Dysregulated NK cell PLCγ2 signaling and activity in juvenile dermatomyositis

Juvenile dermatomyositis (JDM) is a debilitating pediatric autoimmune disease manifesting with characteristic rash and muscle weakness. To delineate signaling abnormalities in JDM, mass cytometry was performed with PBMCs from treatment-naive JDM patients and controls. NK cell percentages were lower while frequencies of naive B cells and naive CD4+ T cells were higher in JDM patients than in controls. These cell frequency differences were attenuated with cessation of active disease. A large number of signaling differences were identified in treatment-naive JDM patients compared with controls. Classification models incorporating feature selection demonstrated that differences in phospholipase Cγ2 (PLCγ2) phosphorylation comprised 10 of 12 features (i.e., phosphoprotein in a specific immune cell subset) distinguishing the 2 groups. Because NK cells represented 5 of these 12 features, further studies focused on the PLCγ2 pathway in NK cells, which is responsible for stimulating calcium flux and cytotoxic granule movement. No differences were detected in upstream signaling or total PLCγ2 protein levels. Hypophosphorylation of PLCγ2 and downstream mitogen-activated protein kinase-activated protein kinase 2 were partially attenuated with cessation of active disease. PLCγ2 hypophosphorylation in treatment-naive JDM patients resulted in decreased calcium flux. The identification of dysregulation of PLCγ2 phosphorylation and decreased calcium flux in NK cells provides potential mechanistic insight into JDM pathogenesis

Circumgalactic Gas at Its Extreme : Tidal Gas Streams around the Whale Galaxy NGC 4631 Explored with HST/COS

We present a detailed analysis of the absorption properties of one of the tidal gas streams around the "Whale" galaxy NGC 4631 in the direction of the quasar 2MASS J12421031+3214268. Our study is based on ultraviolet spectral data obtained with the Cosmic Origins Spectrograph (COS) on board the Hubble Space Telescope (HST) and 21cm-data from the HALOGAS project and the Green Bank Telescope (GBT). We detect strong H I Ly alpha absorption in the velocity range +550 to +800 km s(-1) related to gas from a NGC 4631 tidal stream known as Spur 2. We measure a column density of log (N(H I/cm(-2))) = 18.68 +/- 0.15, indicating that the quasar sightline traces the outer boundary of Spur 2 as seen in the 21 cm data. Metal absorption in Spur 2 is detected in the lines of O I, C II, Si II, and Si III in a complex absorption pattern that reflects the multiphase nature of the gas. We find that the average neutral gas fraction in Spur 2 toward 2MASS J12421031+3214268 is only 14%. This implies that ionized gas dominates the total mass of Spur 2, which then may comprise more than 10(9)M(circle dot). No significant depletion of Si is observed, showing that Spur 2 does not contain significant amounts of dust. From the measured O I/H I column density ratio, we determine an alpha abundance in Spur 2 of 0.131(-0.05)(+0.07) solar ([alpha/H] = -0.90 +/- 0.16), which is substantially lower than what is observed in the NGC 4631 disk. The low metallicity and low dust content suggest that Spur 2 represents metal-deficient gas stripped off a gas-rich satellite galaxy during a recent encounter with NGC 4631.Peer reviewe

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

Polyarticular juvenile idiopathic arthritis (JIA) is among the most challenging of the JIA subtypes to treat. Even with current biologic therapies, the disease remains difficult to control in a substantial subset of patients, highlighting the need for new therapies. The aim of this study was to use the high dimensionality afforded by mass cytometry with phospho-specific antibodies to delineate signaling abnormalities in immune cells from treatment-naive polyarticular JIA patients. Peripheral blood mononuclear cells were isolated from 17 treatment-naive polyarticular JIA patients, 10 of the patients after achieving clinical remission, and 19 healthy controls. Samples were stimulated for 15 minutes with IL-6 or IFN-γ and analyzed by mass cytometry. Following IFN-γ stimulation, increased STAT1 and/or STAT3 phosphorylation was observed in subsets of CD4 T cells and classical monocytes from treatment-naive patients. The enhanced IFN-γ signaling was associated with increased expression of JAK1 and SOCS1 in CD4 T cells. Furthermore, substantial heterogeneity in surface marker expression was observed among the subsets of CD4 T cells and classical monocytes with increased IFN-γ responsiveness. The identification of enhanced IFN-γ signaling in CD4 T cells and classical monocytes from treatment-naive polyarticular JIA patients provides mechanistic support for investigations into therapies that attenuate IFN-γ signaling in this disease

The Ethnic 'Other' in Ukrainian History Textbooks: The Case of Russia and the Russians

This paper examines portrayals of Russia and the Russians in two generations of Ukrainian history textbooks. It observes that the textbooks are highly condemning of Ukraine's main ethnic other in the guise of foreign ruler: the tsarist authorities and the Soviet regime are always attributed dubious and malicious intentions even if there is appreciation for some of their policies. By contrast, the books, certainly those of the second generation, refrain from presenting highly biased accounts of the ethnic other as a national group (i.e. Russians). Instances where negative judgements do fall onto Russians are counterbalanced by excerpts criticizing ethnic Ukrainians or highlighting conflicting interests within the Ukrainian ethnic group. The negative appraisal of the ethnic other as foreign ruler is clearly instrumental for the nation-building project as it sustains a discourse legitimating the existence of Ukraine as independent state. However, recent trends in history education, the paper concludes, suggest that the importance of nurturing patriotism as a national policy objective is diminishing

Creating comprehensive, youth-centered culturally appropriate sex education: What do young gay, bisexual and questioning men want?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106604/1/Creating comprehensive, youth-centered culturally appropriate sex education What do young gay, bisexual and questioning men want.pd

Physico-chemical foundations underpinning microarray and next-generation sequencing experiments

Hybridization of nucleic acids on solid surfaces is a key process involved in high-throughput technologies such as microarrays and, in some cases, next-generation sequencing (NGS). A physical understanding of the hybridization process helps to determine the accuracy of these technologies. The goal of a widespread research program is to develop reliable transformations between the raw signals reported by the technologies and individual molecular concentrations from an ensemble of nucleic acids. This research has inputs from many areas, from bioinformatics and biostatistics, to theoretical and experimental biochemistry and biophysics, to computer simulations. A group of leading researchers met in Ploen Germany in 2011 to discuss present knowledge and limitations of our physico-chemical understanding of high-throughput nucleic acid technologies. This meeting inspired us to write this summary, which provides an overview of the state-of-the-art approaches based on physico-chemical foundation to modeling of the nucleic acids hybridization process on solid surfaces. In addition, practical application of current knowledge is emphasized