The Aryl Hydrocarbon Receptor Plays a Key Role in the Transcriptional Programme of Regulatory B cells

Regulatory B cells (Bregs) play a critical role in the control of autoimmunity and inflammation. IL-10 production is the hallmark for the identification of Bregs. However, the molecular determinants that regulate the transcription of IL-10 and control the Breg developmental program remain unknown. The aryl hydrocarbon receptor (AHR) is an environmental sensor that binds to a variety of ligands, including physiological compounds derived from the digestion of dietary components by commensal microbiota. Here, we demonstrate that AHR regulates the differentiation and function of IL-10-producing CD19+CD21hiCD24hi Bregs and limits their differentiation into B cells that contribute to inflammation. Chromatin profiling and transcriptome analyses show that loss of AHR in B cells reduces expression of IL-10 by skewing the differentiation of CD19+CD21hiCD24hi B cells into a pro-inflammatory program, under Breg-inducing conditions. B cell AHR-deficient mice develop exacerbated arthritis, show significant reductions in IL-10-producing Bregs and regulatory T cells (Tregs), and show an increase in T helper (Th) 1 and Th17 cells compared with B cell AHR-sufficient mice. The most abundant source of AHR ligands are derived from the diet and the metabolism of dietary tryptophan. We have previously established a link between microbiota-driven signals in the gut and the differentiation of Bregs. Of the gut microbiota-derived metabolites, the short-chain fatty acids (SCFAs) are the most well characterised. More recently, the SCFA butyrate has been demonstrated to act as an AHR ligand in an intestinal epithelial cell line. Given the association of butyrate with AHR activation and the supporting findings showing that butyrate promotes Treg function, these data led us to hypothesise that butyrate acts via AHR to enhance Breg suppression. Here, we demonstrate that mice supplemented with butyrate reduces arthritis severity by inhibiting the differentiation of GC B cells and plasma cells, whilst maintaining Breg numbers and promoting the suppressive function of Bregs. We show that supplementation of mice with butyrate, changes the composition of the microbiota to favour species which metabolise tryptophan; a major source of AHR ligands. Therefore, we hypothesised that butyrate controls the balance between pro-arthritogenic and regulatory B cell differentiation, through the generation of microbiota derived AHR ligands. To date, the AHR ligands which direct Breg function are unknown. We rule out that butyrate acts as a direct ligand of AHR and establish that supplementation with butyrate increases the availability of 5-Hydroxyindole-3-acetic acid (5-HIAA), a downstream metabolite of serotonin, which we identify as a novel ligand of AHR in B cells. Mice supplemented with 5-HIAA promote Breg function and suppress arthritis severity, only in mice with AHR-sufficient B cells. Thus, we identify AHR as a relevant contributor to the transcriptional regulation of Breg differentiation and show that microbiota in the gut influence Breg differentiation by increasing the availability of AHR ligands

Spatiotemporal variability of lightning activity in Europe and the relation to the North Atlantic Oscillation teleconnection pattern

Comprehensive lightning statistics are presented for a large, contiguous domain covering several European countries such as France, Germany, Austria, and Switzerland. Spatiotemporal variability of convective activity is investigated based on a 14-year time series (2001–2014) of lightning data. Based on the binary variable thunderstorm day, the mean spatial patterns of lightning activity and regional peculiarities regarding seasonality are discussed. Diurnal cycles are compared among several regions and evaluated with respect to major seasonal changes. Further analyses are performed regarding interannual variability and the impact of teleconnection patterns on convection. Mean convective activity across central Europe is characterized by a strong northwest-to-southeast gradient with pronounced secondary features superimposed. The zone of maximum values of thunderstorm days propagates southwestward along the southern Alpine range from April to July. Diurnal cycles vary substantially between both different months and regions, particularly regarding the incidence of nighttime lightning. The North Atlantic Oscillation (NAO) is shown to have a significant impact on convective activity in several regions, which is primarily caused by variations of the large-scale lifting pattern in both NAO phases. This dynamical effect is partly compensated for by thermodynamical modifications of the pre-convective environment. The results point to a crucial role of large-scale flow in steering the spatiotemporal patterns of convective activity

Spacecraft attitude and velocity control system

A spacecraft attitude and/or velocity control system includes a controller which responds to at least attitude errors to produce command signals representing a force vector F and a torque vector T, each having three orthogonal components, which represent the forces and torques which are to be generated by the thrusters. The thrusters may include magnetic torquer or reaction wheels. Six difference equations are generated, three having the form ##EQU1## where a.sub.j is the maximum torque which the j.sup.th thruster can produce, b.sub.j is the maximum force which the j.sup.th thruster can produce, and .alpha..sub.j is a variable representing the throttling factor of the j.sup.th thruster, which may range from zero to unity. The six equations are summed to produce a single scalar equation relating variables .alpha..sub.j to a performance index Z: ##EQU2## Those values of .alpha. which maximize the value of Z are determined by a method for solving linear equations, such as a linear programming method. The Simplex method may be used. The values of .alpha..sub.j are applied to control the corresponding thrusters

Likelihood Estimation for Block Cipher Keys

In this paper, we give a general framework for the analysis of block ciphers using the statistical technique of likelihood estimation. We show how various recent successful cryptanalyses of block ciphers can be regarded in this framework. By analysing the SAFER block cipher in this framework we expose a cryptographic weakness of that cipher

Success rates of re-excision after positive margins for invasive lobular carcinoma of the breast.

Rates of positive margins after surgical resection of invasive lobular carcinoma (ILC) are high (ranging from 18 to 60%), yet the efficacy of re-excision lumpReceptor subtypeectomy for clearing positive margins is unknown. Concerns about the diffuse nature of ILC may drive increased rates of completion mastectomy to treat positive margins, thus lowering breast conservation rates. We therefore determined the success rate of re-excision lumpectomy in women with ILC and positive margins after surgical resection. We identified 314 cases of stage I-III ILC treated with breast conserving surgery (BCS) at the University of California, San Francisco. Surgical procedures, pathology reports, and outcomes were analyzed using univariate and multivariate statistics and Cox-proportional hazards models. We evaluated outcomes before and after the year 2014, when new margin management consensus guidelines were published. Positive initial margins occurred in 118 (37.6%) cases. Of these, 62 (52.5%) underwent re-excision lumpectomy, which cleared the margin in 74.2%. On multivariate analysis, node negativity was significantly associated with successful re-excision (odds ratio [OR] 3.99, 95% CI 1.15-13.81, p = 0.029). After 2014, we saw fewer initial positive margins (42.7% versus 25.5%, p = 0.009), second surgeries (54.6% versus 20.2%, p < 0.001), and completion mastectomies (27.7% versus 4.5%, p < 0.001). In this large cohort of women with ILC, re-excision lumpectomy was highly successful at clearing positive margins. Additionally, positive margins and completion mastectomy rates significantly decreased over time. These findings highlight improvements in management of ILC, and suggest that completion mastectomy may not be required for those with positive margins after initial BCS