Dendritic cells activated with products released by schistosome larvae drive Th2-type immune responses, which can be inhibited by manipulation of CD40 costimulation

The early immune events in response to infective larvae of the parasitic helminth Schistosoma mansoni are poorly understood, but here for the first time we report on the potential of products released by schistosome larvae (material released in the first 3 It after transformation [0-3hRP]) to stimulate the maturation of dendritic cells (DC) and alter their T-cell-polarizing function. This was performed in comparison with lipopolysaccharide (LPS) and zymosan A, which classically activate DC to prime for Th1- and Th2-type responses, respectively. In our study, immature bone marrow-derived DC stimulated in vitro with 0-3hRP exhibited up-regulated expression of major histocompatibility complex class II, CD40, and CD86 and increased production of interleukin 12p40 (IL-12p40) and IL-6, albeit at lower levels than in response to LPS or zymosan A. Using an in vitro ovalbumin peptide-restricted priming assay, DC matured with 0-3hRP exhibited a potent capacity to drive Th2 polarization of CD4(+) cells from DO11.10 transgenic mice. This was characterized by increased IL-4 production (but not gamma interferon) of a magnitude similar to that primed by DC matured with zymosan A. Inoculation of DO11.10 mice with 0-3hRP-activated DC pulsed with ovalbumin peptide also led to the development of a Th2-type polarized response in the skin-draining lymph nodes and spleen. However, ligation of CD40 on DC by anti-CD40 antibody treatment reversed the ability of 0-3hRP-activated DC to prime for Th2-type responses and instead caused the induction of a more Th1-type response

1SXPS: A deep Swift X-ray Telescope point source catalog with light curves and spectra

We present the 1SXPS (Swift-XRT Point Source) catalog of 151,524 X-ray point-sources detected by the Swift-XRT in 8 years of operation. The catalog covers 1905 square degrees distributed approximately uniformly on the sky. We analyze the data in two ways. First we consider all observations individually, for which we have a typical sensitivity of ~3e-13 erg/cm2/s (0.3--10 keV). Then we co-add all data covering the same location on the sky: these images have a typical sensitivity of ~9e-14 erg/cm2/s (0.3--10 keV). Our sky coverage is nearly 2.5 times that of 3XMM-DR4, although the catalog is a factor of ~1.5 less sensitive. The median position error is 5.5" (90% confidence), including systematics. Our source detection method improves on that used in previous XRT catalogs and we report >68,000 new X-ray sources. The goals and observing strategy of the Swift satellite allow us to probe source variability on multiple timescales, and we find ~30,000 variable objects in our catalog. For every source we give positions, fluxes, time series (in four energy bands and two hardness ratios), estimates of the spectral properties, spectra and spectral fits for the brightest sources, and variability probabilities in multiple energy bands and timescales.Comment: 27 pages, 19 figures; accepted for publication in ApJS. The accompanying website, http://www.swift.ac.uk/1SXPS is live; the Vizier entry should be available shortl

Signaling via interleukin-4, receptor alpha chain is required for successful vaccination against schistosomiasis in BALB/c mice

Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1 and interleukin-1 (IL-1) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10/ mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40 cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia, consistent with their being antigen-presenting cells. Labeling of IL-12 cells for CD11c, CD205, CD8, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c F4/80, suggesting that macrophages were an additional source of IL-12 in the skin

Piperazine-based N4-type 16-membered macroheterocycles and their nickel(II) complexes

Square-planar diamagnetic nickel(II) complexes 5a and 5b containing 16-membered diamino-diimino ligands were prepared from the corresponding open-chain complexes 2a and 2b via condensation with o-phthalic dialdehyde in methanol. The solid-state structure of the starting complex 2b revealed the cisoid conformation of aryl groups compared to the transoid one found in the case of 2a. At the same time, the cisoid conformation is not retained in acetone solution: rather, the tert-Bu-substituted complex 2b was fully transformed into the trans form whereas its analogue 2aexhibits both cis and transforms in acetone solution. The cisoid conformation was also observed for the cyclic structures 5a and 5b by X-ray analysis and VT NMR experiments. The borohydride reduction of 5a with subsequent cyanide-assisted removal of nickel led to a new 16-membered tetraazamacrocycle 6. Its X-ray structure showed a cisoid conformation supported by two intramolecular hydrogen bonds that was also sustained in solution. VT NMR experiments revealed the degenerative interconvertion of a macrocycle with activation energy ca. 41.9±0.8 kJ/mol

Finite-size effects for anisotropic bootstrap percolation: logarithmic corrections

In this note we analyze an anisotropic, two-dimensional bootstrap percolation model introduced by Gravner and Griffeath. We present upper and lower bounds on the finite-size effects. We discuss the similarities with the semi-oriented model introduced by Duarte.Comment: Key words: Bootstrap percolation, anisotropy, finite-size effect

Is \gamma-ray emission from novae affected by interference effects in the 18F(p,\alpha)15O reaction?

The 18F(p,\alpha)15O reaction rate is crucial for constraining model predictions of the \gamma-ray observable radioisotope 18F produced in novae. The determination of this rate is challenging due to particular features of the level scheme of the compound nucleus, 19Ne, which result in interference effects potentially playing a significant role. The dominant uncertainty in this rate arises from interference between J\pi=3/2+ states near the proton threshold (Sp = 6.411 MeV) and a broad J\pi=3/2+ state at 665 keV above threshold. This unknown interference term results in up to a factor of 40 uncertainty in the astrophysical S-factor at nova temperatures. Here we report a new measurement of states in this energy region using the 19F(3He,t)19Ne reaction. In stark contrast with previous assumptions we find at least 3 resonances between the proton threshold and Ecm=50 keV, all with different angular distributions. None of these are consistent with J\pi= 3/2+ angular distributions. We find that the main uncertainty now arises from the unknown proton-width of the 48 keV resonance, not from possible interference effects. Hydrodynamic nova model calculations performed indicate that this unknown width affects 18F production by at least a factor of two in the model considered.Comment: 5 pages, 4 figures. Accepted for publication in Phys. Rev. Let

Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia

Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis. Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D2 (PGD2) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ12,14 PGJ2 (15d-PGJ2). BEZ increased PGD2 synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ2 by inhibiting the PGD2 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD2 to 9α11β-PGF2α. B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ2. Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors. Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ2. These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML

The Mannose Receptor (CD206) is an important pattern recognition receptor (PRR) in the detection of the infective stage of the helminth Schistosoma mansoni and modulates IFNγ production.

In this study, infective larvae of the parasitic helminth Schistosoma mansoni were shown to contain a large number of glycosylated components specific for the Mannose Receptor (MR; CD206), which is an important pattern recognition receptor (PRR) of the innate immune system. MR ligands were particularly rich in excretory/secretory (E/S) material released during transformation of cercariae into schistosomula, a process critical for infection of the host. E/S material from carboxyfluorescein diacetate succinimidyl ester (CFDA-SE)-labelled cercariae showed enhanced binding by cells lines that over-express the MR. Conversely, uptake was significantly lower by bone marrow-derived macrophages (MΦ) from MR(-/-) mice, although they were more active as judged by enhanced pro-inflammatory cytokine production and CD40 expression. After natural percutaneous infection of MR(-/-) mice with CFDA-SE-labelled parasites, there were fewer cells in the skin and draining lymph nodes that were CFDA-SE(+) compared with wild-type mice, implying reduced uptake and presentation of larval parasite antigen. However, antigen-specific proliferation of skin draining lymph node cells was significantly enhanced and they secreted markedly elevated levels of IFNγ but decreased levels of IL-4. In conclusion, we show that the MR on mononuclear phagocytic cells, which are plentiful in the skin, plays a significant role in internalising E/S material released by the invasive stages of the parasite which in turn modulates their production of pro-inflammatory cytokines. In the absence of the MR, antigen-specific CD4(+) cells are Th1 biased, suggesting that ligation of the MR by glycosylated E/S material released by schistosome larvae modulates the production of CD4(+) cell specific IFNγ