New Paradigm in NKT Cell Antigens: MCS-0208 (2-(Hydroxymethyl)phenylthio-phytoceramide) – an Aryl-Phytoceramide Compound with a Single Hydroxyl Group Stimulates NKT Cells

Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS-0208, an unprecedented arylthioether-phytoceramide able to induce potent invariant NKT (iNKT) cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with α-galactosylceramide ( 1 ), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2’-OH and 3’-OH substituents are accepted as the minimal footprint and considered critical for NKT T cell receptor (TCR) recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation.     

Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.     

Evaluation of dynamic modulus measurement for C/C-SiC composites at different temperatures

The determination of elastic properties at application temperature is fundamental for the design of fibre reinforced ceramic composite components. An attractive method to characterize the flexural modulus at room and high temperature under specific atmosphere is the nondestructive Resonant Frequency Damping Analysis (RFDA). The objective of this paper was to evaluate and validate the modulus measurement via RFDA for orthotropic C/C-SiC composites at the application temperature. At room temperature flexural moduli of C/C-SiC with 0/90° reinforcement were measured under quasi-static 4-point bending loads and compared with dynamic moduli measured via RFDA longitudinally to fibre direction. The dynamic modulus of C/C-SiC was then measured via RFDA up to 1250°C under flowing inert gas and showed an increase with temperature which fitted with literature values. The measured fundamental frequencies were finally compared to those resulting from numerical modal analyses. Dynamic and quasi-static flexural moduli are comparable and the numerical analyses proved that bending modes are correctly modeled by means of dynamic modulus measured via RFDA. The nondestructive RFDA as well as the numerical modeling approach are suitable for evaluation of C/C-SiC and may be transferred to other fibre reinforced ceramic composite materials.     

Temperature stability of a pure metakaolin based K-geopolymer: Part 2. Variations in the mesoporous network and its rehydration stability

The thermal behavior of a model MK-based K-geopolymer was investigated between room temperature and 1400°C in order to evaluate its potentiality for high-temperature applications. The purpose of our study was to monitor the behavior of a geopolymer during a temperature rise in order to better understand its variations with respect to temperature. The works from the present paper focus only changes in the porous network; it follows a first part devoted to variations in the mineral matrix. The results obtained here show that the geopolymer material preserves its porous integrity up to 800°C, while maintaining the reversibility of water exchanges corresponding to about 25 weight percent. Together with the results of part 1, the findings of this study allow us to affirm that geopolymer materials are only very little affected by temperatures up to 800°C, or even 900°C (keeping its mesoporous amorphous structure).     

Nebulized Gadolinium‐Based Nanoparticles: A Theranostic Approach for Lung Tumor Imaging and Radiosensitization

Lung cancer is the most common and most fatal cancer worldwide. Thus, improving early diagnosis and therapy is necessary. Previously, gadolinium‐based ultra‐small rigid platforms (USRPs) were developed to serve as multimodal imaging probes and as radiosensitizing agents. In addition, it was demonstrated that USRPs can be detected in the lungs using ultrashort echo‐time magnetic resonance imaging (UTE‐MRI) and fluorescence imaging after intrapulmonary administration in healthy animals. The goal of the present study is to evaluate their theranostic properties in mice with bioluminescent orthotopic lung cancer, after intrapulmonary nebulization or conventional intravenous administration. It is found that lung tumors can be detected non‐invasively using fluorescence tomography or UTE‐MRI after nebulization of USRPs, and this is confirmed by histological analysis of the lung sections. The deposition of USRPs around the tumor nodules is sufficient to generate a radiosensitizing effect when the mice are subjected to a single dose of 10 Gy conventional radiation one day after inhalation (mean survival time of 112 days versus 77 days for irradiated mice without USRPs treatment). No apparent systemic toxicity or induction of inflammation is observed. These results demonstrate the theranostic properties of USRPs for the multimodal detection of lung tumors and improved radiotherapy after nebulization.     

On the Pre-oxidation Treatments of Four Commercial Ni-Based Superalloys in Air and in Ar–H<Subscript>2</Subscript>O at 950 °C

The short-term oxidation behaviour of RA 602CA, Inconel 693, Manaurite 40XO and Sumitomo 696, which are four alloys recommended for hydrocarbon processing, was studied both in air and in Ar–H₂O to determine the conditions of pre-oxidation treatments. Regardless of the considered material, the oxidation rate at 950 °C was systematically higher in Ar–H₂O than in dry air. Surface examination of the Al-containing alloys indicated that they were not uniformly oxidized all over the surface. All Al-containing alloys (from 1.6 to 3.2% wt) formed an external protective alumina scale and behaved as alumina-forming alloys in dry air at 950 °C. In contrast, these alloys developed a rate-controlling chromia scale and severe internal oxidation in a H₂O-containing atmosphere. Compared with their oxidation behaviour in air + H₂O, the phenomenon was significantly enhanced in the atmosphere that coupled water vapour with a low oxygen pressure. Consequently, the Al-containing alloys should not be pre-oxidized in a water vapour atmosphere prior to long exposure to a corrosive atmosphere. In contrast, the chromia-forming Al-free 696 alloy exhibited identical oxidation behaviour in both atmospheres, demonstrating that the degradation of this alloy was not significantly affected by water vapour.     

Quantification of grain boundary defect chemistry in a mixed proton-electron conducting oxide composite

Dual phase oxide membranes have shown promising hydrogen permeation fluxes in syngas applications due to their high mixed proton electron conduction (MPEC). However, the conductivity of grain boundaries can be many orders of magnitude lower than that of the bulk and so limits the total conductivity and hydrogen permeation. In this study, the three-dimensional nanoscale oxygen and cation distributions around grain and phase boundaries in a BaCe_0.8Y_0.2O_3-δ-Ce_0.8Y_0.2O_2-δ (BCY-YDC) membrane were quantified by atom probe tomography (APT) and related to average grain boundary conductivity measured by electrochemical impedance spectroscopy (EIS). Segregation varied among the general high-angle grain boundaries analyzed, but no trend from orientation analysis was determined. Correlative APT and electron energy loss spectroscopy (EELS) of one YDC grain boundary revealed composition and cerium valence information, respectively, allowing for the determination of vacancies at the grain boundary. While a specific MPEC membrane is characterized, the results are relevant to proton and electron conduction in a number of technologically important ceramics.     

Partial Sperm beta1 Integrin Subunit Deletion Proves Its Involvement in Mouse Gamete Adhesion/Fusion

We have previously shown, using antibodies, that the sperm alpha6beta1 integrin is involved in mouse gamete fusion in vitro. Here we report the conditional knockdown of the sperm Itgb1 gene. It induced a drastic failure of sperm fusogenic ability with sperm accumulation in the perivitelline space of in vitro inseminated oocytes deleted or not for the Itgb1 gene. These data demonstrate that sperm, but not oocyte, beta1 integrin subunit is involved in gamete adhesion/fusion. Curiously, knockdown males were fertile in vivo probably because of the incomplete Cre-mediated deletion of the sperm Itgb1 floxed gene. Indeed, this was shown by Western blot analysis and confirmed by both the viability and litter size of pups obtained by mating partially sperm Itgb1 deleted males with females producing completely deleted Itgb1 oocytes. Because of the total peri-implantation lethality of Itgb1 deletion in mice, we assume that sperm that escaped the Itgb1 excision seemed to be preferentially used to fertilize in vivo. Here, we showed for the first time that the deletion, even partial, of the sperm Itgb1 gene makes the sperm unable to normally fertilize oocytes. However, to elucidate the question of the essentiality of its role during fertilization, further investigations using a mouse expressing a recombinase more effective in male germ cells are necessary.