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In 2008 a vast consultation was launched in New Caledonia aimed at establishing a development plan for the territory, directed at the year 2025. If the Caledonian economy has experienced high growth over the past decade, thereby satisfying population and investment needs, the current challenge resides in the capacity to build the society of the future based on the recognition of multi-cultural aspirations and a shared project. Envisaged by the Accord de Nouméa and launched ten years later, the SAD offers all New Caledonians the opportunity to plan the future together. The over-arching strategic reflection and the creation of the broad politic foundations for the project have yet, however, to be determined.

Background Chimeric antigen receptor (CAR) T cell therapy has proven its clinical utility in hematological malignancies. Optimization is still required for its application in solid tumors. Here, the lack of cancer-specific structures along with tumor heterogeneity represent a critical barrier to safety and efficacy. Modular CAR T cells indirectly binding the tumor antigen through CAR-adaptor molecules have the potential to reduce adverse events and to overcome antigen heterogeneity. We hypothesized that a platform utilizing unique traits of clinical grade antibodies for selective CAR targeting would come with significant advantages. Thus, we developed a P329G-directed CAR targeting the P329G mutation in the Fc part of tumor-targeting human antibodies containing P329G L234A/L235A (LALA) mutations for Fc silencing.Methods A single chain variable fragment-based second generation P329G-targeting CAR was retrovirally transduced into primary human T cells. These CAR T cells were combined with IgG1 antibodies carrying P329G LALA mutations in their Fc part targeting epidermal growth factor receptor (EGFR), mesothelin (MSLN) or HER2/neu. Mesothelioma, pancreatic and breast cancer cell lines expressing the respective antigens were used as target cell lines. Efficacy was evaluated in vitro and in vivo in xenograft mouse models.Results Unlike CD16-CAR T cells, which bind human IgG in a non-selective manner, P329G-targeting CAR T cells revealed specific effector functions only when combined with antibodies carrying P329G LALA mutations in their Fc part. P329G-targeting CAR T cells cannot be activated by an excess of human IgG. P329G-directed CAR T cells combined with a MSLN-targeting P329G-mutated antibody mediated pronounced in vitro and in vivo antitumor efficacy in mesothelioma and pancreatic cancer models. Combined with a HER2-targeting antibody, P329G-targeting CAR T cells showed substantial in vitro activation, proliferation, cytokine production and cytotoxicity against HER2-expressing breast cancer cell lines and induced complete tumor eradication in a breast cancer xenograft mouse model. The ability of the platform to target multiple antigens sequentially was shown in vitro and in vivo.Conclusions P329G-targeting CAR T cells combined with antigen-binding human IgG1 antibodies containing the P329G Fc mutation mediate pronounced in vitro and in vivo effector functions in different solid tumor models, warranting further clinical translation of this concept.

T-cell bispecific antibodies (TCBs) are a novel class of engineered immunoglobulins that unite monovalent binding to the T-cell receptor (TCR) CD3e chain and bivalent binding to tumor-associated antigens in order to recruit and activate T-cells for tumor cell killing. In vivo, T-cell activation is usually initiated via the interaction of the TCR with the peptide-HLA complex formed by the human leukocyte antigen (HLA) and peptides derived from intracellular proteins. TCR-like antibodies (TCRLs) that recognize pHLA-epitopes extend the target space of TCBs to peptides derived from intracellular proteins, such as those overexpressed during oncogenesis or created via mutations found in cancer. One challenge during lead identification of TCRL-TCBs is to identify TCRLs that specifically, and ideally exclusively, recognize the desired pHLA, but not unrelated pHLAs. In order to identify TCRLs suitable for TCRL-TCBs, large numbers of TCRLs have to be tested in the TCB format. Here, we propose a novel approach using chimeric antigen receptors (CARs) to facilitate the identification of highly selective TCRLs. In this new so-called TCRL-CAR-J approach, TCRL-candidates are transduced as CARs into Jurkat reporter-cells, and subsequently assessed for their specificity profile. This work demonstrates that the CAR-J reporter-cell assay can be applied to predict the profile of TCRL-TCBs without the need to produce each candidate in the final TCB format. It is therefore useful in streamlining the identification of TCRL-TCBs.

Clipperton Atoll (Île de La Passion) is the only atoll in the Tropical Eastern Pacific (TEP) ecoregion and, owing to its isolation, possesses several endemic species and is likely an important stepping stone between Oceania, the remainder of the TEP, including other oceanic islands and the west coast of Central America. We describe the biodiversity at this remote atoll from shallow water to depths greater than one thousand meters using a mixture of technologies (SCUBA, stereo baited remote underwater video stations, manned submersible, and deep-sea drop cameras). Seventy-four unique taxa of invertebrates were identified during our expedition. The majority (70%) of these taxa were confined to the top 400 m and consisted mostly of sessile organisms. Decapod crustaceans and black corals (Antipatharia) had the broadest depth ranges, 100–1,497 m and 58–967 m, respectively. Decapods were correlated with the deepest depths, while hard corals were correlated with the shallow depths. There were 96 different fish taxa from 41 families and 15 orders, of which 70% were restricted to depths

Targeted therapy of ErbB2-dependent tumours often provokes an adaptive response leading to reactivation of the PI3K/AKT pathway. Here the authors identify an ErbB3-independent compensatory mechanism comprising Ras/PI3K activation directly by ErbB2, and develop biparatopic panErbB inhibitors to block this mode of resistance.

To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.

The quality of DNA-labeled affinity probes is critical in DNA-assisted protein analyses, such as proximity ligation and extension assays, immuno-PCR, and immuno-rolling circle amplification reactions. Efficient, high-performance methods are therefore required for isolation of pure conjugates from reactions where DNA strands have been coupled to antibodies or recombinant affinity reagents. Here we describe a universal, scalable approach for preparing high-quality oligonucleotide-protein conjugates by sequentially removing any unconjugated affinity reagents and remaining free oligonucleotides from conjugation reactions. We applied the approach to generate high-quality probes using either antibodies or recombinant affinity reagents. The purified high-grade probes were used in proximity ligation assays in solution and in situ, demonstrating both augmented assay sensitivity and improved signal-to-noise ratios.

Designed Ankyrin Repeat Proteins are a class of novel binding proteins that can be selected and evolved to bind to targets with high affinity and specificity. We are interested in the DARPin H10-2-G3, which has been evolved to bind with very high affinity to the human epidermal growth factor receptor 2 (HER2). HER2 is found to be over-expressed in 30% of breast cancers, and is the target for the FDA-approved therapeutic monoclonal antibodies trastuzumab and pertuzumab and small molecule tyrosine kinase inhibitors. Here, we use computational macromolecular docking, coupled with several interface metrics such as shape complementarity, interaction energy, and electrostatic complementarity, to model the structure of the complex between the DARPin H10-2-G3 and HER2. We analyzed the interface between the two proteins and then validated the structural model by showing that selected HER2 point mutations at the putative interface with H10-2-G3 reduce the affinity of binding up to 100-fold without affecting the binding of trastuzumab. Comparisons made with a subsequently solved X-ray crystal structure of the complex yielded a backbone atom root mean square deviation of 0.84-1.14 Ångstroms. The study presented here demonstrates the capability of the computational techniques of structural bioinformatics in generating useful structural models of protein-protein interactions.

Interactions between individuals and the structure of their environment play a crucial role in shaping self-organized collective behaviors. Recent studies have shown that ants crossing asymmetrical bifurcations in a network of galleries tend to follow the branch that deviates the least from their incoming direction. At the collective level, the combination of this tendency and the pheromone-based recruitment results in a greater likelihood of selecting the shortest path between the colony's nest and a food source in a network containing asymmetrical bifurcations. It was not clear however what the origin of this behavioral bias is. Here we propose that it results from a simple interaction between the behavior of the ants and the geometry of the network, and that it does not require the ability to measure the angle of the bifurcation. We tested this hypothesis using groups of ant-like robots whose perceptual and cognitive abilities can be fully specified. We programmed them only to lay down and follow light trails, avoid obstacles and move according to a correlated random walk, but not to use more sophisticated orientation methods. We recorded the behavior of the robots in networks of galleries presenting either only symmetrical bifurcations or a combination of symmetrical and asymmetrical bifurcations. Individual robots displayed the same pattern of branch choice as individual ants when crossing a bifurcation, suggesting that ants do not actually measure the geometry of the bifurcations when travelling along a pheromone trail. Finally at the collective level, the group of robots was more likely to select one of the possible shorter paths between two designated areas when moving in an asymmetrical network, as observed in ants. This study reveals the importance of the shape of trail networks for foraging in ants and emphasizes the underestimated role of the geometrical properties of transportation networks in general.

The last decades have seen an increasing interest in modeling collective animal behavior. Some studies try to reproduce as accurately as possible the collective dynamics and patterns observed in several animal groups with biologically plausible, individual behavioral rules. The objective is then essentially to demonstrate that the observed collective features may be the result of self-organizing processes involving quite simple individual behaviors. Other studies concentrate on the objective of establishing or enriching links between collective behavior researches and cognitive or physiological ones, which then requires that each individual rule be carefully validated. Here we discuss the methodological consequences of this additional requirement. Using the example of corpse clustering in ants, we first illustrate that it may be impossible to discriminate among alternative individual rules by considering only observational data collected at the group level. Six individual behavioral models are described: They are clearly distinct in terms of individual behaviors, they all reproduce satisfactorily the collective dynamics and distribution patterns observed in experiments, and we show theoretically that it is strictly impossible to discriminate two of these models even in the limit of an infinite amount of data whatever the accuracy level. A set of methodological steps are then listed and discussed as practical ways to partially overcome this problem. They involve complementary experimental protocols specifically designed to address the behavioral rules successively, conserving group-level data for the overall model validation. In this context, we highlight the importance of maintaining a sharp distinction between model enunciation, with explicit references to validated biological concepts, and formal translation of these concepts in terms of quantitative state variables and fittable functional dependences. Illustrative examples are provided of the benefits expected during the often long and difficult process of refining a behavioral model, designing adapted experimental protocols and inversing model parameters.

On the uninhabited atoll of Clipperton, the fourth French Pacific territory, the land and lagoon ecosystems are in drastic degradation while natural hazards are severe. Since the sixties, a desertification process has occurred apparently due to the elimination of pigs introduced by the end of the 19th century, and consequently to the proliferation of millions of omnivorous crabs and thousands of birds. The lack of vegetal cover was already the natural stage before human presence showing therefore a positive human impact on this exceptional environment. Considering these environmental stakes, and enlightened by economic and geopolitical issues of the region, the author proposes, after a limited planning, a land partition between a fully protected area and a human settlement sector which would guarantee French sovereignty on this zone lusted for its resources.

Abstract  Recent studies have introduced computer tomography (CT) as a tool for the visualisation and characterisation of insect architectures. Here, we use CT to map the three-dimensional networks of galleries inside Cubitermes nests in order to analyse them with tools from graph theory. The structure of these networks indicates that connections inside the nest are rearranged during the whole nest life. The functional analysis reveals that the final network topology represents an excellent compromise between efficient connectivity inside the nest and defence against attacking predators. We further discuss and illustrate the usefulness of CT to disentangle environmental and specific influences on nest architecture. [ABSTRACT FROM AUTHOR]