Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease indications. Here we compare the clinically approved IL-2 molecule, Proleukin, with two engineered IL-2 molecules with long half-lives owing to their fusion in monovalent and bivalent stoichiometry to a non-FcRγ binding human IgG1. Using nonhuman primates, we demonstrate that single ultra-low doses of IL-2 fusion proteins induce a prolonged state of in vivo activation that increases Tregs for an extended period of time similar to multiple-dose Proleukin. One of the common pleiotropic effects of high dose IL-2 treatment, eosinophilia, is eliminated at doses of the IL-2 fusion proteins that greatly expand Tregs. The long half-lives of the IL-2 fusion proteins facilitated a detailed characterization of an IL-2 dose response driving Treg expansion that correlates with increasingly sustained, suprathreshold pSTAT5a induction and subsequent sustained increases in the expression of CD25, FOXP3 and Ki-67 with retention of Treg-specific epigenetic signatures at FOXP3 and CTLA4.This work was supported by Wellcome Trust Grant 091157, JDRF International Grant 9-2011-253, the National Institute for Health Research Cambridge Biomedical Research Centre, and the Medical Research Council Cusrow Wadia Fund. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). U.M.N. was the recipient of a Hoffmann-La Roche postdoctoral fellowship.This is thefinal version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S089684111400146

Linear band pottery culture materials from site 8 in Zakrzów, Niepołomice municipality

Artykuł stanowi dalszą część opracowania wyników badań wykopaliskowych prowadzonych przez Muzeum Żup Krakowskich Wieliczka w Wieliczce (MŻKW) na wielokulturowym stanowisku archeologicznym nr 8 w Zakrzowie, gm. Niepołomice (AZP 103-58/24). Analizie poddano ślady osadnictwa neolitycznego reprezentującego kulturę ceramiki wstęgowej rytej (KCWR). Nieliczne obiekty kulturowe związane z tą fazą zasiedlenia, zarejestrowane podczas wykopalisk, są najprawdopodobniej pozostałościami jam o bliżej nieokreślonej funkcji gospodarczej, ulokowanych w pewnym oddaleniu od nierozpoznanej jeszcze w tym miejscu osady. Zachowane fragmenty ceramiki naczyniowej pozwoliły na powiązanie tych struktur z tzw. stylem zofipolskim, znanym m.in. z pobliskich stanowisk „autostradowych” usytuowanych na północnym skraju Pogórza Wielickiego. Odkrycia te stanowią istotny przyczynek do stanu wiedzy na temat wczesnych faz rozwojowych KCWR w dorzeczu górnej Wisły. Lokalizacja stanowiska w strefie obfitującej w źródła słone, a także zidentyfikowane ślady młodszego osadnictwa związanego z warzelnictwem solnym, skłaniają również do refleksji nad problematyką eksploatacji solanek już w początkach neolitu.This article is a continuation of the published results of Cracow Saltworks Museum in Wieliczka (Muzeum Żup Krakowskich Wieliczka – MŻKW)’s excavations at the multicultural archaeological site no. 8 in Zakrzów, Niepołomice municipality (AZP 103-58/24). Traces of Neolithic settlement representing the Linear Band Pottery culture (LBK) were analysed. Sparse cultural objects relating to this settlement phase, registered during the excavations, are most probably the remains of burrows serving an unspecified economic function, situated at a certain distance from a settlement not yet recognized at this site. Preserved fragments of vessel pottery permitted the linking of these structures with the socalled Zofipole style, known among others from the nearby ‘motorway’ sites situated on the north fringe of Wieliczka Foothills. These discoveries make an important contribution to our knowledge of the LBK’s early development stages in the upper Vistula estuary. The site’s location in an area replete with salty waters, as well as identified traces of younger settlement connected with saltworks, also prompt reflection on the use of salty waters already at the onset of the Neolithic age

What drives the dividend decisions in BRICS countries?

Research background: We examine the dividend payout policies across companies listed on the main stock exchanges in Brazil, Russia, India, China, and South Africa (BRICS). Unlike the highly developed capital markets, the literature regarding dividend policy on BRICS' stock exchanges is scarce.  Purpose of the article: The purpose of this paper is threefold: verification of the existence of dividend smoothing pattern; selection of the significant drivers that affect both dividend levels and dividend smoothing; examination of differences between dividend policy of cross- and single-listed companies. Methods: Based on a dataset of 564 companies that paid dividends for at least 11 consecutive years in the period of 1995-2015, we apply a GMM two-step estimator to assess the speed of dividend adjustment (SOA) coefficient. Further we employ the linear panel regression to indicate the individual and market determinants of the dividend levels and SOAs. In the latter case, we base on time series of the SOAs obtained from the rolling estimation technique. Finally, we conduct separate estimations for cross-listed companies. Findings & value added: We confirm a moderate level of dividend smoothing within BRICS countries. Among the firm-level characteristics affecting the SOA the most important are: ownership dispersion, age and size of a firm, retained earnings, leverage, long term debt, asset tangibility, liquidity risk ratio, and issuing the depositary receipts (DR). Two relevant market factors are found: market capitalisation and turnover in relation to GDP. Similar characteristics have a significant impact on dividends' levels in the entire sample, whereas in the subsample of cross-listed companies fewer variables are significant. Our paper is the first comprehensive attempt to investigate the dividend policy and determinants of dividend smoothing among BRICS countries

Serotoninergics Attenuate Hyperlocomotor Activity in Rats. Potential New Therapeutic Strategy for Hyperactivity

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such as amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMPreleases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) - induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP(attenuation of hyperlocomotion) were produced by m-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect of m-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD