Direct conversion of methane under non-oxidative conditions

Abstract available p.i

Direct conversion of methane under non-oxidative conditions

Abstract available p.i

Dynamic telomerase gene suppression via network effects of GSK3 inhibition

<b>Background</b>: Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression. <b>Methodology/Principal Findings</b>: In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3′-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFκB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc. <b>Conclusions/Significance</b>: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting

Identification of a selective G1-phase benzimidazolone inhibitor by a senescence-targeted virtual screen using artificial neural networks

Cellular senescence is a barrier to tumorigenesis in normal cells and tumour cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. 147 virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase (SA-β-gal) assays. Among the found hits a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced SA-β-gal activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1 and CDC25C. Additionally, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long term treatments. Preliminary structure-activity and structure clustering analyses are reported and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells

Social prescribing and behaviour change : proposal of a new behaviour change technique concerning the ‘connection’ step

Publisher PDFPeer reviewe

Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials

AIMS/HYPOTHESIS: Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. METHODS: Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. RESULTS: A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC0-t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC0-t ratio range: 1.6-1.9 for GLP-1 and 1.4-1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI -16%, -39%) lower bioavailability (least squares mean ratio of metformin AUC0-24) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values. CONCLUSIONS/INTERPRETATION: Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment. TRIAL REGISTRATION: Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: : This study was funded by Elcelyx Therapeutics Inc

Space Environments and Spacecraft Effects Organization Concept

The National Aeronautics and Space Administration (NASA) is embarking on a course to expand human presence beyond Low Earth Orbit (LEO) while also expanding its mission to explore the solar system. Destinations such as Near Earth Asteroids (NEA), Mars and its moons, and the outer planets are but a few of the mission targets. Each new destination presents an opportunity to increase our knowledge of the solar system and the unique environments for each mission target. NASA has multiple technical and science discipline areas specializing in specific space environments disciplines that will help serve to enable these missions. To complement these existing discipline areas, a concept is presented focusing on the development of a space environments and spacecraft effects (SENSE) organization. This SENSE organization includes disciplines such as space climate, space weather, natural and induced space environments, effects on spacecraft materials and systems and the transition of research information into application. This space environment and spacecraft effects organization will be composed of Technical Working Groups (TWG). These technical working groups will survey customers and users, generate products, and provide knowledge supporting four functional areas: design environments, engineering effects, operational support, and programmatic support. The four functional areas align with phases in the program mission lifecycle and are briefly described below. Design environments are used primarily in the mission concept and design phases of a program. Engineering effects focuses on the material, component, sub-system and system-level selection and the testing to verify design and operational performance. Operational support provides products based on real time or near real time space weather to mission operators to aid in real time and near-term decision-making. The programmatic support function maintains an interface with the numerous programs within NASA, other federal government agencies, and the commercial sector to ensure that communications are well established and the needs of the programs are being met. The programmatic support function also includes working in coordination with the program in anomaly resolution and generation of lessons learned documentation. The goal of this space environment and spacecraft effects organization is to develop decision-making tools and engineering products to support all mission phases from mission concept through operations by focusing on transitioning research to application. Products generated by this space environments and effects application are suitable for use in anomaly investigations. This paper will describe the scope of the TWGs and their relationship to the functional areas, and discuss an organizational structure for this space environments and spacecraft effects organization

Symbioses with nitrogen-fixing bacteria:nodulation and phylogenetic data across legume genera

How species interactions shape global biodiversity and influence diversification is a central - but also data-hungry - question in evolutionary ecology. Microbially-based mutualisms are widespread and could cause diversification by ameliorating stress and thus allowing organisms to colonize and adapt to otherwise unsuitable habitats. Yet the role of these interactions in generating species diversity has received limited attention, especially across large taxonomic groups. In the massive angiosperm family Leguminosae, plants often associate with root-nodulating bacteria that ameliorate nutrient stress by fixing atmospheric nitrogen. These symbioses are ecologically-important interactions, influencing community assembly, diversity, and succession, contributing ~100-290 million tons of N annually to natural ecosystems, and enhancing growth of agronomically-important forage and crop plants worldwide. In recent work attempting to determine whether mutualism with N-fixing bacteria led to increased diversification across legumes, we were unable to definitively resolve the relationship between diversification and nodulation. We did, however, succeed in compiling a very large searchable, analysis-ready database of nodulation data for 749 legume genera (98% of Leguminosae genera; LPWG 2017), which, along with associated phylogenetic information, will provide a valuable resource for future work addressing this question and others. For each legume genus, we provide information about the species richness, frequency of nodulation, subfamily association, and topological correspondence with an additional data set of 100 phylogenetic trees curated for database compatibility. We found 386 legume genera were confirmed nodulators (i.e., all species examined for nodulation nodulated), 116 were non-nodulating, 4 were variable (i.e., containing both confirmed nodulators and confirmed non-nodulators), and 243 had not been examined for nodulation in published studies. Interestingly, data exploration revealed that nodulating legume genera are ~3× more species-rich than non-nodulating genera, but we did not find evidence that this difference in diversity was due to differences in net diversification rate. Our metadata file describes in more detail the structure of these data that provide a foundational resource for future work as more nodulation data become available, and as greater phylogenetic resolution of this ca. 19,500-species family comes into focus. This article is protected by copyright. All rights reserved.</p