A Search for Diffuse X-ray Emission from GeV Detected Galactic Globular Clusters

Recently, diffuse and extended sources in TeV gamma-rays as well as in X-rays have been detected in the direction of the Galactic globular cluster (GC) Terzan 5. Remarkably, this is among the brightest GCs detected in the GeV regime. The nature of both the TeV and the diffuse X-ray signal from Terzan 5 is not settled yet. These emissions most likely indicate the presence of several non-thermal radiation processes in addition to these giving rise to the GeV signal. The aim of this work is to search for diffuse X-ray emission from the GeV detected GCs M 62, NGC 6388, NGC 6541, M 28, M 80 and NGC 6139 to compare the obtained results with the signal detected from Terzan 5. This study will help to determine whether Terzan 5 stands out amongst other GC or whether a whole population of globular clusters feature similar properties. None of the six GCs show significant diffuse X-ray emission on similar scales as observed from Terzan 5 above the particle and diffuse galactic X-ray background components. The derived upper limits allow to assess the validity of different models that were discussed in the interpretation of the multi-wavelength data of Terzan 5. A scenario based on synchrotron emission from relativistic leptons provided by the millisecond pulsar population can not be securely rejected if a comparable magnetic field strength as in Terzan 5 is assumed for every GC. However, such a scenario seems to be unlikely for NGC 6388 and M 62. An inverse-Compton scenario relying on the presence of a putative GRB remnant with the same properties as the one proposed for Terzan 5 can be ruled out for all of the six GCs. Finally, the assumption that each GC hosts a source with the same luminosity as in Terzan 5 is ruled out for all GCs but NGC 6139. (abridged)Comment: 8 pages, 1 Figure, accepted for publication by Astronomy & Astrophysics, final version after language editin

Very-high energy gamma-ray astronomy: A 23-year success story in high-energy astroparticle physics

Very-high energy (VHE) gamma quanta contribute only a minuscule fraction - below one per million - to the flux of cosmic rays. Nevertheless, being neutral particles they are currently the best "messengers" of processes from the relativistic/ultra-relativistic Universe because they can be extrapolated back to their origin. The window of VHE gamma rays was opened only in 1989 by the Whipple collaboration, reporting the observation of TeV gamma rays from the Crab nebula. After a slow start, this new field of research is now rapidly expanding with the discovery of more than 150 VHE gamma-ray emitting sources. Progress is intimately related with the steady improvement of detectors and rapidly increasing computing power. We give an overview of the early attempts before and around 1989 and the progress after the pioneering work of the Whipple collaboration. The main focus of this article is on the development of experimental techniques for Earth-bound gamma-ray detectors; consequently, more emphasis is given to those experiments that made an initial breakthrough rather than to the successors which often had and have a similar (sometimes even higher) scientific output as the pioneering experiments. The considered energy threshold is about 30 GeV. At lower energies, observations can presently only be performed with balloon or satellite-borne detectors. Irrespective of the stormy experimental progress, the success story could not have been called a success story without a broad scientific output. Therefore we conclude this article with a summary of the scientific rationales and main results achieved over the last two decades.Comment: 45 pages, 38 figures, review prepared for EPJ-H special issue "Cosmic rays, gamma rays and neutrinos: A survey of 100 years of research

VLT Suzaku observations of the Fermi pulsar PSR J1028-5819

We used optical images taken with the Very Large Telescope (VLT) in the B and V bands to search for the optical counterpart of PSR J1028-5819 or constrain its optical brightness. At the same time, we used an archival Suzaku observation to confirm the preliminary identification of the pulsar's X-ray counterpart obtained by Swift. Due to the large uncertainty on the pulsar's radio position and the presence of a bright (V = 13.2) early F-type star at < 4", we could not detect its counterpart down to flux limits of B~25.4 and V ~25.3, the deepest obtained so far for PSR J1028-5819. From the Suzaku observations, we found that the X-ray spectrum of the pulsar's candidate counterpart is best-fit by a power-law with spectral index 1.7 +/- 0.2 and an absorption column density NH < 10^21 cm-2, which would support the proposed X-ray identification. Moreover, we found possible evidence for the presence of diffuse emission around the pulsar. If real, and associated with a pulsar wind nebula (PWN), its surface brightness and angular extent would be compatible with the expectations for a ~100 kyr old pulsar at the PSR J1028-5819 distance.Comment: 10 pages, 9 figures, submitted to Astronomy and Astrophysic

Engineering gamma delta T cells limits tonic signaling associated with chimeric antigen receptors

Despite the benefits of chimeric antigen receptor (CAR)–T cell therapies against lymphoid malignancies, responses in solid tumors have been more limited and off-target toxicities have been more marked. Among the possible design limitations of CAR-T cells for cancer are unwanted tonic (antigen-independent) signaling and off-target activation. Efforts to overcome these hurdles have been blunted by a lack of mechanistic understanding. Here, we showed that single-cell analysis with time course mass cytometry provided a rapid means of assessing CAR-T cell activation. We compared signal transduction in expanded T cells to that in T cells transduced to express second-generation CARs and found that cell expansion enhanced the response to stimulation. However, expansion also induced tonic signaling and reduced network plasticity, which were associated with expression of the T cell exhaustion markers PD-1 and TIM-3. Because this was most evident in pathways downstream of CD3ζ, we performed similar analyses on γδT cells that expressed chimeric costimulatory receptors (CCRs) lacking CD3ζ but containing DAP10 stimulatory domains. These CCR-γδT cells did not exhibit tonic signaling but were efficiently activated and mounted cytotoxic responses in the presence of CCR-specific stimuli or cognate leukemic cells. Single-cell signaling analysis enabled detailed characterization of CAR-T and CCR-T cell activation to better understand their functional activities. Furthermore, we demonstrated that CCR-γδT cells may offer the potential to avoid on-target, off-tumor toxicity and allo-reactivity in the context of myeloid malignancies

Sommerfeld Enhancement from Multiple Mediators

We study the Sommerfeld enhancement experienced by a scattering object that couples to a tower of mediators. This can occur in, e.g., models of secluded dark matter when the mediator scale is generated naturally by hidden-sector confinement. Specializing to the case of a confining CFT, we show that off-resonant values of the enhancement can be increased by ~ 20% for cases of interest when (i) the (strongly-coupled) CFT admits a weakly-coupled dual description and (ii) the conformal symmetry holds up to the Planck scale. Larger enhancements are possible for lower UV scales due to an increase in the coupling strength of the tower.Comment: 17p, 2 figures; v2 JHEP version (inconsequential typo fixed, references added

Galactic Structure Toward the Carina Tangent

This investigation presents a photometric study of the Galactic structure toward the Carina arm tangent. The field is located between 280 deg and 286 deg galactic longitude and -4 deg to 4 deg galactic latitude. All currently available uvbybeta data is used to obtain homogeneous color excesses and distances for more than 260 stars of spectral types O to G. We present revised distances and average extinction for the open clusters and cluster candidates NGC 3293, NGC 3114, Loden 46 and Loden 112. The cluster candidate Loden 112 appears to be a very compact group at a true distance modulus of 11.06 +\- 0.11 (s.e.) (1629 +84,-80 pc), significantly closer than previous estimates. We found other OB stars at that same distance and, based on their proper motions, suggest a new OB association at coordinates 282 deg < l < 285 deg, -2 deg < b < 2 deg. Utilizing BV photometry and spectral classification of the known O-type stars in the very young open cluster Wd 2 we provide a new distance estimate of 14.13 +\-0.16 (s.e.) (6698 +512,-475 pc), in excellent agreement with recent distance determinations to the giant molecular structures in this direction. We also discuss a possible connection between the HII region RCW 45 and the highly-reddened B+ star CPD -55 3036 and provide a revised distance for the luminous blue variable HR Car.Comment: accepted to PAS

Dark Matter and Fundamental Physics with the Cherenkov Telescope Array

The Cherenkov Telescope Array (CTA) is a project for a next-generation observatory for very high energy (GeV-TeV) ground-based gamma-ray astronomy, currently in its design phase, and foreseen to be operative a few years from now. Several tens of telescopes of 2-3 different sizes, distributed over a large area, will allow for a sensitivity about a factor 10 better than current instruments such as H.E.S.S, MAGIC and VERITAS, an energy coverage from a few tens of GeV to several tens of TeV, and a field of view of up to 10 deg. In the following study, we investigate the prospects for CTA to study several science questions that influence our current knowledge of fundamental physics. Based on conservative assumptions for the performance of the different CTA telescope configurations, we employ a Monte Carlo based approach to evaluate the prospects for detection. First, we discuss CTA prospects for cold dark matter searches, following different observational strategies: in dwarf satellite galaxies of the Milky Way, in the region close to the Galactic Centre, and in clusters of galaxies. The possible search for spatial signatures, facilitated by the larger field of view of CTA, is also discussed. Next we consider searches for axion-like particles which, besides being possible candidates for dark matter may also explain the unexpectedly low absorption by extragalactic background light of gamma rays from very distant blazars. Simulated light-curves of flaring sources are also used to determine the sensitivity to violations of Lorentz Invariance by detection of the possible delay between the arrival times of photons at different energies. Finally, we mention searches for other exotic physics with CTA.Comment: (31 pages, Accepted for publication in Astroparticle Physics

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

Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

: Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the HBG transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the -200 region of the HBG promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy - even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of HBG promoters is a safe, universal strategy for treating β-hemoglobinopathies

Avoidance of On-Target Off-Tumor Activation Using a Co-stimulation-Only Chimeric Antigen Receptor

Chimeric antigen receptors (CARs) combine T cell activation with antibody-mediated tumor antigen specificity, bypassing the need for T cell receptor (TCR) ligation. A limitation of CAR technology is on-target off-tumor toxicity caused by target antigen expression on normal cells. Using GD2 as a model cancer antigen, we hypothesized that this could be minimized by using T cells expressing Vγ9Vδ2 TCR, which recognizes transformed cells in a major histocompatibility complex (MHC)-unrestricted manner, in combination with a co-stimulatory CAR that would function independently of the TCR. An anti-GD2 CAR containing a solitary endodomain derived from the NKG2D adaptor DAP10 was expressed in Vγ9Vδ2(+) T cells. Differential ligation of the CAR and/or TCR using antibody-coated beads showed that pro-inflammatory cytokine response depended on activation of both receptors. Moreover, in killing assays, GD2-expressing neuroblastoma cells that engaged the Vγ9Vδ2 TCR were efficiently lysed, whereas cells that expressed GD2 equivalently but did not engage the Vγ9Vδ2 TCR were untouched. Differentiation between X-on tumor and X-off tumor offers potential for safer immunotherapy and broader target selection