Vaccination route matters for mucosal tumors.

Immunization route may be pivotal for tissue-specific localization of the effector T cell response (Sandoval et al., this issue).

A discrete forest in a continuous landscape : investigating interactions between natural resource management and sustainable development

Summary Forests are key ecosystems of the earth and associated with a large range of functions. Many of these functions are beneficial to humans and are referred to as ecosystem services. Sustainable development requires that all relevant ecosystem services are quantified, managed and monitored equally. Natural resource management therefore targets the services associated with ecosystems. The main hypothesis of this thesis is that the spatial and temporal domains of relevant services do not correspond to a discrete forest ecosystem. As a consequence, the services are not quantified, managed and monitored in an equal and sustainable manner. The thesis aims were therefore to test this hypothesis, establish an improved conceptual approach and provide spatial applications for the relevant land cover and structure variables. The study was carried out in western Switzerland and based primarily on data from a countrywide landscape inventory. This inventory is part of the third Swiss national forest inventory and assesses continuous landscape variables based on a regular sampling of true colour aerial imagery. In addition, land cover variables were derived from Landsat 5 TM passive sensor data and land structure variables from active sensor data from a small footprint laserscanning system. The results confirmed the main hypothesis, as relevant services did not scale well with the forest ecosystem. Instead, a new conceptual approach for sustainable management of natural resources was described. This concept quantifies the services as a continuous function of the landscape, rather than a discrete function of the forest ecosystem. The explanatory landscape variables are therefore called continuous fields and the forest becomes a dependent and function-driven management unit. Continuous field mapping methods were established for land cover and structure variables. In conclusion, the discrete forest ecosystem is an adequate planning and management unit. However, monitoring the state of and trends in sustainability of services requires them to be quantified as a continuous function of the landscape. Sustainable natural resource management iteratively combines the ecosystem and gradient approaches. Résumé Les forêts sont des écosystèmes-clés de la terre et on leur attribue un grand nombre de fonctions. Beaucoup de ces fonctions sont bénéfiques pour l'homme et sont nommées services écosystémiques. Le développement durable exige que ces services écosystémiques soient tous quantifiés, gérés et surveillés de façon égale. La gestion des ressources naturelles a donc pour cible les services attribués aux écosystèmes. L'hypothèse principale de cette thèse est que les domaines spatiaux et temporels des services attribués à la forêt ne correspondent pas à un écosystème discret. Par conséquent, les services ne sont pas quantifiés, aménagés et surveillés d'une manière équivalente et durable. Les buts de la thèse étaient de tester cette hypothèse, d'établir une nouvelle approche conceptuelle de la gestion des ressources naturelles et de préparer des applications spatiales pour les variables paysagères et structurelles appropriées. L'étude a été menée en Suisse occidentale principalement sur la base d'un inventaire de paysage à l'échelon national. Cet inventaire fait partie du troisième inventaire forestier national suisse et mesure de façon continue des variables paysagères sur la base d'un échantillonnage régulier sur des photos aériennes couleur. En outre, des variables de couverture ? terrestre ont été dérivées des données d'un senseur passif Landsat 5 TM, ainsi que des variables structurelles, dérivées du laserscanning, un senseur actif. Les résultats confirment l'hypothèse principale, car l'échelle des services ne correspond pas à celle de l'écosystème forestier. Au lieu de cela, une nouvelle approche a été élaborée pour la gestion durable des ressources naturelles. Ce concept représente les services comme une fonction continue du paysage, plutôt qu'une fonction discrète de l'écosystème forestier. En conséquence, les variables explicatives de paysage sont dénommées continuous fields et la forêt devient une entité dépendante, définie par la fonction principale du paysage. Des méthodes correspondantes pour la couverture terrestre et la structure ont été élaborées. En conclusion, l'écosystème forestier discret est une unité adéquate pour la planification et la gestion. En revanche, la surveillance de la durabilité de l'état et de son évolution exige que les services soient quantifiés comme fonction continue du paysage. La gestion durable des ressources naturelles joint donc l'approche écosystémique avec celle du gradient de manière itérative.

Animal dispersal modelling: handling landscape features and related animal choices

Animal dispersal in a fragmented landscape depends on the complex interaction between landscape structure and animal behavior. To better understand how individuals disperse, it is important to explicitly represent the properties of organisms and the landscape in which they move. A common approach to modelling dispersal includes representing the landscape as a grid of equal sized cells and then simulating individual movement as a correlated random walk. This approach uses a priori scale of resolution, which limits the representation of all landscape features and how different dispersal abilities are modelled. We develop a vector-based landscape model coupled with an object-oriented model for animal dispersal. In this spatially explicit dispersal model, landscape features are defined based on their geographic and thematic properties and dispersal is modelled through consideration of an organism's behavior, movement rules and searching strategies (such as visual cues). We present the model's underlying concepts, its ability to adequately represent landscape features and provide simulation of dispersal according to different dispersal abilities. We demonstrate the potential of the model by simulating two virtual species in a real Swiss landscape. This illustrates the model's ability to simulate complex dispersal processes and provides information about dispersal such as colonization probability and spatial distribution of the organism's path.

Map of ecological networks for landscape planning

This paper presents a method based on a geographical information system (GIS) to model ecological networks in a fragmented landscape. The ecological networks are generated with the help of a landscape model (which integrate human activities) and with a wildlife dispersal model. The main results are maps which permit the analysis and the understanding of the impact of human activities on wildlife dispersal. Three applications in a study area are presented: ecological networks at the landscape scale, conflicting areas at the farmstead scale and ecological distance between biotopes. These applications show the flexibility of the model and its potential to give information on ecological networks at different planning scales.

Body context and posture affect mental imagery of hands.

Different visual stimuli have been shown to recruit different mental imagery strategies. However the role of specific visual stimuli properties related to body context and posture in mental imagery is still under debate. Aiming to dissociate the behavioural correlates of mental processing of visual stimuli characterized by different body context, in the present study we investigated whether the mental rotation of stimuli showing either hands as attached to a body (hands-on-body) or not (hands-only), would be based on different mechanisms. We further examined the effects of postural changes on the mental rotation of both stimuli. Thirty healthy volunteers verbally judged the laterality of rotated hands-only and hands-on-body stimuli presented from the dorsum- or the palm-view, while positioning their hands on their knees (front postural condition) or behind their back (back postural condition). Mental rotation of hands-only, but not of hands-on-body, was modulated by the stimulus view and orientation. Additionally, only the hands-only stimuli were mentally rotated at different speeds according to the postural conditions. This indicates that different stimulus-related mechanisms are recruited in mental rotation by changing the bodily context in which a particular body part is presented. The present data suggest that, with respect to hands-only, mental rotation of hands-on-body is less dependent on biomechanical constraints and proprioceptive input. We interpret our results as evidence for preferential processing of visual- rather than kinesthetic-based mechanisms during mental transformation of hands-on-body and hands-only, respectively.

Ecological and land use studies along elevational gradients

Mountain regions and UNESCO Mountain Biosphere Reserves (MBRs) encapsulate broad elevational ranges, cover large gradients of geological, topographical and climatic diversity, and thus host greater biodiversity than the surrounding lowlands. Much of the biological richness in MBRs results from the interaction of climatic contrasts and gravitational forces along elevational gradients. External forces such as atmospheric change and human land use interact with these gradients, and result in distinct landscape patchiness, ie mosaics of land cover types within and across elevational belts. The management of MBRs influences land use and land cover, which affects biodiversity and ecosystem processes, both of which provide goods and services to society. Due to their broad environmental and biological diversity, MBRs are ideally suited for global change research and will be increasingly important in illustrating biodiversity conservation. This article summarizes the ecologically relevant results of an international workshop on elevational gradients that aimed to achieve a synthesis of the major ecosystem and biodiversity conditions and drivers in an altitude context. The workshop developed a core research agenda for MBRs that prioritizes long-term research and changes in land use across a broad elevational range.

Oxidants positively or negatively regulate nuclear factor kappaB in a context-dependent manner.

Redox-based mechanisms play critical roles in the regulation of multiple cellular functions. NF-kappaB, a master regulator of inflammation, is an inducible transcription factor generally considered to be redox-sensitive, but the modes of interactions between oxidant stress and NF-kappaB are incompletely defined. Here, we show that oxidants can either amplify or suppress NF-kappaB activation in vitro by interfering both with positive and negative signals in the NF-kappaB pathway. NF-kappaB activation was evaluated in lung A549 epithelial cells stimulated with tumor necrosis factor alpha (TNFalpha), either alone or in combination with various oxidant species, including hydrogen peroxide or peroxynitrite. Exposure to oxidants after TNFalpha stimulation produced a robust and long lasting hyperactivation of NF-kappaB by preventing resynthesis of the NF-kappaB inhibitor IkappaB, thereby abrogating the major negative feedback loop of NF-kappaB. This effect was related to continuous activation of inhibitor of kappaB kinase (IKK), due to persistent IKK phosphorylation consecutive to oxidant-mediated inactivation of protein phosphatase 2A. In contrast, exposure to oxidants before TNFalpha stimulation impaired IKK phosphorylation and activation, leading to complete prevention of NF-kappaB activation. Comparable effects were obtained when interleukin-1beta was used instead of TNFalpha as the NF-kappaB activator. This study demonstrates that the influence of oxidants on NF-kappaB is entirely context-dependent, and that the final outcome (activation versus inhibition) depends on a balanced inhibition of protein phosphatase 2A and IKK by oxidant species. Our findings provide a new conceptual framework to understand the role of oxidant stress during inflammatory processes.

Update of the FANTOM web resource: from mammalian transcriptional landscape to its dynamic regulation.

The international Functional Annotation Of the Mammalian Genomes 4 (FANTOM4) research collaboration set out to better understand the transcriptional network that regulates macrophage differentiation and to uncover novel components of the transcriptome employing a series of high-throughput experiments. The primary and unique technique is cap analysis of gene expression (CAGE), sequencing mRNA 5'-ends with a second-generation sequencer to quantify promoter activities even in the absence of gene annotation. Additional genome-wide experiments complement the setup including short RNA sequencing, microarray gene expression profiling on large-scale perturbation experiments and ChIP-chip for epigenetic marks and transcription factors. All the experiments are performed in a differentiation time course of the THP-1 human leukemic cell line. Furthermore, we performed a large-scale mammalian two-hybrid (M2H) assay between transcription factors and monitored their expression profile across human and mouse tissues with qRT-PCR to address combinatorial effects of regulation by transcription factors. These interdependent data have been analyzed individually and in combination with each other and are published in related but distinct papers. We provide all data together with systematic annotation in an integrated view as resource for the scientific community (http://fantom.gsc.riken.jp/4/). Additionally, we assembled a rich set of derived analysis results including published predicted and validated regulatory interactions. Here we introduce the resource and its update after the initial release.

Instances d'aliénation: portrait du patient tiraillé 1. Individu et contexte [Instances of alienation: portrait of the torn patient. I. Individual and context].

While the past decades were marked by an increased interest for the existential situation of man suffering from disease, the mechanisms alienating the patient from himself and from his context have been poorly investigated. These mechanisms, though operating in a dynamic interaction, will be discussed here sequentially. The first part of this article focuses on individual mechanisms of alienation emerging from the relationship the patient establishes with his body and psyche and on those related to his relational context. The aim is not to comprehensively describe these phenomena, but to discuss--based on clinical vignettes--some examples and their implications. The second part of the article describes some mechanisms of alienation that are incorporated in the medical apparatus and the dominant discourses.

Monitoring of innate and adaptive immune responses in the context of human immunotherapy

Summary1 SummaryCancer patients have a better clinical outcome when their tumours display marked infiltration by memory Τ cells. Moreover, the overrepresentation of Th1 gene signatures in primary tumours correlates with favourable prognosis. Thus, vaccination to induce Τ cells capable of infiltrating and eradicating the tumour seems a promising strategy for the treatment of cancer. Here, I monitored CD4 Τ cell responses in melanoma patients vaccinated with the long synthetic peptides Melan- A16-35(A27L) and NY-ESO-179.108. Most of the patients developed strong and diverse peptide antigen specific CD4 Τ cell responses. Analysis of the fine specificity of CD4 Τ cell antigen recognition led to the identification of two new epitopes. The peptide Melan-A16_35(A27L) was delivered by virus-like particles (VLPs) derived from bacteriophage Οβ, which themselves displayed strong immunogenicity. I show evidence for induction of Οβ- and Melan-A specific CD4 Τ cell responses that developed a Th1 functional profile after repeated vaccination cycles. They also specifically released the chemokines CCL-3 and CCL-4, which play important roles in attracting CD8 Τ cells to the APC surface for priming and formation of Τ cell memory. We further found induction of robust humoral IgG responses upon VLP vaccination, and the lgG1-lgG4 isotype composition depended on the adjuvant used. Since heavy chain class switching largely dépends on the presence of CD4 Τ cell help, this result suggests that the adjuvant can influence the differentiation of elicited CD4 Τ cells, thereby contributing to the quality and function of both Β cells and CD8 Τ cells. The nature of the inflammatory processes in the tumour microenvironment can modulate CD8 Τ cell function. A collaboration was established for the investigation regulation of inflammasome activation in human primary monocytes. We identified IL- 4 and TGF-β as strong inhibitors of IL-1 β secretion, Indicating some level of regulation from effector Th2 and Treg responses. We further found a potent inhibition of inflammasome activation by type I interferon, and demonstrated in vivo inhibition of IL-1 β responses in monocytes from active multiple sclerosis patients under IFN-β therapy. This finding further offers a possible explanation for its success, which mechanism of action is still largely unclear. Interestingly, type I interferon is also being used as adjuvant treatment for tumour free metastatic cutaneous melanoma patients. While its clinical benefit has remained controversial, recent data suggest that the subset of patients with ulcerated primary melanoma lesions can benefit from this therapy. Future investigations will shed light on the implication of the inflammasome in this context, and may offer new strategies for improved adjuvant treatments of melanoma.2 RésuméLes patients atteints de cancer ont une meilleure chance de survie si leurs tumeurs s'avèrent être largement infiltrées par des cellules Τ mémoires. De plus, la surreprésentation d'une signature génique Th1 est en corrélation avec un pronostic favorable. Ainsi, la vaccination visant à induire des cellules Τ capables d'infiltrer et de détruire la tumeur parait être une stratégie prometteuse pour le traitement du cancer. Dans ce travail, j'ai procédé au monitoring de la réponse des cellules Τ CD4 dans des patients atteints de mélanome vaccinés avec les longs peptides synthétiques Melan-A16_35(A27L) et NY-ESO-179_108. Ces peptides représentent des antigènes tumoraux reconnus par des lymphocytes T. La majorité des patients a développé une réponse forte et diversifiée des cellules Τ CD4 spécifiques contre les peptides. L'analyse de la spécificité fine de la reconnaissance antigénique des cellules Τ CD4 nous a conduits à l'identification de deux nouveaux épitopes. Le peptide Melan-Aie. 35(A27L) a été délivré par des particules de type viral (VLPs) dérivés de bactériophages Qβ, qui ont eux-mêmes démontré une forte immunogénicité. Mon travail montre les preuves d'une induction de réponses spécifiques des cellules Τ CD4 contre les Qβ et Melan-A développant un profil fonctionnel Th1 après plusieurs cycles de vaccination. Elles secrètent aussi spécifiquement les chimiokines CCL-3 et CCL-4, qui jouent un rôle important dans l'attraction des cellules Τ CD8 à la surface des cellules présentatrices d'antigènes et contribuent ainsi à induire et former la mémoire cellulaire Τ CD8. Nous avons également remarqué une induction de fortes réponses humorales IgG après vaccination avec les VLPs, et que la composition des isotypes lgG1-lgG4 dépendait de l'adjuvant utilisé. Etant donné qu'une commutation de classe de la chaîne lourde dépend largement ùie l'aide des cellules Τ CD4, ce résultat suggère que l'adjuvant puisse influencer la différeritiation de cellules Τ CD4 en différent types, contribuant ainsi à la qualité et à la fonction des cellules Β et des cellules Τ CD8.La nature des processus d'inflammation dans le microenvironnement tumoral peut moduler la fonction des cellules Τ CD8. Une collaboration a été établie pour investiguer la régulation de l'activation de l'inflammasome dans des monocytes primaires humains. Nous avons identifié l'IL-4 et le TGF-β comme étant de puissants inhibiteurs de la sécrétion de IL-Ιβ, indiquant une certaine régulation de la réponse inflammatoire induite par les cellules Th2 et Τ régulatrices. Nous avons également trouvé une forte inhibition de l'activation de l'inflammasome par l'interféron type I, et nous avons démontré une inhibition in vivo de la réponse IL-1 β dans des monocytes de patients atteints d'une sclérose en plaque active sous traitement IFN-β. Ce résultat nous offre une possible explication du succès de cette thérapie, dont le mécanisme reste à ce jour encore largement obscur. Il est intéressant de noter que l'interféron de type I est également utilisé pour le traitement de patients atteints de mélanome cutané métastasique sans tumeurs. Bien que le bénéfice clinique de ce traitement reste controversé, des études récentes montrent qu'une partie des patients atteints de mélanome primaire ulcéré peut tirer bénéfice de cette thérapie. De futures investigations pourront mieux nous renseigner sur l'implication de l'inflammasome dans ce contexte et offrir de nouvelles stratégies pour améliorer les traitements adjuvants du mélanome.