Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

Idiosyncratic adverse drug reactions are unpredictable, dose independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkage between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells that required HLA-B*57:01 molecules for their function. However, the mechanism by which abacavir induces this pathologic T cell response remains unclear. Here we show that abacavir can bind within the F-pocket of the peptide-binding groove of HLA-B*57:01 thereby altering its specificity. This supports a novel explanation for HLA-linked idiosyncratic adverse drug reactions; namely that drugs can alter the repertoire of self-peptides presented to T cells thus causing the equivalent of an alloreactive T cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir, and that were recognized by T cells of hypersensitive patients. The assays we have established can be applied to test additional compounds with suspected HLA linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA linked hypersensitivities as well as guide the development of safer drugs

The Vanishing of the Primary Emission Region in PKS 1510-089

In 2021 July, PKS 1510-089 exhibited a significant flux drop in the high-energy γ-ray (by a factor 10) and optical (by a factor 5) bands and remained in this low state throughout 2022. Similarly, the optical polarization in the source vanished, resulting in the optical spectrum being fully explained through the steady flux of the accretion disk and the broad-line region. Unlike the aforementioned bands, the very-high-energy γ-ray and X-ray fluxes did not exhibit a significant flux drop from year to year. This suggests that the steady-state very-high-energy γ-ray and X-ray fluxes originate from a different emission region than the vanished parts of the high-energy γ-ray and optical jet fluxes. The latter component has disappeared through either a swing of the jet away from the line of sight or a significant drop in the photon production efficiency of the jet close to the black hole. Either change could become visible in high-resolution radio images

H.E.S.S. Follow-up Observations of GRB 221009A

GRB 221009A is the brightest gamma-ray burst (GRB) ever detected. To probe the very-high-energy (VHE; >100 GeV) emission, the High Energy Stereoscopic System (H.E.S.S.) began observations 53 hr 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 FUL = 9.7 ´ 10- erg cm- s- 95% 12 2 1 above Ethr = 650 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 spectral energy distribution occurring above the X-ray band. Compared to the VHE-bright GRB 190829A, the upper limits for GRB 221009A 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 GRB 221009A, effectively ruling out an IC-dominated scenario.F. Aharonian ... S. Einecke ... G. Rowell ... et al. (H.E.S.S. Collaboration

The Vanishing of the Primary Emission Region in PKS 1510–089

Published 2023 August 1In 2021 July, PKS 1510−089 exhibited a significant flux drop in the high-energy γ-ray (by a factor 10) and optical (by a factor 5) bands and remained in this low state throughout 2022. Similarly, the optical polarization in the source vanished, resulting in the optical spectrum being fully explained through the steady flux of the accretion disk and the broad-line region. Unlike the aforementioned bands, the very-high-energy γ-ray and X-ray fluxes did not exhibit a significant flux drop from year to year. This suggests that the steady-state very-high-energy γ-ray and X-ray fluxes originate from a different emission region than the vanished parts of the high-energy γ-ray and optical jet fluxes. The latter component has disappeared through either a swing of the jet away from the line of sight or a significant drop in the photon production efficiency of the jet close to the black hole. Either change could become visible in high-resolution radio images.F. Aharonian ... S. Einecke ... G. Rowell ... et al. (H.E.S.S. Collaboration

Search for dark matter annihilation signals in the H.E.S.S. Inner galaxy survey

The central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new observations from an unprecedented γ-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (≳100  GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant γ-ray excess is found in the search region of the 2014-2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section ⟨σv⟩. Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach ⟨σv⟩ values of 3.7×10^{-26}  cm^{3} s^{-1} for 1.5 TeV DM mass in the W^{+}W^{-} annihilation channel, and 1.2×10^{-26}  cm^{3} s^{-1} for 0.7 TeV DM mass in the τ^{+}τ^{-} annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based γ-ray observations thus probe ⟨σv⟩ values expected from thermal-relic annihilating TeV DM particles

Oral processing of hydrogels: Influence of food material properties versus individuals' eating capability

Food material properties play an important role in sensory perception and consumer acceptance of foods. However, the actual oral processing behavior may depend on both the material properties of the food that is being consumed and individuals' oral capabilities. This study aimed to examine the relationships between intrinsic (oral capabilities of healthy participants) and extrinsic (food material properties of a set of hydrogels) variables to the real oral processing behavior. Three κ‐carrageenan hydrogels (κC), differing in fracture mechanics and oral tribology properties, were prepared: native κC, κC with added Na‐alginate, and a κC matrix with added Ca‐alginate beads of 300 μm. A composite score of eating capability (EC) was measured with non‐invasive techniques (maximum bite force and tongue pressure) using a panel of 28 untrained consumers. The oral processing behaviors (number of chews, oral residence time, and chewing rate) were analyzed with the same participants using frame‐by‐frame video analysis. It was found that the EC scores did not correlate with any of the oral processing behaviors. The number of chews and oral residence time showed a strong correlation with the fracture force and friction force at orally relevant speeds (10–100 mm/s), whereas chewing rate did not vary with these properties. The results from this study indicate that oral processing in healthy adults seems mainly motivated by food material properties, and the chewing rate seems to relate more to individual differences and EC than to food properties. Insights from this study, using model hydrogels, have helped to promote knowledge on oral processing behavior in healthy individuals; could bridge the gap between consumer science, psychology, and food science; and may be of interest to product developers in designing foods with pleasant texture properties

A deep spectromorphological study of the γ-ray emission surrounding the young massive stellar cluster Westerlund 1

Context: 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) that are 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-highenergy γ-ray source HESS J1646−458 has been detected in the vicinity of Westerlund 1 in the past, its association could not be firmly identified. Aims: We aim to identify the physical processes responsible for the γ-ray emission around Westerlund 1 and thus to understand the role of massive stellar clusters in the acceleration of Galactic CRs better. Methods: Using 164 h of data recorded with the High Energy Stereoscopic System (H.E.S.S.), we carried out a deep spectromorphological study of the γ-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. Results: We detected large-scale (∼2 ◦ diameter) γ-ray emission with a complex morphology, exhibiting a shell-like structure and showing no significant variation with γ-ray energy. The combined energy spectrum of the emission extends to several tens of TeV, and it is uniform across the entire source region. We did not find a clear correlation of the γ-ray emission with gas clouds as identified through H I and CO observations. Conclusions: We conclude that, of the known objects within the region, only Westerlund 1 can explain the majority of the γ-ray emission. Several CR acceleration sites and mechanisms are conceivable and discussed in detail. While it seems clear that Westerlund 1 acts as a powerful particle accelerator, no firm conclusions on the contribution of massive stellar clusters to the flux of Galactic CRs in general can be drawn at this point.H.E.S.S Collaboration ... F. Aharonian ... G. Rowell ... A. Mitchell ... J. Muller ... M. Sasaki ... et al

A deep spectromorphological study of the γ -ray emission surrounding the young massive stellar cluster Westerlund 1

Context. 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) that are 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 γ-ray source HESS J1646-458 has been detected in the vicinity of Westerlund 1 in the past, its association could not be firmly identified. Aims. We aim to identify the physical processes responsible for the γ-ray emission around Westerlund 1 and thus to understand the role of massive stellar clusters in the acceleration of Galactic CRs better. Methods. Using 164 h of data recorded with the High Energy Stereoscopic System (H.E.S.S.), we carried out a deep spectromorphological study of the γ-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. Results. We detected large-scale (~2 diameter) γ-ray emission with a complex morphology, exhibiting a shell-like structure and showing no significant variation with γ-ray energy. The combined energy spectrum of the emission extends to several tens of TeV, and it is uniform across the entire source region. We did not find a clear correlation of the γ-ray emission with gas clouds as identified through H I and CO observations. Conclusions. We conclude that, of the known objects within the region, only Westerlund 1 can explain the majority of the γ-ray emission. Several CR acceleration sites and mechanisms are conceivable and discussed in detail. While it seems clear that Westerlund 1 acts as a powerful particle accelerator, no firm conclusions on the contribution of massive stellar clusters to the flux of Galactic CRs in general can be drawn at this point

The College News, 1923-01-24, Vol. 09, No. 13

Bryn Mawr College student newspaper. Merged with The Haverford News in 1968 to form the Bi-college News (with various titles from 1968 on). Published weekly (except holidays) during the academic year

Fast and slow responses of Southern Ocean sea surface temperature to SAM in coupled climate models

We investigate how sea surface temperatures (SSTs) around Antarctica respond to the Southern An- nular Mode (SAM) on multiple timescales. To that end we examine the relationship between SAM and SST within unperturbed preindustrial control simulations of coupled general circulation models (GCMs) included in the Climate Modeling Intercomparison Project phase 5 (CMIP5). We develop a technique to extract the re- sponse of the Southern Ocean SST (55◦S−70◦S) to a hypothetical step increase in the SAM index. We demonstrate that in many GCMs, the expected SST step re- sponse function is nonmonotonic in time. Following a shift to a positive SAM anomaly, an initial cooling regime can transition into surface warming around Antarctica. However, there are large differences across the CMIP5 ensemble. In some models the step response function never changes sign and cooling persists, while in other GCMs the SST anomaly crosses over from negative to positive values only three years after a step increase in the SAM. This intermodel diversity can be related to differences in the models’ climatological thermal ocean stratification in the region of seasonal sea ice around Antarctica. Exploiting this relationship, we use obser- vational data for the time-mean meridional and vertical temperature gradients to constrain the real Southern Ocean response to SAM on fast and slow timescales