Highly Active Microbial Phosphoantigen Induces Rapid yet Sustained MEK/Erk- and PI-3K/Akt-Mediated Signal Transduction in Anti-Tumor Human γδ T-Cells

BACKGROUND: The unique responsiveness of Vgamma9Vdelta2 T-cells, the major gammadelta subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current gammadelta T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human gammadelta T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR)-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vgamma9Vdelta2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), produced by Eubacteria and Protozoa, and examined its gammadelta T-cell activation and anti-tumor properties. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparative study between HMB-PP and the anti-CD3epsilon monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular gammadelta T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vgamma9(+) T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including gammadelta T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vgamma9(+) TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains gammadelta T-cell activation upon re-stimulation. This ultimately translates in potent human gammadelta T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The development of efficient cancer immunotherapy strategies critically depends on our capacity to maximize anti-tumor effector T-cell responses. By characterizing the intracellular mechanisms of HMB-PP-mediated activation of the highly cytotoxic Vgamma9(+) T-cell subset, our data strongly support the usage of this microbial antigen in novel cancer clinical trials

The VANDELS ESO public spectroscopic survey: Observations and first data release

This paper describes the observations and the first data release (DR1) of the ESO public spectroscopic survey “VANDELS, a deep VIMOS survey of the CANDELS CDFS and UDS fields”. The main targets of VANDELS are star-forming galaxies at redshift 2.4 < z < 5.5, an epoch when the Universe had not yet reached 20% of its current age, and massive passive galaxies in the range 1 < z < 2.5. By adopting a strategy of ultra-long exposure times, ranging from a minimum of 20 h to a maximum of 80 h per source, VANDELS is specifically designed to be the deepest-ever spectroscopic survey of the high-redshift Universe. Exploiting the red sensitivity of the refurbished VIMOS spectrograph, the survey is obtaining ultra-deep optical spectroscopy covering the wavelength range 4800–10 000 Å with a sufficiently high signal-to-noise ratio to investigate the astrophysics of high-redshift galaxy evolution via detailed absorption line studies of well-defined samples of high-redshift galaxies. VANDELS-DR1 is the release of all medium-resolution spectroscopic data obtained during the first season of observations, on a 0.2 square degree area centered around the CANDELS-CDFS (Chandra deep-field south) and CANDELS-UDS (ultra-deep survey) areas. It includes data for all galaxies for which the total (or half of the total) scheduled integration time was completed. The DR1 contains 879 individual objects, approximately half in each of the two fields, that have a measured redshift, with the highest reliable redshifts reaching zspec ~ 6. In DR1 we include fully wavelength-calibrated and flux-calibrated 1D spectra, the associated error spectrum and sky spectrum, and the associated wavelength-calibrated 2D spectra. We also provide a catalog with the essential galaxy parameters, including spectroscopic redshifts and redshift quality flags measured by the collaboration. We present the survey layout and observations, the data reduction and redshift measurement procedure, and the general properties of the VANDELS-DR1 sample. In particular, we discuss the spectroscopic redshift distribution and the accuracy of the photometricredshifts for each individual target category, and we provide some examples of data products for the various target typesand the different quality flags. All VANDELS-DR1 data are publicly available and can be retrieved from the ESO archive. Two further data releases are foreseen in the next two years, and a final data release is currently scheduled for June 2020, which will include an improved rereduction of the entire spectroscopic data set

Network analysis provide new perspectives to identify plant bioregions: a case study in the Mediterranean region of France

International audienceThe delimitation of bioregions helps understand historical and ecological drivers of species distribution. The Mediterranean basin offers a rich mosaic of plant distribution patterns, whose description constitutes a great challenge toward a global understanding of the ora. In particular, transition areas between biomes have raised difficulties to set comprehensive limit between bioregions. We performed a network analysis of plants distribution in south of France (Languedoc-Roussillon and Provence-Alpes-C^ote d'Azur) to analyze the biogeographical structure of the French Mediterranean flora. We analyzed a large database containing 2.5 millions of geolocalized plant records, corresponding to more than 3,500 plant species. This method allowed us to identify biogeographical regions under the form of spatial network communities, and analyze their interactions based on the relative contribution of plant species to each bioregion. First, we identified 2 sub-networks that distinguish mediterranean and temperate-mountainous biota. Then, we separated eight statistically significant bioregions that present a complex spatial structure. Some of them are spatially well delimited, and match with particular geological entities. On the other hand fuzzy transitions arise between adjacent bioregions that share a common geological setting, but are spread along a climatic gradient. This is exemplified by the identification of the cluster "Mediterranean border", that constitutes a transition entity between the two biomes. The proposed network approach illustrates the biogeographical structure of the flora and provides precise insights into the relationships among bioregions. It gives analytic clues to spatially identify the Mediterranean bioregion, whose delimitation has been long debated among biogeographers. This approach demonstrates how climatic gradients and geological substrate shapes biodiversity patterns in the Mediterranean, and exemplifies why fragmented distributions are common in the Mediterranean region, isolating groups of species that share a similar eco-evolutionary history

Adaptive deep brain stimulation for movement disorders: the long road to clinical therapy.

Continuous high-frequency DBS is an established treatment for essential tremor and Parkinson's disease. Current developments focus on trying to widen the therapeutic window of DBS. Adaptive DBS (aDBS), where stimulation is dynamically controlled by feedback from biomarkers of pathological brain circuit activity, is one such development. Relevant biomarkers may be central, such as local field potential activity, or peripheral, such as inertial tremor data. Moreover, stimulation may be directed by the amplitude or the phase (timing) of the biomarker signal. In this review, we evaluate existing aDBS studies as proof-of-principle, discuss their limitations, most of which stem from their acute nature, and propose what is needed to take aDBS into a chronic setting. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Societ

Biogeographical network analysis of plant species distribution in the Mediterranean region

International audienceThe delimitation of bioregions helps to understand historical and ecological drivers of species distribution. In this work, we performed a network analysis of the spatial distribution patterns of plants in south of France (Languedoc-Roussillon and Provence-Alpes-Côte d'Azur) to analyze the biogeographical structure of the French Mediterranean flora at different scales. We used a network approach to identify and characterize biogeographical regions, based on a large database containing 2.5 million of geolocalized plant records corresponding to more than 3,500 plant species. This methodology is performed following five steps, from the biogeographical bipartite network construction to the identification of biogeographical regions under the form of spatial network communities, the analysis of their interactions, and the identification of clusters of plant species based on the species contribution to the biogeographical regions. First, we identified two sub-networks that distinguish Mediterranean and temperate biota. Then, we separated eight statistically significant bioregions that present a complex spatial structure. Some of them are spatially well delimited and match with particular geological entities. On the other hand, fuzzy transitions arise between adjacent bioregions that share a common geological setting, but are spread along a climatic gradient. The proposed network approach illustrates the biogeographical structure of the flora in southern France and provides precise insights into the relationships between bioregions. This approach sheds light on ecological drivers shaping the distribution of Mediterranean biota: The interplay between a climatic gradient and geological substrate shapes biodiversity patterns. Finally, this work exemplifies why fragmented distributions are common in the Mediterranean region, isolating groups of species that share a similar eco-evolutionary history