X-ray Flares from Markarian 501

Motivated by the recent finding of hierarchical X-ray flaring phenomenon in Mrk 421, we conducted a systematic search for X-ray flares from Mrk 501, another well-known TeV blazar, by making use of the rich {\em RXTE} archival database. We detected flares over a wide range of timescales, from months down to minutes, as in the case of Mrk 421. However, the flares do not seem to occur nearly as frequently in Mrk 501 as in Mrk 421 on any of the timescales. The flaring hierarchy also seems apparent in Mrk 501, suggesting that it might be common among TeV blazars. The results seem to imply a scale-invariant physical origin of the flares (large or small). The X-ray spectrum of the source shows a general trend of hardening toward the peak of long-duration flares, with indication of spectral hysteresis, which is often seen in TeV blazars. However, the data are not of sufficient quality to allow us to draw definitive conclusions about spectral variability associated with more rapid but weaker flares. We critically examine a reported sub-hour X-ray flare from Mrk 501, in light of intense background flaring activity at the time of the observation, and concluded that the flare is likely an artifact. On the other hand, we did identify a rapid X-ray flare that appears to be real. It lasted only for about 15 minutes, during which the flux of the source varied by about 30%. Sub-structures are apparent in its profile, implying variabilities on even shorter timescales. Such rapid variabilities of Mrk 501 place severe constraints on the physical properties of the flaring region in the jet, which have serious implications on the emission models proposed for TeV blazars.Comment: 23 pages, 11 figures, accepted for publication in Ap

The interferon-stimulated gene IFITM3 restricts West Nile virus infection and pathogenesis

The interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance of Ifitm3 in vivo in restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice. Ifitm3(−/−) mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this, Ifitm3(−/−) fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infected Ifitm3(−/−) mice showed decreases in the total number of B cells, CD4(+) T cells, and antigen-specific CD8(+) T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells. IMPORTANCE As part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact of IFITM genes on viral pathogenesis in vivo. In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion of Ifitm3. Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types

Upper Limits on the Extragalactic Background Light from the Gamma-Ray Spectra of Blazars

The direct measurement of the extragalactic background light (EBL) is difficult at optical to infrared wavelengths because of the strong foreground radiation originating in the Solar System. Very high energy (VHE, E$>$100 GeV) gamma rays interact with EBL photons of these wavelengths through pair production. In this work, the available VHE spectra from six blazars are used to place upper limits on the EBL. These blazars have been detected over a range of redshifts and a steepening of the spectral index is observed with increasing source distance. This can be interpreted as absorption by the EBL. In general, knowledge of the intrinsic source spectrum is necessary to determine the density of the intervening EBL. Motivated by the observed spectral steepening with redshift, upper limits on the EBL are derived by assuming that the intrinsic spectra of the six blazars are $\propto E^{-1.8}$. Upper limits are then placed on the EBL flux at discrete energies without assuming a specific spectral shape for the EBL. This is an advantage over other methods since the EBL spectrum is uncertain.Comment: 33 pages, 14 figures, accepted by Ap

Krabbe disease successfully treated via monotherapy of intrathecal gene therapy

Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically