Comparing different approaches for generating random numbers device-independently using a photon pair source

What is the most efficient way to generate random numbers device-independently using a photon pair source based on spontaneous parametric down conversion (SPDC)? We consider this question by comparing two implementations of a detection-loophole-free Bell test. In particular, we study in detail a scenario where a heralded single photon source (HSPS) is used to herald path-entangled states, i.e. entanglement between two spatial modes sharing a single photon and where non-locality is revealed using photon counting preceded by small displacement operations. We start by giving a theoretical description of such a measurement. We then show how to optimize the Bell-CHSH violation through a non-perturbative calculation, taking the main experimental imperfections into account. We finally bound the amount of randomness that can be extracted and compare it to the one obtained with the conventional scenario using photon pairs entangled e.g. in polarization and analyzed through photon counting. While the former requires higher overall detection efficiencies, it is far more efficient in terms of both the entropy per experimental run and the rate of random bit generation.Comment: 12 pages, 5 figure

Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis. Differentiated HepaRG cells treated with the fatty acid sodium oleate (fatty dHepaRG) recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing STAT3-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-STAT3 binding sites were identified in fatty dHepaRG cells and several STAT3 and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of STAT3 activity decreased lipid accumulation and deregulated STAT3-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-STAT3-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging-dependent hepatic vesicular steatosis. Our results identified a microRNAs-phosphoSTAT3 pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting

Factors associated with SARS-CoV-2 infection risk among healthcare workers of an italian university hospital

We report the results of a study on the cumulative incidence of SARS-CoV-2 infections in about 6000 workers of the University Hospital of Modena, Northern Italy, in the period March 2020–January 2021, and the relations with some individual and occupational factors. Overall, in healthcare workers (HCW) the cumulative incidence of COVID-19 during the period was 13.8%. Results confirm the role of overweight and obesity as significant risk factors for SARS-CoV-2 infection. Chronic respiratory diseases, including asthma, also proved to be significantly associated with the infection rate. Considering occupational factors, the COVID-19 risk was about threefold (OR: 2.7; 95% CI 1.7–4.5) greater in nurses and nurse aides than in non-HCW, and about double (OR: 1.9; 95% CI 1.2–3.2) in physicians. Interestingly, an association was also observed between infection risk and nightshifts at work (OR: 1.8; 95% CI 1.4–2.3), significantly related to the total number of shifts in the whole eleven-month period. Even if the vaccination campaign has now greatly modified the scenario of SARS-CoV-2 infections among HCW, the results of this study can be useful for further development of health and policy strategies to mitigate the occupational risk related to the new variants of coronavirus, and therefore the evolution of the pandemic

Fluorescent probe for the identification of potent inhibitors of the macrophage infectivity potentiator (Mip) protein of Burkholderia pseudomallei.

This is the final version. Available from Elsevier via the DOI in this record. The macrophage infectivity potentiator (Mip) protein belongs to the immunophilin superfamily. This class of enzymes catalyzes the interconversion between the cis and trans configuration of proline-containing peptide bonds. Mip has been shown to be important for the virulence of a wide range of pathogenic microorganisms, including the Gram-negative bacterium Burkholderia pseudomallei. Small molecules derived from the natural product rapamycin, lacking its immunosuppression-inducing moiety, inhibit Mip's peptidyl-prolyl cis-trans isomerase (PPIase) activity and lead to a reduction in pathogen load in vitro. Here, a fluorescence polarization assay (FPA) to enable the screening and effective development of BpMip inhibitors was established. A fluorescent probe was prepared, derived from previous pipecolic scaffold Mip inhibitors labeled with fluorescein. This probe showed moderate affinity for BpMip and enabled a highly robust FPA suitable for screening large compound libraries with medium- to high-throughput (Z factor ∼ 0.89) to identify potent new inhibitors. The FPA results are consistent with data from the protease-coupled PPIase assay. Analysis of the temperature dependence of the probe's binding highlighted that BpMip's ligand binding is driven by enthalpic rather than entropic effects. This has considerable consequences for the use of low-temperature kinetic assays.North Atlantic Treaty OrganizationGerman Research Foundation (DFG, Deutsche Forschungsgemeinschaft)Federal Ministry of Education and Research (Germany)Biotechnology and Biological Sciences Research CouncilDMTC Limited (Australia)UK Research and Innovatio

Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases (article)

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordThe dataset associated with this article is available in ORE at https://doi.org/10.24378/exe.3724The sugars streptose and dihydrohydroxystreptose (DHHS) are unique to the bacteria Streptomyces griseus and Coxiella burnetii, respectively. Streptose forms the central moiety of the antibiotic streptomycin, whilst DHHS is found in the O-antigen of the zoonotic pathogen C. burnetii. Biosynthesis of these sugars has been proposed to follow a similar path to that of TDP-rhamnose, catalyzed by the enzymes RmlA, RmlB, RmlC, and RmlD, but the exact mechanism is unclear. Streptose and DHHS biosynthesis unusually requires a ring contraction step that could be performed by orthologues of RmlC or RmlD. Genome sequencing of S. griseus and C. burnetii has identified StrM and CBU1838 proteins as RmlC orthologues in these respective species. Here, we demonstrate that both enzymes can perform the RmlC 3'',5'' double epimerization activity necessary to support TDP-rhamnose biosynthesis in vivo. This is consistent with the ring contraction step being performed on a double epimerized substrate. We further demonstrate that proton exchange is faster at the 3''-position than the 5''-position, in contrast to a previously studied orthologue. We additionally solved the crystal structures of CBU1838 and StrM in complex with TDP, and show that they form an active site highly similar to those of the previously characterized enzymes RmlC, EvaD, and ChmJ. These results support the hypothesis that streptose and DHHS are biosynthesized using the TDP pathway and that an RmlD paralogue most likely performs ring contraction following double epimerization. This work will support the elucidation of the full pathways for biosynthesis of these unique sugars.Biotechnology and Biological Sciences Research Council (BBSRC)DstlJohn Innes FoundationInnovate U

Linac-LHC EP Collider Options

We describe various parameter scenarios for a ring-linac ep collider based on LHC and an independent electron linac. Luminosities between $10^{31}$ and $10^{33} cm^{-2}s^{-1}$ can be achieved with a s.c. linac, operated either in pulsed or in cw mode, with optional recirculation, at a total electric wallplug power of order 20 MW. Higher luminosities, of several $10^{33} cm^{-2}s^{-1}$ can be reached by investing more electric power or by energy recovery. Finally, merits of a linac-ring ep collider are discussed

Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major

Background The macrophage infectivity potentiator (Mip) protein, which belongs to the immunophilin superfamily, is a peptidyl-prolyl cis/trans isomerase (PPIase) enzyme. Mip has been shown to be important for virulence in a wide range of pathogenic microorganisms. It has previously been demonstrated that small-molecule compounds designed to target Mip from the Gram-negative bacterium Burkholderia pseudomallei bind at the site of enzymatic activity of the protein, inhibiting the in vitro activity of Mip. Objectives In this study, co-crystallography experiments with recombinant B. pseudomallei Mip (BpMip) protein and Mip inhibitors, biochemical analysis and computational modelling were used to predict the efficacy of lead compounds for broad-spectrum activity against other pathogens. Methods Binding activity of three lead compounds targeting BpMip was verified using surface plasmon resonance spectroscopy. The determination of crystal structures of BpMip in complex with these compounds, together with molecular modelling and in vitro assays, was used to determine whether the compounds have broad-spectrum antimicrobial activity against pathogens. Results Of the three lead small-molecule compounds, two were effective in inhibiting the PPIase activity of Mip proteins from Neisseria meningitidis, Klebsiella pneumoniae and Leishmania major. The compounds also reduced the intracellular burden of these pathogens using in vitro cell infection assays. Conclusions These results indicate that Mip is a novel antivirulence target that can be inhibited using small-molecule compounds that prove to be promising broad-spectrum drug candidates in vitro. Further optimization of compounds is required for in vivo evaluation and future clinical applications

The CLIC Positron Sources Based on Compton Schemes

International audienceThe CLIC polarized positron source is based on a positron production scheme in which polarized photons are produced by Compton process. Compton backscattering happens in a so-called "Compton ring" where an electron beam of 1.06 GeV interacts with a powerful laser beam amplified in an optical resonator. The circularly-polarized gamma rays are sent on to a target, producing pairs of longitudinally polarized electrons and positrons. An Adiabatic Matching Device maximizes the capture of the positrons. A normal-conducting 2 GHz Linac accelerates the beam up to 2.424 GeV before injection into the Pre-Damping Ring (PDR). The nominal CLIC bunch population is 4.4x10**9 particles per bunch. Since the photon flux coming out from a "Compton ring" is not sufficient to obtain the requested charge, a stacking process is required in the PDR. Another option is to use a "Compton Energy Recovery Linac" where a quasi-continual stacking in the PDR could be achieved. A third option is to use a "Compton Linac" which would not require stacking. We describe the overall scheme as well as advantages and constraints of the three different options