Degradation of pathogen quorum-sensing molecules by soil bacteria: a preventive and curative biological control mechanism.

Abstract The plasmid pME6863, carrying the aiiA gene from the soil bacterium Bacillus sp. A24 that encodes a lactonase enzyme able to degrade N-acyl-homoserine lactones (AHLs), was introduced into the rhizosphere isolate Pseudomonas fluorescens P3. This strain is not an effective biological control agent against plant pathogens. The transformant P. fluorescens P3/pME6863 acquired the ability to degrade AHLs. In planta, P. fluorescens P3/pME6863 significantly reduced potato soft rot caused by Erwinia carotovora and crown gall of tomato caused by Agrobacterium tumefaciens to a similar level as Bacillus sp. A24. Little or no disease reduction was observed for the wild-type strain P3 carrying the vector plasmid without aiiA. Suppression of potato soft rot was observed even when the AHL-degrading P. fluorescens P3/pME6863 was applied to tubers 2 days after the pathogen, indicating that biocontrol was not only preventive but also curative. When antagonists were applied individually with the bacterial plant pathogens, biocontrol activity of the AHL degraders was greater than that observed with several Pseudomonas 2,4-diacetylphloroglucinol-producing strains and with Pseudomonas chlororaphis PCL1391, which relies on production of phenazine antibiotic for disease suppression. Phenazine production by this well characterized biological control strain P. chlororaphis PCL1391 is regulated by AHL-mediated quorum sensing. When P. chlororaphis PCL1391 was co-inoculated with P. fluorescens P3/pME6863 in a strain mixture, the AHL degrader interfered with the normally excellent ability of the antibiotic producer to suppress tomato vascular wilt caused by Fusarium oxysporum f. sp. lycopersici. Our results demonstrate AHL degradation as a novel biocontrol mechanism, but also demonstrate the potential for non-target interactions that can interfere with the biocontrol efficacy of other strains.

Heterogeneity as a coordination device

A model of directed search with a finite number of buyers and sellers is considered, where sellers compete in direct mechanisms. Buyer heterogeneity and Nash equilibrium results in perfect sorting. The restriction to complementary inputs, that the match value function Q is supermodular, in addition coordinates the sellers strategies. In that case, equilibrium implements positive assortative matching, which is efficient and consistent with the stable (cooperative equilibrium) outcome. This provides a non-cooperative and decentralizedsolution for the Assignment Game. Conversely, if buyers are identical, no such coordination is possible, and there is a continuum of equilibria, one of which exhibits price posting, another yields competition in auctions.

A morphometric study of mechanotransductively induced dermal neovascularization.

BACKGROUND:: Mechanical stretch has been shown to induce vascular remodeling and increase vessel density, but the pathophysiologic mechanisms and the morphologic changes induced by tensile forces to dermal vessels are poorly understood. METHODS:: A custom computer-controlled stretch device was designed and applied to the backs of C57BL/6 mice (n = 38). Dermal and vascular remodeling was studied over a 7-day period. Corrosion casting and three-dimensional scanning electron microscopy and CD31 staining were performed to analyze microvessel morphology. Hypoxia was assessed by immunohistochemistry. Western blot analysis of vascular endothelial growth factor (VEGF) and mRNA expression of VEGF receptors was performed. RESULTS:: Skin stretching was associated with increased angiogenesis as demonstrated by CD31 staining and vessel corrosion casting where intervascular distance and vessel diameter were decreased (p < 0.01). Immediately after stretching, VEGF dimers were increased. Messenger RNA expression of VEGF receptor 1, VEGF receptor 2, neuropilin 1, and neuropilin 2 was increased starting as early as 2 hours after stretching. Highly proliferating epidermal cells induced epidermal hypoxia starting at day 3 (p < 0.01). CONCLUSIONS:: Identification of significant hypoxic cells occurred after identification of neovessels, suggesting an alternative mechanism. Increased expression of angiogenic receptors and stabilization of VEGF dimers may be involved in a mechanotransductive, prehypoxic induction of neovascularization.

Gene expression profiling of human glioblastomas for the identification of predictive factors and characterisation of molecular mechanism implicated in response to therapy and outcome

ABSTRACT Poor outcome for glioblastoma patients is largely due to resistance to chemoradiation therapy. While epigenetic inactivation of MGMT mediated DNA repair is highly predictive for benefit from the alkylating agent therapy Temozolomide, additional mechanisms for resistance associated with molecular alterations exist. Furthermore, new concepts in cancer suggest that resistance to treatment may be linked to cancer stem cells that escape therapy and act as source for tumour recurrence. We determined gene expression signatures associated with outcome in glioblastoma patients enrolled in a phase II and phase III clinical trial establishing the new combination therapy of radiation plus concomitant and adjuvant Temozolomide. Correlating stable gene clusters emerging from unsupervised analysis with survival of 42 treated patients identified a number of biological processes associated with outcome. Most prominent, a gene cluster dominated by HOX genes and comprising PROM1, was associated with resistance. PROM1 encodes CD133, a marker for a subpopulation of tumour cells enriched for glioblastoma stem- like cells. The core of this correlated HOX cluster was comprised in the top genes of a "self-renewal signature" defined in a mouse model for MLL-AF9 initiated leukaemia. The association of the HOX gene cluster with tumour resistance was confirmed in two external data sets of 146 malignant glioma As additional resistance factors we identified over-expression of the epidermal growth factor receptor gene, EGFR, while increased gene expression related to biological features of tumour host interaction, including markers for tumour vascular and cell adhesion, and innate immune response, were associated with better outcome. The "self-renewal" signature associated with resistance to the new combination chemoradiation therapy provides first clinical evidence that glioma stem like cells may implicated in resistance in a uniformly treated cohort of glioblastoma patients. This study underlines the need to target the tumour stem cell compartment, and provides some testable hypothesis for biological mechanisms relevant for malignant behaviour of glioblastoma that may be targeted in new treatment approaches. Résumé Le glioblastome, tumeur cérébrale primaire maligne la plus fréquente, est connue pour son mauvais pronostique. Des avancées chimiothérapeutiques récentes avec des agents alkylants comme le témozolomide (TMZ), ont permis une amélioration notable dans la survie de certains patients. Les bénéficiaires ont la caractéristique commune de présenter une particularité génétique, la methylation du MGMT (methylguanine methyltransferase). Néanmoins, d'autres mécanismes de résistance en fonction des aberrations moléculaires existent. Nous avons établi les profils d'expressions génétiques des patients traités par irradiation et TMZ dans des études cliniques de phase II et III. En combinant des méthodes non-supervisées et supervisées, de l'étude de la cohorte des patients traités nous avons découvert des groupes de gènes associés à la survie. Un ensemble de gènes contenant les gènes Hox semble lié au mécanisme de résistance au traitement. Récemment, les gènes Hox ont été décrits comme faisant partie d"une signature d'autorenouvellement (self-renewal) des cellules souches cancéreuses de la leucémie. L'autorenouvellement est un processus grâce auquel les cellules souches se maintiennent tout au long de la vie. Cette association à la résistance est confirmée dans deux autres études indépendantes. Un autre facteur de résistance au traitement est la surexpression du gène EGFR. D'autre part, deux groupes de gènes associés à la relation entre hôte-tumeur tels que les marqueurs des vaisseaux tumoraux et de la réponse immunitaire innée s'avèrent avoir un effet positif sur la survie des patients traités. La découverte de la signature d'autorenouvellement comme facteur de résistance à la nouvelle chimio-radiothérapie offre une preuve clinique que les cellules souches cancéreuses sont impliquées dans la résistance au traitement. If est donc logique de penser que le traitement ciblé contre des cellules souches cancéreuses va dans l'avenir permettre des thérapies anticancéreuses plus performantes.

Consistent solutions in exchange economies: A characterization of the price mechanism

We characterize the Walrasian allocations correspondence by means offour axioms: consistency, replica invariance, individual rationality andPareto optimality. It is shown that for any given class of exchange economiesany solution that satisfies the axioms is a selection from the Walrasianallocations with slack. Preferences are assumed to be smooth, but may besatiated and non--convex. A class of economies is defined as all economieswhose agents' preferences belong to an arbitrary family (finite or infinite)of types. The result can be modified to characterize equal budget Walrasianallocations with slack by replacing individual rationality with individualrationality from equal division. The results are valid also for classes ofeconomies in which core--Walras equivalence does not hold.

Corporate finance and the monetary transmission mechanism

This paper analyzes the transmission mechanisms of monetarypolicy in a general equilibrium model of securities marketsand banking with asymmetric information. Banks' optimal asset/liability policy is such that in equilibrium capital adequacy constraints are always binding. Asymmetric information about banks' net worth adds a cost to outside equity capital, which limits the extent to which banks can relax their capital constraint. In this context monetarypolicy does not affect bank lending through changes in bank liquidity. Rather, it has the effect of changing theaggregate composition of financing by firms. The model also produces multiple equilibria, one of which displays all the features of a "credit crunch". Thus, monetary policy can also have large effects when it induces a shift from one equilibrium to the other.

The biased balance: Observation, formalism and interpretation of a dissymmetric measuring device

This paper studies a balance whose unobservable fulcrum is not necessarilylocated at the middle of its two pans. It presents three differentmodels, showing how this lack of symmetry modifies the observation, theformalism and the interpretation of such a biased measuring device. Itargues that the biased balance can be an interesting source of inspirationfor broadening the representational theory of measurement.

Implementing interactive computing in an object-oriented environment

Statistical computing when input/output is driven by a Graphical User Interface is considered. A proposal is made for automatic control ofcomputational flow to ensure that only strictly required computationsare actually carried on. The computational flow is modeled by a directed graph for implementation in any object-oriented programming language with symbolic manipulation capabilities. A complete implementation example is presented to compute and display frequency based piecewise linear density estimators such as histograms or frequency polygons.

Diplostigmaty in plants: a novel mechanism that provides reproductive assurance.

Differentiation of female sexual organs in flowering plants is rare and contrasts with the wide range of male reproductive strategies. An unusual example involves diplostigmaty, the possession of spatially and temporally distinct stigmas in Sebaea (Gentianaceae). Here, the single pistil within a flower has an apical stigma, as occurs in most flowering plants, but also a secondary stigma that occurs midway down the style, which is physically discrete and receptive several days after the apical stigma. We examined the function of diplostigmaty in Sebaea aurea, an insect-pollinated species of the Western Cape of South Africa. Floral manipulations and measurements of fertility and mating patterns provided evidence that basal stigmas function to enable autonomous delayed self-pollination, without limiting opportunities for outcrossing and thus avoiding the costs of seed discounting. We suggest that delayed selfing serves as a mechanism of reproductive assurance in populations with low plant density. The possession of dimorphic stigma function provides a novel example of a flexible mixed-mating strategy in plants that is responsive to changing demographic conditions.

Computing congruences of modular forms and Galois representations modulo prime powers

This article starts a computational study of congruences of modular forms and modular Galoisrepresentations modulo prime powers. Algorithms are described that compute the maximum integermodulo which two monic coprime integral polynomials have a root in common in a sensethat is defined. These techniques are applied to the study of congruences of modular forms andmodular Galois representations modulo prime powers. Finally, some computational results withimplications on the (non-)liftability of modular forms modulo prime powers and possible generalisationsof level raising are presented.

Investigation of Restraint Device use in Iowa's County Jail

Executive Summary The use of full-body restraint devices is a widespread practice in Iowa’s county jails. Full-body restraints come in the form of restraint chairs, boards, and beds, including two such devices manufactured in Iowa. Iowa law, which refers to these as four- and fivepoint restraints, states they are only to be used when an inmate is a threat to self, others, or jail security. However, the Ombudsman found they were also used on inmates who caused minor disruptions or in response to an inmate’s verbal abuse. In some cases, the restraints were used on inmates with known mental illness who were acting out, though no attempts were made to seek medical or mental health reviews for those inmates while restrained, leading to extended use of the restraint device.