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Abstract Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN’s Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations.

An experimental scheme is presented for generating low-divergence, ultradense, relativistic, electron-positron beams using 400 GeV/c protons available at facilities such as HiRadMat and AWAKE at CERN. Preliminary Monte Carlo and particle-in-cell simulations demonstrate the possibility of generating beams containing 10^{13}–10^{14} electron-positron pairs at sufficiently high densities to drive collisionless beam-plasma instabilities, which are expected to play an important role in magnetic field generation and the related radiation signatures of relativistic astrophysical phenomena. The pair beams are quasineutral, with size exceeding several skin depths in all dimensions, allowing the examination of the effect of competition between transverse and longitudinal instability modes on the growth of magnetic fields. Furthermore, the presented scheme allows for the possibility of controlling the relative density of hadrons to electron-positron pairs in the beam, making it possible to explore the parameter spaces for different astrophysical environments.

Fluidized tungsten powder has been proposed as a potential target technology for particle accelerator applications with very high power highly focused pulsed beams. This has motivated a series of experiments carried out at the HiRadMat facility at CERN to study the response of a tungsten powder sample to an impinging high energy proton beam pulse. The main observation was that of beam induced lifting of the powder sample which was recorded by high speed video. In this paper we consider three mechanisms to explain the observed powder lift including aerodynamic, thermal expansion and induced charge effects. Simulations of the aerodynamic effect revealed that this could not explain the magnitude of the observed eruptions especially during tests carried out with the powder in a vacuum. Thermal expansion of tungsten particles giving rise to the eruption seems implausible due to the propensity for the powder to absorb perturbations. We show that the observations can be explained by a Coulombic eruption of the tungsten particles. The high energy beam leaves a pattern of charge distributed in the poorly conducting powder sample, which creates an electric field that consequently results in a force acting on the individual charged particles. We calculate the charge deposited, the electric field and the resulting acceleration and show that this is a plausible mechanism for causing the observed eruptions. We believe the response of a granular conductive sample to an incident proton beam has not previously been explained.

This paper reports the results from single-pulse experiments of a 440 GeV/c proton beam interacting with granular tungsten samples in both vacuum and helium environments. Remote high-speed photography and laser Doppler vibrometry were used to observe the effect of the beam on the sample grains. The majority of the results were derived from a trough containing ∼45 μm diameter spheres (not compacted) reset between experiments to maintain the same initial conditions. Experiments were also carried out on other open and contained samples for the purposes of comparison both with the 45 μm grain results and with a previous experiment carried out with sub-250 μm mixed crystalline tungsten powder in helium [Phys. Rev. ST Accel. Beams 17, 101005 (2014)PRABFM1098-440210.1103/PhysRevSTAB.17.101005]. The experiments demonstrate that a greater dynamic response is produced in a vacuum than in a helium environment and in smaller grains compared with larger grains. The examination of the dynamics of the grains after a beam impact leads to the hypothesis that the grain response is primarily the result of a charge interaction of the proton beam with the granular medium.

The Long Baseline Neutrino Facility (LBNF, formerly the Long Baseline Neutrino Experiment) is under design as a next generation neutrino oscillation experiment, with primary objectives to search for CP violation in the leptonic sector, to determine the neutrino mass hierarchy and to provide a precise measurement of θ_{23}. The facility will generate a neutrino beam at Fermilab by the interaction of a proton beam with a target material. At the ultimate anticipated proton beam power of 2.3 MW the target material must dissipate a heat load of between 10 and 25 kW depending on the target size. This paper presents a target concept based on an array of spheres and compares it to a cylindrical monolithic target such as that which currently operates at the T2K facility. Simulation results show that the proposed technology offers efficient cooling and lower stresses whilst delivering a neutrino production comparable with that of a conventional solid cylindrical target.

The properties of the neutrino provide a unique window on physics beyond that described by the standard model. The study of subleading effects in neutrino oscillations, and the race to discover CP-invariance violation in the lepton sector, has begun with the recent discovery that θ_{13}>0. The measured value of θ_{13} is large, emphasizing the need for a facility at which the systematic uncertainties can be reduced to the percent level. The neutrino factory, in which intense neutrino beams are produced from the decay of muons, has been shown to outperform all realistic alternatives and to be capable of making measurements of the requisite precision. Its unique discovery potential arises from the fact that only at the neutrino factory is it practical to produce high-energy electron (anti)neutrino beams of the required intensity. This paper presents the conceptual design of the neutrino factory accelerator facility developed by the European Commission Framework Programme 7 EUROν Design Study consortium. EUROν coordinated the European contributions to the International Design Study for the Neutrino Factory (the IDS-NF) collaboration. The EUROν baseline accelerator facility will provide 10^{21} muon decays per year from 12.6 GeV stored muon beams serving a single neutrino detector situated at a source-detector distance of between 1 500 km and 2 500 km. A suite of near detectors will allow definitive neutrino-scattering experiments to be performed.

The experiment described in this paper is the first study of the response of a static tungsten powder sample to an impinging high energy proton beam pulse. The experiment was carried out at the HiRadMat facility at CERN. Observations include high speed videos of a proton beam induced perturbation of the powder sample as well as data from a laser Doppler vibrometer measuring the oscillations of the powder container. A comparison with a previous analogous experiment which studied a proton beam interaction with mercury is made.

We present a new design study of the neutrino Super Beam based on the Superconducting Proton Linac at CERN. This beam is aimed at megaton mass physics, a large water Cherenkov detector, proposed for the Laboratoire Souterrain de Modane in France, with a baseline of 130 km. The aim of this proposed facility is to study CP violation in the neutrino sector. In the study reported here, we have developed the conceptual design of the neutrino beam, especially the target and the magnetic focusing device. Indeed, this beam presents several unprecedented challenges, related to the high primary proton beam power (4 MW), the high repetition rate (50 Hz), and the low kinetic energy of the protons (4.5 GeV). The design is completed by a study of all the main components of the system, starting from the transport system to guide the beam to the target up to the beam dump. This is the first complete study of a neutrino beam based on a pebble-bed target capable of standing the large heat deposition of MW class proton beams.

The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Fréjus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of μ^{+} and μ^{-} beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular ^{6}He and ^{18}Ne, also stored in a ring. The far detector is also the MEMPHYS detector in the Fréjus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive.

Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN's Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations., (© 2024. The Author(s).)

Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells. Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K. Amighi, N. Wauthoz, and R. Rosière are inventors of patents related to some technologies described in the paper and are co-founders of InhaTarget Therapeutics. R. Rosière is also the CSO of InhaTarget Therapeutics and a scientific collaborator of the Unit of Pharmaceutics and Biopharmaceutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Varicella-Zoster virus (VZV) causes chickenpox and shingles. Although the infection is associated with severe morbidity in some individuals, molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was required for type I interferon (IFN) induction during VZV infection and that recognition of VZV by cGAS restricted its replication. Screening of a VZV ORF expression library identified the essential VZV tegument protein ORF9 as a cGAS antagonist. Ectopically or virally expressed ORF9 bound to endogenous cGAS leading to reduced type I IFN responses to transfected DNA. Confocal microscopy revealed co-localisation of cGAS and ORF9. ORF9 and cGAS also interacted directly in a cell-free system and phase-separated together with DNA. Furthermore, ORF9 inhibited cGAMP production by cGAS. Taken together, these results reveal the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identify a VZV immune antagonist that partially but directly interferes with DNA sensing via cGAS., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Purine nucleoside phosphorylase inhibitors (PNP-Is) were developed to ablate transformed lymphocytes. However, only some patients with leukemia benefit from PNP-Is. We provide a molecular explanation: the deoxyribonucleoside triphosphate (dNTP) hydrolase SAM and HD domain-containing protein 1 (SAMHD1) prevents the accumulation of toxic dNTP levels during purine nucleoside phosphorylase inhibition. We propose PNP-Is for targeted therapy of patients with acquired SAMHD1 mutations., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The anti-leukemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphate (dNTP), protects cells against the effects of dNTP imbalances. SAMHD1-deficient cells induce intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine act synergistically to kill cells lacking SAMHD1. Using mass cytometry, we find that these compounds kill SAMHD1-deficient malignant cells in patients with chronic lymphocytic leukemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation are unaffected. We therefore propose to use forodesine as a precision medicine for leukemia, stratifying patients by SAMHD1 genotype or expression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This phase I trial evaluated the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost, previously demonstrated to be protective in animal studies, in healthy UK adults., Methods: We enrolled 42 healthy, BCG-vaccinated adults into 4 groups: low dose Starter Group (n = 6; ChAdOx1 85A alone), high dose groups; Group A (n = 12; ChAdOx1 85A), Group B (n = 12; ChAdOx1 85A prime - MVA85A boost) or Group C (n = 12; ChAdOx1 85A - ChAdOx1 85A prime - MVA85A boost). Safety was determined by collection of solicited and unsolicited vaccine-related adverse events (AEs). Immunogenicity was measured by antigen-specific ex-vivo IFN-γ ELISpot, IgG serum ELISA, and antigen-specific intracellular IFN-γ, TNF-α, IL-2 and IL-17., Results: AEs were mostly mild/moderate, with no Serious Adverse Events. ChAdOx1 85A induced Ag85A-specific ELISpot and intracellular cytokine CD4+ and CD8+ T cell responses, which were not boosted by a second dose, but were boosted with MVA85A. Polyfunctional CD4+ T cells (IFN-γ, TNF-α and IL-2) and IFN-γ+, TNF-α+ CD8+ T cells were induced by ChAdOx1 85A and boosted by MVA85A. ChAdOx1 85A induced serum Ag85A IgG responses which were boosted by MVA85A., Conclusion: A ChAdOx1 85A prime - MVA85A boost is well tolerated and immunogenic in healthy UK adults., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Toll-like receptor 7 (TLR7) is an innate immune sensor for single-strand RNA (ssRNA). Recent structural analysis revealed that TLR7 has an additional binding site for nucleosides such as guanosine, and is activated when both guanosine and ssRNA bind. The nucleoside binding site also accommodates imidazoquinoline derivatives such as R848, which activate TLR7 in the absence of ssRNA. Here, we report that deoxyguanosine (dG) triggered cytokine production in murine bone marrow derived macrophages and plasmacytoid dendritic cells, as well as in human peripheral blood mononuclear cells, including type I interferons and pro-inflammatory factors such as TNF and IL-6. This signalling activity of dG was dependent on TLR7 and its adaptor MyD88 and did not require amplification via the type I interferon receptor. dG-triggered cytokine production required endosomal maturation but did not depend on the concurrent provision of RNA. We conclude that dG induces an inflammatory response through TLR7 and propose that dG is an RNA-independent TLR7 agonist., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chronic hepatitis B is one of the world's unconquered diseases with more than 240 million infected subjects at risk of developing liver disease and hepatocellular carcinoma. Hepatitis B virus reverse transcribes pre-genomic RNA to relaxed circular DNA (rcDNA) that comprises the infectious particle. To establish infection of a naïve target cell, the newly imported rcDNA is repaired by host enzymes to generate covalently closed circular DNA (cccDNA), which forms the transcriptional template for viral replication. SAMHD1 is a component of the innate immune system that regulates deoxyribonucleoside triphosphate levels required for host and viral DNA synthesis. Here, we show a positive role for SAMHD1 in regulating cccDNA formation, where KO of SAMHD1 significantly reduces cccDNA levels that was reversed by expressing wild-type but not a mutated SAMHD1 lacking the nuclear localization signal. The limited pool of cccDNA in infected Samhd1 KO cells is transcriptionally active, and we observed a 10-fold increase in newly synthesized rcDNA-containing particles, demonstrating a dual role for SAMHD1 to both facilitate cccDNA genesis and to restrict reverse transcriptase-dependent particle genesis., (© 2019 Wing et al.)

We report on type-I phase-matched second harmonic generation (SHG) in three nonlinear crystals: DKDP (98% deuteration), YCOB (XZ plane), and LBO (XY plane), of 8 J, 10 Hz cryogenic gas cooled Yb:YAG laser operating at 1029.5 nm. DKDP exhibited an efficiency of 45% at a peak fundamental intensity of 0.24 GW/cm 2 for 10 Hz operation at 10 ns. At the same intensity and repetition rate, YCOB and LBO showed 50% and 65% conversion efficiencies, respectively. Significant improvement in conversion efficiency, to a maximum of 82%, was demonstrated in LBO at 0.7 GW/cm 2 and 10 Hz, generating output energy of 5.6 J at 514.75 nm, without damage or degradation. However, no improvement in conversion efficiency was recorded for YCOB at this increased intensity. Additionally, we present theoretically calculated temperature maps for both 10 J and 100 J operation at 10 Hz, and discuss the suitability of these three crystals for frequency conversion of a 100 J, 10 Hz diode pumped solid state laser (DPSSL).

Mycobacterium tuberculosis (M.tb) has co-evolved with humans for thousands of years, to cause tuberculosis (TB). The success of M.tb as a pathogen is in part because of the ways in which M.tb evades and exploits different cell subsets, to persist and cause disease. M.tb expresses numerous molecules to prevent its recognition and destruction by immune cells. The only licensed vaccine against TB, Bacillle Calmette-Guerin (BCG), is effective at preventing disseminated disease in infants but confers highly variable efficacy against pulmonary TB in adults, particularly in the developing world. A greater understanding of the reasons for this variability, together with a better understanding of the early, innate, and non-antigen specific mechanisms of protection would facilitate the design and development of more effective vaccines.

Cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA during virus infection and induces an antiviral state. cGAS signals by synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING). We show that cGAMP is incorporated into viral particles, including lentivirus and herpesvirus virions, when these are produced in cGAS-expressing cells. Virions transferred cGAMP to newly infected cells and triggered a STING-dependent antiviral program. These effects were independent of exosomes and viral nucleic acids. Our results reveal a way by which a signal for innate immunity is transferred between cells, potentially accelerating and broadening antiviral responses. Moreover, infection of dendritic cells with cGAMP-loaded lentiviruses enhanced their activation. Loading viral vectors with cGAMP therefore holds promise for vaccine development., (Copyright © 2015, American Association for the Advancement of Science.)