Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.

Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesity.

OBJECTIVE: Although debated, metabolic health characterizes 10-25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown. METHODS: Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases. RESULTS AND CONCLUSIONS: Our study showed that glucose intolerance and insulin resistance co-operate to remodel adipocyte transcriptome. We also identified the Nuclear Export Mediator Factor (NEMF) and the Ectoderm-Neural Cortex 1 (ENC1) as novel potential targets in the management of metabolic health in human obesity.

Towards High Capacity Li-ion Batteries Based on Silicon-Graphene Composite Anodes and Sub-micron V-doped LiFePO4 Cathodes.

Lithium iron phosphate, LiFePO4 (LFP) has demonstrated promising performance as a cathode material in lithium ion batteries (LIBs), by overcoming the rate performance issues from limited electronic conductivity. Nano-sized vanadium-doped LFP (V-LFP) was synthesized using a continuous hydrothermal process using supercritical water as a reagent. The atomic % of dopant determined the particle shape. 5 at. % gave mixed plate and rod-like morphology, showing optimal electrochemical performance and good rate properties vs. Li. Specific capacities of >160 mAh g-1 were achieved. In order to increase the capacity of a full cell, V-LFP was cycled against an inexpensive micron-sized metallurgical grade Si-containing anode. This electrode was capable of reversible capacities of approximately 2000 mAh g-1 for over 150 cycles vs. Li, with improved performance resulting from the incorporation of few layer graphene (FLG) to enhance conductivity, tensile behaviour and thus, the composite stability. The cathode material synthesis and electrode formulation are scalable, inexpensive and are suitable for the fabrication of larger format cells suited to grid and transport applications.

Direct and continuous synthesis of VO2 nanoparticles.

Monoclinic VO2 nanoparticles are of interest due to the material's thermochromic properties, however, direct synthesis routes to VO2 nanoparticles are often inaccessible due to the high synthesis temperatures or long reaction times required. Herein, we present a two-step synthesis route for the preparation of monoclinic VO2 nanoparticles using Continuous Hydrothermal Flow Synthesis (CHFS) followed by a short post heat treatment step. A range of particle sizes, dependent on synthesis conditions, were produced from 50 to 200 nm by varying reaction temperatures and the residence times in the process. The nanoparticles were characterised by powder X-ray diffraction, Raman and UV/Vis spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The nanoparticles were highly crystalline with rod and sphere-like morphologies present in TEM micrographs, with the size of both the rod and spherical particles being highly dependent on both reaction temperature and residence time. SEM micrographs showed the surface of the powders produced from the CHFS process to be highly uniform. The samples were given a short post synthesis heat treatment to ensure that they were phase pure monoclinic VO2, which led to them exhibiting a large and reversible switch in optical properties (at near-IR wavelengths), which suggests that if such materials can be incorporated into coatings or in composites, they could be used for fenestration in architectural applications.

Bio-inspired CO2 conversion by iron sulfide catalysts under sustainable conditions.

The mineral greigite presents similar surface structures to the active sites found in many modern-day enzymes. We show that particles of greigite can reduce CO2 under ambient conditions into chemicals such as methanol, formic, acetic and pyruvic acid. Our results also lend support to the Origin of Life theory on alkaline hydrothermal vents.

Loss of IGFBP7 expression and persistent AKT activation contribute to SMARCB1/Snf5-mediated tumorigenesis.

SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in malignant rhabdoid tumors (MRT) and atypical teratoid/rhabdoid tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. SMARCB1 is a core subunit of Swi/Snf chromatin remodeling complexes, and loss of SMARCB1 or other subunits of these complexes has been observed in a variety of tumor types. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors, which developed in Smarcb1 heterozygous p53(-/-) mice. We find that while re-introduction of Smarcb1 does not induce growth arrest, it restores sensitivity to programmed cell death and completely abolishes the ability of the tumor cells to grow as xenografts. We describe persistent activation of AKT signaling in Smarcb1-deficient cells, which stems from PI3K (phosphatidylinositol 3'-kinase)-mediated signaling and which contributes to the survival and proliferation of the tumor cells. We further demonstrate that inhibition of AKT is effective in preventing proliferation of Smarcb1-deficient cells in vitro and inhibits the development of xenografted tumors in vivo. Profiling Smarcb1-dependent gene expression, we find genes that require Smarcb1 and Swi/Snf for their expression to be enriched for extracellular matrix and cell adhesion functions. We find that Smarcb1 is required for transcriptional activation of Igfbp7, a member of the insulin-like growth factor-binding proteins family and a tumor suppressor in itself, and show that re-introduction of Igfbp7 alone can hinder tumor development. Our results define a novel mechanism for Smarcb1-mediated tumorigenesis and highlight potential therapeutic targets.

Synthesis of poly(sebacic anhydride)-indomethacin controlled release composites via supercritical carbon dioxide assisted impregnation.

Poly(sebacic anhydride), PSA and indomethacin drug composite (DC) formulations were prepared using supercritical CO(2) (sc-CO(2)) aided mixing. The effect of the experimental temperature and sebacic acid purity on the physical properties of PSA-indomethacin DCs was investigated using a range of analytical techniques. The nature of the PSA-indomethacin interaction in composites after processing in sc-CO(2) under various conditions was investigated using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, and powder X-ray diffraction (XRD) methods, respectively. The results indicate that processing at 130 degrees C of a 4:1 (w/w) ratio PSA-indomethacin mixture, renders the indomethacin amorphous and dispersed within the polymer matrix. The primary interaction between PSA and indomethacin appears to be hydrogen bonding between the carboxylic acid OH of indomethacin and the carbonyl group of PSA. In vitro dissolution studies revealed that the processed composites exhibit a substantially enhanced dissolution rate compared to the physical mixtures. Also, through the control of experimental conditions, the initial burst effect of the drug release was largely alleviated. Instead, the erosion of PSA (zero order degradation) became the dominant factor in controlling the drug release rate.

Controlled release of chlorhexidine diacetate from a porous methacrylate system: supercritical fluid assisted foaming and impregnation.

The release of chlorhexidine diacetate (CX) from a self-curing polymeric system based on poly(ethylmethacrylate) and tetrahydrofurfurylmethacrylate (PEM/THFM) was developed in this study. Supercritical fluid assisted impregnation and foaming was employed for preparing porous CX-PEM/THFM drug release system. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) show that the crystallinity of CX significantly decreased after supercritical processing, whilst Raman spectroscopy suggested a hydrogen bonding interaction between the CX and PEM in the product. A UV-Vis dissolution study revealed that the drug release rate is almost as seven times faster in the SCF processed drug delivery system than conventional cured samples.

Supercritical fluid assisted impregnation of indomethacin into chitosan thermosets for controlled release applications.

Supercritical carbon dioxide (sc-CO(2)) was used to impregnate indomethacin (a non-steroidal anti-inflammatory drug) into chitosan thermosets for the preparation of controlled release formulations. The products were analyzed by a range of methods including powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). The effects of the experimental temperature and pressure of the sc-CO(2) on the thermal behavior of chitosan-indomethacin drug composites (DCs) was investigated via differential scanning calorimeter (DSC). The interaction of chitosan and indomethacin after impregnation was then studied by Fourier transform infrared (FTIR) and Raman spectroscopy, respectively. Our results suggest that the supercritical fluid impregnation process results in indomethacin being amorphously dispersed within the chitosan matrix. FTIR data suggest that the aliphatic carbonyl group of indomethacin interacts with the NH(2) group of the chitosan backbone. In vitro dissolution studies (via UV-vis spectroscopy) reveal that the dissolution rate of indomethacin substantially increases after processing in sc-CO(2), particularly, under the experimental conditions 20.7 MPa and 70 degrees C.

Formation and characterization of porous indomethacin-PVP coprecipitates prepared using solvent-free supercritical fluid processing.

Supercritical carbon dioxide (sc-CO2) was used to prepare coprecipitates of indomethacin (IM) and poly(vinylpyrrolidone) (PVP) with the aim to improve the dissolution rate of IM. The coprecipitates of IM and PVP at various proportions were prepared using a stirred batch reactor containing sc-CO2 as a gas saturated solution (i.e., the compressible CO2 is dissolved in the molten compound). Temperatures between 40 and 90 degrees C and pressure of 150 or 200 bar were employed. The coprecipitates prepared at 75 degrees C and 150 bar were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXD), scanning electron microscopy (SEM), and dissolution testing. The results suggested that IM was totally amorphous at PVP weight fraction of 0.80 and above (indeed, as a molecular composite in which the drug molecules interact with the polymer backbone). As the PVP weight fraction decreased, IM displayed an increasing amount of crystalline material. The SEM photographs of coprecipitates showed a foamed and porous structure. The dissolution rate of IM was increased by incorporation of PVP. IM and PVP at various weight fractions exhibited comparatively higher dissolution rates than that of crystalline IM alone. The sc-CO2 based process produced a solvent free, completely amorphous porous IM solid dispersion with a rapid dissolution rate.

Titania nanospheres from supercritical fluids.

Surfactant-coated amorphous titania nanospheres have been synthesised using templating 'water-in-supercritical carbon dioxide' emulsion droplets; the process represents a clean and controlled method for the manufacture of high-purity nanoparticles.

Metal organic chemical vapour deposition (MOCVD) of bone mineral like carbonated hydroxyapatite coatings.

For the first time, the MOCVD technique has been used to deposit carbonated hydroxyapatite onto Ti6AL4V substrates using volatile monomeric (liquid) complexes [Ca(beta-diketonate)(2)(L)] and P(OEt)(3).

Synthesis and characterization of nano-biomaterials with potential osteological applications.

The manufacture of high-surface area, un-agglomerated nano-sized (1-100 nm) bioceramic particles are of interest for many applications including injectable/controlled setting bone cements, high strength porous/non-porous synthetic bone grafts, and the reinforcing phase in nano-composites that attempt to mimic the complex structure and superior mechanical properties of bone. In the present study, we report on the manufacture of nano-particle hydroxyapatite powders by several wet chemical methods, which incorporate a freeze-drying step. In particular, it was found that the emulsion-based syntheses yielded powders with high surface areas and small primary particle sizes. Freeze drying rather than oven drying of powders prepared by conventional wet chemical synthesis yielded a nano-sized powder with a comparatively higher surface area of 113 m(2)/g. All powders were calcined in air in a furnace at 900 degrees C to investigate the effects of synthesis method on phase purity and surface area. The materials were characterized by a range of analytical methods including Fourier-transform infrared spectroscopy employing the photo acoustic (PAS-FTIR) sampling technique, BET surface area analysis, X-ray powder diffraction (XRD), and the particles were examined using a transmission electron microscope (TEM).

Survival and PHA-stimulation of gamma-irradiated human peripheral blood T lymphocyte subpopulations.

Human peripheral blood T lymphocyte subpopulations were identified and isolated on the basis of their ability to bind IgG (T-G), IgM (T-M), or neither immunoglobulin class (T-null). Lymphocytes were exposed to 0, 0.5, 1.0, 2.5 or 5.0 Gy of 60Co gamma-rays either as a T-cell suspension or as separated T cell subsets. Survival curves, determined 5 days after irradiation, revealed that each subset has radiosensitive and radioresistant portions, and that the T-G cell is the most sensitive subset. Mitotic indices of 48-h cultures showed that the response of unirradiated T lymphocytes to PHA varied greatly among the subsets, the highest indices being obtained for the T-M and the lowest for the T-G cells. With the possible exception of the T-G cells, the subsets are relatively resistant to mitotic effects of gamma-rays. T-G cells suppress the PHA-induced mitotic response of the other T lymphocyte subsets, and this suppressor effect is radiosensitive, being abolished by 1.0 Gy. It is concluded that lymphocytes exposed to greater than or equal to 1 Gy of gamma-rays will have very few dividing B lymphocytes or T-G cells. This together with radiation-induced loss of T-G suppressor action means that the predominant lymphocyte types in mitosis after greater than or equal to 1 Gy are the radioresistant T-M and T-null cells.