Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes

Dust and star formation properties of a complete sample of local galaxies drawn from the Planck Early Release Compact Source Catalogue

We combine Planck High Frequency Instrument data at 857, 545, 353 and 217 GHz with data from Wide-field Infrared Survey Explorer (WISE), Spitzer, IRAS and Herschel to investigate the properties of a well-defined, flux-limited sample of local star-forming galaxies. A 545 GHz flux density limit was chosen so that the sample is 80 per cent complete at this frequency, and the resulting sample contains a total of 234 local, star-forming galaxies. We investigate the dust emission and star formation properties of the sample via various models and calculate the local dust mass function. Although single-component-modified blackbodies fit the dust emission longward of 80 \u3bcm very well, with a median \u3b2 = 1.83, the known degeneracy between dust temperature and \u3b2 also means that the spectral energy distributions are very well described by a dust component with dust emissivity index fixed at \u3b2 = 2 and temperature in the range 10-25 K. Although a second, warmer dust component is required to fit shorter wavelength data, and contributes approximately a third of the total infrared emission, its mass is negligible. No evidence is found for a very cold (6-10 K) dust component. The temperature of the cold dust component is strongly influenced by the ratio of the star formation rate to the total dust mass. This implies, contrary to what is often assumed, that a significant fraction of even the emission from \u2dc20 K dust is powered by ongoing star formation, whether or not the dust itself is associated with star-forming clouds or `cirrus'. There is statistical evidence of a free-free contribution to the 217 GHz flux densities of 7220 per cent. We find a median dust-to-stellar mass ratio of 0.0046; and that this ratio is anticorrelated with galaxy mass. There is good correlation between dust mass and atomic gas mass (median Md/MHI = 0.022), suggesting that galaxies that have more dust (higher values of Md/M*) have more interstellar medium in general. Our derived dust mass function implies a mean dust mass density of the local Universe (for dust within galaxies), of 7.0 \ub1 1.4 7 105 M 99 Mpc-3, significantly greater than that found in the most recent estimate using Herschel data. \ua9 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society

Fitting the integrated Spectral Energy Distributions of Galaxies

Fitting the spectral energy distributions (SEDs) of galaxies is an almost universally used technique that has matured significantly in the last decade. Model predictions and fitting procedures have improved significantly over this time, attempting to keep up with the vastly increased volume and quality of available data. We review here the field of SED fitting, describing the modelling of ultraviolet to infrared galaxy SEDs, the creation of multiwavelength data sets, and the methods used to fit model SEDs to observed galaxy data sets. We touch upon the achievements and challenges in the major ingredients of SED fitting, with a special emphasis on describing the interplay between the quality of the available data, the quality of the available models, and the best fitting technique to use in order to obtain a realistic measurement as well as realistic uncertainties. We conclude that SED fitting can be used effectively to derive a range of physical properties of galaxies, such as redshift, stellar masses, star formation rates, dust masses, and metallicities, with care taken not to over-interpret the available data. Yet there still exist many issues such as estimating the age of the oldest stars in a galaxy, finer details ofdust properties and dust-star geometry, and the influences of poorly understood, luminous stellar types and phases. The challenge for the coming years will be to improve both the models and the observational data sets to resolve these uncertainties. The present review will be made available on an interactive, moderated web page (sedfitting.org), where the community can access and change the text. The intention is to expand the text and keep it up to date over the coming years.Comment: 54 pages, 26 figures, Accepted for publication in Astrophysics & Space Scienc

Observations of the High Redshift Universe

(Abridged) In these lectures aimed for non-specialists, I review progress in understanding how galaxies form and evolve. Both the star formation history and assembly of stellar mass can be empirically traced from redshifts z~6 to the present, but how the various distant populations inter-relate and how stellar assembly is regulated by feedback and environmental processes remains unclear. I also discuss how these studies are being extended to locate and characterize the earlier sources beyond z~6. Did early star-forming galaxies contribute significantly to the reionization process and over what period did this occur? Neither theory nor observations are well-developed in this frontier topic but the first results presented here provide important guidance on how we will use more powerful future facilities.Comment: To appear in `First Light in Universe', Saas-Fee Advanced Course 36, Swiss Soc. Astrophys. Astron. in press. 115 pages, 64 figures (see http://www.astro.caltech.edu/~rse/saas-fee.pdf for hi-res figs.) For lecture ppt files see http://obswww.unige.ch/saas-fee/preannouncement/course_pres/overview_f.htm

The fast and the fractalous: speed and tortuosity trade off in running ants

The thermal sensitivity of locomotor performance has often been described in terms of speed, but the trajectory of locomotion may play an equally important role in capturing prey or escaping predators. Hypotheses based on physical constraints or behavioural plasticity predict relationships between the speed and the tortuosity of running, which should affect the thermal sensitivity of locomotion. We measured the speed and tortuosity of running by leaf-cutter ants over a range of temperatures from 10 °C to 40 °C. Tortuosity was estimated by the fractal dimension of each path. As we expected, ants ran faster at higher temperatures, but they also followed straighter (less tortuous) paths. A negative relationship between speed and tortuosity was observed both within and among thermal environments. Both biomechanical and behavioural mechanisms might have caused the observed relationship. Turning at high speeds should be more difficult because of the force needed to overcome inertia, and turning at low speeds could help ants evade a predator. Staged encounters with predators should help to define the ecological significance of the trade-off between speed and tortuosity

Potential impacts of climate change on Sub-Saharan African plant priority area selection.

The Global Strategy for Plant Conservation (GSPC) aims to protect 50% of the most important areas for plant diversity by 2010. This study selects sets of 1-degree grid cells for 37 sub-Saharan African countries on the basis of a large database of plant species distributions. We use two reserve selection algorithms that attempt to satisfy two of the criteria set by the GSPC. The grid cells selected as important plant cells (IPCs) are compared between algorithms and in terms of country and continental rankings between cells. The conservation value of the selected grid cells are then considered in relation to their future species complement given the predicted climate change in three future periods (2025, 2055, and 2085). This analysis uses predicted climate suitability for individual species from a previous modelling exercise. We find that a country-by-country conservation approach is suitable for capturing most, but not all, continentally IPCs. The complementarity-based reserve selection algorithms suggest conservation of a similar set of grid cells, suggesting that areas of high plant diversity and rarity may be well protected by a single pattern of conservation activity. Although climatic conditions are predicted to deteriorate for many species under predicted climate change, the cells selected by the algorithms are less affected by climate change predictions than non-selected cells. For the plant species that maintain areas of climatic suitability in the future, the selected set will include cells with climate that is highly suitable for the species in the future. The selected cells are also predicted to conserve a large proportion of the species richness remaining across the continent under climate change, despite the network of cells being less optimal in terms of future predicted distributions