Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells

Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3−/− mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti–PD-1 mAbs. Batf3−/− mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti–CD137- and anti–PD-1–mediated immunostimulation in tumor therapy against B16-ovalbumin–derived melanomas, whereas this function was lost in Batf3−/− mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects

Deterministic and empirical approach for millimeter-wave complex outdoor smart parking solution deployments

The characterization of different vegetation/vehicle densities and their corresponding effects on large-scale channel parameters such as path loss can provide important information during the deployment of wireless communications systems under outdoor conditions. In this work, a deterministic analysis based on ray-launching (RL) simulation and empirical measurements for vehicle-to-infrastructure (V2I) communications for outdoor parking environments and smart parking solutions is presented. The study was carried out at a frequency of 28 GHz using directional antennas, with the transmitter raised above ground level under realistic use case conditions. Different radio channel impairments were weighed in, considering the progressive effect of first, the density of an incremental obstructed barrier of trees, and the effect of different parked vehicle densities within the parking lot. On the basis of these scenarios, large-scale parameters and temporal dispersion characteristics were obtained, and the effect of vegetation/vehicle density changes was assessed. The characterization of propagation impairments that different vegetation/vehicle densities can impose onto the wireless radio channel in the millimeter frequency range was performed. Finally, the results obtained in this research can aid communication deployment in outdoor parking conditions.Ministerio de Ciencia, Innovación y Universidades | Ref. RTI2018-095499-B-C3

Management of Nothofagus genetic resources: Definition of genetic zones based on a combination of nuclear and chloroplast marker data

Development of appropriate forest conservation and management measures for a given tree species includes the identification of distinct genetically homogeneous units across its overall distribution range, which depends on the availability of knowledge on genetic, morphological and adaptive variation. This has important implications for germplasm transfer within and between areas, for example in reforestation or restoration activities. Genetic zones are defined as genetically more or less homogeneous regions within which propagation material can be transferred with relative certainty not to cause changes at the genetic structure level. The main goal of this study was to define genetic zones for Nothofagus nervosa and Nothofagus obliqua within their Argentinean natural distribution range. A total of 823 individuals belonging to 24 populations (14 of N. nervosa and 10 of N. obliqua, μ= 34 ± 5) were genotyped by means of seven nuclear microsatellite markers. The geographic clustering encountered through the application of a Bayesian approach was analysed in combination with additional information on diversity parameters, chloroplast DNA and isozymes. For assembling the maps showing the distribution of clusters, we averaged cluster membership values of trees in each grid cell. This allowed us to distinguish five genetic zones for N. nervosa and three for N. nervosa. The identified genetic zones were consistent with the management history of the species, and display a certain level of geographic congruence. To visualize geographical patterns in nSRR richness and the distribution of different clusters of both species, we carried out grid-based spatial analyses using 30 seconds grid cells (~1 km at the equator) as the unit of analyses. We observed higher allelic richness values in the surroundings of areas identified as potential glacial refuges, which suggest that the distribution pattern of allelic richness is closely associated with the glacial history of the species within the region. We expect this information to constitute a valuable tool for the identification of seed transfer zones, and to guide recruitment and plantation activities in the context of domestication programs of both species in Argentina. For migration assisted programs under progressive climate change the identification of these zones together with knowledge concerning hotspots at genetic diversity level should constitute an input for planning the activities.Fil: Azpilicueta, María Marta. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: Gallo, L. A.. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: van Zonneveld, M.. Bioversity International. Regional Office for the Americas; ColombiaFil: Thomas, E.. Bioversity International. Regional Office for the Americas; ColombiaFil: Moreno, Angela Carolina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marchelli, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; Argentin

fruit set. In both the exotic species and one simultaneously fruiting native species (Schinus patagonicus), high numbers of ripe fruits with a high proportion of viable seeds remained on the plants at a time when fruits of other native species were either

The northernmost ‘robles’ of Argentina, located in Lagunas de Epulauquen (northwest Patagonia), are considered a population of Nothofagus obliqua, even though they differ in some respects from individuals of other populations of the species. In order to analyse a possible genetic basis of their distinctive character, we revised previous information and added new evidence based on biochemical (isozyme) and molecular (chloroplast DNA and nuclear microsatellite) markers, as well as quantitative trait variation (seed traits, leaf morphology, plant architecture and field performance). The comparison of Lagunas de Epulauquen specimens with specimens from other areas in Argentina demonstrated their genetic distinction. Glacial history, in conjunction with hybridisation processes, provides support for the main hypothesis to explain these results. Future research lines are proposed, aimed at identifying the taxonomic status of the Lagunas de Epulauquen population. The conservation value of these forests is highlighted.Los robles más septentrionales de la Argentina, ubicados en Lagunas de Epulauquen (noroeste de Patagonia) son considerados una población de la especie Nothofagus obliqua, pero presentan características diferenciales respecto al resto de las poblaciones argentinas de esa especie. El presente trabajo reúne información generada previamente y otra original que demuestra el carácter genéticamente distintivo de esa población. Se presentan los resultados logrados a través de análisis genéticos con marcadores bioquímicos (isoenzimas) y moleculares (de ADN de cloroplasto y marcadores de microsatélites nucleares), con caracteres cuantitativos seminales, de morfología foliar, de arquitectura de las plantas y de aptitud a campo. La historia glacial de la región, en conjunción con procesos de hibridación pasados, se postula como la causa de esta diferenciación. Se propone la realización de nuevas líneas de investigación que permitan confirmar o re-definir el estatus taxonómico de los árboles de esta población. Adicionalmente se presenta una breve consideración sobre el valor de conservación de los bosques en Lagunas de Epulauquen, en relación a los resultados aquí presentados.Fil: Azpilicueta, María M.. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: Pastorino, Mario Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: Puntieri, Javier Guido. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Patagonia Norte. Instituto de Investigación En Biodiversidad y Medioambiente; Argentina. Universidad Nacional de Rio Negro; ArgentinaFil: Barbero, Fernando Alvaro. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martínez Meier, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: Marchelli, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; ArgentinaFil: Gallo, Leonardo. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche; Argentin

Toward a SIRGAS service for mapping the ionosphere’s F2 peack parameters

Postprint (published version

Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires Batf3-dependent dendritic cells

Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3−/− mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti–PD-1 mAbs. Batf3−/− mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti–CD137- and anti–PD-1–mediated immunostimulation in tumor therapy against B16-ovalbumin–derived melanomas, whereas this function was lost in Batf3−/− mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects

PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector

Non-invasive in vivo imaging of transgene expression is currently providing very important means to optimize gene therapy regimes. Results in non-human primates are considered the most predictive models for the outcome in patients. In this study, we have documented that tumour and primary cell lines from human and non-human primates are comparably gene-transduced in vitro by serotype 5 adenovirus expressing HSV1-thymidine kinase. Transgene expression can be quantified in human and monkey cultured cells by positron emission tomography (PET) imaging when transduced cells are incubated with a fluoride-18 labelled penciclovir analogue. In our hands, PET images of cell cultures estimate the number of transduced cells rather than intensity of transgene expression once a threshold of TK per cell is reached. Interestingly, in vivo systemic administration of a clinical grade recombinant adenovirus expressing TK into macaques gives rise to an intense retention of the radiotracer in the liver parenchyma, providing an experimental system to visualize transgene expression that ought to be similar in human and macaques. Such imaging methodology might contribute to improve strategies based on adenoviral vectors