Modelling and simulating change in reforesting mountain landscapes using a social-ecological framework

Natural reforestation of European mountain landscapes raises major environmental and societal issues. With local stakeholders in the Pyrenees National Park area (France), we studied agricultural landscape colonisation by ash (Fraxinus excelsior) to enlighten its impacts on biodiversity and other landscape functions of importance for the valley socio-economics. The study comprised an integrated assessment of land-use and land-cover change (LUCC) since the 1950s, and a scenario analysis of alternative future policy. We combined knowledge and methods from landscape ecology, land change and agricultural sciences, and a set of coordinated field studies to capture interactions and feedback in the local landscape/land-use system. Our results elicited the hierarchically-nested relationships between social and ecological processes. Agricultural change played a preeminent role in the spatial and temporal patterns of LUCC. Landscape colonisation by ash at the parcel level of organisation was merely controlled by grassland management, and in fact depended on the farmer's land management at the whole-farm level. LUCC patterns at the landscape level depended to a great extent on interactions between farm household behaviours and the spatial arrangement of landholdings within the landscape mosaic. Our results stressed the need to represent the local SES function at a fine scale to adequately capture scenarios of change in landscape functions. These findings orientated our modelling choices in the building an agent-based model for LUCC simulation (SMASH - Spatialized Multi-Agent System of landscape colonization by ASH). We discuss our method and results with reference to topical issues in interdisciplinary research into the sustainability of multifunctional landscapes

Physiological roles of macrophages

Macrophages are present in mammals from midgestation, contributing to physiologic homeostasis throughout life. Macrophages arise from yolk sac and foetal liver progenitors during embryonic development in the mouse and persist in different organs as heterogeneous, self-renewing tissue-resident populations. Bone marrow-derived blood monocytes are recruited after birth to replenish tissue-resident populations and to meet further demands during inflammation, infection and metabolic perturbations. Macrophages of mixed origin and different locations vary in replication and turnover, but are all active in mRNA and protein synthesis, fulfilling organ-specific and systemic trophic functions, in addition to host defence. In this review we emphasise selected properties and non-immune functions of tissue macrophages which contribute to physiologic homeostasis

Synthetic lethal therapies for cancer: what's next after PARP inhibitors?

The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Les fonctionnalités de l'espace : une approche de la multifonctionnalité pour évaluer les impacts des changements d'usage de l'espace sur la durabilité

[Departement_IRSTEA]GT [TR1_IRSTEA]RURAMEN / AMANDEInternational audienceThe dramatic changes in land use observed in Europe in the last fifty years have generally resulted in improvement of human welfare and economic development. On the other hand, they have caused serious environmental problems. There is therefore a need for approaches that help to understand in an integrative way the economic, environmental and societal impacts that land use changes have on sustainability. Sustainability Impact Assessment (SIA), which assesses the impact of policies on sustainability, addresses this challenge. SIA partly builds on the concept of the multifunctionality of land which helps to deal with the complexity of interactions between different land uses, their temporal and spatial changes, and finally how policies might steer those changes towards sustainability. Following this need for true integration of economic, environmental and societal issues across policy areas at a meaningful spatial scale, an nterdisciplinary team in the SENSOR project has developed an innovative conceptual framework to assess the impact of policies on land sustainability at various levels of spatial aggregation i.e. the Land Use Functions (LUFs) framework. LUFs are the goods and services provided by the different land uses that summarise the most relevant economic, environmental and societal issues of a region. The LUFs framework integrates the changes observed in a large set of impact indicators into nine Land Use Functions (LUFs), which are balanced among the three pillars of sustainability. The LUFs framework makes it possible for policy makers, scientists and stakeholders to identify at a glance those functions of the land which are hindered or enhanced under various scenarios of land use change, and makes it possible to explore the trade-offs between them. The LUFs framework allows therefore the building of assessment across disciplines, sectors and the three sustainability dimensions. It has proved to be very helpful for the systematisation of relevant sustainability indicators within SENSOR and is intended to be further used in other projects as a tool for Sustainability Impact Assessment. The rationale leading to the LUFs concept, its definition and the conceptual framework is described in this chapter. We conclude that the concept of LUFs allows users to make explicit the analytical links between multifunctional land use and sustainable development, and therefore to look at multifunctionality as a way towards sustainability.Dans le cadre du projet SENSOR, une équipe interdisciplinaire a développé un cadre conceptuel pour l'évaluation des impacts des politiques sur la durabilité des usages de l'espace. Il repose sur l'identification de diverses fonctions assurées par l'espace et permet d'évaluer les effets des changements des usages de l'espace sur ces fonctions. Le concept permet de mettre en relation la multifonctionnalité des usages de l'espace et la durabilité du développement : maintenir la première conditionne la seconde