Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects

3-Oxo-5-alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6-endo-dig cyclization reactions to furnish either 2-pyrones or 4-pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the π-acid. This transformation is compatible with a variety of acid-sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4-pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co-solvent, which is thought to favor the protodeauration of the reactive alkenyl-gold intermediates as the likely rate-determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off-cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem-diaurated complexes 12 and 15. Furthermore, silver catalysis allowed access to be gained to 2-alkoxypyridine and 2-alkoxyisoquinoline derivatives starting from readily available imidate precursors

An intermittent extreme BL Lac: MWL study of 1ES 2344+514 in an enhanced state

Extreme high-frequency BL Lacs (EHBL) feature their synchrotron peak of the broad-band spectral energy distribution (SED) at vs ≥ 1017 Hz. The BL Lac object 1ES 2344+514 was included in the EHBL family because of its impressive shift of the synchrotron peak in 1996. During the following years, the source appeared to be in a low state without showing any extreme behaviours. In 2016 August, 1ES 2344+514 was detected with the groundbased γ -ray telescope FACT during a high γ -ray state, triggering multiwavelength (MWL) observations. We studied the MWL light curves of 1ES 2344+514 during the 2016 flaring state, using data from radio to very-high-energy (VHE) γ -rays taken with OVRO, KAIT, KVA, NOT, some telescopes of the GASP-WEBT collaboration at the Teide, Crimean, and St. Petersburg observatories, Swift-UVOT, Swift-XRT, Fermi-LAT, FACT, and MAGIC. With simultaneous observations of the flare, we built the broad-band SED and studied it in the framework of a leptonic and a hadronic model. The VHE γ -ray observations show a flux level of 55 per cent of the Crab Nebula flux above 300 GeV, similar to the historical maximum of 1995. The combination of MAGIC and Fermi-LAT spectra provides an unprecedented characterization of the inverse-Compton peak for this object during a flaring episode. The _ index of the intrinsic spectrum in the VHE γ -ray band is 2.04 ± 0.12stat ± 0.15sys.We find the source in an extreme state with a shift of the position of the synchrotron peak to frequencies above or equal to 1018 Hz.The financial support of the German BMBF and MPG, the Italian INFN and INAF, the Swiss National Fund SNF, the ERDF under the Spanish MINECO (FPA2017-87859-P, FPA2017-85668-P, FPA2017-82729-C6-2-R, FPA2017-82729-C6-6-R, FPA2017-82729-C6-5-R, AYA2015-71042-P, AYA2016-76012-C3-1-P, ESP2017-87055-C2-2-P, and FPA2017-90566-REDC), the Indian Department of Atomic Energy, the Japanese JSPS and MEXT, the Bulgarian Ministry of Education and Science, National RI Roadmap Project DO1-153/28.08.2018, and the Academy of Finland grant no. 320045 is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia ‘Severo Ochoa’ SEV-2016-0588 and SEV-2015-0548, and Unidad de Excelencia ‘María de Maeztu’ MDM-2014-0369, by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02, by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3, the Polish National Research Centre grant UMO-2016/22/M/ST9/00382 and by the Brazilian MCTIC, CNPq, and FAPERJ. The FACT collaboration acknowledges the important contributions from ETH Zurich grants ETH-10.08-2 and ETH-27.12-1 as well as the funding by the Swiss SNF and the German BMBF (Verbundforschung Astro- und Astroteilchenphysik) and HAP (Helmoltz Alliance for Astroparticle Physics) are gratefully acknowledged. Part of this work is supported by Deutsche Forschungsgemeinschaft (DFG) within the Collaborative Research Center SFB 876 ‘Providing Information by Resource-Constrained Analysis’, project C3

Detection of variable VHE gamma-ray emission from the extra-galactic gamma-ray binary LMC P3

Context. Recently, the high-energy (HE, 0.1-100 GeV) $\gamma$-ray emission from the object LMC P3 in the Large Magellanic Cloud (LMC) has been discovered to be modulated with a 10.3-day period, making it the first extra-galactic $\gamma$-ray binary. Aims. This work aims at the detection of very-high-energy (VHE, >100 GeV) $\gamma$-ray emission and the search for modulation of the VHE signal with the orbital period of the binary system. Methods. LMC P3 has been observed with the High Energy Stereoscopic System (H.E.S.S.); the acceptance-corrected exposure time is 100 h. The data set has been folded with the known orbital period of the system in order to test for variability of the emission. Energy spectra are obtained for the orbit-averaged data set, and for the orbital phase bin around the VHE maximum. Results. VHE $\gamma$-ray emission is detected with a statistical significance of 6.4 $\sigma$. The data clearly show variability which is phase-locked to the orbital period of the system. Periodicity cannot be deduced from the H.E.S.S. data set alone. The orbit-averaged luminosity in the $1-10$ TeV energy range is $(1.4 \pm 0.2) \times 10^{35}$ erg/s. A luminosity of $(5 \pm 1) \times 10^{35}$ erg/s is reached during 20% of the orbit. HE and VHE $\gamma$-ray emissions are anti-correlated. LMC P3 is the most luminous $\gamma$-ray binary known so far.Comment: 5 pages, 3 figures, 1 table, accepted for publication in A&

Characterizing the gamma-ray long-term variability of PKS 2155-304 with H.E.S.S. and Fermi-LAT

Studying the temporal variability of BL Lac objects at the highest energies provides unique insights into the extreme physical processes occurring in relativistic jets and in the vicinity of super-massive black holes. To this end, the long-term variability of the BL Lac object PKS 2155-304 is analyzed in the high (HE, 100 MeV 200 GeV) gamma-ray domain. Over the course of ~9 yr of H.E.S.S observations the VHE light curve in the quiescent state is consistent with a log-normal behavior. The VHE variability in this state is well described by flicker noise (power-spectral-density index {\ss}_VHE = 1.10 +0.10 -0.13) on time scales larger than one day. An analysis of 5.5 yr of HE Fermi LAT data gives consistent results ({\ss}_HE = 1.20 +0.21 -0.23, on time scales larger than 10 days) compatible with the VHE findings. The HE and VHE power spectral densities show a scale invariance across the probed time ranges. A direct linear correlation between the VHE and HE fluxes could neither be excluded nor firmly established. These long-term-variability properties are discussed and compared to the red noise behavior ({\ss} ~ 2) seen on shorter time scales during VHE-flaring states. The difference in power spectral noise behavior at VHE energies during quiescent and flaring states provides evidence that these states are influenced by different physical processes, while the compatibility of the HE and VHE long-term results is suggestive of a common physical link as it might be introduced by an underlying jet-disk connection.Comment: 11 pages, 16 figure

A revised evolutionary history of the CYP1A subfamily : gene duplication, gene conversion, and positive selection

Author Posting. © The Authors, 2005. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Molecular Evolution 62 (2006): 708-717, doi:10.1007/s00239-005-0134-z.Members of cytochrome P450 subfamily 1A (CYP1As) are involved in detoxification and bioactivation of common environmental pollutants. Understanding the functional evolution of these genes is essential to predicting and interpreting species differences in sensitivity to toxicity by such chemicals. The CYP1A gene subfamily comprises a single ancestral representative in most fish species and two paralogs in higher vertebrates, including birds and mammals. Phylogenetic analysis of complete coding sequences suggests that mammalian and bird paralog pairs (CYP1A1/2 and CYP1A4/5, respectively) are the result of independent gene duplication events. However, comparison of vertebrate genome sequences revealed that CYP1A genes lie within an extended region of conserved fine-scale synteny, suggesting that avian and mammalian CYP1A paralogs share a common genomic history. Algorithms designed to detect recombination between nucleotide sequences indicate that gene conversion has homogenized most of the length of the chicken CYP1A genes, as well as the 5’ end of mammalian CYP1As. Together, these data indicate that avian and mammalian CYP1A paralog pairs resulted from a single gene duplication event and that extensive gene conversion is responsible for the exceptionally high degree of sequence similarity between CYP1A4 and CYP1A5. Elevated non-synonymous/synonymous substitution ratios within a putatively unconverted stretch of ~250 bp suggests that positive selection may have reduced the effective rate of gene conversion in this region, which contains two substrate recognition sites. This work significantly alters our understanding of functional evolution in the CYP1A subfamily, suggesting that gene conversion and positive selection have been the dominant processes of sequence evolution.Funding for this work was provided by the NIH Superfund Basic Research Program at Boston University (5-P42-ES-07381) and by the Woods Hole Oceanographic Institution

Down selecting adjuvanted vaccine formulations: a comparative method for harmonized evaluation.

The need for rapid and accurate comparison of panels of adjuvanted vaccine formulations and subsequent rational down selection, presents several challenges for modern vaccine development. Here we describe a method which may enable vaccine and adjuvant developers to compare antigen/adjuvant combinations in a harmonized fashion. Three reference antigens: Plasmodium falciparum apical membrane antigen 1 (AMA1), hepatitis B virus surface antigen (HBsAg), and Mycobacterium tuberculosis antigen 85A (Ag85A), were selected as model antigens and were each formulated with three adjuvants: aluminium oxyhydroxide, squalene-in-water emulsion, and a liposome formulation mixed with the purified saponin fraction QS21. The nine antigen/adjuvant formulations were assessed for stability and immunogenicity in mice in order to provide benchmarks against which other formulations could be compared, in order to assist subsequent down selection of adjuvanted vaccines. Furthermore, mouse cellular immune responses were analyzed by measuring IFN-γ and IL-5 production in splenocytes by ELISPOT, and humoral responses were determined by antigen-specific ELISA, where levels of total IgG, IgG1, IgG2b and IgG2c in serum samples were determined. The reference antigens and adjuvants described in this study, which span a spectrum of immune responses, are of potential use as tools to act as points of reference in vaccine development studies. The harmonized methodology described herein may be used as a tool for adjuvant/antigen comparison studies

New Hard-TeV Extreme Blazars Detected with the MAGIC Telescopes

Extreme high-frequency-peaked BL Lac objects (EHBLs) are blazars that exhibit extremely energetic synchrotron emission. They also feature nonthermal gamma-ray emission whose peak lies in the very high-energy (VHE, E > 100 GeV) range, and in some sources exceeds 1 TeV: this is the case for hard-TeV EHBLs such as 1ES 0229+200. With the aim of increasing the EHBL population, 10 targets were observed with the MAGIC telescopes from 2010 to 2017, for a total of 265 hr of good-quality data. The data were complemented by coordinated Swift observations. The X-ray data analysis confirms that all but two sources are EHBLs. The sources show only a modest variability and a harder-when-brighter behavior, typical for this class of objects. At VHE gamma-rays, three new sources were detected and a hint of a signal was found for another new source. In each case, the intrinsic spectrum is compatible with the hypothesis of a hard-TeV nature of these EHBLs. The broadband spectral energy distributions (SEDs) of all sources are built and modeled in the framework of a single-zone, purely leptonic model. The VHE gamma-ray-detected sources were also interpreted with a spine-layer model and a proton synchrotron model. The three models provide a good description of the SEDs. However, the resulting parameters differ substantially in the three scenarios, in particular the magnetization parameter. This work presents the first mini catalog of VHE gamma-ray and multiwavelength observations of EHBLs

Monitoring of the radio galaxy M87 during a low emission state from 2012 to 2015 with MAGIC

M87 is one of the closest (z=0.00436) extragalactic sources emitting at very-high-energies (VHE, E > 100 GeV). The aim of this work is to locate the region of the VHE gamma-ray emission and to describe the observed broadband spectral energy distribution (SED) during the low VHE gamma-ray state. The data from M87 collected between 2012 and 2015 as part of a MAGIC monitoring programme are analysed and combined with multi-wavelength data from Fermi-LAT, Chandra, HST, EVN, VLBA and the Liverpool Telescope. The averaged VHE gamma-ray spectrum can be fitted from 100GeV to 10TeV with a simple power law with a photon index of (-2.41 $\pm$ 0.07), while the integral flux above 300GeV is $(1.44 \pm 0.13) \times 10^{-12} cm^{-2} s^{-1}$. During the campaign between 2012 and 2015, M87 is generally found in a low emission state at all observed wavelengths. The VHE gamma-ray flux from the present 2012-2015 M87 campaign is consistent with a constant flux with some hint of variability ($\sim3\sigma$) on a daily timescale in 2013. The low-state gamma-ray emission likely originates from the same region as the flare-state emission. Given the broadband SED, both a leptonic synchrotron self Compton and a hybrid photo-hadronic model reproduce the available data well, even if the latter is preferred. We note, however, that the energy stored in the magnetic field in the leptonic scenario is very low suggesting a matter dominated emission region

Study of the GeV to TeV morphology of the γ Cygni SNR (G 78.2+2.1) with MAGIC and Fermi-LAT: Evidence for cosmic ray escape

Context. Diffusive shock acceleration (DSA) is the most promising mechanism that accelerates Galactic cosmic rays (CRs) in the shocks of supernova remnants (SNRs). It is based on particles scattering caused by turbulence ahead and behind the shock. The turbulence upstream is supposedly generated by the CRs, but this process is not well understood. The dominant mechanism may depend on the evolutionary state of the shock and can be studied via the CRs escaping upstream into the interstellar medium (ISM). Aims. Previous observations of the γ Cygni SNR showed a difference in morphology between GeV and TeV energies. Since this SNR has the right age and is at the evolutionary stage for a significant fraction of CRs to escape, our aim is to understand γ-ray emission in the vicinity of the γ Cygni SNR. Methods. We observed the region of the γ Cygni SNR with the MAGIC Imaging Atmospheric Cherenkov telescopes between 2015 May and 2017 September recording 87 h of good-quality data. Additionally, we analysed Fermi-LAT data to study the energy dependence of the morphology as well as the energy spectrum in the GeV to TeV range. The energy spectra and morphology were compared against theoretical predictions, which include a detailed derivation of the CR escape process and their γ-ray generation. Results. The MAGIC and Fermi-LAT data allowed us to identify three emission regions that can be associated with the SNR and that dominate at different energies. Our hadronic emission model accounts well for the morphology and energy spectrum of all source components. It constrains the time-dependence of the maximum energy of the CRs at the shock, the time-dependence of the level of turbulence, and the diffusion coefficient immediately outside the SNR shock. While in agreement with the standard picture of DSA, the time-dependence of the maximum energy was found to be steeper than predicted, and the level of turbulence was found to change over the lifetime of the SNR. © 2023 EDP Sciences. All rights reserved