The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma

The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel–/– mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counterintuitively, c-rel–/– Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel–/– Eμ-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel–/– TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild-type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel–/– mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-κB/IκB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF-κB signalling in cancer

Generalized Euler-Poincar\'e equations on Lie groups and homogeneous spaces, orbit invariants and applications

We develop the necessary tools, including a notion of logarithmic derivative for curves in homogeneous spaces, for deriving a general class of equations including Euler-Poincar\'e equations on Lie groups and homogeneous spaces. Orbit invariants play an important role in this context and we use these invariants to prove global existence and uniqueness results for a class of PDE. This class includes Euler-Poincar\'e equations that have not yet been considered in the literature as well as integrable equations like Camassa-Holm, Degasperis-Procesi, $\mu$CH and $\mu$DP equations, and the geodesic equations with respect to right invariant Sobolev metrics on the group of diffeomorphisms of the circle

On the Reliability of Meta-Analytic Reviews

The article addresses the issue of intercoder reliability in meta-analyses. The current practice of reporting a single, mean intercoder agreement score in meta-analytic research leads to systematic bias and overestimates the true reliability. An alternative approach is recommended in which average intercoder agreement scores or other reliability statistics are calculated within clusters of coded variables. These clusters form a hierarchy in which the correctness of coding decisions at a given level of the hierarchy is contingent on decisions made at higher levels. Two separate studies of intercoder agreement in meta-analysis are presented to assess the validity of the model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67840/2/10.1177_0193841X9301700303.pd

Simvastatin Prevents and Reverses Depigmentation in a Mouse Model of Vitiligo

Vitiligo is a common autoimmune disease of the skin that results in disfiguring white spots. There are no Food and Drug Administration (FDA)-approved treatments, and current treatments are time-consuming, expensive, and of low efficacy. We sought to identify new treatments for vitiligo, and first considered repurposed medications because of the availability of safety data and expedited regulatory approval. We previously reported that the IFN-γ-induced chemokine CXCL10 is expressed in lesional skin from vitiligo patients, and that it is critical for the progression and maintenance of depigmentation in our mouse model of vitiligo. We hypothesized that targeting IFN-γ signaling might be an effective new treatment strategy. Activation of signal transducer and activator of transcription 1 (STAT1) is required for IFN-γ signaling and recent studies revealed that simvastatin, an FDA-approved cholesterol-lowering medication, inhibited STAT1 activation in vitro. Therefore, we hypothesized that simvastatin may be an effective treatment for vitiligo. We found that simvastatin both prevented and reversed depigmentation in our mouse model of vitiligo, and reduced the number of infiltrating autoreactive CD8+ T cells in the skin. Treatment of melanocyte-specific, CD8+ T cells in vitro decreased proliferation and IFN-γ production, suggesting additional effects of simvastatin directly on T cells. Based on these data, simvastatin may be a safe, targeted treatment option for patients with vitiligo. © 2015 The Society for Investigative Dermatology

Dynamic Evolution Model of Isothermal Voids and Shocks

We explore self-similar hydrodynamic evolution of central voids embedded in an isothermal gas of spherical symmetry under the self-gravity. More specifically, we study voids expanding at constant radial speeds in an isothermal gas and construct all types of possible void solutions without or with shocks in surrounding envelopes. We examine properties of void boundaries and outer envelopes. Voids without shocks are all bounded by overdense shells and either inflows or outflows in the outer envelope may occur. These solutions, referred to as type $\mathcal{X}$ void solutions, are further divided into subtypes $\mathcal{X}_{\rm I}$ and $\mathcal{X}_{\rm II}$ according to their characteristic behaviours across the sonic critical line (SCL). Void solutions with shocks in envelopes are referred to as type $\mathcal{Z}$ voids and can have both dense and quasi-smooth edges. Asymptotically, outflows, breezes, inflows, accretions and static outer envelopes may all surround such type $\mathcal{Z}$ voids. Both cases of constant and varying temperatures across isothermal shock fronts are analyzed; they are referred to as types $\mathcal{Z}_{\rm I}$ and $\mathcal{Z}_{\rm II}$ void shock solutions. We apply the `phase net matching procedure' to construct various self-similar void solutions. We also present analysis on void generation mechanisms and describe several astrophysical applications. By including self-gravity, gas pressure and shocks, our isothermal self-similar void (ISSV) model is adaptable to various astrophysical systems such as planetary nebulae, hot bubbles and superbubbles in the interstellar medium as well as supernova remnants.Comment: 24 pages, 13 figuers, accepted by ApS

Fluid Models of Many-server Queues with Abandonment

We study many-server queues with abandonment in which customers have general service and patience time distributions. The dynamics of the system are modeled using measure- valued processes, to keep track of the residual service and patience times of each customer. Deterministic fluid models are established to provide first-order approximation for this model. The fluid model solution, which is proved to uniquely exists, serves as the fluid limit of the many-server queue, as the number of servers becomes large. Based on the fluid model solution, first-order approximations for various performance quantities are proposed

Atomic detail visualization of photosynthetic membranes with GPU-accelerated ray tracing

The cellular process responsible for providing energy for most life on Earth, namely, photosynthetic light-harvesting, requires the cooperation of hundreds of proteins across an organelle, involving length and time scales spanning several orders of magnitude over quantum and classical regimes. Simulation and visualization of this fundamental energy conversion process pose many unique methodological and computational challenges. We present, in two accompanying movies, light-harvesting in the photosynthetic apparatus found in purple bacteria, the so-called chromatophore. The movies are the culmination of three decades of modeling efforts, featuring the collaboration of theoretical, experimental, and computational scientists. We describe the techniques that were used to build, simulate, analyze, and visualize the structures shown in the movies, and we highlight cases where scientific needs spurred the development of new parallel algorithms that efficiently harness GPU accelerators and petascale computers

Sciatic Neuroma Presenting Forty Years After Above-Knee Amputation

We report a case of a sciatic neuroma presenting forty years after above knee amputation. Patients developing neuroma following a limb amputation can present with stump pain which is commonly resistant to medical intervention. The length of interval from the initial injury to presentation is widely variable. Diagnosis relies on clinical suspicion and accurate assessment, radiological imaging and, if indicated, surgical exploration. MRI provides a better soft tissue definition than CT and is more accurate in identifying small lesions than ultrasound. The aim of treatment for symptomatic neuroma is pain relief and improvement of function. This is often achieved by surgical excision

Diffuse inverse Compton and synchrotron emission from dark matter annihilations in galactic satellites

Annihilating dark matter particles produce roughly as much power in electrons and positrons as in gamma ray photons. The charged particles lose essentially all of their energy to inverse Compton and synchrotron processes in the galactic environment. We discuss the diffuse signature of dark matter annihilations in satellites of the Milky Way (which may be optically dark with few or no stars), providing a tail of emission trailing the satellite in its orbit. Inverse Compton processes provide X-rays and gamma rays, and synchrotron emission at radio wavelengths might be seen. We discuss the possibility of detecting these signals with current and future observations, in particular EGRET and GLAST for the gamma rays.Comment: 13 pages, 5 figure