The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes.

addresses: Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Plymouth, UK.The final publication is available at link.springer.com/article/10.1007%2Fs00125-009-1276-0Evidence that the beta cells of human patients with type 1 diabetes can be infected with enterovirus is accumulating, but it remains unclear whether such infections occur at high frequency and are important in the disease process. We have now assessed the prevalence of enteroviral capsid protein vp1 (vp1) staining in a large cohort of autopsy pancreases of recent-onset type 1 diabetic patients and a range of controls

Immunohistochemical analysis of the relationship between islet cell proliferation and the production of the enteroviral capsid protein, VP1, in the islets of patients with recent-onset type 1 diabetes

Aims/hypothesis: The enteroviral capsid protein, VP1, was recently shown to be present in some beta cells in more than 60% of patients with recent-onset type 1 diabetes but in very few age-matched controls. The rate of proliferation of islet cells was also markedly increased in the type 1 diabetic patients. As it has been suggested that enteroviruses replicate most efficiently in proliferating cells, we have investigated whether VP1 is preferentially present in proliferating beta cells in type 1 diabetes.<p></p> Methods: Combined immunoperoxidase and immunofluorescence staining was used to record the presence of enteroviral VP1, insulin and Ki67 in the islets of recent-onset type 1 diabetic patients.<p></p> Results: From a total of 1,175 islets, 359 (30.5%) contained insulin. VP1-producing endocrine cells were found in 72 islets (6.1% of total), all of which retained insulin. Ki67+ endocrine cells were present in 52 (4.4%) islets, with 44 (84.6%) of these being insulin-positive. Overall, 28 of 1,175 (2.4%) islets contained both Ki67+ cells and VP1+ cells. Dual positivity of these markers accounted for 38.9% of the total VP1+ islets and 53.8% of the total Ki67+ islets. No individual islet cells were dual-positive for Ki67 and VP1.<p></p> Conclusions/interpretation: Ki67+ cells were frequently observed in islets that also contained VP1+ cells, suggesting that the factors facilitating viral replication may also drive islet cell proliferation. However, in an individual cell, VP1 production does not require concurrent beta cell proliferation.<p></p&gt

Persistent infection of thymic epithelial cells with coxsackievirus B4 results in a decreased expression of insulin-like growth factor 2

It has been hypothesized that a disturbance of central self-tolerance to islet β-cell may play a role in the enteroviral pathogenesis of type 1 diabetes. Whether enteroviruses can induce an impaired expression of β-cell self-antigens in thymic epithelial cells has been investigated in a murine thymic epithelial (MTE) cell line. This cell line was permissive to the diabetogenic strain CV-B4 E2 and spontaneously expressed type 2 insulin-like growth factor (Igf2), the dominant self-antigen of the insulin family. In this model, a persistent replication of CV-B4 E2 was obtained as attested by the prolonged detection of intracellular positive and negative-strand viral RNA by RT-PCR, and capsid protein VP1 by IF and by the release of infectious particles in culture supernatant fluids. The chronic stage of the infection was characterized by a low proportion of VP1-positive cells (1-2%) whereas many cells harbored enteroviral RNA as displayed by RT-PCR without extraction applied directly on a few cells. Igf2 mRNA and IGF-2 protein were dramatically decreased in CV-B4 E2-infected MTE cultures compared with mock-infected cultures, whereas housekeeping and Il6 genes expression were maintained and Igf1 mRNA was decreased but at a lower extent. Inoculation of CV-B3-, CV-B4 JVB- or Echovirus 1 resulted in a low level of IGF-2 in culture supernatant fluids as well, whereas HSV-1 stimulated the production of the protein. Thus, a persistent infection of a thymic epithelial cell line with enteroviruses, like CV-B4 E2 can result in a disturbed production of IGF-2, a protein involved in central self-tolerance towards islet β-cells.FP6 Integrated Project Eurothymaid

Search for Very High-Energy Emission from the millisecond pulsar PSR J0218+4232

PSR J0218+4232 is one of the most energetic millisecond pulsars known and has long been considered as one of the best candidates for very high-energy (VHE; >100 GeV) gamma-ray emission. Using 11.5 years of Fermi Large Area Telescope (LAT) data between 100 MeV and 870 GeV, and ~90 hours of MAGIC observations in the 20 GeV to 20 TeV range, we have searched for the highest energy gamma-ray emission from PSR J0218+4232. Based on the analysis of the LAT data, we find evidence for pulsed emission above 25 GeV, but see no evidence for emission above 100 GeV (VHE) with MAGIC. We present the results of searches for gamma-ray emission, along with theoretical modeling, to interpret the lack of VHE emission. We conclude that, based on the experimental observations and theoretical modeling, it will remain extremely challenging to detect VHE emission from PSR J0218+4232 with the current generation of Imaging Atmospheric Cherenkov Telescopes (IACTs), and maybe even with future ones, such as the Cherenkov Telescope Array (CTA)...

First detection of VHE gamma-ray emission from TXS 1515-273, study of its X-ray variability and spectral energy distribution

We report here on the first multiwavelength (MWL) campaign on the blazar TXS 1515-273, undertaken in 2019 and extending from radio to very-high-energy gamma-rays (VHE). Up until now, this blazar had not been the subject of any detailed MWL observations. It has a rather hard photon index at GeV energies and was considered a candidate extreme high-synchrotron-peaked source. MAGIC observations resulted in the first-time detection of the source in VHE with a statistical significance of 7.6\u3c3. The average integral VHE flux of the source is 6 \ub1 1 per cent of the Crab nebula flux above 400 GeV. X-ray coverage was provided by Swift-XRT, XMM-Newton, and NuSTAR. The long continuous X-ray observations were separated by ~9 h, both showing clear hour scale flares. In the XMM-Newton data, both the rise and decay time-scales are longer in the soft X-ray than in the hard X-ray band, indicating the presence of a particle cooling regime. The X-ray variability time-scales were used to constrain the size of the emission region and the strength of the magnetic field. The data allowed us to determine the synchrotron peak frequency and classify the source as a flaring high, but not extreme synchrotron-peaked object. Considering the constraints and variability patterns from the X-ray data, we model the broad-band spectral energy distribution. We applied a simple one-zone model, which could not reproduce the radio emission and the shape of the optical emission, and a two-component leptonic model with two interacting components, enabling us to reproduce the emission from radio to VHE band...

Author Correction: Proton acceleration in thermonuclear nova explosions revealed by gamma rays (Nature Astronomy, (2022), 6, 6, (689-697), 10.1038/s41550-022-01640-z)

In the version of this article initially published, there was an error in the scale described in the right-hand y-axis label of Fig. 1. Flux density (Jy), now presented on a scale from “1, 10, 102”, was originally shown as “10, 102”. The image has been corrected in the HTML and PDF versions of the article. Further, the Source Data for Fig. 1 have now been replaced online