Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2-and Tr1-biased T-cell immunity

Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatin-treated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-kappa B signaling pathways without altering the levels of TNF-alpha and IL-12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10(-/-) mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3(+)CD4(+)LAG-3(+)CD49b(+)CD25(-)Foxp3(-) Tr1 cells, that was significantly increased without altering the Foxp3(+) regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonist-induced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system.1123Ysciescopu

Synthetically tuneable biomimetic artificial photosynthetic reaction centres that closely resemble the natural system in purple bacteria

© 2016 The Royal Society of Chemistry. Porphyrin-based photosynthetic reaction centre (PRC) mimics, ZnPQ-Q2HP-C60 and MP2Q-Q2HP-C60 (M = Zn or 2H), designed to have a similar special-pair electron donor and similar charge-separation distances, redox processes and photochemical reaction rates to those in the natural PRC from purple bacteria, have been synthesised and extensive photochemical studies performed. Mechanisms of electron-transfer reactions are fully investigated using femtosecond and nanosecond transient absorption spectroscopy. In benzonitrile, all models show picosecond-timescale charge-separations and the final singlet charge-separations with the microsecond-timescale. The established lifetimes are long compared to other processes in organic solar cells or other organic light harvesting systems. These rigid, synthetically flexible molecules provide the closest mimics to the natural PRC so far synthesised and present a future direction for the design of light harvesters with controllable absorption, redox, and kinetics properties

Surface modification of HVOF thermal sprayed WC–CoCr coatings by laser treatment

In this work the affects of laser characteristics on microstructure and microhardness of high velocity oxygen fuel sprayed (HVOF) WC–CoCr coatings were investigated. The coating was deposited with a Sulzer Metco WokaJet™-400 kerosene fuel and the laser surface treatments were applied using CO2 laser with 10.6 μm wavelength. Large variations in surface properties were produced from variation in the laser processing parameters. In total, four levels of peak power (100, 200, 300 and 350 W), four levels of spot diameter (0.2, 0.4, 0.6 and 1 mm) and three levels of pulse repetition frequency (PRF) were investigated. An initial set of tests were followed by a more detailed 33 factorial design of experiments. Pulse repetition frequency and duty cycle were set in order to maintain the same overlap in the x and y directions for the raster scanned sample spot impact dimensions. Overlaps of 30% were used in the initial tests and 10% in the more detailed trials. The results have shown that care must be taken to keep the irradiance at a relatively low level compared to uncoated surfaces. High irradiance can in this case result in rough and porous surfaces. Lower levels of irradiance are shown to provide more uniform microstructures, reduced porosity and increased microhardness

Exploiting disorder for perfect focusing

We demonstrate experimentally that disordered scattering can be used to improve, rather than deteriorate, the focusing resolution of a lens. By using wavefront shaping to compensate for scattering, light was focused to a spot as small as one tenth of the diffraction limit of the lens. We show both experimentally and theoretically that it is the scattering medium, rather than the lens, that determines the width of the focus. Despite the disordered propagation of the light, the profile of the focus was always exactly equal to the theoretical best focus that we derived.Comment: 4 pages, 4 figure

Solving the Topological String on K3 Fibrations

We present solutions of the holomorphic anomaly equations for compact two-parameter Calabi-Yau manifolds which are hypersurfaces in weighted projective space. In particular we focus on K3-fibrations where due to heterotic type II duality the topological invariants in the fibre direction are encoded in certain modular forms. The formalism employed provides holomorphic expansions of topological string amplitudes everywhere in moduli space.Comment: 60 pages, 1 figure, With an appendix by Sheldon Kat

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels

Scientific complications and controversies noted in the field of CdS/CdTe thin film solar cells and the way forward for further development

Cadmium telluride-based solar cell is the most successfully commercialised thin film solar cell today. The laboratory-scale small devices have achieved ~ 22%, and commercial solar panels have reached ~ 18% conversion efficiencies. However, there are various technical complications and some notable scientific contradictions that appear in the scientific literature published since the early 1970s. This review paper discusses some of these major complications and controversies in order to focus future research on issues of material growth and characterisation, post-growth processing, device architectures and interpretation of the results. Although CdTe can be grown using more than 14 different growth techniques, successful commercialisation has been taken place using close-space sublimation and electrodeposition techniques only. The experimental results presented in this review are mainly based on electrodeposition. Historical trends of research and commercial successes have also been discussed compared to the timeline of novel breakthroughs in this field. Deeper understanding of these issues may lead to further increase in conversion efficiencies of this solar cell. Some novel ideas for further development of thin film solar cells are also discussed towards the end of this paper

Time delay between images of the lensed quasar UM673

We study brightness variations in the double lensed quasar UM673 (Q0142-100) with the aim of measuring the time delay between its two images. In the paper we combine our previously published observational data of UM673 obtained during the 2003 - 2005 seasons at the Maidanak Observatory with archival and recently observed Maidanak and CTIO UM673 data. We analyze the V, R and I-band light curves of the A and B images of UM673, which cover ten observational seasons from August 2001 to November 2010. We also analyze the time evolution of the difference in magnitudes between images A and B of UM673 over more than ten years. We find that the quasar exhibits both short-term (with amplitude of \sim 0.1 mag in the R band) and high-amplitude (\sim 0.3 mag) long-term variability on timescales of about several months and several years, respectively. These brightness variations are used to constrain the time delay between the images of UM673. From cross-correlation analysis of the A and B quasar light curves and error analysis we measure the mean time delay and its error of 89 \pm11 days. Given the input time delay of 88 days, the most probable value of the delay that can be recovered from light curves with the same statistical properties as the observed R-band light curves of UM673 is 95{+5/-16}{+14/-29} days (68 and 95 % confidence intervals). Analysis of the V - I color variations and V, R and I-band magnitude differences of the quasar images does not show clear evidence of the microlensing variations between 1998 and 2010.Comment: Submitted to A&A, 11 pages, 9 figure

Improvement of composition of CdTe thin films during heat treatment in the presence of CdCl2

CdCl2 treatment is a crucial step in development of CdS/CdTe solar cells. Although this rocessing step has been used over a period of three decades, full understanding is not yet achieved. This paper reports the experimental evidence for improvement of composition of CdTe layers during CdCl2 treatment. This investigation makes use of four selected analytical techniques; Photo-electro-chemical (PEC) cell, X-ray diffraction (XRD), Raman spectroscopy and Scanning electron microscopy (SEM). CdTe layers used were electroplated using three Cd precursors; CdSO4, Cd(NO3)2 and CdCl2. Results show the improvement of stoichiometry of CdTe layers during CdCl2 treatment through chemical reaction between Cd from CdCl2 and elemental Te that usually precipitate during CdTe growth, due to its natural behaviour. XRD and SEM results show that the low-temperature (~85ºC) electroplated CdTe layers consist of ~(20-60) nm size crystallites, but after CdCl2 treatment, the layers show drastic recrystallisation with grains becoming a few microns in size. These CdCl2 treated layers are then comparable to high temperature grown CdTe layers by the size of grains

Salmonella typhimurium Suppresses Tumor Growth via the Pro-Inflammatory Cytokine Interleukin-1 beta

Although strains of attenuated Salmonella typhimurium and wild-type Escherichia coli show similar tumor-targeting capacities, only S. typhimurium significantly suppresses tumor growth in mice. The aim of the present study was to examine bacteria-mediated immune responses by conducting comparative analyses of the cytokine profiles and immune cell populations within tumor tissues colonized by E. coli or attenuated Salmonellae. CT26 tumor-bearing mice were treated with two different bacterial strains: S. typhimurium defective in ppGpp synthesis (Delta ppGpp Salmonellae) or wild-type E. coli MG1655. Cytokine profiles and immune cell populations in tumor tissue colonized by these two bacterial strains were examined at two time points based on the pattern of tumor growth after Delta ppGpp Salmonellae treatment: 1) when tumor growth was suppressed ('suppression stage') and 2) when they began to re-grow ('re-growing stage'). The levels of IL-1 beta and TNF-alpha were markedly increased in tumors colonized by Delta ppGpp Salmonellae. This increase was associated with tumor regression; the levels of both IL-1 beta and TNF-alpha returned to normal level when the tumors started to re-grow. To identify the immune cells primarily responsible for Salmonellae-mediated tumor suppression, we examined the major cell types that produce IL-1 beta and TNF-alpha. We found that macrophages and dendritic cells were the main producers of TNF-alpha and IL-1 beta. Inhibiting IL-1 beta production in Salmonellae-treated mice restored tumor growth, whereas tumor growth was suppressed for longer by local administration of recombinant IL-1 beta or TNF-alpha in conjunction with Salmonella therapy. These findings suggested that IL-1 beta and TNF-alpha play important roles in Salmonella-mediated cancer therapy. A better understanding of host immune responses in Salmonella therapy may increase the success of a given drug, particularly when various strategies are combined with bacteriotherapy.111715Ysciescopu