Advanced turboprop multidisciplinary design and optimization within agile project

The present paper deals with the design, analysis and optimization of a 90 passengers turboprop aircraft with a design range of 1200 nautical miles and a cruise Mach number equal to 0.56. The prescribed aircraft is one of the use cases of the AGILE European project, aiming to provide a 3rd generation of multidisciplinary design and optimization chain, following the collaborative and remote aircraft design paradigm, through an heterogenous team of experts. The multidisciplinary aircraft design analysis is set-up involving tools provided by AGILE partners distributed worldwide and run locally from partners side. A complete design of experiment, focused on wing planform variables, is performed to build response surfaces suitable for optimization purposes. The goal of the optimization is the direct operating cost, subject to wing design variables and top-level aircraft requirements

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient\u2019s immune system to recognize and destroy cancer cells. Preclinical and clinical studies, based on the use of T cells and more recently NK cells genetically modified with chimeric antigen receptors retargeting the adoptive cell therapy towards tumor cells, have already shown remarkable results. In this review, we outline the latest highlights and progress in immunotherapies for the treatment of Diffuse Large B-cell Lymphoma (DLBCL) patients, focusing on CD19-targeted immunotherapies. We also discuss current clinical trials and opportunities of using immunotherapies to treat DLBCL patients

Different features of tumor-associated NK cells in patients with low-grade or high-grade peritoneal carcinomatosis

Peritoneal carcinomatosis (PC) is a rare disease defined as diffused implantation of neoplastic cells in the peritoneal cavity. This clinical picture occurs during the evolution of peritoneal tumors, and it is the main cause of morbidity and mortality of patients affected by these pathologies, though cytoreductive surgery with heated intra-peritoneal chemotherapy (CRS/HIPEC) is yielding promising results. In the present study, we evaluated whether the tumor microenvironment of low-grade and high-grade PC could affect the phenotypic and functional features and thus the anti-tumor potential of NK cells. We show that while in the peritoneal fluid (PF) of low-grade PC most CD56dim NK cells show a relatively immature phenotype (NKG2A+KIR\u2013CD57\u2013CD16dim), in the PF of high-grade PC NK cells are, in large majority, mature (CD56dimKIR+CD57+CD16bright). Furthermore, in low-grade PC, PF-NK cells are characterized by a sharp down-regulation of some activating receptors, primarily NKp30 and DNAM-1, while, in high-grade PC, PF-NK cells display a higher expression of the PD-1 inhibitory checkpoint. The compromised phenotype observed in low-grade PC patients corresponds to a functional impairment. On the other hand, in the high-grade PC patients PF-NK cells show much more important defects that only partially reflect the compromised phenotype detected. These data suggest that the PC microenvironment may contribute to tumor escape from immune surveillance by inducing different NK cell impaired features leading to altered anti-tumor activity. Notably, after CRS/HIPEC treatment, the altered NK cell phenotype of a patient with a low-grade disease and favorable prognosis was reverted to a normal one. Our present data offer a clue for the development of new immunotherapeutic strategies capable of restoring the NK-mediated anti-tumor responses in association with the CRS/HIPEC treatment to increase the effectiveness of the current therapy

PD-L1 expression in metastatic neuroblastoma as an additional mechanism for limiting immune surveillance

The prognosis of high-risk neuroblastoma (NB) remains poor, although immunotherapies with anti-GD2 antibodies have been reported to provide some benefit. Immunotherapies can be associated with an IFNγ storm that induces in tumor cells the “adaptive immune resistance” characterized by the de-novo expression of Programmed Death Ligands (PD-Ls). Tumor cells can also constitutively express PD-Ls in response to oncogenic signaling. Here, we analyze the constitutive and the inducible surface expression of PD-Ls in NB cells. We show that virtually all HLA class Ipos NB cell lines constitutively express PD-L1, whereas PD-L2 is rarely detected. IFNγ upregulates or induces PD-L1 both in NB cell lines in vitro and in NB engrafted nude/nude mice. Importantly, after IFNγ stimulation PD-L1 can be acquired by NB cell lines, as well as by metastatic neuroblasts isolated from bone marrow aspirates of high-risk NB patients, characterized by different MYCN amplification status. Interestingly, in one patient NB cells were poorly responsive to IFNγ stimulation, pointing out that responsiveness to IFNγ might represent a further element of heterogeneity in metastatic neuroblasts. Finally, we document the presence of lymphocytes expressing the PD-1 receptor in NB-infiltrated bone marrow of patients. PD-1pos cells are mainly represented by αβ T cells, but also include small populations of γδ T cells and NK cells. Moreover, PD-1pos T cells have a higher expression of activation markers. Overall, our data show that a PD-L1-mediated immune resistance mechanism occurs in metastatic neuroblasts and provide a biological rationale for blocking the PD-1/PD-Ls axis in future combined immunotherapeutic approaches

Reutilizar purines de tambo como oportunidad para reciclar nitrógeno y reducir su impacto ambiental

Los purines de tambo (excretas mezcladas con agua de las instalaciones de ordeñe) se pueden reutilizar en la producción agrícola como reemplazo de los fertilizantes sintéticos. Sin embargo, su alta concentración nitrogenada podría estimular la volatilización de amoníaco (NH3 ) y la emisión de óxido nitroso (N2 O), con consecuencias sobre el calentamiento global. Nuestros objetivos fueron cuantificar las salidas de NH3 y N2 O en un cultivo de maíz fertilizado con purín o urea aplicados superficialmente y relacionar las emisiones de N2 O con los cambios en el contenido de amonio, nitrato y agua del suelo. Se realizó un experimento manipulativo a campo en el que se midieron ambas salidas gaseosas durante una campaña agrícola. El purín estimuló la volatilización de NH3 al día siguiente de la aplicación (2.7±0.25 vs. 1.1±0.25 y 0.6±0.25 kg N-NH3 .ha-1.dia-1 para purín, urea y control, respectivamente), y la emisión directa de N2 O durante los tres días siguientes a la aplicación (75±13 vs. 28±5 y 26±6 µg N-N2 O. m-2.h-1 para purín, urea y control, respectivamente). A partir del cuarto día, la volatilización de NH3 fue mayor con urea y las emisiones de N2 O se equipararon entre tratamientos. La volatilización acumulada durante el ciclo de maíz fue mayor con urea, y la emisión directa de N2 O acumulada fue similar para ambos fertilizantes. Las emisiones de N2 O estuvieron asociadas a la humedad del suelo, que aumentó inicialmente por el agua del purín y luego por las lluvias. Las salidas de NH3 +N2 O de los fertilizantes luego de descontar el control fueron mayores con urea que con purín (10.8±1.2 y 3.1±0.7 kg N/ha o 0.53±0.06 y 0.18±0.04 kg N/t MS), y el rendimiento de maíz fue similar entre tratamientos (19.0±0.7 t MS/ha). Estos resultados muestran que el uso de purines es una práctica promisoria para reducir el impacto ambiental de los fertilizantes sintéticos.Dairy cattle slurry (liquid mixture of manure and water from the milking operation) can be reused for agricultural production in replacement for synthetic fertilizers. However, its high nitrogen (N) concentration could stimulate the volatilization of ammonia (NH3) and nitrous oxide (N2O) emission, with consequences for global warming. Our objectives were: to quantify NH3 and N2O loss in maize fertilized with surface-applied dairy cattle slurry or urea, and to relate N2O emission with soil ammonium, nitrate and water contents. We performed a manipulative field experiment where we measured both gaseous losses during an agricultural campaign. Slurry enhanced NH3 volatilization the day after the application (2.7±0.25 vs. 1.1±0.25 and 0.6±0.25 kg N-NH3 .ha-1 .day-1 for slurry, urea and the control, respectively) and direct N2O emission during three days after the application (75±13 vs. 28±5 y 26±6 μg N-N2O .m-2 .h-1 for slurry, urea and the control, respectively). Four days after application, volatilization was higher with urea and N2O emissions were similar between treatments. The loss of NH3 accumulated throughout the maize growing season was higher for urea than for slurry, and the accumulated N2O emission was similar for both fertilizers. Nitrous oxide emissions were related to soil water content, initially introduced with slurry and then with rainfall. The loss of NH3+N2O from the fertilizers after subtracting that of the control, was higher after the application of urea than slurry (10.8±1.2 and 3.1±0.7 kg N/ha or 0.53±0.06 and 0.18±0.04 kg N/t MS), and maize yield was similar for both fertilization treatments (19.0±0.7 t MS/ha). These results show that fertilization with dairy cattle slurry is a promising practice because it has a lower environmental footprint compared to synthetic fertilizers.EEA PergaminoFil: Portela, Silvina Isabel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Pergamino. Laboratorio de Suelos; ArgentinaFil: Araujo, Patricia Inés. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Pergamino. Laboratorio de Suelo; ArgentinaFil: Araujo, Patricia Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Restovich, Silvina B. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Pergamino. Laboratorio de Suelos; ArgentinaFil: Della Chiesa, Tomas. Universidad de Buenos Aires. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Della Chiesa, Tomas. Universidad de Buenos Aires. Facultad de Agronomía. Catedra de Climatología y Fenología Agrícolas; ArgentinaFil: Ponsa, Juliana M. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Escuela de Ciencias Agrarias, Naturales y Ambientales; ArgentinaFil: Peña Ballesteros, Andrea. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Escuela de Ciencias Agrarias, Naturales y Ambientales; Argentin

Hepatitis B Virus Lacks Immune Activating Capacity, but Actively Inhibits Plasmacytoid Dendritic Cell Function

Chronic hepatitis B virus (HBV) infection is caused by inadequate anti-viral immunity. Activation of plasmacytoid dendritic cells (pDC) leading to IFNα production is important for effective anti-viral immunity. Hepatitis B virus (HBV) infection lacks IFNα induction in animal models and patients and chronic HBV patients display impaired IFNα production by pDC. Therefore, HBV and HBV-derived proteins were examined for their effect on human pDC in vitro. In addition, the in vitro findings were compared to the function of pDC derived from chronic HBV patients ex vivo. In contrast to other viruses, HBV did not activate pDC. Moreover, HBV and HBsAg abrogated CpG-A/TLR9-induced, but not Loxoribine/TLR7-induced, mTOR-mediated S6 phosphorylation, subsequent IRF7 phosphorylation and IFNα gene transcription. HBV/HBsAg also diminished upregulation of co-stimulatory molecules, production of TNFα, IP-10 and IL-6 and pDC-induced NK cell function, whereas TLR7-induced pDC function was hardly affected. In line, HBsAg preferentially bound to TLR9-triggered pDC demonstrating that once pDC are able to bind HBV/HBsAg, the virus exerts its immune regulatory effect. HBV not only directly interfered with pDC function, but also indirectly by interfering with monocyte-pDC interaction. Also HBeAg diminished pDC function to a certain extent, but via another unknown mechanism. Interestingly, patients with HBeAg-positive chronic hepatitis B displayed impaired CpG-induced IFNα production by pDC without significant alterations in Loxoribine-induced pDC function compared to HBeAg-negative patients and healthy controls. The lack of activation and the active inhibition of pDC by HBV may both contribute to HBV persistence. The finding that the interaction between pDC and HBV may change upon activation may aid in the identification of a scavenging receptor supporting immunosuppressive effects of HBV and also in the design of novel treatment strategies for chronic HBV

The role of South American grazing lands in mitigating greenhouse gas emissions:A reply to "Reassessing the role of grazing lands in carbon-balance estimations: Meta-analysis and review", by Viglizzo et al., (2019)

The paper by Viglizzo et al. (2019) "Reassessing the role of grazing lands in carbon-balance estimations: Meta-analysis and review" proposed a new methodology to assess changes in soil organic carbon (SOC) stock associated with land use, and applied it to four countries of South America: Argentina, Brazil, Paraguay, and Uruguay, all members of the MERCOSUR trade bloc. One finding of their assessment was that grazing lands are currently accumulating SOC at rates high enough to"... generate C surpluses that could not only offset rural emissions, but could alsopartially or totally offset the emissions of non-rural sectors".Fil: Villarino, Sebastián Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias. Laboratorio de Agroecología; ArgentinaFil: Pinto, Priscila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Della Chiesa, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Jobbagy Gampel, Esteban Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi". Universidad Nacional de San Luis. Facultad de Ciencias Físico, Matemáticas y Naturales. Instituto de Matemática Aplicada de San Luis "Prof. Ezio Marchi"; ArgentinaFil: Studdert, Guillermo Alberto. Universidad Nacional de Mar del Plata; ArgentinaFil: Bazzoni, Bruno. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Conti, Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Rufino, Mariana Cristina. Lancaster University; Reino UnidoFil: Alvarez, Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Boddey, Robert. Embrapa Agrobiologia; BrasilFil: Bayer, Cimélio. Universidade Federal do Rio Grande do Sul; BrasilFil: de F. Carvalho, Paulo C.. Embrapa Agrobiologia; BrasilFil: Fernández, Roberto J.. Universidade Federal do Rio Grande do Sul; BrasilFil: Lattanzi, Fernando Alfredo. Universidade Federal do Rio Grande do Sul; BrasilFil: Oesterheld, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Oyhantçabal, Walter. Instituto Nacional de Investigación Agropecuaria; UruguayFil: Paruelo, José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Pravia, Virginia. Ministerio de Ganadería; UruguayFil: Piñeiro, Gervasio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentin

Escape of HIV-1-Infected Dendritic Cells from TRAIL-Mediated NK Cell Cytotoxicity during NK-DC Cross-Talk—A Pivotal Role of HMGB1

Early stages of Human Immunodeficiency Virus-1 (HIV-1) infection are associated with local recruitment and activation of important effectors of innate immunity, i.e. natural killer (NK) cells and dendritic cells (DCs). Immature DCs (iDCs) capture HIV-1 through specific receptors and can disseminate the infection to lymphoid tissues following their migration, which is associated to a maturation process. This process is dependent on NK cells, whose role is to keep in check the quality and the quantity of DCs undergoing maturation. If DC maturation is inappropriate, NK cells will kill them (“editing process”) at sites of tissue inflammation, thus optimizing the adaptive immunity. In the context of a viral infection, NK-dependent killing of infected-DCs is a crucial event required for early elimination of infected target cells. Here, we report that NK-mediated editing of iDCs is impaired if DCs are infected with HIV-1. We first addressed the question of the mechanisms involved in iDC editing, and we show that cognate NK-iDC interaction triggers apoptosis via the TNF-related apoptosis-inducing ligand (TRAIL)-Death Receptor 4 (DR4) pathway and not via the perforin pathway. Nevertheless, once infected with HIV-1, DCHIV become resistant to NK-induced TRAIL-mediated apoptosis. This resistance occurs despite normal amounts of TRAIL released by NK cells and comparable DR4 expression on DCHIV. The escape of DCHIV from NK killing is due to the upregulation of two anti-apoptotic molecules, the cellular-Flice like inhibitory protein (c-FLIP) and the cellular inhibitor of apoptosis 2 (c-IAP2), induced by NK-DCHIV cognate interaction. High-mobility group box 1 (HMGB1), an alarmin and a key mediator of NK-DC cross-talk, was found to play a pivotal role in NK-dependent upregulation of c-FLIP and c-IAP2 in DCHIV. Finally, we demonstrate that restoration of DCHIV susceptibility to NK-induced TRAIL killing can be obtained either by silencing c-FLIP and c-IAP2 by specific siRNA, or by inhibiting HMGB1 with blocking antibodies or glycyrrhizin, arguing for a key role of HMGB1 in TRAIL resistance and DCHIV survival. These findings provide evidence for a new strategy developed by HIV to escape immune attack, they challenge the question of the involvement of HMGB1 in the establishment of viral reservoirs in DCs, and they identify potential therapeutic targets to eliminate infected DCs