Toll-like Receptor-8 Agonistic Activities in C2, C4, and C8 Modified Thiazolo[4,5-c]quinolines

Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers

A fast radio burst with a low dispersion measure

Fast radio bursts (FRBs) are millisecond pulses of radio emission of seemingly extragalactic origin. More than 50 FRBs have now been detected, with only one seen to repeat. Here we present a new FRB discovery, FRB 110214, which was detected in the high latitude portion of the High Time Resolution Universe South survey at the Parkes telescope. FRB 110214 has one of the lowest dispersion measures of any known FRB (DM = 168.9$\pm$0.5 pc cm$^{-3}$), and was detected in two beams of the Parkes multi-beam receiver. A triangulation of the burst origin on the sky identified three possible regions in the beam pattern where it may have originated, all in sidelobes of the primary detection beam. Depending on the true location of the burst the intrinsic fluence is estimated to fall in the range of 50 -- 2000 Jy ms, making FRB 110214 one of the highest-fluence FRBs detected with the Parkes telescope. No repeating pulses were seen in almost 100 hours of follow-up observations with the Parkes telescope down to a limiting fluence of 0.3 Jy ms for a 2-ms pulse. Similar low-DM, ultra-bright FRBs may be detected in telescope sidelobes in the future, making careful modeling of multi-beam instrument beam patterns of utmost importance for upcoming FRB surveys.Comment: 8 pages, 3 figures, accepted for publication in MNRA

Fermi LAT observations of the Geminga pulsar

We report on the \textit{Fermi}-LAT observations of the Geminga pulsar, the second brightest non-variable GeV source in the $\gamma$-ray sky and the first example of a radio-quiet $\gamma$-ray pulsar. The observations cover one year, from the launch of the $Fermi$ satellite through 2009 June 15. A data sample of over 60,000 photons enabled us to build a timing solution based solely on $\gamma$ rays. Timing analysis shows two prominent peaks, separated by $\Delta \phi$ = 0.497 $\pm$ 0.004 in phase, which narrow with increasing energy. Pulsed $\gamma$ rays are observed beyond 18 GeV, precluding emission below 2.7 stellar radii because of magnetic absorption. The phase-averaged spectrum was fitted with a power law with exponential cut-off of spectral index $\Gamma$ = (1.30 $\pm$ 0.01 $\pm$ 0.04), cut-off energy $E_{0}$ = (2.46 $\pm$ 0.04 $\pm$ 0.17) GeV and an integral photon flux above 0.1 GeV of (4.14 $\pm$ 0.02 $\pm$ 0.32) $\times$ 10$^{-6}$ cm$^{-2}$ s$^{-1}$. The first uncertainties are statistical and the second are systematic. The phase-resolved spectroscopy shows a clear evolution of the spectral parameters, with the spectral index reaching a minimum value just before the leading peak and the cut-off energy having maxima around the peaks. Phase-resolved spectroscopy reveals that pulsar emission is present at all rotational phases. The spectral shape, broad pulse profile, and maximum photon energy favor the outer magnetospheric emission scenarios.Comment: 32 pages, 12 figures, 3 tables. Accepted for publication in The Astrophysical Journal. Corresponding authors: Denis Dumora ([email protected]), Fabio Gargano ([email protected]), Massimiliano Razzano ([email protected]

Pulsar-wind nebulae and magnetar outflows: observations at radio, X-ray, and gamma-ray wavelengths

We review observations of several classes of neutron-star-powered outflows: pulsar-wind nebulae (PWNe) inside shell supernova remnants (SNRs), PWNe interacting directly with interstellar medium (ISM), and magnetar-powered outflows. We describe radio, X-ray, and gamma-ray observations of PWNe, focusing first on integrated spectral-energy distributions (SEDs) and global spectral properties. High-resolution X-ray imaging of PWNe shows a bewildering array of morphologies, with jets, trails, and other structures. Several of the 23 so far identified magnetars show evidence for continuous or sporadic emission of material, sometimes associated with giant flares, and a few possible "magnetar-wind nebulae" have been recently identified.Comment: 61 pages, 44 figures (reduced in quality for size reasons). Published in Space Science Reviews, "Jets and Winds in Pulsar Wind Nebulae, Gamma-ray Bursts and Blazars: Physics of Extreme Energy Release

Fermi Large Area Telescope Observations of the Crab Pulsar and Nebula

We report on gamma-ray observations of the Crab Pulsar and Nebula using 8 months of survey data with the Fermi Large Area Telescope (LAT). The high quality light curve obtained using the ephemeris provided by the Nancay and Jodrell Bank radio telescopes shows two main peaks stable in phase with energy. The first gamma-ray peak leads the radio main pulse by (281 \pm 12 \pm 21) mus, giving new constraints on the production site of non-thermal emission in pulsar magnetospheres. The improved sensitivity and the unprecedented statistics afforded by the LAT enable precise measurement of the Crab Pulsar spectral parameters: cut-off energy at E_c = (5.8 \pm 0.5 \pm 1.2) GeV, spectral index of Gamma = (1.97 \pm 0.02 \pm 0.06) and integral photon flux above 100 MeV of (2.09 \pm 0.03 \pm 0.18) x 10^{-6} cm^{-2} s^{-1}. The first errors represent the statistical error on the fit parameters, while the second ones are the systematic uncertainties. Pulsed gamma-ray photons are observed up to ~ 20 GeV which precludes emission near the stellar surface, below altitudes of around 4 to 5 stellar radii in phase intervals encompassing the two main peaks. The spectrum of the nebula in the energy range 100 MeV - 300 GeV is well described by the sum of two power-laws of indices Gamma_{sync} = (3.99 \pm 0.12 \pm 0.08) and Gamma_{IC} = (1.64 \pm 0.05 \pm 0.07), corresponding to the falling edge of the synchrotron and the rising edge of the inverse Compton components, respectively. This latter, which links up naturally with the spectral data points of Cherenkov experiments, is well reproduced via inverse Compton scattering from standard Magnetohydrodynamics (MHD) nebula models, and does not require any additional radiation mechanism.Comment: 17 pages, 9 figures, Accepted for publications in Astrophysical Journa

Fermi-LAT Search for Pulsar Wind Nebulae around gamma-ray Pulsars

The high sensitivity of the Fermi-LAT (Large Area Telescope) offers the first opportunity to study faint and extended GeV sources such as pulsar wind nebulae (PWNe). After one year of observation the LAT detected and identified three pulsar wind nebulae: the Crab Nebula, Vela-X and the PWN inside MSH 15-52. In the meantime, the list of LAT detected pulsars increased steadily. These pulsars are characterized by high energy loss rates from ~3 \times 10^{33} erg s$^{-1}$ to 5 \times 10$^{38}$ erg s$^{-1}$ and are therefore likely to power a PWN. This paper summarizes the search for PWNe in the off-pulse windows of 54 LAT-detected pulsars using 16 months of survey observations. Ten sources show significant emission, seven of these likely being of magnetospheric origin. The detection of significant emission in the off-pulse interval offers new constraints on the gamma-ray emitting regions in pulsar magnetospheres. The three other sources with significant emission are the Crab Nebula, Vela-X and a new pulsar wind nebula candidate associated with the LAT pulsar PSR J1023-5746, coincident with the TeV source HESS J1023-575. We further explore the association between the H.E.S.S. and the Fermi source by modeling its spectral energy distribution. Flux upper limits derived for the 44 remaining sources are used to provide new constraints on famous PWNe that have been detected at keV and/or TeV energies.Comment: Accepted for publication in Astrophysical Journal, 42 pages, 17 figure

A poisson regression approach for modelling spatial autocorrelation between geographically referenced observations

Abstract Background Analytic methods commonly used in epidemiology do not account for spatial correlation between observations. In regression analyses, omission of that autocorrelation can bias parameter estimates and yield incorrect standard error estimates. Methods We used age standardised incidence ratios (SIRs) of esophageal cancer (EC) from the Babol cancer registry from 2001 to 2005, and extracted socioeconomic indices from the Statistical Centre of Iran. The following models for SIR were used: (1) Poisson regression with agglomeration-specific nonspatial random effects; (2) Poisson regression with agglomeration-specific spatial random effects. Distance-based and neighbourhood-based autocorrelation structures were used for defining the spatial random effects and a pseudolikelihood approach was applied to estimate model parameters. The Bayesian information criterion (BIC), Akaike's information criterion (AIC) and adjusted pseudo R2, were used for model comparison. Results A Gaussian semivariogram with an effective range of 225 km best fit spatial autocorrelation in agglomeration-level EC incidence. The Moran's I index was greater than its expected value indicating systematic geographical clustering of EC. The distance-based and neighbourhood-based Poisson regression estimates were generally similar. When residual spatial dependence was modelled, point and interval estimates of covariate effects were different to those obtained from the nonspatial Poisson model. Conclusions The spatial pattern evident in the EC SIR and the observation that point estimates and standard errors differed depending on the modelling approach indicate the importance of accounting for residual spatial correlation in analyses of EC incidence in the Caspian region of Iran. Our results also illustrate that spatial smoothing must be applied with care.</p