Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease

© 2008 Zhu et al. This article is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).Maintaining tolerance of T cells to self-antigens is essential to avoid autoimmune disease. How self-reactive T cells are kept functionally inactive is, however, unknown. In this study, we show that early growth response gene 2 (Egr-2), a zinc-finger transcription factor, is expressed in CD44(high) T cells and controls their proliferation and activation. In the absence of Egr-2, CD44(high), but not CD44(low) T cells, are hyperreactive and hyperproliferative in vivo. The accumulation of activated CD4(+)CD44(high) T cells leads to the development of a late onset lupuslike autoimmune disease characterized by the accumulation of interferon (IFN)-gamma and interleukin (IL)-17-producing CD4(+) T cells, loss of tolerance to nuclear antigens, massive infiltration of T cells into multiple organs and glomerulonephritis. We found that the expression of cyclin-dependent kinase inhibitor p21cip1 was impaired in Egr-2-deficient T cells, whereas the expression of IFN-gamma and IL-17 in response to T cell receptor ligation was significantly increased, suggesting that Egr-2 activates the expression of genes involved in the negative regulation of T cell proliferation and inflammation. These results demonstrate that Egr-2 is an intrinsic regulator of effector T cells and controls the expansion of self-reactive T cells and development of autoimmune disease.The Biotechnology and Biological Sciences Research Council, the Medical Research Council and the Wellcome Trust

Computational methods for Bayesian model choice

In this note, we shortly survey some recent approaches on the approximation of the Bayes factor used in Bayesian hypothesis testing and in Bayesian model choice. In particular, we reassess importance sampling, harmonic mean sampling, and nested sampling from a unified perspective.Comment: 12 pages, 4 figures, submitted to the proceedings of MaxEnt 2009, July 05-10, 2009, to be published by the American Institute of Physic

Protein kinase C theta is required for efficient induction of IL-10-secreting T cells

<div><p>Secretion of interleukin-10 (IL-10) by CD4⁺ T cells is an essential immunoregulatory mechanism. The work presented here assesses the role of the signaling molecule protein kinase C theta (PKCθ) in the induction of IL-10 expression in CD4⁺ T cells. Using wildtype and PKCθ-deficient Tg4 T cell receptor transgenic mice, we implemented a well-described protocol of repeated doses of myelin basic protein (MBP)Ac1-9[4Y] antigen to induce Tr1-like IL-10⁺ T cells. We find that PKCθ is required for the efficient induction of IL-10 following antigen administration. Both serum concentrations of IL-10 and the proportion of IL-10⁺ T cells were reduced in PKCθ-deficient mice relative to wildtype mice following [4Y] treatment. We further characterized the T cells of [4Y] treated PKCθ-deficient Tg4 mice and found reduced expression of the transcription factors cMaf, Nfil3 and FoxP3 and the surface receptors PD-1 and Tim3, all of which have been associated with the differentiation or function of IL-10⁺ T cells. Finally, we demonstrated that, unlike [4Y] treated wildtype Tg4 T cells, cells from PKCθ-deficient mice were unable to suppress the priming of naïve T cells <i>in vitro</i> and <i>in vivo</i>. In summary, we present data demonstrating a role for PKCθ in the induction of suppressive, IL-10-secreting T cells induced in TCR-transgenic mice following chronic antigen administration. This should be considered when contemplating PKCθ as a suitable drug target for inducing immune suppression and graft tolerance.</p></div

Dark energy constraints and correlations with systematics from CFHTLS weak lensing, SNLS supernovae Ia and WMAP5

We combine measurements of weak gravitational lensing from the CFHTLS-Wide survey, supernovae Ia from CFHT SNLS and CMB anisotropies from WMAP5 to obtain joint constraints on cosmological parameters, in particular, the dark energy equation of state parameter w. We assess the influence of systematics in the data on the results and look for possible correlations with cosmological parameters. We implement an MCMC algorithm to sample the parameter space of a flat CDM model with a dark-energy component of constant w. Systematics in the data are parametrised and included in the analysis. We determine the influence of photometric calibration of SNIa data on cosmological results by calculating the response of the distance modulus to photometric zero-point variations. The weak lensing data set is tested for anomalous field-to-field variations and a systematic shape measurement bias for high-z galaxies. Ignoring photometric uncertainties for SNLS biases cosmological parameters by at most 20% of the statistical errors, using supernovae only; the parameter uncertainties are underestimated by 10%. The weak lensing field-to-field variance pointings is 5%-15% higher than that predicted from N-body simulations. We find no bias of the lensing signal at high redshift, within the framework of a simple model. Assuming a systematic underestimation of the lensing signal at high redshift, the normalisation sigma_8 increases by up to 8%. Combining all three probes we obtain -0.10<1+w<0.06 at 68% confidence (-0.18<1+w<0.12 at 95%), including systematic errors. Systematics in the data increase the error bars by up to 35%; the best-fit values change by less than 0.15sigma. [Abridged]Comment: 14 pages, 10 figures. Revised version, matches the one to be published in A&A. Modifications have been made corresponding to the referee's suggestions, including reordering of some section

Sorption and fractionation of dissolved organic matter and associated phosphorus in agricultural soil

Molibility of dissolved organic matter (DOM) strongly affects the export of nitrogen (N) and phosphorus (P) from oils to surface waters. To study the sorption an mobility of dissolved organic C and P (DOC, DOP) in soil, the pH-dependent sorption of DOM to samples from Ap, EB, and Bt horizons from a Danish agircultural Humic Hapludult was investigated and a kinetic model applicable in field-scale model tested. Sorption experiments of 1 to 72 h duration were conducted at two pH levels (pH 5.0 and 7.0) and six initial DOC concentrtions (0-4.7 mmol L-1). Most sorption/desorption occurred during the first few hours. Dissolved organic carbon and DOP sorption decreased strongly with increased pH and desorption dominated at pH 7, especially for DOC. Due to fractionation during DOM sorption/desorption at DOC concentrations up to 2 mmol L-1, the solution fraction of DOM was enriched in P indicating preferred leaching of DOP. The kinetics of sorption was expressed as a function of how far the solution DOC or DOP concentrations deviate from "equilibrium". The model was able to simulate the kinetics of DOC and DOP sorption/desorption at all concentrations investigated and at both pH levels making it useful for incorporation in field-scale models for quantifying DOC and DOP dynamics

Isomer shift and magnetic moment of the long-lived 1/2+^{+} isomer in 3079^{79}_{30}Zn49_{49}: signature of shape coexistence near 78^{78}Ni

Collinear laser spectroscopy has been performed on the $^{79}_{30}$Zn$_{49}$ isotope at ISOLDE-CERN. The existence of a long-lived isomer with a few hundred milliseconds half-life was confirmed, and the nuclear spins and moments of the ground and isomeric states in $^{79}$Zn as well as the isomer shift were measured. From the observed hyperfine structures, spins $I = 9/2$ and $I = 1/2$ are firmly assigned to the ground and isomeric states. The magnetic moment $\mu$ ($^{79}$Zn) = $-$1.1866(10) $\mu_{\rm{N}}$, confirms the spin-parity $9/2^{+}$ with a $\nu g_{9/2}^{-1}$ shell-model configuration, in excellent agreement with the prediction from large scale shell-model theories. The magnetic moment $\mu$ ($^{79m}$Zn) = $-$1.0180(12) $\mu_{\rm{N}}$ supports a positive parity for the isomer, with a wave function dominated by a 2h-1p neutron excitation across the $N = 50$ shell gap. The large isomer shift reveals an increase of the intruder isomer mean square charge radius with respect to that of the ground state: $\delta \langle r^{2}_{c}\rangle^{79,79m}$ = +0.204(6) fm$^{2}$, providing first evidence of shape coexistence.Comment: 5 pages, 4 figures, 1 table, Accepeted by Phys. Rev. Lett. (2016

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants &lt;8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Bayesian Fit of Exclusive b→sℓˉℓb \to s \bar\ell\ell Decays: The Standard Model Operator Basis

We perform a model-independent fit of the short-distance couplings $C_{7,9,10}$ within the Standard Model set of $b\to s\gamma$ and $b\to s\bar\ell\ell$ operators. Our analysis of $B \to K^* \gamma$, $B \to K^{(*)} \bar\ell\ell$ and $B_s \to \bar\mu\mu$ decays is the first to harness the full power of the Bayesian approach: all major sources of theory uncertainty explicitly enter as nuisance parameters. Exploiting the latest measurements, the fit reveals a flipped-sign solution in addition to a Standard-Model-like solution for the couplings $C_i$. Each solution contains about half of the posterior probability, and both have nearly equal goodness of fit. The Standard Model prediction is close to the best-fit point. No New Physics contributions are necessary to describe the current data. Benefitting from the improved posterior knowledge of the nuisance parameters, we predict ranges for currently unmeasured, optimized observables in the angular distributions of $B\to K^*(\to K\pi)\,\bar\ell\ell$.Comment: 42 pages, 8 figures; v2: Using new lattice input for f_Bs, considering Bs-mixing effects in BR[B_s->ll]. Main results and conclusion unchanged, matches journal versio

Developments for resonance ionization laser spectroscopy of the heaviest elements at SHIP

The experimental determination of atomic levels and the first ionization potential of the heaviest elements (Z >= 100) is key to challenge theoretical predictions and to reveal changes in the atomic shell structure. These elements are only artificially produced in complete-fusion evaporation reactions at on-line facilities such as the GSI in Darmstadt at a rate of, at most, a few atoms per second. Hence, highly sensitive spectroscopic methods are required. Laser spectroscopy is one of the most powerful and valuable tools to investigate atomic properties. In combination with a buffer-gas filled stopping cell, the Radiation Detected Resonance Ionization Spectroscopy (RADRIS) technique provides the highest sensitivity for laser spectroscopy on the heaviest elements. The RADRIS setup, as well as the measurement procedure, have been optimized and characterized using the a-emitter 155Yb in on-line conditions, resulting in an overall efficiency well above 1%. This paves the way for a successful search of excited atomic levels in nobelium and heavier elements.publisher: Elsevier articletitle: Developments for resonance ionization laser spectroscopy of the heaviest elements at SHIP journaltitle: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms articlelink: http://dx.doi.org/10.1016/j.nimb.2016.06.001 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved.status: publishe

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed