Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers.

Mitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10-250 µM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.

Endocytosis of very low-density lipoproteins: an unexpected mechanism for lipid acquisition by breast cancer cells.

We previously described the expression of CD36 and LPL by breast cancer (BC) cells and tissues and the growth-promoting effect of VLDL observed only in the presence of LPL. We now report a model in which LPL is bound to a heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to internalize VLDLs via receptor-mediated endocytosis. We also demonstrate that gene-expression programs for lipid synthesis versus uptake respond robustly to triglyceride-rich lipoprotein availability. The literature emphasizes de novo FA synthesis and exogenous free FA uptake using CD36 as paramount mechanisms for lipid acquisition by cancer cells. We find that the uptake of intact lipoproteins is also an important mechanism for lipid acquisition and that the relative reliance on lipid synthesis versus uptake varies among BC cell lines and in response to VLDL availability. This metabolic plasticity has important implications for the development of therapies aimed at the lipid dependence of many types of cancer, in that the inhibition of FA synthesis may elicit compensatory upregulation of lipid uptake. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.-.

Comparison of membrane affinity-based method with size-exclusion chromatography for isolation of exosome-like vesicles from human plasma.

BACKGROUND: Plasma extracellular vesicles (EVs), especially exosome-like vesicles (ELVs), are being increasingly explored as a source of potential noninvasive disease biomarkers. The discovery of blood-based biomarkers associated with ELVs requires methods that isolate high yields of these EVs without significant contamination with highly abundant plasma proteins and lipoproteins. The rising interest in blood-based EV-associated biomarkers has led to the rapid development of novel EV isolation methods. However, the field suffers from a lack of standardization and often, new techniques are used without critical evaluation. Size exclusion chromatography (SEC) has become the method of choice for rapid isolation of relatively pure EVs from plasma, yet it has technical limitations for certain downstream applications. The recently released exoEasy kit (Qiagen) is a new membrane affinity spin column method for the isolation of highly pure EVs from biofluids with the potential to overcome most of the limitations of SEC. METHODS: By using multiple complementary techniques we assessed the performance of the exoEasy kit in isolating ELVs from 2 ml of human plasma and compared it with the SEC qEV column (Izon Science). RESULTS: Our data show that exoEasy kit isolates a heterogenous mixture of particles with a larger median diameter, broader size range and a higher yield than the SEC qEV column. The exclusive presence of small RNAs in the particles and the total RNA yield were comparable to the SEC qEV column. Despite being less prone to low density lipoprotein contamination than the SEC qEV column, the overall purity of exoEasy kit EV preparations was suboptimal. The low particle-protein ratio, significant amount of albumin, very low levels of exosome-associated proteins and propensity to triglyceride-rich lipoprotein contamination suggest isolation of mainly non-ELVs and co-isolation of plasma proteins and certain lipoproteins by the exoEasy kit. CONCLUSIONS: We demonstrate that performance of exoEasy kit for the isolation of ELVs for biomarker discovery is inferior to the SEC qEV column. This comprehensive evaluation of a novel EV isolation method contributes to the acceleration of the discovery of EV-associated biomarkers and the development of EV-based diagnostics.

Sustainable Packaging Design for Molded Expanded Polystyrene Cushion.

A molded expanded polystyrene (EPS) cushion is a flexible, closed-cell foam that can be molded to fit any packing application and is effective at absorbing shock. However, the packaging waste of EPS cushions causes pollution to landfills and the environment. Despite being known to cause pollution, this sustainable packaging actually has the potential to reduce this environmental pollution because of its reusability. Therefore, the objective of this study is to identify the accurate design parameter that can be emphasized in producing a sustainable design of EPS cushion packaging. An experimental method of drop testing and design simulation analysis was conducted. The effectiveness of the design parameters was also verified. Based on the results, there are four main elements that necessitate careful consideration: rib positioning, EPS cushion thickness, package layout, and packing size. These parameter findings make a significant contribution to sustainable design, where these elements were integrated directly to reduce and reuse packaging material. Thus, it has been concluded that 48 percent of the development cost of the cushion was decreased, 25 percent of mold modification time was significantly saved, and 27 percent of carbon dioxide (CO2) reduction was identified. The findings also aided in the development of productive packaging design, in which these design elements were beneficial to reduce environmental impact. These findings had a significant impact on the manufacturing industry in terms of the economics and time of the molded expanded polystyrene packaging development.

Near-Infrared (NIR) Silver Sulfide (Ag2S) Semiconductor Photocatalyst Film for Degradation of Methylene Blue Solution.

A silver sulfide (Ag2S) semiconductor photocatalyst film has been successfully synthesized using a solution casting method. To produce the photocatalyst films, two types of Ag2S powder were used: a commercialized and synthesized powder. For the commercialized powder (CF/comAg2S), the Ag2S underwent a rarefaction process to reduce its crystallite size from 52 nm to 10 nm, followed by incorporation into microcrystalline cellulose using a solution casting method under the presence of an alkaline/urea solution. A similar process was applied to the synthesized Ag2S powder (CF/syntAg2S), resulting from the co-precipitation process of silver nitrate (AgNO3) and thiourea. The prepared photocatalyst films and their photocatalytic efficiency were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and UV-visible spectroscopy (UV-Vis). The results showed that the incorporation of the Ag2S powder into the cellulose films could reduce the peak intensity of the oxygen-containing functional group, which indicated the formation of a composite film. The study of the crystal structure confirmed that all of the as-prepared samples featured a monoclinic acanthite Ag2S structure with space group P21/C. It was found that the degradation rate of the methylene blue dye reached 100% within 2 h under sunlight exposure when using CF/comAg2S and 98.6% for the CF/syntAg2S photocatalyst film, and only 48.1% for the bare Ag2S powder. For the non-exposure sunlight samples, the degradation rate of only 33-35% indicated the importance of the semiconductor near-infrared (NIR) Ag2S photocatalyst used.

Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model.

Ochratoxin A (OTA) is a widely studied compound due to its role in renal toxicity and carcinogenicity. However, there is still no consensus on the exact mechanisms of toxicity or carcinogenicity. In the current study, we analysed the effect of OTA on three human renal proximal tubular models (human primary, RPTEC/TERT1 and HK-2 cells) and two rat renal proximal tubular models (rat primary and NRK-52E cells). Global transcriptomics analysis at two exposure times was performed to generate a set of 756 OTA sensitive genes. This gene set was then compared in more detail across all models and additionally to a rat in vivo renal cortex model. The results demonstrate a well-conserved response across all models. OTA resulted in deregulation of a number of pathways including cytoskeleton, nucleosome regulation, translation, transcription, ubiquitination and cell cycle pathways. Interestingly, the oxidative stress activated Nrf2 pathway was not enriched. These results point to an epigenetic action of OTA, perhaps initiated by actin binding as the actin remodelling gene, advillin was the highest up-regulated in all models. The largest model differences were observed between the human and the rat in vitro models. However, since the human in vitro models were more similar to the rat in vivo model, it is more likely that these differences are model-specific rather than species-specific per se. This study demonstrates the usefulness of in vitro cell culture models combined with transcriptomic analysis for the investigation of mechanisms of toxicity and carcinogenicity. In addition, these results provide further evidence supporting a non-genotoxic mechanism of OTA-induced carcinogenicity.

Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells.

Potassium bromate (KBrO(3)) is an oxidising agent that has been widely used in the food and cosmetic industries. It has shown to be both a nephrotoxin and a renal carcinogen in in vivo and in vitro models. Here, we investigated the effects of KBrO(3) in the human and rat proximal tubular cell lines RPTEC/TERT1 and NRK-52E. A genome-wide transcriptomic screen was carried out from cells exposed to a sub-lethal concentration of KBrO(3) for 6, 24 and 72 h. Pathway analysis identified "glutathione metabolism", "Nrf2-mediated oxidative stress" and "tight junction (TJ) signalling" as the most enriched pathways. TJ signalling was less impacted in the rat model, and further studies revealed low transepithelial electrical resistance (TEER) and an absence of several TJ proteins in NRK-52E cells. In RPTEC/TERT1 cells, KBrO(3) exposure caused a decrease in TEER and resulted in altered expression of several TJ proteins. N-Acetylcysteine co-incubation prevented these effects. These results demonstrate that oxidative stress has, in conjunction with the activation of the cytoprotective Nrf2 pathway, a dramatic effect on the expression of tight junction proteins. The further understanding of the cross-talk between these two pathways could have major implications for epithelial repair, carcinogenesis and metastasis.

Potential of Rapid Tooling in Rapid Heat Cycle Molding: A Review.

Rapid tooling (RT) and additive manufacturing (AM) are currently being used in several parts of industry, particularly in the development of new products. The demand for timely deliveries of low-cost products in a variety of geometrical patterns is continuing to increase year by year. Increased demand for low-cost materials and tooling, including RT, is driving the demand for plastic and rubber products, along with engineering and product manufacturers. The development of AM and RT technologies has led to significant improvements in the technologies, especially in testing performance for newly developed products prior to the fabrication of hard tooling and low-volume production. On the other hand, the rapid heating cycle molding (RHCM) injection method can be implemented to overcome product surface defects generated by conventional injection molding (CIM), since the surface gloss of the parts is significantly improved, and surface marks such as flow marks and weld marks are eliminated. The most important RHCM technique is rapid heating and cooling of the cavity surface, which somewhat improves part quality while also maximizing production efficiencies. RT is not just about making molds quickly; it also improves molding productivity. Therefore, as RT can also be used to produce products with low-volume production, there is a good potential to explore RHCM in RT. This paper reviews the implementation of RHCM in the molding industry, which has been well established and undergone improvement on the basis of different heating technologies. Lastly, this review also introduces future research opportunities regarding the potential of RT in the RHCM technique.

The Effects of Various Concentrations of NaOH on the Inter-Particle Gelation of a Fly Ash Geopolymer Aggregate.

Aggregates can be categorized into natural and artificial aggregates. Preserving natural resources is crucial to ensuring the constant supply of natural aggregates. In order to preserve these natural resources, the production of artificial aggregates is beginning to gain the attention of researchers worldwide. One of the methods involves using geopolymer technology. On this basis, this current research focuses on the inter-particle effect on the properties of fly ash geopolymer aggregates with different molarities of sodium hydroxide (NaOH). The effects of synthesis parameters (6, 8, 10, 12, and 14 M) on the mechanical and microstructural properties of the fly ash geopolymer aggregate were studied. The fly ash geopolymer aggregate was palletized manually by using a hand to form a sphere-shaped aggregate where the ratio of NaOH/Na2SiO3 used was constant at 2.5. The results indicated that the NaOH molarity has a significant effect on the impact strength of a fly ash geopolymer aggregate. The highest aggregate impact value (AIV) was obtained for samples with 6 M NaOH molarity (26.95%), indicating the lowest strength among other molarities studied and the lowest density of 2150 kg/m3. The low concentration of sodium hydroxide in the alkali activator solution resulted in the dissolution of fly ash being limited; thus, the inter-particle volume cannot be fully filled by the precipitated gels.

Hybrid Mold: Comparative Study of Rapid and Hard Tooling for Injection Molding Application Using Metal Epoxy Composite (MEC).

The mold-making industry is currently facing several challenges, including new competitors in the market as well as the increasing demand for a low volume of precision moldings. The purpose of this research is to appraise a new formulation of Metal Epoxy Composite (MEC) materials as a mold insert. The fabrication of mold inserts using MEC provided commercial opportunities and an alternative rapid tooling method for injection molding application. It is hypothesized that the addition of filler particles such as brass and copper powders would be able to further increase mold performance such as compression strength and thermal properties, which are essential in the production of plastic parts for the new product development. This study involved four phases, which are epoxy matrix design, material properties characterization, mold design, and finally the fabrication of the mold insert. Epoxy resins filled with brass (EB) and copper (EC) powders were mixed separately into 10 wt% until 30 wt% of the mass composition ratio. Control factors such as degassing time, curing temperature, and mixing time to increase physical and mechanical properties were optimized using the Response Surface Method (RSM). The study provided optimum parameters for mixing epoxy resin with fillers, where the degassing time was found to be the critical factor with 35.91%, followed by curing temperature with 3.53% and mixing time with 2.08%. The mold inserts were fabricated for EB and EC at 30 wt% based on the optimization outcome from RSM and statistical ANOVA results. It was also revealed that the EC mold insert offers better cycle time compared to EB mold insert material.

Properties of a New Insulation Material Glass Bubble in Geo-Polymer Concrete.

This paper details analytical research results into a novel geopolymer concrete embedded with glass bubble as its thermal insulating material, fly ash as its precursor material, and a combination of sodium hydroxide (NaOH) and sodium silicate (Na2SiO3) as its alkaline activator to form a geopolymer system. The workability, density, compressive strength (per curing days), and water absorption of the sample loaded at 10% glass bubble (loading level determined to satisfy the minimum strength requirement of a load-bearing structure) were 70 mm, 2165 kg/m3, 52.58 MPa (28 days), 54.92 MPa (60 days), and 65.25 MPa (90 days), and 3.73 %, respectively. The thermal conductivity for geopolymer concrete decreased from 1.47 to 1.19 W/mK, while the thermal diffusivity decreased from 1.88 to 1.02 mm2/s due to increased specific heat from 0.96 to 1.73 MJ/m3K. The improved physicomechanical and thermal (insulating) properties resulting from embedding a glass bubble as an insulating material into geopolymer concrete resulted in a viable composite for use in the construction industry.

Effect of Aluminium Powder on Kaolin-Based Geopolymer Characteristic and Removal of Cu2.

This current work focuses on the synthesis of geopolymer-based adsorbent which uses kaolin as a source material, mixed with alkali solution consisting of 10M NaOH and Na2SiO3 as well as aluminium powder as a foaming agent. The experimental range for the aluminium powder was between 0.6, 0.8, 1.0 and 1.2wt%. The structure, properties and characterization of the geopolymer were examined using X-Ray Diffraction (XRD), Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). Adsorption capacity and porosity were analysed based on various percentages of aluminium powder added. The results indicate that the use of aluminium powder exhibited a better pore size distribution and higher porosity, suggesting a better heavy metal removal. The maximum adsorption capacity of Cu2+ approached approximately 98%. The findings indicate that 0.8% aluminium powder was the optimal aluminium powder content for geopolymer adsorbent. The removal efficiency was affected by pH, adsorbent dosage and contact time. The optimum removal capacity of Cu2+ was obtained at pH 6 with 1.5 g geopolymer adsorbent and 4 h contact time. Therefore, it can be concluded that the increase in porosity increases the adsorption of Cu2+.

Comparison of Hook and Straight Steel Fibers Addition on Malaysian Fly Ash-Based Geopolymer Concrete on the Slump, Density, Water Absorption and Mechanical Properties.

Geopolymer concrete has the potential to replace ordinary Portland cement which can reduce carbon dioxide emission to the environment. The addition of different amounts of steel fibers, as well as different types of end-shape fibers, could alter the performance of geopolymer concrete. The source of aluminosilicate (fly ash) used in the production of geopolymer concrete may lead to a different result. This study focuses on the comparison between Malaysian fly ash geopolymer concrete with the addition of hooked steel fibers and geopolymer concrete with the addition of straight-end steel fibers to the physical and mechanical properties. Malaysian fly ash was first characterized by X-ray fluorescence (XRF) to identify the chemical composition. The sample of steel fiber reinforced geopolymer concrete was produced by mixing fly ash, alkali activators, aggregates, and specific amounts of hook or straight steel fibers. The steel fibers addition for both types of fibers are 0%, 0.5%, 1.0%, 1.5%, and 2.0% by volume percentage. The samples were cured at room temperature. The physical properties (slump, density, and water absorption) of reinforced geopolymer concrete were studied. Meanwhile, a mechanical performance which is compressive, as well as the flexural strength was studied. The results show that the pattern in physical properties of geopolymer concrete for both types of fibers addition is almost similar where the slump is decreased with density and water absorption is increased with the increasing amount of fibers addition. However, the addition of hook steel fiber to the geopolymer concrete produced a lower slump than the addition of straight steel fibers. Meanwhile, the addition of hook steel fiber to the geopolymer concrete shows a higher density and water absorption compared to the sample with the addition of straight steel fibers. However, the difference is not significant. Besides, samples with the addition of hook steel fibers give better performance for compressive and flexural strength compared to the samples with the addition of straight steel fibers where the highest is at 1.0% of fibers addition.

Role of Sintering Temperature in Production of Nepheline Ceramics-Based Geopolymer with Addition of Ultra-High Molecular Weight Polyethylene.

The primary motivation of developing ceramic materials using geopolymer method is to minimize the reliance on high sintering temperatures. The ultra-high molecular weight polyethylene (UHMWPE) was added as binder and reinforces the nepheline ceramics based geopolymer. The samples were sintered at 900 °C, 1000 °C, 1100 °C, and 1200 °C to elucidate the influence of sintering on the physical and microstructural properties. The results indicated that a maximum flexural strength of 92 MPa is attainable once the samples are used to be sintered at 1200 °C. It was also determined that the density, porosity, volumetric shrinkage, and water absorption of the samples also affected by the sintering due to the change of microstructure and crystallinity. The IR spectra reveal that the band at around 1400 cm-1 becomes weak, indicating that sodium carbonate decomposed and began to react with the silica and alumina released from gels to form nepheline phases. The sintering process influence in the development of the final microstructure thus improving the properties of the ceramic materials.

Optimisation of Shrinkage and Strength on Thick Plate Part Using Recycled LDPE Materials.

Achieving good quality of products from plastic injection moulding processes is very challenging, since the process comprises many affecting parameters. Common defects such as warpage are hard to avoid, and the defective parts will eventually go to waste, leading to unnecessary costs to the manufacturer. The use of recycled material from postindustrial waste has been studied by a few researchers. However, the application of an optimisation method by which to optimise processing parameters to mould parts using recycled materials remains lacking. In this study, Response Surface Methodology (RSM) and Particle Swarm Optimisation (PSO) methods were conducted on thick plate parts moulded using virgin and recycled low-density polyethylene (LDPE) materials (100:0, 70:30, 60:40 and 50:50; virgin to recycle material ratios) to find the optimal input parameters for each of the material ratios. Shrinkage in the x and y directions increased in correlation with the recycled ratio, compared to virgin material. Meanwhile, the tensile strength of the thick plate part continued to decrease when the recycled ratio increased. R30 (70:30) had the optimum shrinkage in the x direction with respect to R0 (100:0) material where the shrinkage increased by 24.49% (RSM) and 33.20% (PSO). On the other hand, the shrinkage in the y direction for R30 material increased by 4.48% (RSM) and decreased by 2.67% (PSO), while the tensile strength of R30 (70:30) material decreased by 0.51% (RSM) and 2.68% (PSO) as compared to R0 (100:0) material. Validation tests indicated that the optimal setting of processing parameter suggested by PSO and RSM for R0 (100:0), R30 (70:30), R40 (60:40) and R50 (50:50) was less than 10%.

The multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes.

Growing evidence supports the importance of the p53 tumor suppressor in metabolism but the mechanisms underlying p53-mediated control of metabolism remain poorly understood. Here, we identify the multifunctional E4F1 protein as a key regulator of p53 metabolic functions in adipocytes. While E4F1 expression is upregulated during obesity, E4f1 inactivation in mouse adipose tissue results in a lean phenotype associated with insulin resistance and protection against induced obesity. Adipocytes lacking E4F1 activate a p53-dependent transcriptional program involved in lipid metabolism. The direct interaction between E4F1 and p53 and their co-recruitment to the Steaoryl-CoA Desaturase-1 locus play an important role to regulate monounsaturated fatty acids synthesis in adipocytes. Consistent with the role of this E4F1-p53-Steaoryl-CoA Desaturase-1 axis in adipocytes, p53 inactivation or diet complementation with oleate partly restore adiposity and improve insulin sensitivity in E4F1-deficient mice. Altogether, our findings identify a crosstalk between E4F1 and p53 in the control of lipid metabolism in adipocytes that is relevant to obesity and insulin resistance.

Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition.

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.

ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer.

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. SIGNIFICANCE: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.

The effect of trichloroethylene metabolites on the hepatic vitamin B12-dependent methionine salvage pathway and its relevance to increased excretion of formic acid in the rat.

The industrial solvent trichloroethylene (TCE) and its two major metabolites trichloroethanol (TCE-OH) and trichloroacetic acid (TCA) cause formic aciduria in male F344 rats. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE (16mk/kg, po), completely prevented formic aciduria, but had no effect on formic acid excretion produced by TCA (8 or 16 mg/kg, po), suggesting TCA may be the proximate metabolite producing this response. Dow and Green reported an increase in the concentration of 5-methyltetrahydrofolate (5-MTHF) in the plasma of rats treated with TCE-OH, suggesting a block in the cycling of 5-MTHF to tetrahydrofolate (THF). This pathway is under the control of the vitamin B12-dependent methionine salvage pathway. We therefore treated rats with three daily doses of methylcobalamin (CH3Cbl) or hydroxocobalamin (OHCbl), a cofactor for methionine synthase, or L-methionine, followed by TCE (16 mg/kg) to determine if they could alleviate the formic aciduria. These pretreatments only partially reduced the excretion of formic acid in the urine. Although prior treatment with S-adenosyl-L-methionine had no effect on formic acid excretion. Consistent with these findings, the activity of methionine synthase in the liver of TCE-treated rats was not inhibited. Transcriptomic analysis of the liver-identified nine differential expressed genes, of note, was downregulation of Lmbrd1 involved in the conversion of vitamin B12 into CH3Cbl, a cofactor for methionine synthase. Our findings indicate that the formic aciduria produced by TCE-OH and TCA may be the result of a block in the recycling of 5-MTHF to THF, the effect on the methionine salvage pathway being a secondary response following acute exposure.

The Magnetisation Process of Bulk Amorphous Alloys: Fe36+xCo36-xY8B20, Where: x = 0, 3, 7, or 12.

Amorphous Fe- and Co-based alloys possess so-called soft magnetic properties. Due to the high sensitivity of the magnetisation vector to any inhomogeneities occurring in these alloys, it is possible to assess indirectly structural defects. This paper presents the results of research on the structure and magnetic properties of bulk amorphous alloys with a high content of Fe and Co. The magnetic properties of the produced alloys were tested using a Faraday magnetic balance and a vibrating sample magnetometer (VSM). Analysis of the magnetisation process in the region known as the approach to ferromagnetic saturation was carried out in accordance with Kronmüller's theorem. Magnetisation in magnetic fields of greater than the effective anisotropy field (Holstein-Primakoff para-process) was also studied. For the studied alloys, it was found that an increase in Fe content causesan increase in saturation magnetisation, and decreases in the values of the coercive field and thespin-wave stiffness parameter, Dspf. A relationship was observed between the width of the amorphous halo and the value of the coercive field. However, no significant links were found between either the presence of structural defects and the properties of these materials, or between the Co content and the value of the coercive field.