252 research outputs found
Interleukin-1β Produced in Response to Islet Autoantigen Presentation Differentiates T-Helper 17 Cells at the Expense of Regulatory T-Cells: Implications for the Timing of Tolerizing Immunotherapy
OBJECTIVE-The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelB(lo) DCs, generated in the presence of an nuclear factor-kappa B inhibitor, induce T-regulatory (Treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (IL)-1 beta is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates Treg cells, and accelerates diabetes in NOD mice. We investigated the relationship between IL-1 beta production and the response to RelB(lo) DCs in the prediabetic period
Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches
are required. Our previous studies have demonstratedthat heparan sulfate (HS), a
glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels
inside normal mouse beta cells. Intracellular HS was shownto be critical for beta cell survival and
protection from oxidative damage. T1D development
in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by
inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated
the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal
human islets, a role for HS in human beta cell viability and the clinical relevance of intraislet
HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS
(identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the
HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive
islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase
was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS
mimetics showed significantly improved survival and protection against hydrogen peroxideinduced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important
mechanism in the pathogenesis of human T1D.
Our findings raise the possibility that intervention therapy with dual activity HS replacers/
heparanase inhibitors could help to protect the residual beta cell mass in patients recently
diagnosed with T1D.: This work was supported by a National
Health and Medical Research Council of Australia
(NHMRC; https://www.nhmrc.gov.au/)/Juvenile
Diabetes Research Foundation (JDRF) Special
Program Grant in Type 1 Diabetes (#418138), The
Canberra Hospital Private Practice Fund (http://
www.health.act.gov.au/research-publications/research/ppf-major-grants), JDRF nPOD Research
Grant (#25-2010-716; http://www.jdrf.org), JDRF
Research Grant (#47-2012-746) and NHMRC
Project Grant (#1043284
The insulin A-chain epitope recognized by human T cells is posttranslationally modified
The autoimmune process that destroys the insulin-producing pancreatic β cells in type 1 diabetes (T1D) is targeted at insulin and its precursor, proinsulin. T cells that recognize the proximal A-chain of human insulin were identified recently in the pancreatic lymph nodes of subjects who had T1D. To investigate the specificity of proinsulin-specific T cells in T1D, we isolated human CD4+ T cell clones to proinsulin from the blood of a donor who had T1D. The clones recognized a naturally processed, HLA DR4–restricted epitope within the first 13 amino acids of the A-chain (A1–13) of human insulin. T cell recognition was dependent on the formation of a vicinal disulfide bond between adjacent cysteine residues at A6 and A7, which did not alter binding of the peptide to HLA DR4. CD4+ T cell clones that recognized this epitope were isolated from an HLA DR4+ child with autoantibodies to insulin, and therefore, at risk for T1D, but not from two healthy HLA DR4+ donors. We define for the first time a novel posttranslational modification that is required for T cell recognition of the insulin A-chain in T1D
Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
Acute renal impairment in coronavirus-associated severe acute respiratory syndrome.BackgroundSevere acute respiratory syndrome (SARS) is a newly emerged infection from a novel coronavirus (SARS-CoV). Apart from fever and respiratory complications, acute renal impairment has been observed in some patients with SARS. Herein, we describe the clinical, pathologic, and laboratory features of the acute renal impairment complicating this new viral infection.MethodsWe conducted a retrospective analysis of the plasma creatinine concentration and other clinical parameters of the 536 SARS patients with normal plasma creatinine at first clinical presentation, admitted to two regional hospitals following a major outbreak in Hong Kong in March 2003. Kidney tissues from seven other patients with postmortem examinations were studied by light microscopy and electron microscopy.ResultsAmong these 536 patients with SARS, 36 (6.7%) developed acute renal impairment occurring at a median duration of 20 days (range 5–48 days) after the onset of viral infection despite a normal plasma creatinine level at first clinical presentation. The acute renal impairment reflected the different prerenal and renal factors that exerted renal insult occurring in the context of multiorgan failure. Eventually, 33 SARS patients (91.7%) with acute renal impairment died. The mortality rate was significantly higher among patients with SARS and acute renal impairment compared with those with SARS and no renal impairment (91.7% vs. 8.8%) (P < 0.0001). Renal tissues revealed predominantly acute tubular necrosis with no evidence of glomerular pathology. The adjusted relative risk of mortality associated with the development of acute renal impairment was 4.057 (P < 0.001). By multivariate analysis, acute respiratory distress syndrome and age were the most significant independent risk factors predicting the development of acute renal impairment in SARS.ConclusionAcute renal impairment is uncommon in SARS but carries a high mortality. The acute renal impairment is likely to be related to multi-organ failure rather than the kidney tropism of the virus. The development of acute renal impairment is an important negative prognostic indicator for survival with SARS
SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine
AbstractMice lacking suppressor of cytokine signaling-1 (SOCS1) develop a complex fatal neonatal disease. In this study, SOCS1−/− mice were shown to exhibit excessive responses typical of those induced by interferon γ (IFNγ), were hyperresponsive to viral infection, and yielded macrophages with an enhanced IFNγ-dependent capacity to kill L. major parasites. The complex disease in SOCS1−/− mice was prevented by administration of anti-IFNγ antibodies and did not occur in SOCS1−/− mice also lacking the IFNγ gene. Although IFNγ is essential for resistance to a variety of infections, the potential toxic action of IFNγ, particularly in neonatal mice, appears to require regulation. Our data indicate that SOCS1 is a key modulator of IFNγ action, allowing the protective effects of this cytokine to occur without the risk of associated pathological responses
Glucose Induces Pancreatic Islet Cell Apoptosis That Requires the BH3-Only Proteins Bim and Puma and Multi-BH Domain Protein Bax
OBJECTIVE: High concentrations of circulating glucose are believed to contribute to defective insulin secretion and beta-cell function in diabetes and at least some of this effect appears to be caused by glucose-induced beta-cell apoptosis. In mammalian cells, apoptotic cell death is controlled by the interplay of proapoptotic and antiapoptotic members of the Bcl-2 family. We investigated the apoptotic pathway induced in mouse pancreatic islet cells after exposure to high concentrations of the reducing sugars ribose and glucose as a model of beta-cell death due to long-term metabolic stress. RESEARCH DESIGN AND METHODS: Islets isolated from mice lacking molecules implicated in cell death pathways were exposed to high concentrations of glucose or ribose. Apoptosis was measured by analysis of DNA fragmentation and release of mitochondrial cytochrome c. RESULTS: Deficiency of interleukin-1 receptors or Fas did not diminish apoptosis, making involvement of inflammatory cytokine receptor or death receptor signaling in glucose-induced apoptosis unlikely. In contrast, overexpression of the prosurvival protein Bcl-2 or deficiency of the apoptosis initiating BH3-only proteins Bim or Puma, or the downstream apoptosis effector Bax, markedly reduced glucose- or ribose-induced killing of islets. Loss of other BH3-only proteins Bid or Noxa, or the Bax-related effector Bak, had no impact on glucose-induced apoptosis. CONCLUSIONS: These results implicate the Bcl-2 regulated apoptotic pathway in glucose-induced islet cell killing and indicate points in the pathway at which interventional strategies can be designed
Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events
The - oscillation frequency has been measured with a sample of
23 million \B\bar B pairs collected with the BABAR detector at the PEP-II
asymmetric B Factory at SLAC. In this sample, we select events in which both B
mesons decay semileptonically and use the charge of the leptons to identify the
flavor of each B meson. A simultaneous fit to the decay time difference
distributions for opposite- and same-sign dilepton events gives ps.Comment: 7 pages, 1 figure, submitted to Physical Review Letter
Microflares and the Statistics of X-ray Flares
This review surveys the statistics of solar X-ray flares, emphasising the new
views that RHESSI has given us of the weaker events (the microflares). The new
data reveal that these microflares strongly resemble more energetic events in
most respects; they occur solely within active regions and exhibit
high-temperature/nonthermal emissions in approximately the same proportion as
major events. We discuss the distributions of flare parameters (e.g., peak
flux) and how these parameters correlate, for instance via the Neupert effect.
We also highlight the systematic biases involved in intercomparing data
representing many decades of event magnitude. The intermittency of the
flare/microflare occurrence, both in space and in time, argues that these
discrete events do not explain general coronal heating, either in active
regions or in the quiet Sun.Comment: To be published in Space Science Reviews (2011
Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector
The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements
A search for resonances decaying into a Higgs boson and a new particle X in the XH → qqbb final state with the ATLAS detector
A search for heavy resonances decaying into a Higgs boson (H) and a new particle (X) is reported, utilizing 36.1 fb−1 of proton–proton collision data at collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle X is assumed to decay to a pair of light quarks, and the fully hadronic final state is analysed. The search considers the regime of high XH resonance masses, where the X and H bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of XH mass versus X mass is scanned for evidence of a signal, over a range of XH resonance mass values between 1 TeV and 4 TeV, and for X particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of XH and X masses, on the production cross-section of the resonance
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