Minimax Estimation of Nonregular Parameters and Discontinuity in Minimax Risk

When a parameter of interest is nondifferentiable in the probability, the existing theory of semiparametric efficient estimation is not applicable, as it does not have an influence function. Song (2014) recently developed a local asymptotic minimax estimation theory for a parameter that is a nondifferentiable transform of a regular parameter, where the nondifferentiable transform is a composite map of a continuous piecewise linear map with a single kink point and a translation-scale equivariant map. The contribution of this paper is two fold. First, this paper extends the local asymptotic minimax theory to nondifferentiable transforms that are a composite map of a Lipschitz continuous map having a finite set of nondifferentiability points and a translation-scale equivariant map. Second, this paper investigates the discontinuity of the local asymptotic minimax risk in the true probability and shows that the proposed estimator remains to be optimal even when the risk is locally robustified not only over the scores at the true probability, but also over the true probability itself. However, the local robustification does not resolve the issue of discontinuity in the local asymptotic minimax risk

Differential selection pressures exerted by host resistance quantitative trait loci on a pathogen population: a case study in an apple × Venturia inaequalis pathosystem

Understanding how pathogens evolve according to pressures exerted by their plant hosts is essential for the derivation of strategies aimed at the durable management of resistant cultivars. The spectrum of action of the resistance factors in the partially resistant cultivars is thought to be an important determinant of resistance durability. However, it has not yet been demonstrated whether the pressures exerted by quantitative resistance are different according to their spectrum of action.To investigate selection pressures exerted by apple genotypes harbouring various resistance quantitative trait loci (QTLs) on a mixed inoculum of the scab disease agent, Venturia inaequalis, we monitored V. inaequalis isolate proportions on diseased apple leaves of an F1 progeny using quantitative pyrosequencing technology and QTL mapping. Broad-spectrum resistances did not exert any differential selection pressures on the mixed inoculum, whereas narrow-spectrum resistances decreased the frequencies of some isolates in the mixture relative to the susceptible host genotypes. Our results suggest that the management of resistant cultivars should be different according to the spectrum of action of their resistance factors. The pyramiding of broad-spectrum factors or the use of a mixture of apple genotypes that carry narrow-spectrum resistance factors are two possible strategies for the minimization of resistance erosion

The threat of wild habitat to scab resistant apple cultivars

Evaluations of plant resistance to pathogens are rarely made using isolates from wild habitats, although the heterogeneity of such habitats may generate pathogen diversity which could be a source of new virulence in cultivated habitats. The aim of this study was to investigate whether scab resistance factors, identified and characterized in apples using isolates of Venturia inaequalis from a cultivated habitat, remained effective against isolates from a wild habitat. Three V. inaequalis core collections originating from the cultivated apple Malus × domestica and from two wild species, M. sieversii and M. sylvestris, were established to maximize pathogen diversity. For each core collection, 10 isolates were inoculated in mixtures onto 51 genotypes from an apple progeny segregating for two qualitative resistance genes and six quantitative resistance loci (QRL). On each apple genotype, isolates that contributed to the scab symptoms were identified within the mixture using microsatellite markers. The most frequently detected isolates were inoculated singly to compare their aggressiveness according to their host origin. The results showed that isolates from a wild habitat were able to infect the susceptible apple genotypes. However, these isolates were never more aggressive than isolates from the cultivated habitat on the resistance factors tested. It can therefore be concluded that the resistance factors used in this study, identified with V. inaequalis isolates from a cultivated habitat, remained effective against isolates from M. sylvestris and M. sieversii

NADPH-oxidase-driven oxygen radical production determines chondrocyte death and partly regulates metalloproteinase-mediated cartilage matrix degradation during interferon-γ-stimulated immune complex arthritis

In previous studies we have found that FcγRI determines chondrocyte death and matrix metalloproteinase (MMP)-mediated cartilage destruction during IFN-γ-regulated immune complex arthritis (ICA). Binding of immune complexes (ICs) to FcγRI leads to the prominent production of oxygen radicals. In the present study we investigated the contribution of NADPH-oxidase-driven oxygen radicals to cartilage destruction by using p47phox(-/- )mice lacking a functional NADPH oxidase complex. Induction of a passive ICA in the knee joints of p47phox(-/- )mice resulted in a significant elevation of joint inflammation at day 3 when compared with wild-type (WT) controls as studied by histology. However, when IFN-γ was overexpressed by injection of adenoviral IFN-γ in the knee joint before ICA induction, a similar influx of inflammatory cells was found at days 3 and 7, comprising mainly macrophages in both mouse strains. Proteoglycan depletion from the cartilage layers of the knee joints in both groups was similar at days 3 and 7. Aggrecan breakdown in cartilage caused by MMPs was further studied by immunolocalisation of MMP-mediated neoepitopes (VDIPEN). VDIPEN expression in the cartilage layers of arthritic knee joints was markedly lower (between 30 and 60%) in IFN-γ-stimulated arthritic p47phox(-/- )mice at day 7 than in WT controls, despite significant upregulation of mRNA levels of various MMPs such as MMP-3, MMP-9, MMP-12 and MMP-13 in synovia and MMP-13 in cartilage layers as measured with quantitative RT-PCR. The latter observation suggests that oxygen radicals are involved in the activation of latent MMPs. Chondrocyte death, determined as the percentage of empty lacunae in articular cartilage, ranged between 20 and 60% at day 3 and between 30 and 80% at day 7 in WT mice, and was completely blocked in p47phox(-/- )mice at both time points. FcγRI mRNA expression was significantly lower, and FcγRII and FcγRIII were higher, in p47phox(-/- )mice than in controls. NADPH-oxidase-driven oxygen radical production determines chondrocyte death and aggravates MMP-mediated cartilage destruction during IFN-γ-stimulated IC-mediated arthritis. Upregulation of FcγRI by oxygen radicals may contribute to cartilage destruction

Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation

During immune-complex-mediated arthritis (ICA), severe cartilage destruction is mediated by Fcγ receptors (FcγRs) (mainly FcγRI), cytokines (e.g. IL-1), and enzymes (matrix metalloproteinases (MMPs)). IL-13, a T helper 2 (Th2) cytokine abundantly found in synovial fluid of patients with rheumatoid arthritis, has been shown to reduce joint inflammation and bone destruction during experimental arthritis. However, the effect on severe cartilage destruction has not been studied in detail. We have now investigated the role of IL-13 in chondrocyte death and MMP-mediated cartilage damage during ICA. IL-13 was locally overexpressed in knee joints after injection of an adenovirus encoding IL-13 (AxCAhIL-13), 1 day before the onset of arthritis; injection of AxCANI (an empty adenoviral construct) was used as a control. IL-13 significantly increased the amount of inflammatory cells in the synovial lining and the joint cavity, by 30% to 60% at day 3 after the onset of ICA. Despite the enhanced inflammatory response, chondrocyte death was diminished by two-thirds at days 3 and 7. The mRNA level of FcγRI, a receptor shown to be crucial in the induction of chondrocyte death, was significantly down-regulated in synovium. Furthermore, MMP-mediated cartilage damage, measured as neoepitope (VDIPEN) expression using immunolocalization, was halved. In contrast, mRNA levels of MMP-3, -9, -12, and -13 were significantly higher and IL-1 protein, which induces production of latent MMPs, was increased fivefold by IL-13. This study demonstrates that IL-13 overexpression during ICA diminished both chondrocyte death and MMP-mediated VDIPEN expression, even though joint inflammation was enhanced

Pression de sélection exercée par des génotypes de Malus x domestica partiellement résistants sur des populations de Venturia inaequalis provenant des compartiments sauvages et cultivés

Le déploiement de variétés résistantes portant des gènes majeurs peut avoir un impact fort sur la structuration des populations de pathogène. Chez le pommier, l’utilisation des variétés résistantes à la tavelure portant le gène majeur Vf a conduit à l’augmentation en fréquence de souches virulentes, probablement issues du compartiment sauvage, menant à la perte d’efficacité de ce gène. Les résistances partielles sont considérées plus durables. Cependant l’adaptation des pathogènes à ce type de résistance a été beaucoup moins étudiée. Dans cette étude, nous testons l’hypothèse (1) d’une adaptation différentielle des souches selon leur compartiment d’origine (2) d’une sélection des souches les plus agressives par les résistances partielles. Deux cultivars sensibles et 51 génotypes appartenant à une descendance F1 où ségrégent 8 facteurs de résistance (QTLs et gènes majeurs) ont été inoculés en conditions contrôlées par 3 core collections de V. inaequalis isolées de M. x domestica et d’espèces endémiques asiatique, M. sieversii et européenne, M. sylvestris. Chaque core collection est constituée de 10 souches inoculées en mélange. La sévérité de la maladie a été notée, l’identité des souches sporulantes a ensuite été définie à l’aide de marqueurs microsatellites. Enfin, les souches identifiées ont été inoculées seules sur certains génotypes F1 ainsi que sur les cultivars sensibles afin de comparer leur agressivité. Concernant le compartiment sauvage, 2 souches sont toujours présentes quelque soit le génotype testé suggérant que l’effet de compétition entre souches serait plus important que l’effet du génotype hôte. En revanche, les fréquences de détection des souches issues de M. x domestica varient selon le génotype. De plus, c’est dans ce compartiment que l’on détecte le plus de souches multivirulentes. Le lien entre résistances partielles et niveau d’agressivité sera présenté