Low-temperature rate constants for rotational excitation and de-excitation of C3 (X 1∑g +) by collisions with He (1S)

The low-temperature rotational (de-) excitation of C3 (X 1∑g 1) by collisions with He (1S) is studied using an ab initio potential energy surface (PES). This PES has been calculated using the single- and double-excitation coupled-cluster approach with noniterative perturbational treatment of triple excitations [CCSD(T)] and the augmented correlation-consistent triple-ζ basis set (aug-cc-pVTZ) with bond functions. This PES is then incorporated in full close-coupling quantum scattering calculations for collision energies between 0.1 and 50 cm -1 in order to deduce the rate constants for rotational levels of C3 up to j = 10, covering the temperature range 5-15 K. © 2008. The American Astronomical Society. All rights reserved.The Agencia Española de Cooperación Internacional (project A/8083/07, CSIC-Université Tunis El Manar) and the Spanish Ministerio de Educación y Ciencia (project AYA 2005-00702) are thanked for financial supportPeer Reviewe

A hydrogel based on lipid nanocapsules to kill residual glioblastoma cells after surgical resection - GLIOGEL - 8th Joint Call of EuroNanoMed3 (ERA-Net)

Despite their low prevalence (annual global incidence of 5 cases out of 100,000 in the European Union and United States), glioblastoma (GBM), malignant brain tumours, result in high morbidity and mortality. Due to recurrences from infiltrating GBM cells at the border of resection, the median survival is 14 months with the current standard of care (surgical resection combined with adjuvant radiotherapy and/or chemotherapy). The objective of this research project is to develop an implantable hydrogel technology which will bridge the current therapeutic needs between surgical resection and initiation of systemic regimens. In this project, a polymer-free hydrogel prepared from biodegradable lipid nanocapsules (LNCs) will act as a sustained-release matrix to deliver targeted therapeutic nanoparticles specifically to cancer cells. This technology is expected to limit GBM recurrences by i) maintaining therapeutic concentrations of anticancer drugs at the resection border (without the necessity of crossing the blood-brain barrier) and ii) targeting GBM cells specifically using a unique proprietary targeting peptide (NFL-TBS.40-63) (NFL).Preliminary data shows that the peptide NFL can adsorb at the surface of LNCs. This surface functionalization can be used to target drug-loaded LNCs to GBM cells in vivo, and achieve therapeutic efficacy. In parallel, when using a crosslinking agent, LNCs can self-associate in a network forming a polymer-free hydrogel. When loaded with drugs, this hydrogel can provide sustained release and improve in vivo therapeutic efficacy compared to the drug alone. The GLIOGEL project will combine these two independent technologies to create unique synergy and to address an existing clinical need

Continuum and line modeling of disks around young stars II. Line diagnostics for GASPS from the DENT grid

Aims. We want to understand the chemistry and physics of disks on the basis of a large unbiased and statistically relevant grid of disk models. One of the main goals is to explore the diagnostic power of various gas emission lines and line ratios for deriving main disk parameters such as the gas mass. Methods. We explore the results of the DENT grid (Disk Evolution with Neat Theory) that consists of 300 000 disk models with 11 free parameters. Through a statistical analysis, we search for correlations and trends in an effort to find tools for disk diagnostic. Results. All calculated quantities like species masses, temperatures, continuum and line fluxes differ by several orders of magnitude across the entire parameter space. The broad distribution of these quantities as a function of input parameters shows the limitation of using a prototype T Tauri or Herbig Ae/Be disk model. The statistical analysis of the DENT grid shows that CO gas is rarely the dominant carbon reservoir in disks. Models with large inner radii (10 times the dust condensation radius) and/or shallow surface density gradients lack massive gas phase water reservoirs. Also, 60% of the disks have gas temperatures averaged over the oxygen mass in the range between 15 and 70 K; the average gas temperatures for CO and O differ by less than a factor two. Studying the observational diagnostics, the [CII] 158 \mum fine structure line flux is very sensitive to the stellar UV flux and presence of a UV excess and it traces the outer disk radius (Rout). In the submm, the CO low J rotational lines also trace Rout. Low [OI] 63/145 line ratios (< a few) can be explained with cool atomic O gas in the uppermost surface layers leading to self-absorption in the 63 \mum line; this occurs mostly for massive non-flaring, settled disk models without UV excess. ... abbreviatedComment: 15 pages, 25 figures, accepted for publication in A&

Surface-functionalization with NFL peptide of Lipid NanoCapsules LNC: preferential entry into human glioblastoma cells

Glioblastoma (GBM) is one of the most fatal brain cancers with median survival of only 14.6 months. Hence, more efficacious therapies are necessary. Ferrocifen (FcTriOH) is an organometallic antitumor compound, selectively active on cancer cells [1]. However, this metallocomplexe is highly insoluble in water, requiring a formulation stage before being in vivo administered. Lipid nanocapsules (LNC), prepared via a solvent free process of emulsion phase inversion, could be a suitable vehicle for FcTriOH [2]. Moreover, NFL peptide is able to enter massively into glioblastoma cells, and poorly in healthy neurons and astrocytes (NHA) [3]. Indeed, the aim of the study was to evaluate the effect of the surface-functionalizing NFL concentrations on LNC uptake in U87MG human GBM cells. Moreover, FcTriOH was encapsulated in LNC and their in vitro efficacy on U87MG cells was evaluated. Finally, in vivo antitumor effect was evaluated in ectopic and orthotopic murine U87MG tumor models. Fluorescent LNC (F1), LNC with 0.86% w/w and LNC with 2.58% w/w surface-adsorbed NFL (F2 and F3 respectively) were prepared and characterized. FACS analysis revealed that cellular uptake of F3 into U87MG cells was 31.5 and 1.6-folds higher after 6 h compared to F1 and F2 respectively. Moreover, uptake of F3 was significantly higher in the GBM cells compared to NHA, whereas F1 was internalized preferentially in NHA. Uptake of F3 in U87MG cells was energy dependent. Macropinocytosis was possibly the major uptake pathway, followed by clathrin-dependent endocytosis. Then, FcTriOH loaded LNCs have been successfully prepared with a drug loading of 2.4 % and an encapsulation efficacy of 99 %. MTS assay on U87MG cells revealed an IC50 of 0.46 µM for F3-FcTriOH (free FcTriOH: IC50 = 1.31 µM). Preliminary in vivo experiments on subcutaneous U87MG tumor bearing nude mice showed significantly reduced relative tumor volume after two intravenous injections of F1-FcTriOH and F3-FcTriOH compared to saline. Moreover, intracranial administration of F3/F3-FcTriOH in orthotopic U87MG tumor bearing mice revealed 2 to 3-folds higher apparent diffusion coefficients (ADC) near the injection site in diffusion tensor imaging, compared to F1/F1-FcTriOH. Although dose adjustment will be necessary to avoid toxic effects, the results are promising as therapy induced increased ADC values could indicate possible cell necrosis/lysis.   References [1] Laine A.L. et al. (2014), Nanomedicine, 10, pp.1667-1677. [2] Heurtault B. et al. (2003), EJPS, 8, pp. 55-61. [3] Balzeau J. et al. (2013), Biomaterials, 34, pp.3381-3389

Enhanced internalization of lipid nanocapsules in human glioblastoma cells: Influence of the concentration of surface-functionalizing NFL peptide

Glioblastoma multiforme (GBM) patients have median survival of 14 months after current treatments. Therefore, more efficacious therapies are necessary. Lipid nanocapsules (LNC) functionalized with NFL.TBS-40.63 peptide (NFL) showed enhanced internalization in mouse GBM cells. The aim of the study was to evaluate the effect of the surface-functionalizing FAM-NFL (fluoNFL) concentrations on LNC uptake in U87MG human GBM cells. A ferrocifen-type anticancer molecule (FcTriOH) was encapsulated in the nanocarriers and their in vitro efficacy on U87MG cells was evaluated. Finally, in vivo antitumor effect of the formulations were evaluated in ectopic U87MG tumor model in mice

Vibrio cholerae Proteome-Wide Screen for Immunostimulatory Proteins Identifies Phosphatidylserine Decarboxylase as a Novel Toll-Like Receptor 4 Agonist

Recognition of conserved bacterial components provides immediate and efficient immune responses and plays a critical role in triggering antigen-specific adaptive immunity. To date, most microbial components that are detected by host innate immune system are non-proteinaceous structural components. In order to identify novel bacterial immunostimulatory proteins, we developed a new high-throughput approach called “EPSIA”, Expressed Protein Screen for Immune Activators. Out of 3,882 Vibrio cholerae proteins, we identified phosphatidylserine decarboxylase (PSD) as a conserved bacterial protein capable of activating host innate immunity. PSD in concentrations as low as 100 ng/ml stimulated RAW264.7 murine macrophage cells and primary peritoneal macrophage cells to secrete TNFα and IL-6, respectively. PSD-induced proinflammatory response was dependent on the presence of MyD88, a known adaptor molecule for innate immune response. An enzymatically inactive PSD mutant and heat-inactivated PSD induced ∼40% and ∼15% of IL-6 production compared to that by native PSD, respectively. This suggests that PSD induces the production of IL-6, in part, via its enzymatic activity. Subsequent receptor screening determined TLR4 as a receptor mediating the PSD-induced proinflammatory response. Moreover, no detectable IL-6 was produced in TLR4-deficient mouse macrophages by PSD. PSD also exhibited a strong adjuvant activity against a co-administered antigen, BSA. Anti-BSA response was decreased in TLR4-deficient mice immunized with BSA in combination with PSD, further proving the role of TLR4 in PSD signaling in vivo. Taken together, these results provide evidence for the identification of V. cholerae PSD as a novel TLR4 agonist and further demonstrate the potential application of PSD as a vaccine adjuvant

Specific Evolution of F1-Like ATPases in Mycoplasmas

F1F0 ATPases have been identified in most bacteria, including mycoplasmas which have very small genomes associated with a host-dependent lifestyle. In addition to the typical operon of eight genes encoding genuine F1F0 ATPase (Type 1), we identified related clusters of seven genes in many mycoplasma species. Four of the encoded proteins have predicted structures similar to the α, β, γ and ε subunits of F1 ATPases and could form an F1-like ATPase. The other three proteins display no similarity to any other known proteins. Two of these proteins are probably located in the membrane, as they have three and twelve predicted transmembrane helices. Phylogenomic studies identified two types of F1-like ATPase clusters, Type 2 and Type 3, characterized by a rapid evolution of sequences with the conservation of structural features. Clusters encoding Type 2 and Type 3 ATPases were assumed to originate from the Hominis group of mycoplasmas. We suggest that Type 3 ATPase clusters may spread to other phylogenetic groups by horizontal gene transfer between mycoplasmas in the same host, based on phylogeny and genomic context. Functional analyses in the ruminant pathogen Mycoplasma mycoides subsp. mycoides showed that the Type 3 cluster genes were organized into an operon. Proteomic analyses demonstrated that the seven encoded proteins were produced during growth in axenic media. Mutagenesis and complementation studies demonstrated an association of the Type 3 cluster with a major ATPase activity of membrane fractions. Thus, despite their tendency toward genome reduction, mycoplasmas have evolved and exchanged specific F1-like ATPases with no known equivalent in other bacteria. We propose a model, in which the F1-like structure is associated with a hypothetical X0 sector located in the membrane of mycoplasma cells