited for tunnels. The main results of the project are: (i) to have successfully tested the application of electrical resistivity and VLF-electromagnetic surveys to asses water-bearing zones during tunnel drilling; (ii) to have verified the usefulness of noble gas, major ion and stable isotope compositions as proxies for the detection of faults and to understand the origin of the groundwater and its flow regimes (direct rain water infiltration or groundwater of long residence time); and (iii) to have convincingly tested the combined application of a geochemical and geophysical approach to assess and predict the vulnerability of springs to tunnel drilling. - L'interférence entre eaux souterraines et des tunnels pose des problèmes environnementaux et de génie civile. En fait, la construction d'un tunnel peut faire abaisser le niveau des nappes piézométriques et faire infiltrer de l'eau dans le tunnel et ainsi créer des problème pendant l'excavation. Alors que l'influence de la construction d'un tunnel sur la circulation régionale de l'eau souterraine dans des milieux poreux peut être prédite relativement facilement par des solution analytiques de modèles, ceci devient difficile dans des milieux fissurés. Dans ce cas-là, des solutions numériques sont préférables et plusieurs approches conceptuelles ont été proposées pour décrire et modéliser la circulation d'eau souterraine à travers les roches fissurées, en allant de modèles d'équivalence continue à des modèles de simulation de réseaux de fissures discrètes. Par contre, leur application demande des investigations importantes concernant le comportement du système d'eau souterraine basées sur des données hydrochimiques et structurales. Dans le but d'étudier des grands systèmes de circulation d'eau souterraine dans une région de montagnes, une étude complète a été fait en Suisse italienne, basée sur deux grandes infrastructures actuellement en construction: (i) Le tunnel ferroviaire de base du Monte Ceneri (Tessin) et (ii) le tunnel routière de San Fedele (Roveredo, Grisons). L'approche choisie dans cette étude est la combinaison de variations temporelles et spatiales des mesures géochimiques et géophysiques. Environs 60 localités situées à la surface ainsi que dans les tunnels soujacents ont été suiviès du point de vue temporel et spatial pendant plus de un an. Dans un premier temps le projet se focalisait sur la collecte de données hydrochimiques et structurales. Un certain nombre de sources, sélectionnées dans les environs des infrastructures étudiées ont été suivies pour le débit, la conductivité électrique, le pH et la température. De l'eau (sources, infiltration d'eau de tunnel et pluie) a été échantillonnés pour des analyses isotopiques; ce sont surtout les isotopes stables (δ2Η, δ180) qui peuvent indiquer l'origine d'une eaux, à cause de la dépendance d'effets spatiaux (altitude de recharge, topographie etc.) ainsi que temporels (saisonaux) sur les précipitations météoriques , qui de suite influencent ainsi la composition isotopique de l'eau souterraine. Les infiltrations d'eau dans les tunnels dans les parties accessibles ont également été échantillonnées et si possible suivies au cours du temps. La concentration de gaz nobles et leurs rapports isotopiques ont également été utilisées pour quelques localités pour mieux comprendre l'origine et la circulation de l'eau souterraine. En plus, des campagnes de mesures de la résistivité électrique et électromagnétique de type VLF ont été menées afin d'identifier des zone de fractures ou d'altération qui pourraient interférer avec les tunnels en profondeur pendant la construction. Le but principal de cette étude était de démontrer que ces données hydrogéologiques et géophysiques peuvent être utilisées avec succès pour développer des modèles hydrogéologiques conceptionels de tunnels. Les résultats principaux de ce travail sont : i) d'avoir testé avec succès l'application de méthodes de la tomographie électrique et des campagnes de mesures électromagnétiques de type VLF afin de trouver des zones riches en eau pendant l'excavation d'un tunnel ; ii) d'avoir prouvé l'utilité des gaz nobles, des analyses ioniques et d'isotopes stables pour déterminer l'origine de l'eau infiltrée (de la pluie par le haut ou ascendant de l'eau remontant des profondeurs) et leur flux et pour déterminer la position de failles ; et iii) d'avoir testé d'une manière convainquant l'application combinée de méthodes géochimiques et géophysiques pour juger et prédire la vulnérabilité de sources lors de la construction de tunnels. - L'interazione dei tunnel con il circuito idrico sotterraneo costituisce un problema sia dal punto di vista ambientale che ingegneristico. Lo scavo di un tunnel puô infatti causare abbassamenti dei livelli piezometrici, inoltre le venute d'acqua in galleria sono un notevole problema sia in fase costruttiva che di esercizio. Nel caso di acquiferi in materiale sciolto, l'influenza dello scavo di un tunnel sul circuito idrico sotterraneo, in genere, puô essere adeguatamente predetta attraverso l'applicazione di soluzioni analitiche; al contrario un approccio di questo tipo appare inadeguato nel caso di scavo in roccia. Per gli ammassi rocciosi fratturati sono piuttosto preferibili soluzioni numeriche e, a tal proposito, sono stati proposti diversi approcci concettuali; nella fattispecie l'ammasso roccioso puô essere modellato come un mezzo discreto ο continuo équivalente. Tuttavia, una corretta applicazione di qualsiasi modello numerico richiede necessariamente indagini preliminari sul comportamento del sistema idrico sotterraneo basate su dati idrogeochimici e geologico strutturali. Per approfondire il tema dell'idrogeologia in ammassi rocciosi fratturati tipici di ambienti montani, è stato condotto uno studio multidisciplinare nel sud della Svizzera sfruttando come casi studio due infrastrutture attualmente in costruzione: (i) il tunnel di base del Monte Ceneri (canton Ticino) e (ii) il tunnel autostradale di San Fedele (Roveredo, canton Grigioni). L'approccio di studio scelto ha cercato di integrare misure idrogeochimiche sulla qualité e quantité delle acque e indagini geofisiche. Nella fattispecie sono state campionate le acque in circa 60 punti spazialmente distribuiti sia in superficie che in sotterraneo; laddove possibile il monitoraggio si è temporalmente prolungato per più di un anno. In una prima fase, il progetto di ricerca si è concentrato sull'acquisizione dati. Diverse sorgenti, selezionate nelle aree di possibile influenza attorno allé infrastrutture esaminate, sono state monitorate per quel che concerne i parametri fisico-chimici: portata, conduttività elettrica, pH e temperatura. Campioni d'acqua sono stati prelevati mensilmente su sorgenti, venute d'acqua e precipitazioni, per analisi isotopiche; nella fattispecie, la composizione in isotopi stabili (δ2Η, δ180) tende a riflettere l'origine delle acque, in quanto, variazioni sia spaziali (altitudine di ricarica, topografia, etc.) che temporali (variazioni stagionali) della composizione isotopica delle precipitazioni influenzano anche le acque sotterranee. Laddove possibile, sono state campionate le venute d'acqua in galleria sia puntualmente che al variare del tempo. Le concentrazioni dei gas nobili disciolti nell'acqua e i loro rapporti isotopici sono stati altresi utilizzati in alcuni casi specifici per meglio spiegare l'origine delle acque e le tipologie di circuiti idrici sotterranei. Inoltre, diverse indagini geofisiche di resistività elettrica ed elettromagnetiche a bassissima frequenza (VLF) sono state condotte al fine di individuare le acque sotterranee circolanti attraverso fratture dell'ammasso roccioso. Principale obiettivo di questo lavoro è stato dimostrare come misure idrogeochimiche ed indagini geofisiche possano essere integrate alio scopo di sviluppare opportuni modelli idrogeologici concettuali utili per lo scavo di opere sotterranee. I principali risultati ottenuti al termine di questa ricerca sono stati: (i) aver testato con successo indagini geofisiche (ERT e VLF-EM) per l'individuazione di acque sotterranee circolanti attraverso fratture dell'ammasso roccioso e che possano essere causa di venute d'acqua in galleria durante lo scavo di tunnel; (ii) aver provato l'utilità di analisi su gas nobili, ioni maggiori e isotopi stabili per l'individuazione di faglie e per comprendere l'origine delle acque sotterranee (acque di recente infiltrazione ο provenienti da circolazioni profonde); (iii) aver testato in maniera convincente l'integrazione delle indagini geofisiche e di misure geochimiche per la valutazione della vulnérabilité delle sorgenti durante lo scavo di nuovi tunnel. - "La NLFA (Nouvelle Ligne Ferroviaire à travers les Alpes) axe du Saint-Gothard est le plus important projet de construction de Suisse. En bâtissant la nouvelle ligne du Saint-Gothard, la Suisse réalise un des plus grands projets de protection de l'environnement d'Europe". Cette phrase, qu'on lit comme présentation du projet Alptransit est particulièrement éloquente pour expliquer l'utilité des nouvelles lignes ferroviaires transeuropéens pour le développement durable. Toutefois, comme toutes grandes infrastructures, la construction de nouveaux tunnels ont des impacts inévitables sur l'environnement. En particulier, le possible drainage des eaux souterraines réalisées par le tunnel peut provoquer un abaissement du niveau des nappes piézométriques. De plus, l'écoulement de l'eau à l'intérieur du tunnel, conduit souvent à des problèmes d'ingénierie. Par exemple, d'importantes infiltrations d'eau dans le tunnel peuvent compliquer les phases d'excavation, provoquant un retard dans l'avancement et dans le pire des cas, peuvent mettre en danger la sécurité des travailleurs. Enfin, l'infiltration d'eau peut être un gros problème pendant le fonctionnement du tunnel. Du point de vue de la science, avoir accès à des infrastructures souterraines représente une occasion unique d'obtenir des informations géologiques en profondeur et pour échantillonner des eaux autrement inaccessibles. Dans ce travail, nous avons utilisé une approche pluridisciplinaire qui intègre des mesures d'étude hydrogéochimiques effectués sur les eaux de surface et des investigations géophysiques indirects, tels que la tomographic de résistivité électrique (TRE) et les mesures électromagnétiques de type VLF. L'étude complète a été fait en Suisse italienne, basée sur deux grandes infrastructures actuellement en construction, qui sont le tunnel ferroviaire de base du Monte Ceneri, une partie du susmentionné projet Alptransit, situé entièrement dans le canton Tessin, et le tunnel routière de San Fedele, situé a Roveredo dans le canton des Grisons. Le principal objectif était de montrer comment il était possible d'intégrer les deux approches, géophysiques et géochimiques, afin de répondre à la question de ce que pourraient être les effets possibles dû au drainage causés par les travaux souterrains. L'accès aux galeries ci-dessus a permis une validation adéquate des enquêtes menées confirmant, dans chaque cas, les hypothèses proposées. A cette fin, nous avons fait environ 50 profils géophysiques (28 imageries électrique bidimensionnels et 23 électromagnétiques) dans les zones de possible influence par le tunnel, dans le but d'identifier les fractures et les discontinuités dans lesquelles l'eau souterraine peut circuler. De plus, des eaux ont été échantillonnés dans 60 localités situées la surface ainsi que dans les tunnels subjacents, le suivi mensuelle a duré plus d'un an. Nous avons mesurés tous les principaux paramètres physiques et chimiques: débit, conductivité électrique, pH et température. De plus, des échantillons d'eaux ont été prélevés pour l'analyse mensuelle des isotopes stables de l'hydrogène et de l'oxygène (δ2Η, δ180). Avec ces analyses, ainsi que par la mesure des concentrations des gaz rares dissous dans les eaux et de leurs rapports isotopiques que nous avons effectués dans certains cas spécifiques, il était possible d'expliquer l'origine des différents eaux souterraines, les divers modes de recharge des nappes souterraines, la présence de possible phénomènes de mélange et, en général, de mieux expliquer les circulations d'eaux dans le sous-sol. Le travail, même en constituant qu'une réponse partielle à une question très complexe, a permis d'atteindre certains importants objectifs. D'abord, nous avons testé avec succès l'applicabilité des méthodes géophysiques indirectes (TRE et électromagnétiques de type VLF) pour prédire la présence d'eaux souterraines dans le sous-sol des massifs rocheux. De plus, nous avons démontré l'utilité de l'analyse des gaz rares, des isotopes stables et de l'analyses des ions majeurs pour la détection de failles et pour comprendre l'origine des eaux souterraines (eau de pluie par le haut ou eau remontant des profondeurs). En conclusion, avec cette recherche, on a montré que l'intégration des ces informations (géophysiques et géochimiques) permet le développement de modèles conceptuels appropriés, qui permettant d'expliquer comment l'eau souterraine circule. Ces modèles permettent de prévoir les infiltrations d'eau dans les tunnels et de prédire la vulnérabilité de sources et des autres ressources en eau lors de construction de tunnels.
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Postprint (published version)
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LB11058 is a new synthetic cephalosporin with good affinity for staphylococcal penicillin-binding protein 2a (PBP2a). LB11058 was tested in vitro and in rats with experimental aortic endocarditis against three methicillin-resistant Staphylococcus aureus (MRSA) strains, one penicillinase-negative strain (strain COL), and two penicillinase-producing strains (COL-Bla+ and P8-Hom). The MICs of LB11058 for the organisms were 1 mg/liter. The MICs of vancomycin and ceftriaxone were 1 and >/=64 mg/liter, respectively. In population analysis profiles, none of the MRSA strains grew at >/=2 mg of LB11058/liter. Rats with endocarditis were treated for 5 days. LB11058 was highly bound to serum proteins in rats (>/=98%). However, binding was saturable above a threshold of 250 mg/liter. Therefore, continuous concentrations of 250 mg/liter in serum were infused to ensure a free fraction (>/=5 mg/liter) above the drug's MIC for the entire infusion period. Control treatments included simulation of human serum kinetics produced by intravenous vancomycin (1 g twice daily, free drug concentration above MIC, >/=90% of infusion period) or ceftriaxone (2 g/24 h, free drug concentrations above the MIC, 0% of infusion period). LB11058 successfully treated 10 of 10 (100%) and 13 of 14 (93%) of rats infected with COL-Bla+ and P8-Hom, respectively. This was comparable to vancomycin (sterilization of 8 of 12 [66%] and 6 of 8 [75%] rats, respectively). Ceftriaxone was inactive. Low concentrations of LB11058 (5 and 10 mg/liter, continuously infused) in serum were ineffective, as predicted by the pharmacodynamic parameters. At appropriate doses, LB11058 was highly effective both in vitro and in vivo. This finding supports the development of this beta-lactam with high PBP2a affinity for the treatment of MRSA infections.
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To determine incidence and type of major cardiac adverse events in patients with mutated desmin (DES) gene, we retrospectively reviewed baseline medical information, and examined the long-term outcomes of 28 DES patients (17 men, baseline mean age=37.7±14.4 years [min=9, max=71]) from 19 families. Baseline studies revealed skeletal muscle involvement in 21 patients and cardiac abnormalities in all but one patient. Over a mean follow-up of 10.4±9.4 years [min=1, max=35], cardiac death occurred in three patients, death due to cardiac comorbidities in two, one or more major cardiac adverse events in 13 patients. Among the 19 patients with mild conduction defects at baseline, eight developed high-degree conduction blocks requiring permanent pacing. Cardiac involvement was neither correlated with the type of DES mutation nor with the severity of skeletal muscle involvement. Our study underscores that in DES patients in-depth cardiac investigations are needed to prevent cardiac conduction system disease.
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The objective of this work was to determine, through the use of the bearing capacity model, the traffic effects of the forest harvest operations on the preconsolidation pressure (sigmap), during one cycle of the eucalyptus plantation. The work was conducted using undisturbed soil samples, collected at the surface of the A horizon and in the top of the B horizon of an Udult (PA), Aquox (FX) and Udox (LA) soils. The undisturbed soil samples were used in the uniaxial compression tests. The soil sampling was done before and after the harvest operations. The operations performed with the Forwarder caused greater soil compaction than the ones done with the Feller Büncher and Harvester. The percentage of soil samples, in the region with additional soil compaction, indicated that the Udult was the soil class more susceptible to soil compaction, followed by the Aquox and Udox. Despite Udult is the more susceptible to soil compaction, the regeneration of the soil structure in this soil class was more efficient than in Aquox. The percentage of soil samples with sigmap values in the region with additional soil compaction in 1996, 1998 and 2004, after harvest operations, indicated a sustainable forest exploration in this period.
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Streptococci of the viridans group have long been considered to be minor pathogens, except in bacterial endocarditis. For some years, however, these microorganisms have been the cause of serious bacteraemia in neutropenic patients receiving intensive chemotherapy. These infections can lead to severe complications such as endocarditis, respiratory distress syndromes or shock, and are associated with a mortality rate ranging from 6-30%. The principal risk factors for these infections are profound neutropenia, antibiotic prophylaxis with quinolones or cotrimoxazole, large doses of cytosine arabinoside, a recent history of chemotherapy, oropharyngeal mucositis and viridans streptococcal colonization. Protective factors are the early administration of parenteral antibiotics during periods of neutropenia, or the prophylactic administration of penicillin. Although the introduction of penicillin to prophylactic antibiotic regimens has led to a decrease in the incidence of these infections, the emergence of strains resistant to beta-lactams is a worrying problem which could compromise this type of treatment.
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Portland cement concrete is an outstanding structural material but stresses and cracks often occur in large structures due to drying shrinkage. The objective of this research was to determine the change in length due to loss of moisture from placement through complete drying of portland cement concrete. The drying shrinkage was determined for four different combinations of Iowa DOT structural concrete mix proportions and materials. The two mix proportions used were an Iowa DOT D57 (bridge deck mix proportions) and a water reduced modified C4 mix. Three 4"x 4"x 18" beams were made for each mix. After moist curing for three days, all beams were maintained in laboratory dry air and the length and weight were measured at 73°F ± 3°F. The temperature was cycled on alternate days from 73°F to 90°F through four months. From four months through six months, the temperature was cycled one day at 73°F and six days at 130°F. It took approximately six months for the concrete to reach a dry condition with these temperatures. The total drying shrinkage for the four mixes varied from .0106 in. to .0133 in. with an average of .0120 in. The rate of shrinkage was approximately .014% shrinkage per 1% moisture loss for all four mixes. The rate and total shrinkage for all four mixes was very similar and did not seem to depend on the type of coarse aggregate or the use of a retarder.
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The presence of intralesional natural regulatory T cells, characterized by the expression of Foxp3 mRNA, was analyzed in patients with localized leishmaniasis due to Leishmania guyanensis infection that was unresponsive to treatment with pentamidine isethionate. Foxp3 mRNA levels were associated with unresponsiveness to treatment among patients with a lesion duration of 1 month, but this association was not observed among patients with a lesion duration of <1 month. In conclusion, high intralesional expression of Foxp3 might be an indicator of poor response to treatment, depending on the duration of lesions.
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Our objective was to evaluate efficacy and patency of metallic stent placement for symptomatic Budd-Chiari syndrome (BCS) due to prothrombotic disorders. Eleven patients with proved BCS due to prothrombotic disorders were referred for endovascular treatment because of refractory ascites (n=9), abdominal pain (n=8), jaundice (n=6), and/or gastrointestinal bleeding (n=4). Stents were inserted for stenosed hepatic vein (n=7), inferior vena cava (n=2), or mesenterico-caval shunt (n=2). Clinical efficacy and stent patency was evaluated by clinical and Doppler follow-up. After a mean follow-up of 21 months, 6 patients had fully patent stents without reintervention (primary stent patency: 55%). Two patients with hepatic vein stenosis had stent thrombosis and died 4 months after procedure. Restenosis occurred in 3 cases (2 hepatic vein and 1 mesenterico-caval shunt stenosis) and were successfully treated by balloon angioplasty (n=2) and addition of new stents (n=1) leading to a 82% secondary stent patency. Of 9 patients with patent stent, 7 were asymptomatic (77%) at the end of the study. Stent placement is a safe and effective procedure to control of symptomatic BCS. Prothrombotic disorder does not seem to jeopardize patency in anticoagulated patients.
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PURPOSE: Acute pyelonephritis is a common condition in children, and can lead to renal scarring. The aim of this study was to analyze the progression of renal scarring with time and its impact on renal growth. MATERIALS AND METHODS: A total of 50 children who had renal scarring on dimercapto-succinic acid scan 6 months after acute pyelonephritis underwent a repeat scan 3 years later. Lesion changes were evaluated by 3 blinded observers, and were classified as no change, partial resolution or complete disappearance. Renal size at time of acute pyelonephritis and after 3 years was obtained by ultrasound, and renal growth was assessed comparing z-score for age between the 2 measures. Robust linear regression was used to identify determinants of renal growth. RESULTS: At 6 months after acute pyelonephritis 88 scars were observed in 100 renal units. No change was observed in 27%, partial resolution in 63% and complete disappearance in 9% of lesions. Overall, 72% of lesions improved. Increased number of scars was associated with high grade vesicoureteral reflux (p = 0.02). Multivariate analysis showed that the number of scars was the most important parameter leading to decreased renal growth (CI -1.05 to -0.35, p <0.001), and with 3 or more scars this finding was highly significant on univariate analysis (-1.59, CI -2.10 to -1.09, p <0.0001). CONCLUSIONS: Even 6 months after acute pyelonephritis 72% of dimercapto-succinic acid defects improved, demonstrating that some of the lesions may be not definitive. The number of scars was significantly associated with loss of renal growth at 3 years.
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The objective of this work was to evaluate if corn plants damaged by the lesser cornstalk borer (Elasmopalpus lignosellus) larvae release volatile organic compounds capable of attracting the egg parasitoid Trichogramma pretiosum. The treatments consisted of plants subjected to harm caused by E. lignosellus larvae, plants subjected to mechanical damage, and undamaged plants. The parasitoid was more attracted by the volatiles released by the insect damaged plants than to those released by undamaged corn plants, after 24 and 72 hours. The volatiles (Z)-3-hexenyl acetate, β-pinene, β-myrcene, (E)-4,8-dimethylnona-1,3,7-triene, and benzothiazole were released in significantly larger quantities by damaged plants. Volatiles released by corn plants damaged by E. lignosellus larvae may act as an indirect defense, attracting by T. pretiosum.
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Most odors in natural environments are mixtures of several compounds. Perceptually, these can blend into a new "perfume," or some components may dominate as elements of the mixture. In order to understand such mixture interactions, it is necessary to study the events at the olfactory periphery, down to the level of single-odorant receptor cells. Does a strong ligand present at a low concentration outweigh the effect of weak ligands present at high concentrations? We used the fruit fly receptor dOr22a and a banana-like odor mixture as a model system. We show that an intermediate ligand at an intermediate concentration alone elicits the neuron's blend response, despite the presence of both weaker ligands at higher concentration, and of better ligands at lower concentration in the mixture. Because all of these components, when given alone, elicited significant responses, this reveals specific mixture processing already at the periphery. By measuring complete dose-response curves we show that these mixture effects can be fully explained by a model of syntopic interaction at a single-receptor binding site. Our data have important implications for how odor mixtures are processed in general, and what preprocessing occurs before the information reaches the brain.