CYP17 inhibitors for prostate cancer therapy

Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues' androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. Article from the special issue on Targeted Inhibitors.     

Additive inheritance of histone modifications in Arabidopsis thaliana intra-specific hybrids

Plant genomes are earmarked with defined patterns of chromatin marks. Little is known about the stability of these epigenomes when related, but distinct genomes are brought together by intra‐species hybridization. Arabidopsis thaliana accessions and their reciprocal hybrids were used as a model system to investigate the dynamics of histone modification patterns. The genome‐wide distribution of histone modifications H3K4me2 and H3K27me3 in the inbred parental accessions Col‐0, C24 and Cvi and their hybrid offspring was compared by chromatin immunoprecipitation in combination with genome tiling array hybridization. The analysis revealed that, in addition to DNA sequence polymorphisms, chromatin modification variations exist among accessions of A. thaliana. The range of these variations was higher for H3K27me3 (typically a repressive mark) than for H3K4me2 (typically an active mark). H3K4me2 and H3K27me3 were rather stable in response to intra‐species hybridization, with mainly additive inheritance in hybrid offspring. In conclusion, intra‐species hybridization does not result in gross changes to chromatin modifications.     

Seasonal and wastewater stream variation of trace organic compounds in a dairy processing plant aerobic bioreactor

Bioreactors are often an integral part of dairy factory efforts to reduce the biological oxygen demand of their wastewater. In this study, infeed, mixed liquor and supernatant samples of an aerobic bioreactor used by a dairy factory in South-Eastern Australia were analyzed for nutrients and organic compounds using gas chromatography-mass spectrometry and physicochemical analyses. Despite different concentrations of organic inputs into the bioreactor, nutrients and trace organic compounds were reduced significantly (i.e. average concentration of trace organic compounds: infeed = 1681 μg/L; mixed liquor = 257 μg/L; supernatant = 23 μg/L). However, during one sampling period the bioreactor was adversely affected by the organic loading. Trace organic compounds in the samples were predominantly fatty acids associated with animal products. The analyses suggest that it is possible to trace a disruptive input (i.e. infeed with high organic carbon concentrations) into an aerobic bioreactor by measuring concentrations of fatty acids or ammonia.     

Sustainability of algae derived biodiesel: a mass balance approach

A rigorous chemical engineering mass balance/unit operations approach is applied here to bio-diesel from algae mass culture. An equivalent of 50,000,000 gallons per year (0.006002 m3/s) of petroleum-based Number 2 fuel oil (US, diesel for compression-ignition engines, about 0.1% of annual US consumption) from oleaginous algae is the target. Methyl algaeate and ethyl algaeate diesel can according to this analysis conceptually be produced largely in a technologically sustainable way albeit at a lower available diesel yield. About 11 square miles of algae ponds would be needed with optimistic assumptions of 50 g biomass yield per day and m2 pond area. CO2 to foster algae growth should be supplied from a sustainable source such as a biomass-based ethanol production. Reliance on fossil-based CO2 from power plants or fertilizer production renders algae diesel non-sustainable in the long term.     

Increasing variation in taxonomic distinctness reveals clusters of specialists in the deep sea

Changes in biodiversity with latitude or along a given environmental gradient have been described in many studies, including for marine ecosystems. Currently there is no scientific consensus, however, regarding macroecological patterns of diversity vs depth. Here, we describe variation in the biodiversity of fishes along a depth gradient from 0 to 2000 m in the region of the Norfolk Ridge and Lord Howe Rise (Western Pacific), using data obtained during the NORFANZ voyage. We modelled α diversity (richness), β diversity (using Jaccard's coefficient), evenness, taxonomic distinctness and taxonomic resemblances among fish communities. Although α diversity did not change appreciably with depth, β diversity decreased significantly in deeper strata. Both taxonomic resemblances and Jaccard similarities diminished with depth, indicating convergence in community structure. In addition, average taxonomic distinctness showed no clear pattern with depth, but taxonomic trees constructed among species within deeper samples had more variable path‐lengths than those in shallower samples. The presence of taxonomically distinct clusters of highly related species at depth indicates specialised niches that have developed in a relatively extreme (dark, pressurized) yet stable environment. We propose that reduced β diversity and increased variation in taxonomic distinctness might serve as indicators of ecological communities living in harsh environments – a hypothesis that should be tested in other systems, such as deserts, high altitudes or latitudes.     

Role of G(i/o)-Src kinase-PI3K/Akt pathway and caveolin-1 in β₂-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery

Activation of the β₂-adrenoceptor (β₂-AR) elicits an endothelial nitric oxide synthase (eNOS)-dependent relaxation in mouse pulmonary artery, which, contrary to the muscarinic receptor-dependent relaxation, is preserved in hypoxic pulmonary arterial hypertension. We therefore characterized the signaling pathways underlying the β₂-AR-mediated eNOS activation, with special focus on G_i/o proteins, protein kinases and caveolae. Functional studies (for evaluation of vasorelaxant response), Western blotting (for assessment of eNOS and caveolin-1 phosphorylation) and transmission electron microscopy (for visualization of caveolae) were conducted in pulmonary arteries from wild-type or caveolin-1 knockout mice. In wild-type isolated arteries, relaxation to the selective β₂-AR agonist procaterol was reduced by inhibitors of G_i/o proteins (pertussis toxin, PTX), phosphatidylinositol 3-kinase (PI3K; wortmannin or LY 294002), Akt (Akt inhibitor X) and Src-kinase (PP2) and by cholesterol depletion (using methyl-β-cyclodextrin). Procaterol induced eNOS phosphorylation at Ser¹¹⁷⁷, which was prevented by PTX, PP2 or Akt inhibitor. Procaterol also promoted caveolin-1 phosphorylation at Tyr¹⁴, which was decreased by PTX or PP2. Caveolin-1 gene deletion resulted in endothelial caveolae disruption in mouse pulmonary artery and in potentiation of procaterol-induced relaxation. Unlike procaterol, acetylcholine-induced relaxation was unaffected by PTX, methyl-β-cyclodextrin or caveolin-1 gene deletion. To conclude, the mouse pulmonary endothelial β₂-AR is coupled to a G_i/o-Src kinase-PI3K/Akt pathway to promote eNOS phosphorylation at Ser¹¹⁷⁷ leading to a NO-dependent vasorelaxation. Caveolin-1 exerts a negative control on this response that is abrogated by its phosphorylation at Tyr¹⁴, through a G_i/o-Src kinase pathway. Since pulmonary β₂-AR- and muscarinic receptor-mediated relaxations differentiate in their respective signaling pathways leading to eNOS activation and sensitivities during hypoxia-induced pulmonary arterial hypertension, mechanisms underlying eNOS activation might be key determinants of pulmonary endothelial dysfunction.     

Rethinking motor learning and savings in adaptation paradigms: model-free memory for successful actions combines with internal models

Although motor learning is likely to involve multiple processes, phenomena observed in error-based motor learning paradigms tend to be conceptualized in terms of only a single process: adaptation, which occurs through updating an internal model. Here we argue that fundamental phenomena like movement direction biases, savings (faster relearning), and interference do not relate to adaptation but instead are attributable to two additional learning processes that can be characterized as model-free: use-dependent plasticity and operant reinforcement. Although usually "hidden" behind adaptation, we demonstrate, with modified visuomotor rotation paradigms, that these distinct model-based and model-free processes combine to learn an error-based motor task. (1) Adaptation of an internal model channels movements toward successful error reduction in visual space. (2) Repetition of the newly adapted movement induces directional biases toward the?repeated movement. (3) Operant reinforcement through association of the adapted movement with successful error reduction is responsible for savings.     

Ethanol production from selected lignocellulosic hydrolysates by genome shuffled strains of Scheffersomyces stipitis

Two genome-shuffled Scheffersomyces stipitis strains, GS301 and GS302, exhibiting improved tolerance to hardwood spent sulphite liquor, were tested for growth and fermentation performance on three wood hydrolysates: (a) steam-pretreated enzymatically hydrolyzed poplar hydrolysate from Mascoma Canada, (b) steam pretreated poplar hydrolysate from University of British Columbia Forest Products Biotechnology Laboratory, and (c) mixed hardwoods pre-hydrolysate from FPInnovations (FPI). In the FPI hydrolysate, the wild type (WT) died off within 25 h, while GS301 and GS302 survived beyond 100 h. In fermentation tests, GS301 and GS302 completely utilized glucose and xylose in each hydrolysate and produced 0.39–1.4% (w/v) ethanol. In contrast, the WT did not utilize or poorly utilized glucose and xylose and produced non-detectable to trace amounts of ethanol. The results demonstrated cross tolerance of the mutants to inhibitors in three different wood hydrolysates and reinforced the utility of mating-based genome shuffling approach in industrial yeast strain improvement.     

Thermo-mechanical extrusion pretreatment for conversion of soybean hulls to fermentable sugars

Thermo-mechanical extrusion pretreatment for lignocellulosic biomass was investigated using soybean hulls as the substrate. The enzyme cocktail used to hydrolyze pretreated soybean hulls to fermentable sugars was optimized using response surface methodology (RSM). Structural changes in substrate and sugar yields from thermo-mechanical processing were compared with two traditional pretreatment methods that utilized dilute acid (1% sulfuric acid) and alkali (1% sodium hydroxide). Extrusion processing parameters (barrel temperature, in-barrel moisture, screw speed) and processing aids (starch, ethylene glycol) were studied with respect to reducing sugar and glucose yields. The conditions resulting in the highest cellulose to glucose conversion (95%) were screw speed 350 rpm, maximum barrel temperature 80 °C and in-barrel moisture content 40% wb. Compared with untreated soybean hulls, glucose yield from enzymatic hydrolysis of soybean hulls increased by 69.6%, 128.7% and 132.2%, respectively, when pretreated with dilute acid, alkali and extrusion.