PGE2-Induced IDO1 Inhibits the Capacity of Fully Mature DCs to Elicit an In Vitro Antileukemic Immune Response.

In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2-matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4(+) and CD8(+) T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2

Recursive internetwork architecture, investigating RINA as an alternative to TCP/IP (IRATI)

Driven by the requirements of the emerging applications and networks, the Internet has become an architectural patchwork of growing complexity which strains to cope with the changes. Moore’s law prevented us from recognising that the problem does not hide in the high demands of today’s applications but lies in the flaws of the Internet’s original design. The Internet needs to move beyond TCP/IP to prosper in the long term, TCP/IP has outlived its usefulness. The Recursive InterNetwork Architecture (RINA) is a new Internetwork architecture whose fundamental principle is that networking is only interprocess communication (IPC). RINA reconstructs the overall structure of the Internet, forming a model that comprises a single repeating layer, the DIF (Distributed IPC Facility), which is the minimal set of components required to allow distributed IPC between application processes. RINA supports inherently and without the need of extra mechanisms mobility, multi-homing and Quality of Service, provides a secure and configurable environment, motivates for a more competitive marketplace and allows for a seamless adoption. RINA is the best choice for the next generation networks due to its sound theory, simplicity and the features it enables. IRATI’s goal is to achieve further exploration of this new architecture. IRATI will advance the state of the art of RINA towards an architecture reference model and specifcations that are closer to enable implementations deployable in production scenarios. The design and implemention of a RINA prototype on top of Ethernet will permit the experimentation and evaluation of RINA in comparison to TCP/IP. IRATI will use the OFELIA testbed to carry on its experimental activities. Both projects will benefit from the collaboration. IRATI will gain access to a large-scale testbed with a controlled network while OFELIA will get a unique use-case to validate the facility: experimentation of a non-IP based Internet

AGN impact on the molecular gas in galactic centres as probed by CO lines

We present a detailed analysis of the X-ray, infrared, and carbon monoxide (CO) emission for a sample of 35 local (z ≤ 0.15), active (LX ≥ 1042 erg s-1) galaxies. Our goal is to infer the contribution of far-ultraviolet (FUV) radiation from star formation (SF), and X-ray radiation from the active galactic nuclei (AGNs), respectively, producing photodissociation regions (PDRs) and X-ray-dominated regions (XDRs), to the molecular gas heating. To this aim, we exploit the CO spectral line energy distribution (CO SLED) as traced by Herschel, complemented with data from single-dish telescopes for the low-J lines, and high-resolution ALMA images of the mid-J CO emitting region. By comparing our results to the Schmidt-Kennicutt relation, we find no evidence for AGN influence on the cold and low-density gas on kpc-scales. On nuclear (r = 250 pc) scales, we find weak correlations between the CO line ratios and either the FUV or X-ray fluxes: this may indicate that neither SF nor AGN radiation dominates the gas excitation, at least at r = 250 pc. From a comparison of the CO line ratios with PDR and XDR models, we find that PDRs can reproduce observations only in presence of extremely high gas densities (n > 105 cm-3). In the XDR case, instead, the models suggest moderate densities (n ≈ 102-4 cm-3). We conclude that a mix of the two mechanisms (PDR for the mid-J, XDR, or possibly shocks for the high-J) is necessary to explain the observed CO excitation in active galaxies

Experimental evaluation of a recursive internetwork architecture prototype

The Recursive InterNetwork Architecture (RINA) is a recently proposed network architecture based on first principles, which promises to solve a number of issues present in the current Internet such as the lack of inherent security. In this paper, we present the experimental evaluation of the first performance-oriented implementation of RINA, the IRATI stack. Our open source stack is designed for GNU/Linux Operating Systems, with key components developed in kernel space for optimal performance. After briefly introducing the architecture, we present the main features of the stack, give some details about the implementation and discuss some trade-offs that had to be taken into account. We present use case scenarios for the evaluation, which were implemented in a test environment, and present the performance, achieving a goodput close to line rate on a GbE link, even when multiple Distributed Inter Process Communication Facilities (DIFs) are stacked

The molecular gas properties in local Seyfert 2 galaxies

Aims. We present a multiwavelength study of the molecular gas properties of a sample of local Seyfert 2 galaxies to assess if, and to what extent, the presence of an active galactic nucleus (AGN) can affect the interstellar medium (ISM) properties in a sample of 33 local Seyfert 2 galaxies. Methods. We compare the molecular gas content (MH2) derived from new and archival low-J CO line measurements of a sample of AGN and a control sample of star-forming galaxies (SFGs). Both the AGN and the control sample are characterized in terms of host-galaxy properties, for example stellar and dust masses (M* and Mdust, respectively) and the star formation rate (SFR). We also investigate the effect of AGN activity on the emission of polycyclic aromatic hydrocarbon (PAH) molecules in the mid-infrared (MIR), a waveband where the dust-reprocessed emission from the obscured AGN contributes the most. Result. The AGN hosted in less massive galaxies (i.e., M* < 1010.5 M⊙; Mdust < 107.5 M⊙) show larger molecular gas contents with respect to SFGs that have the same stellar and dust masses. When comparing their depletion times (tdep ≈ MH2/SFR), AGN show tdep ∼ 0.3-1.0 Gyr, similar to the times observed in the control sample of SFGs. Seyfert 2 galaxies show fainter PAH luminosity the larger the dominance of the nuclear activity in the MIR. Conclusions. We find no clear evidence for a systematic reduction in the molecular gas reservoir at galactic scales in Seyfert galaxies with respect to SFGs. This is in agreement with recent studies that show that molecular gas content is only reduced in sub-kiloparsec-sized regions, where emission from the accreting supermassive black hole dominates. Nonetheless, we show that the impact of AGN activity on the ISM is clearly visible as a suppression of the PAH luminosity

Toxicity after moderately hypofractionated versus conventionally fractionated prostate radiotherapy: A systematic review and meta-analysis of the current literature

Background: Moderately hypofractionated radiotherapy (RT) currently represents the standard RT approach for all prostate cancer (PCa) risk categories. We performed a systematic review and meta-analysis of available literature, focusing on acute and late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) of moderate hypofractionation for localized PCa. Materials and methods: Literature search was performed and two independent reviewers selected the records according to the following Population (P) Intervention (I) Comparator (C) and Outcomes (O) (PICO) question: “In patients affected by localized PCa (P), moderately hypofractionated RT (defined as a treatment schedule providing a single dose per fraction of 3–4.5 Gy) (I) can be considered equivalent to conventionally fractionated RT (C) in terms of G > 2 GI and GU acute and late adverse events (O)?”. Bias assessment was performed using Cochrane Cochrane Collaboration's Tool for Assessing Risk of Bias. Results: Thirteen records were identified and a meta-analysis was performed. Risk of acute GI and GU > 2 adverse events in the moderately hypofractionated arm was increased by 9.8 % (95 %CI 4.8 %–14.7 %; I2 = 57 %) and 1.5 % (95 % CI -1.5 %-4.4 %; I2 = 0%), respectively. Discussion: Overall, majority of trials included in our meta-analysis suggested that moderately hypofractionated RT is equivalent, in terms of GI and GU adverse events, to conventional fractionation. Pooled analysis showed a trend to increased GI toxicity after hypofractionated treatment, but this might be related to dose escalation rather than hypofractionation

The SOCS3-independent expression of IDO2 supports the homeostatic generation of T regulatory cells by human dendritic cells.

Dendritic cells (DCs) are professional APCs that have a role in the initiation of adaptive immune responses and tolerance. Among the tolerogenic mechanisms, the expression of the enzyme IDO1 represents an effective tool to generate T regulatory cells. In humans, different DC subsets express IDO1, but less is known about the IDO1-related enzyme IDO2. In this study, we found a different pattern of expression and regulation between IDO1 and IDO2 in human circulating DCs. At the protein level, IDO1 is expressed only in circulating myeloid DCs (mDCs) and is modulated by PGE2, whereas IDO2 is expressed in both mDCs and plasmacytoid DCs and is not modulated by PGE2. In healthy subjects, IDO1 expression requires the presence of PGE2 and needs continuous transcription and translation, whereas IDO2 expression is constitutive, independent from suppressor of cytokine signaling 3 activity. Conversely, in patients suffering from inflammatory arthritis, circulating DCs express both IDO1 and IDO2. At the functional level, both mDCs and plasmacytoid DCs generate T regulatory cells through an IDO1/IDO2-dependent mechanism. We conclude that, in humans, whereas IDO1 provides an additional mechanism of tolerance induced by proinflammatory mediators, IDO2 is stably expressed in steady-state conditions and may contribute to the homeostatic tolerogenic capacity of DCs

c-Maf enforces cytokine production and promotes memory-like responses in mouse and human type 2 innate lymphoid cells

Group-2 innate lymphoid cells (ILC2s), which are involved in type 2 inflammatory diseases such as allergy, can exhibit immunological memory, but the basis of this ILC2 "trained immunity" has remained unclear. Here, we found that stimulation with IL-33/IL-25 or exposure to the allergen papain induces the expression of the transcription factor c-Maf in mouse ILC2s. Chronic papain exposure results in high production of IL-5 and IL-13 cytokines and lung eosinophil recruitment, effects that are blocked by c-Maf deletion in ILCs. Transcriptomic analysis revealed that knockdown of c-Maf in ILC2s suppresses expression of type 2 cytokine genes, as well as of genes linked to a memory-like phenotype. Consistently, c-Maf was found highly expressed in human adult ILC2s but absent in cord blood and required for cytokine production in isolated human ILC2s. Furthermore, c-Maf-deficient mouse or human ILC2s failed to exhibit strengthened (“trained”) responses upon repeated challenge. Thus, the expression of c-Maf is indispensable for optimal type 2 cytokine production and proper memory-like responses in group-2 innate lymphoid cells

Nanoselective area growth of GaN by metalorganic vapor phase epitaxy on 4H-SiC using epitaxial graphene as a mask

International audienceWe report the growth of high-quality triangular GaN nanomesas, 30-nm thick, on the C-face of 4H-SiC using nano selective area growth (NSAG) with patterned epitaxial graphene grown on SiC as an embedded mask. NSAG alleviates the problems of defective crystals in the heteroepitaxial growth of nitrides, and the high mobility graphene film can readily provide the back low-dissipative electrode in GaN-based optoelectronic devices. The process consists in first growing a 5-8 graphene layers film on the C-face of 4H- SiC by confinement-controlled sublimation of silicon carbide. The graphene film is then patterned and arrays of 75-nanometer-wide openings are etched in graphene revealing the SiC substrate. 30-nanometer-thick GaN is subsequently grown by metal organic vapor phase epitaxy. GaN nanomesas grow epitaxially with perfect selectivity on SiC, in openings patterned through graphene, with no nucleation on graphene. The up-or-down orientation of the mesas on SiC, their triangular faceting, and cross-sectional scanning transmission electron microscopy show that they are biphasic. The core is a zinc blende monocrystal surrounded with single-crystal hexagonal wurtzite. The GaN crystalline nanomesas have no threading dislocations, and do not show any V-pit. This NSAG process potentially leads to integration of high-quality III-nitrides on the wafer scalable epitaxial graphene / silicon carbide platform