Bacteriomimetic Liposomes Improve Antibiotic Activity of a Novel Energy-Coupling Factor Transporter Inhibitor

Liposomes have been studied for decades as nanoparticulate drug delivery systems for cytostatics, and more recently, for antibiotics. Such nanoantibiotics show improved antibacterial efficacy compared to the free drug and can be effective despite bacterial recalcitrance. In this work, we present a loading method of bacteriomimetic liposomes for a novel, hydrophobic compound (HIPS5031) inhibiting energy-coupling factor transporters (ECF transporters), an underexplored antimicrobial target. The liposomes were composed of DOPG (18:1 (Δ9-cis) phosphatidylglycerol) and CL (cardiolipin), resembling the cell membrane of Gram-positive Staphylococcus aureus and Streptococcus pneumoniae, and enriched with cholesterol (Chol). The size and polydispersity of the DOPG/CL/± Chol liposomes remained stable over 8 weeks when stored at 4 °C. Loading of the ECF transporter inhibitor was achieved by thin film hydration and led to a high encapsulation efficiency of 33.19% ± 9.5% into the DOPG/CL/Chol liposomes compared to the phosphatidylcholine liposomes (DMPC/DPPC). Bacterial growth inhibition assays on the model organism Bacillus subtilis revealed liposomal HIPS5031 as superior to the free drug, showing a 3.5-fold reduction in CFU/mL at a concentration of 9.64 µM. Liposomal HIPS5031 was also shown to reduce B. subtilis biofilm. Our findings present an explorative basis for bacteriomimetic liposomes as a strategy against drug-resistant pathogens by surpassing the drug-formulation barriers of innovative, yet unfavorably hydrophobic, antibiotics

Bacteriomimetic Liposomes Improve Antibiotic Activity of a Novel Energy-Coupling Factor Transporter Inhibitor

Liposomes have been studied for decades as nanoparticulate drug delivery systems for cytostatics, and more recently, for antibiotics. Such nanoantibiotics show improved antibacterial efficacy compared to the free drug and can be effective despite bacterial recalcitrance. In this work, we present a loading method of bacteriomimetic liposomes for a novel, hydrophobic compound (HIPS5031) inhibiting energy-coupling factor transporters (ECF transporters), an underexplored antimicrobial target. The liposomes were composed of DOPG (18:1 (∆9-cis) phosphatidylglycerol) and CL (cardiolipin), resembling the cell membrane of Gram-positive Staphylococcus aureus and Streptococcus pneumoniae, and enriched with cholesterol (Chol). The size and polydispersity of the DOPG/CL/± Chol liposomes remained stable over 8 weeks when stored at 4 ◦C. Loading of the ECF transporter inhibitor was achieved by thin film hydration and led to a high encapsulation efficiency of 33.19% ± 9.5% into the DOPG/CL/Chol liposomes compared to the phosphatidylcholine liposomes (DMPC/DPPC). Bacterial growth inhibition assays on the model organism Bacillus subtilis revealed liposomal HIPS5031 as superior to the free drug, showing a 3.5-fold reduction in CFU/mL at a concentration of 9.64 µM. Liposomal HIPS5031 was also shown to reduce B. subtilis biofilm. Our findings present an explorative basis for bacteriomimetic liposomes as a strategy against drug resistant pathogens by surpassing the drug-formulation barriers of innovative, yet unfavorably hydrophobic, antibiotics

Implementation of synthetic fast-ion loss detector and imaging heavy ion beam probe diagnostics in the 3D hybrid kinetic-MHD code MEGA

A synthetic fast-ion loss (FIL) detector and an imaging Heavy Ion Beam Probe (i-HIBP) have been implemented in the 3D hybrid kinetic-magnetohydrodynamic code MEGA. First synthetic measurements from these two diagnostics have been obtained for neutral beam injection-driven Alfvén Eigenmode (AE) simulated with MEGA. The synthetic FILs show a strong correlation with the AE amplitude. This correlation is observed in the phase-space, represented in coordinates (P, E), being toroidal canonical momentum and energy, respectively. FILs and the energy exchange diagrams of the confined population are connected with lines of constant E, a linear combination of E and P. First i-HIBP synthetic signals also have been computed for the simulated AE, showing displacements in the strike line of the order of ∼1 mm, above the expected resolution in the i-HIBP scintillator of ∼100 μm.This work received funding from the European Starting Grant (ERC) from project 3D-FIREFLUC and from the Spanish Ministry of Science under Grant No. FPU19/02267. This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014-2018 and 2019-2020 under grant agreement No 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission

Characterization of scintillator screens under irradiation of low energy 133Cs ions

An imaging heavy ion beam probe (i-HIBP) diagnostic, for the simultaneous measurement of plasma density, magnetic field and electrostatic potential in the plasma edge, has been installed at ASDEX Upgrade. Unlike standard heavy ion beam probes, in the i-HIBP the probing (heavy) ions are collected by a scintillator detector, creating a light pattern or strike-line, which is then imaged by a camera. Therefore, a good characterization of the scintillator response is needed. Previous works focused on the scintillator behaviour against irradiation with light ions such as hydrogen and alpha particles. In this work we present the characterization of several scintillator screens — TG-Green (SrGa2S4:Eu2+), YAG-Ce (Y3Al5O12:Ce3+) and P11 (ZnS:Ag) — against irradiation with 133Cs+ ions, in an energy range between 5 and 70 keV and ion currents between 105 and 107ions/(s·cm2). Three main properties of the scintillators have been studied: the ionolumenescence efficiency or yield, the linearity and the degradation as a function of the fluence. The highest yield was delivered by the TG-Green scintillator screen with > 8·103 photons/ion at 50 keV. All the samples showed a linear response with increasing incident ion flux. The degradation was quantified in terms of the fluence F1/2, which leads to a reduction of the emissivity by a factor of 2. TG-Green showed the lowest degradation with F1/2= 5.4·1014ions/cm2. After the irradiation the samples were analyzed by Scanning Electron Microscopy (SEM), Rutherford Backscattering Spectrometry (RBS) and Particle Induced X-ray Emission (PIXE). No trace of Cs was found in the irradiated regions. These results indicate that, among the tested materials, TG-Green is the best candidate for the i-HIBP detector.European Union’s Horizon 2020 (grant agreement No. 805162)Helmholtz Association VHNG-1350Spanish Ministry of Science and Innovation FJC2019-041092-I

Characterization of scintillator screens under irradiation of low energy 133Cs ions

An imaging heavy ion beam probe (i-HIBP) diagnostic, for the simultaneous measurement of plasma density, magnetic field and electrostatic potential in the plasma edge, has been installed at ASDEX Upgrade. Unlike standard heavy ion beam probes, in the i-HIBP the probing (heavy) ions are collected by a scintillator detector, creating a light pattern or strike-line, which is then imaged by a camera. Therefore, a good characterization of the scintillator response is needed. Previous works focused on the scintillator behaviour against irradiation with light ions such as hydrogen and alpha particles. In this work we present the characterization of several scintillator screens - TG-Green (SrGa2S4:Eu2+), YAG-Ce (Y3Al5O12:Ce3+) and P11 (ZnS:Ag) - against irradiation with 133Cs+ ions, in an energy range between 5 and 70 keV and ion currents between 105 and 107 ions/(s·cm2). Three main properties of the scintillators have been studied: the ionolumenescence efficiency or yield, the linearity and the degradation as a function of the fluence. The highest yield was delivered by the TG-Green scintillator screen with > 8·103 photons/ion at 50 keV. All the samples showed a linear response with increasing incident ion flux. The degradation was quantified in terms of the fluence F1/2, which leads to a reduction of the emissivity by a factor of 2. TG-Green showed the lowest degradation with F1/2= 5.4·1014 ions/cm2. After the irradiation the samples were analyzed by Scanning Electron Microscopy (SEM), Rutherford Backscattering Spectrometry (RBS) and Particle Induced X-ray Emission (PIXE). No trace of Cs was found in the irradiated regions. These results indicate that, among the tested materials, TG-Green is the best candidate for the i-HIBP detector.This work received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 805162). G. Birkenmeier acknowledges funding from the Helmholtz Association under grant no. VHNG-1350. J. Galdon-Quiroga acknowledges funding from the Spanish Ministry of Science and Innovation under grant no. FJC2019-041092-I

CCL28 Induces Mucosal Homing of HIV-1-Specific IgA-Secreting Plasma Cells in Mice Immunized with HIV-1 Virus-Like Particles

Mucosae-associated epithelial chemokine (MEC or CCL28) binds to CCR3 and CCR10 and recruits IgA-secreting plasma cells (IgA-ASCs) in the mucosal lamina propria. The ability of this chemokine to enhance migration of IgA-ASCs to mucosal sites was assessed in a mouse immunization model using HIV-1IIIB Virus-like particles (VLPs). Mice receiving either HIV-1IIIB VLPs alone, CCL28 alone, or the irrelevant CCL19 chemokine were used as controls. Results showed a significantly increased CCR3 and CCR10 expression on CD19+ splenocytes of HIV-1IIIB VPL-CCL28-treated mice. HIV-1 Env-specific IFN-γ, IL-4 and IL-5 production, total IgA, anti-Env IgA as well as gastro-intestinal mucosal IgA-secreting plasma cells were also significantly augmented in these mice. Notably, sera and vaginal secretions from HIV-1IIIB VLP-CCL28-treated mice exhibited an enhanced neutralizing activity against both a HIV-1/B-subtype laboratory strain and a heterologous HIV-1/C-subtype primary isolate. These data suggest that CCL28 could be useful in enhancing the IgA immune response that will likely play a pivotal role in prophylactic HIV vaccines

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies : an international multicenter retrospective study

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n 5 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term.disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups