126 research outputs found
Recognition of vitamin B metabolites by mucosal-associated invariant T cells
The mucosal-associated invariant T-cell antigen receptor (MAIT TCR) recognizes MR1 presenting vitamin B metabolites. Here we describe the structures of a human MAIT TCR in complex with human MR1 presenting a non-stimulatory ligand derived from folic acid and an agonist ligand derived from a riboflavin metabolite. For both vitamin B antigens, the MAIT TCR docks in a conserved manner above MR1, thus acting as an innate-like pattern recognition receptor. The invariant MAIT TCR a-chain usage is attributable to MR1-mediated interactions that prise open the MR1 cleft to allow contact with the vitamin B metabolite. Although the non-stimulatory antigen does not contact the MAIT TCR, the stimulatory antigen does. This results in a higher affinity of the MAIT TCR for a stimulatory antigen in comparison with a non-stimulatory antigen. We formally demonstrate a structural basis for MAIT TCR recognition of vitamin B metabolites, while illuminating how TCRs recognize microbial metabolic signatures
Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation
Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM
Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma
BACKGROUND: Mucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer. METHODOLOGY/PRINCIPLE FINDINGS: We analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455), colon (192) and rectal (271) cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31-5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44) and long (47, 50 and 54), according to their TR (tandem repeats) lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93-16.42; p = 0.00036). Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement. CONCLUSIONS/SIGNIFICANCE: Our observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells
Constraints on the intergalactic magnetic field using Fermi-LAT and H.E.S.S. blazar observations
Magnetic fields in galaxies and galaxy clusters are believed to be the result
of the amplification of intergalactic seed fields during the formation of
large-scale structures in the universe. However, the origin, strength, and
morphology of this intergalactic magnetic field (IGMF) remain unknown. Lower
limits on (or indirect detection of) the IGMF can be obtained from observations
of high-energy gamma rays from distant blazars. Gamma rays interact with the
extragalactic background light to produce electron-positron pairs, which can
subsequently initiate electromagnetic cascades. The -ray signature of
the cascade depends on the IGMF since it deflects the pairs. Here we report on
a new search for this cascade emission using a combined data set from the Fermi
Large Area Telescope and the High Energy Stereoscopic System. Using
state-of-the-art Monte Carlo predictions for the cascade signal, our results
place a lower limit on the IGMF of G for a coherence
length of 1 Mpc even when blazar duty cycles as short as 10 yr are assumed.
This improves on previous lower limits by a factor of 2. For longer duty cycles
of () yr, IGMF strengths below G
( G) are excluded, which rules out specific models for IGMF
generation in the early universe.Comment: 20 pages, 7 figures, 4 tables. Accepted for publication in ApJ
Letters. Auxiliary data is provided in electronic format at
https://zenodo.org/record/801431
HESS J1809193: a halo of escaped electrons around a pulsar wind nebula?
Context. HESS J1809193 is an unassociated very-high-energy -ray
source located on the Galactic plane. While it has been connected to the nebula
of the energetic pulsar PSR J18091917, supernova remnants and molecular
clouds present in the vicinity also constitute possible associations. Recently,
the detection of -ray emission up to energies of 100 TeV with the
HAWC observatory has led to renewed interest in HESS J1809193.
Aims. We aim to understand the origin of the -ray emission of HESS
J1809193.
Methods. We analysed 93.2 h of data taken on HESS J1809193 above 0.27 TeV
with the High Energy Stereoscopic System (H.E.S.S.), using a multi-component,
three-dimensional likelihood analysis. In addition, we provide a new analysis
of 12.5 yr of Fermi-LAT data above 1 GeV within the region of HESS J1809193.
The obtained results are interpreted in a time-dependent modelling framework.
Results. For the first time, we were able to resolve the emission detected
with H.E.S.S. into two components: an extended component that exhibits a
spectral cut-off at 13 TeV, and a compact component that is located close
to PSR J18091917 and shows no clear spectral cut-off. The Fermi-LAT analysis
also revealed extended -ray emission, on scales similar to that of the
extended H.E.S.S. component.
Conclusions. Our modelling indicates that based on its spectrum and spatial
extent, the extended H.E.S.S. component is likely caused by inverse Compton
emission from old electrons that form a halo around the pulsar wind nebula. The
compact component could be connected to either the pulsar wind nebula or the
supernova remnant and molecular clouds. Due to its comparatively steep
spectrum, modelling the Fermi-LAT emission together with the H.E.S.S.
components is not straightforward. (abridged)Comment: 14 pages, 10 figures. Accepted for publication in A&A. Corresponding
authors: Vikas Joshi, Lars Mohrman
Detection of extended gamma-ray emission around the Geminga pulsar with H.E.S.S
Geminga is an enigmatic radio-quiet gamma-ray pulsar located at a mere 250 pc
distance from Earth. Extended very-high-energy gamma-ray emission around the
pulsar was discovered by Milagro and later confirmed by HAWC, which are both
water Cherenkov detector-based experiments. However, evidence for the Geminga
pulsar wind nebula in gamma rays has long evaded detection by imaging
atmospheric Cherenkov telescopes (IACTs) despite targeted observations. The
detection of gamma-ray emission on angular scales > 2 deg poses a considerable
challenge for the background estimation in IACT data analysis. With recent
developments in understanding the complementary background estimation
techniques of water Cherenkov and atmospheric Cherenkov instruments, the
H.E.S.S. IACT array can now confirm the detection of highly extended gamma-ray
emission around the Geminga pulsar with a radius of at least 3 deg in the
energy range 0.5-40 TeV. We find no indications for statistically significant
asymmetries or energy-dependent morphology. A flux normalisation of
cmsTeV at 1 TeV is obtained
within a 1 deg radius region around the pulsar. To investigate the particle
transport within the halo of energetic leptons around the pulsar, we fitted an
electron diffusion model to the data. The normalisation of the diffusion
coefficient obtained of
cms, at an electron energy of 100 TeV, is compatible with values
previously reported for the pulsar halo around Geminga, which is considerably
below the Galactic average.Comment: 16 pages, 15 figures, 7 tables. Accepted for publication in Astronomy
& Astrophysic
A deep spectromorphological study of the -ray emission surrounding the young massive stellar cluster Westerlund 1
Young massive stellar clusters are extreme environments and potentially
provide the means for efficient particle acceleration. Indeed, they are
increasingly considered as being responsible for a significant fraction of
cosmic rays (CRs) accelerated within the Milky Way. Westerlund 1, the most
massive known young stellar cluster in our Galaxy is a prime candidate for
studying this hypothesis. While the very-high-energy -ray source HESS
J1646-458 has been detected in the vicinity of Westerlund 1 in the past, its
association could not be firmly identified. We aim to identify the physical
processes responsible for the -ray emission around Westerlund 1 and
thus to better understand the role of massive stellar clusters in the
acceleration of Galactic CRs. Using 164 hours of data recorded with the High
Energy Stereoscopic System (H.E.S.S.), we carried out a deep
spectromorphological study of the -ray emission of HESS J1646-458. We
furthermore employed H I and CO observations of the region to infer the
presence of gas that could serve as target material for interactions of
accelerated CRs. We detected large-scale ( diameter) -ray
emission with a complex morphology, exhibiting a shell-like structure and
showing no significant variation with -ray energy. The combined energy
spectrum of the emission extends to several tens of TeV, and is uniform across
the entire source region. We did not find a clear correlation of the
-ray emission with gas clouds as identified through H I and CO
observations. We conclude that, of the known objects within the region, only
Westerlund 1 can explain the bulk of the -ray emission. Several CR
acceleration sites and mechanisms are conceivable, and discussed in detail.
(abridged)Comment: 15 pages, 9 figures. Corresponding authors: L. Mohrmann, S. Ohm, R.
Rauth, A. Specoviu
H.E.S.S. follow-up observations of GRB221009A
GRB221009A is the brightest gamma-ray burst ever detected. To probe the
very-high-energy (VHE, \!100 GeV) emission, the High Energy Stereoscopic
System (H.E.S.S.) began observations 53 hours after the triggering event, when
the brightness of the moonlight no longer precluded observations. We derive
differential and integral upper limits using H.E.S.S. data from the third,
fourth, and ninth nights after the initial GRB detection, after applying
atmospheric corrections. The combined observations yield an integral energy
flux upper limit of above GeV. The
constraints derived from the H.E.S.S. observations complement the available
multiwavelength data. The radio to X-ray data are consistent with synchrotron
emission from a single electron population, with the peak in the SED occurring
above the X-ray band. Compared to the VHE-bright GRB190829A, the upper limits
for GRB221009A imply a smaller gamma-ray to X-ray flux ratio in the afterglow.
Even in the absence of a detection, the H.E.S.S. upper limits thus contribute
to the multiwavelength picture of GRB221009A, effectively ruling out an IC
dominated scenario.Comment: 10 pages, 4 figures. Accepted for publication in APJL. Corresponding
authors: J. Damascene Mbarubucyeye, H. Ashkar, S. J. Zhu, B. Reville, F.
Sch\"ussle
T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids
The hallmark function of αβ T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen–presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses
A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells
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