2-(2-methyl-2-nitrovinyl)furan but not furvina interfere with staphylococcus aureus agr quorum-sensing system and potentiate the action of fusidic acid against biofilms

Quorum sensing (QS) plays an essential role in the production of virulence factors, in biofilm formation and antimicrobial resistance. Consequently, inhibiting QS is being consid-ered a promising target for antipathogenic/anti-virulence therapies. This study aims to screen 2-nitrovinylfuran derivatives structurally related to Furvina (a broad-spectrum antibiotic already used for therapeutic purposes) for their effects on QS and in biofilm prevention/control. Furvina and four 2-nitrovinylfuran derivatives (compounds 1–4) were tested to assess the ability to interfere with QS of Staphylococcus aureus using bioreporter strains (S. aureus ALC1742 and ALC1743). The activity of Furvina and the most promising quorum-sensing inhibitor (QSI) was evaluated in biofilm prevention and in biofilm control (combined with fusidic acid). The biofilms were further characterized in terms of biofilm mass, viability and membrane integrity. Compound 2 caused the most significant QS inhibition with reductions between 60% and 80%. Molecular docking simulations indicate that this compound interacts preferentially with the protein hydrophobic cleft in the LytTR domain of AgrA pocket. Metabolic inactivations of 40% for S. aureus ALC1742 and 20% for S. aureus ALC1743 were reached. A 24 h-old biofilm formed in the presence of the QSI increased the metabolic inactivation by fusidic acid to 80%, for both strains. The overall results highlight the effects of compound 2 as well as the potential of combining QSI with in-use antibiotics for the management of skin and soft tissues infections

Indirect Impact of PD-1/PD-L1 Blockade on a Murine Model of NK Cell Exhaustion

The induction of exhaustion on effector immune cells is an important limiting factor for cancer immunotherapy efficacy as these cells undergo a hierarchical loss of proliferation and cytolytic activity due to chronic stimulation. Targeting PD-1 has shown unprecedented clinical benefits for many cancers, which have been attributed to the prevention of immune suppression and exhaustion with enhanced anti-tumor responses. In this study, we sought to evaluate the role of the PD-1/PD-L1 pathway in murine natural killer (NK) cell activation, function, and exhaustion. In an in vivo IL-2-dependent exhaustion mouse model, neutralization of the PD-1/PD-L1 pathway improved NK cell activation after chronic stimulation when compared to control-treated mice. These cells displayed higher proliferative capabilities and enhanced granzyme B production. However, the blockade of these molecules during long-term in vitro IL-2 stimulation did not alter the progression of NK cell exhaustion (NCE), suggesting an indirect involvement of PD-1/PD-L1 on NCE. Given the expansion of CD8 T cells and regulatory T cells (Tregs) observed upon acute and chronic stimulation with IL-2, either of these two populations could influence NK cell homeostasis after PD-L1/PD-1 therapy. Importantly, CD8 T cell activation and functional phenotype were indeed enhanced by PD-1/PD-L1 therapy, particularly with anti-PD-1 treatment that resulted in the highest upregulation of CD25 during chronic stimulation and granted an advantage for IL-2 over NK cells. These results indicate a competition for resources between NK and CD8 T cells that arguably delays the onset of NCE rather than improving its activation during chronic stimulation. Supporting this notion, the depletion of CD8 T cells reversed the benefits of PD-1 therapy on chronically stimulated NK cells. These data suggest a bystander effect of anti-PD1 on NK cells, resulting from the global competition that exists between NK and CD8 T cells for IL-2 as a key regulator of these cells’ activation. Thus, achieving an equilibrium between these immune cells might be important to accomplish long-term efficacy during anti-PD-1/IL-2 therapy

Cytomegalovirus Viral Load and Virus-Specific Immune Reconstitution after Peripheral Blood Stem Cell versus Bone Marrow Transplantation

Peripheral blood stem cell (PBSC) products contain more T cells and monocytes when compared with bone marrow (BM), leading to fewer bacterial and fungal infections. Cytomegelovirus (CMV) viral load and disease as well as CMV-specific immune reconstitution were compared in patients enrolled in a randomized trial comparing PSBC and BM transplantation. There was a higher rate of CMV infection and disease during the first 100 days after transplantation among PBSC recipients (any antigenemia/DNAemia: PBSC, 63% vs BM, 42%, P = .04; CMV disease: PBSC, 17% vs BM, 4%, P = .03). By 2 years, CMV disease rates were similar. The early increase in CMV events correlated temporarily with lower CMV-specific CD4+ T helper and CD8+ cytotoxic T lymphocyte function at 30 days after transplantation in PBSC recipients. By 3 months after transplantation and thereafter, CMV-specific immune responses were similar between BM and PBSC recipients. In conclusion, higher CMV infection and disease rates occurred in PBSC transplant recipients early after transplantation. These differences may be because of a transient delay in CMV-specific immune reconstitution following PBSC transplantation

Cutting-edge R&D activities of CIRTEN in support of the Technology Park annexed to the Italian National Repository of radioactive waste

R&D activities taking place at the institutions belonging to Consorzio Interuniversitario per la Ricerca TEcnologica Nucleare are here presented and discussed. A special focus is on Technology Park annexed to the Italian National Repository of radioactive waste

Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: Results of a prospective double-blind randomized trial

AbstractWe have previously demonstrated a decrease in the incidence of acute graft-versus-host disease (GVHD) with the addition of methotrexate (MTX) to cyclosporine (CSP) and prednisone (PSE) chemotherapy in patients with leukemia. We have now completed a prospective randomized trial comparing the 3-drug regimen (CSP/MTX/PSE, including 3 doses of MTX) to the standard 2-drug regimen (CSP/MTX, including 4 doses of MTX) to investigate the benefit of PSE used up front for the prevention of acute and chronic GVHD. In the trial, 193 patients were randomized and 186 were included in the final analysis. All patients received a bone marrow graft from a fully histocompatible sibling donor. The preparatory regimen consisted of fractionated total-body irradiation (fTBI) and etoposide in all but 13 patients, who received fTBI and cyclophosphamide. The patients were randomized to receive either CSP/MTX/PSE or CSP/MTX. The 2 groups were well balanced with respect to diagnosis, disease stage, age, donor-recipient sex, and parity. In an intent-to-treat analysis, the incidence of acute GVHD was 18% (95% confidence interval [CI] 12-28) for the CSP/MTX/PSE group compared with 20% (CI 10-26) for the CSP/,MTX group (P = .60), with a median follow up of 2.2 years. Overall survival was 65% for those receiving CSP/MTX/PSE and 72% for those receiving CSP/MTX (P = .10); the relapse rate was 15% for the CSP/MTX/PSE group and 12% for the CSP/MTX group (P = .83). The incidence of chronic GVHD was similar (46% versus 52%; P = .38), with a follow-up of 0.7 to 6.0 years. Of interest, 21 patients went off study due to GVHD (5 in the CSP/MTX/PSE group and 16 in the CSP/MITX group [P = .02]), and 11 patients went off study because of alveolar hemorrhage (3 in the CSP/MTX/PSE group and 8 in the CSP/MTX group [P = .22]). The addition of PSE did not result in a higher incidence of infectious complications, bacterial (66% versus 58%), viral (77% versus 66%), or fungal (20% versus 20%), in those receiving CSP/MTX/PSE versus CSP/MTX, respectively. These data suggest that the addition of PSE was associated with a somewhat lower incidence of early posttransplantation complications but did not have a positive impact on the incidence of acute or chronic GVHD or event-free or overall survival.Biol Blood Marrow Transplant 2000;6(3):254-61

Gonadotropin-Releasing Hormone Increased Pregnancy in Suckled Beef Cows Not Detected in Estrus and Subjected to a Split-Time Artificial Insemination Program

Estrus-synchronization programs allow insemination of all females in a herd at one fixed time on the first day of the breeding season. Inseminating cows after they have expressed estrus increases pregnancy rate (PR) compared with cows that do not display estrus in a timed AI (TAI) program. Identification of estrus status can be facilitated by using estrus-detection patches. Varying AI timing according to estrus status has increased PR in some previous studies. Reducing the number of injections in a TAI program decreases labor requirements, stress on cows, and overall cost of the program. Previous studies have demonstrated that PR is not compromised in cows displaying estrus when the GnRH injection administered at AI is eliminated. A split-time AI program decreases the time between estrus expression and insemination compared with a single fixed-time AI when the first AI occurs before the recommended standard 60- to 66-h fixed time. Previous research has demonstrated that delaying AI results in approxi­mately 50% more cows displaying estrus when compared with a single insemination time. Eliminating the GnRH injection at AI for cows displaying estrus in a split TAI program can reduce the number of GnRH injections required and the program cost. The objective of this study was to test the hypothesis that GnRH injection concurrent with split TAI program improves PR only in cows not displaying estrus

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix

The Space Weather Atmosphere Models and Indices (SWAMI) project: Overview and first results

This is the final version. Available on open access from EDP Open via the DOI in this recordSpace weather driven atmospheric density variations affect low Earth orbit (LEO) satellites during all phases of their operational lifetime. Rocket launches, re-entry events and space debris are also similarly affected. A better understanding of space weather processes and their impact on atmospheric density is thus critical for satellite operations as well as for safety issues. The Horizon 2020 project Space Weather Atmosphere Model and Indices (SWAMI) project, which started in January 2018, aims to enhance this understanding by: Developing improved neutral atmosphere and thermosphere models, and combining these models to produce a new whole atmosphere model. Developing new geomagnetic activity indices with higher time cadence to enable better representation of thermospheric variability in the models, and improving the forecast of these indices. The project stands out by providing an integrated approach to the satellite neutral environment, in which the main space weather drivers are addressed together with model improvement. The outcomes of SWAMI will provide a pathway to improved space weather services as the project will not only address the science issues, but also the transition of models into operational services. The project aims to develop a unique new whole atmosphere model, by extending and blending the Unified Model (UM), which is the Met Office weather and climate model, and the Drag Temperature Model (DTM), which is a semi-empirical model which covers the 120–1500 km altitude range. A user-focused operational tool for satellite applications shall be developed based on this. In addition, improved geomagnetic indices shall be developed and shall be used in the UM and DTM for enhanced nowcast and forecast capability. In this paper, we report on progress with SWAMI to date. The UM has been extended from its original upper boundary of 85 km to run stably and accurately with a 135 km lid. Developments to the UM radiation scheme to enable accurate performance in the mesosphere and lower thermosphere are described. These include addition of non-local thermodynamic equilibrium effects and extension to include the far ultraviolet and extreme ultraviolet. DTM has been re-developed using a more accurate neutral density observation database than has been used in the past. In addition, we describe an algorithm to develop a new version of DTM driven by geomagnetic indices with a 60 minute cadence (denoted Hp60) rather than 3-hourly Kp indices (and corresponding ap indices). The development of the Hp60 index, and the Hp30 and Hp90 indices, which are similar to Hp60 but with 30 minute and 90 minute cadences, respectively, is described, as is the development and testing of neural network and other machine learning methods applied to the forecast of geomagnetic indices.European Union Horizon 202