Molecular dynamics studies of trinucleotide repeat DNA involved in neurodegenerative disorders.

Expansion of trinucleotide repeat DNA of the classes CAG�·CTG, CGG�·CCG and GAA�·TTC are found to be associated with several neurodegenerative disorders. Different mechanisms have been attributed to the expansion of triplets, mainly involving the formation of alternate secondary structures by such repeats. This paper reports the molecular dynamics simulation of triplet repeat DNA sequences to study the basic structural features of DNA that are responsible for the formation of structures such as hairpins and slip-strand DNA leading to expansion. All the triplet repeat sequences studied were found to be more flexible compared to the control sequence unassociated with disease. Moreover, flexibility was found to be in the order CAG�·CTG > CGG�·CCG = GAA�·TTC, the highly flexible CAG�·CTG repeat being the most common cause of neurodegenerative disorders. In another simulation, a single G�·C to T�·A mutation at the 9th position of the CAG�·CTG repeat exhibited a reduction in bending compared to the pure 15-mer CAGâ�¢CTG repeat. EPM1 dodecamer repeat associated with the pathogenesis of progressive myoclonus epilepsy was also simulated and showed flexible nature suggesting a similar expansion mechanism.

WASP-4b: A 12th magnitude transiting hot Jupiter in the southern hemisphere

We report the discovery of WASP-4b, a large transiting gas-giant planet with an orbital period of 1.34 days. This is the first planet to be discovered by the SuperWASP-South observatory and CORALIE collaboration and the first planet orbiting a star brighter than 16th magnitude to be discovered in the southern hemisphere. A simultaneous fit to high-quality light curves and precision radial velocity measurements leads to a planetary mass of 1.22(-0.08)(+0.09) M-Jup and a planetary radius of 1.42(-0.04)(+0.07) R-Jup. The host star is USNO-B1.0 0479-0948995, a G7 V star of visual magnitude 12.5. As a result of the short orbital period, the predicted surface temperature of the planet is 1761 K, making it an ideal candidate for detections of the secondary eclipse at infrared wavelengths.

Updated parameters for the transiting exoplanet WASP-3b using RISE, a new fast camera for the Liverpool Telescope

Some of the first results are reported from RISE - a new fast camera mounted on the Liverpool Telescope primarily designed to obtain high time-resolution light curves of transiting extrasolar planets for the purpose of transit timing. A full and partial transit of WASP-3 are presented, and a Markov-Chain Monte Carlo analysis is used to update the parameters from the discovery paper. This results in a planetary radius of 1.29(-0.12)(+0.05) R-J and therefore a density of 0.82(-0.09)(+0.14) rho(J), consistent with previous results. The inclination is 85.06(-0.15)(+0.16) deg, in agreement (but with a significant improvement in the precision) with the previously determined value. Central transit times are found to be consistent with the ephemeris given in the discovery paper; however, a new ephemeris calculated using the longer baseline results in T-c(0) = 2 454 605.55915 +/- 0.00023 HJD and P = 1.846835 +/- 0.000002 days.

The 0.5M(J) transiting exoplanet WASP-13b

We report the discovery of WASP-13b, a low-mass M-p = 0.46(-0.05)(+0.06) M-J transiting exoplanet with an orbital period of 4.35298 +/- 0.00004 days. The transit has a depth of 9 mmag, and although our follow-up photometry does not allow us to constrain the impact parameter well (0 <b <0.46), with radius in the range R-p similar to 1.06-1.21 R-J the location of WASP-13b in the mass-radius plane is nevertheless consistent with H/He-dominated, irradiated, low core mass and core-free theoretical models. The G1V host star is similar to the Sun in mass (M-* = 1.03(-0.09)(+0.11) M-circle dot) and metallicity ([M/H] = 0.0 +/- 0.2), but is possibly older (8.5(-4.9)(+5.5) Gyr).

A Transit Timing Analysis of Mine RISE Light Curves of the Exoplanet System TrES-3

We present nine newly observed transits of TrES-3, taken as part of a transit timing program using the RISE instrument on the Liverpool Telescope. A Markov-Chain Monte Carlo analysis was used to determine the planet star radius ratio and inclination of the system, which were found to be R-p/R-star = 0.1664(-0.0018)(+0.0011) and i = 81.73(-0.04)(+0.13), respectively, consistent with previous results. The central transit times and uncertainties were also calculated, using a residual-permutation algorithm as an independent check on the errors. A re-analysis of eight previously published TrES-3 light curves was conducted to determine the transit times and uncertainties using consistent techniques. Whilst the transit times were not found to be in agreement with a linear ephemeris, giving chi(2) = 35.07 for 15 degrees of freedom, we interpret this to be the result of systematics in the light curves rather than a real transit timing variation. This is because the light curves that show the largest deviation from a constant period either have relatively little out-of-transit coverage or have clear systematics. A new ephemeris was calculated using the transit times and was found to be T-c(0) = 2454632.62610 +/- 0.00006 HJD and P = 1.3061864 +/- 0.0000005 days. The transit times were then used to place upper mass limits as a function of the period ratio of a potential perturbing planet, showing that our data are sufficiently sensitive to have probed sub-Earth mass planets in both interior and exterior 2:1 resonances, assuming that the additional planet is in an initially circular orbit.

WASP-14b: 7.3 M-J transiting planet in an eccentric orbit

We report the discovery of a 7.3 M-J exoplanet WASP-14b, one of the most massive transiting exoplanets observed to date. The planet orbits the 10th-magnitude F5V star USNO-B1 11118-0262485 with a period of 2.243 752 d and orbital eccentricity e = 0.09. A simultaneous fit of the transit light curve and radial velocity measurements yields a planetary mass of 7.3 +/- 0.5 M-J and a radius of 1.28 +/- 0.08 R-J. This leads to a mean density of about 4.6 g cm(-3) making it the densest transiting exoplanets yet found at an orbital period less than 3 d. We estimate this system to be at a distance of 160 +/- 20 pc. Spectral analysis of the host star reveals a temperature of 6475 +/- 100 K, log g = 4.07 cm s(-2) and v sin i = 4.9 +/- 1.0 km s(-1), and also a high lithium abundance, log N(Li) = 2.84 +/- 0.05. The stellar density, effective temperature and rotation rate suggest an age for the system of about 0.5-1.0 Gyr.

WASP-10b: a 3M(J), gas-giant planet transiting a late-type K star

We report the discovery of WASP-10b, a new transiting extrasolar planet (ESP) discovered by the Wide Angle Search for Planets ( WASP) Consortium and confirmed using Nordic Optical Telescope FIbre-fed Echelle Spectrograph and SOPHIE radial velocity data. A 3.09-d period, 29 mmag transit depth and 2.36 h duration are derived for WASP-10b using WASP and high-precision photometric observations. Simultaneous fitting to the photometric and radial velocity data using a Markov Chain Monte Carlo procedure leads to a planet radius of 1.28R(J), a mass of 2.96M(J) and eccentricity of approximate to 0.06. WASP-10b is one of the more massive transiting ESPs, and we compare its characteristics to the current sample of transiting ESP, where there is currently little information for masses greater than approximate to 2M(J) and non-zero eccentricities. WASP-10's host star, GSC 2752-00114 (USNO-B1.0 1214-0586164) is among the fainter stars in the WASP sample, with V = 12.7 and a spectral type of K5. This result shows promise for future late-type dwarf star surveys.

A transit timing analysis of seven RISE light curves of the exoplanet system HAT-P-3

We present seven light curves of the exoplanet system HAT-P-3, taken as part of a transit timing programme using the rapid imager to search for exoplanets instrument on the Liverpool Telescope. The light curves are analysed using a Markov chain Monte Carlo algorithm to update the parameters of the system. The inclination is found to be i = 86.75+0.22-0.21°, the planet-star radius ratio to be Rp/R* = 0.1098+0.0010-0.0012 and the stellar radius to be R* = 0.834+0.018-0.026Rsolar, consistent with previous results but with a significant improvement in the precision. Central transit times and uncertainties for each light curve are also determined, and a residual permutation algorithm is used as an independent check on the errors. The transit times are found to be consistent with a linear ephemeris, and a new ephemeris is calculated as Tc(0) = 2454856.70118 +/- 0.00018 HJD and P = 2.899738 +/- 0.000007 d. Model timing residuals are fitted to the measured timing residuals to place upper mass limits for a hypothetical perturbing planet as a function of the period ratio. These show that we have probed for planets with masses as low as 0.33 and 1.81 M? in the interior and exterior 2:1 resonances, respectively, assuming the planets are initially in circular orbits.

SuperWASP observations of the 2007 outburst of Comet 17P/Holmes

We present wide-field imaging of the 2007 outburst of Comet 17P/Holmes obtained serendipitously by SuperWASP-North on 17 nights over a 42-night period beginning on the night (2007 October 22-23) immediately prior to the outburst. Photometry of 17P's unresolved coma in SuperWASP data taken on the first night of the outburst is consistent with exponential brightening, suggesting that the rapid increase in the scattering cross-section of the coma could be largely due to the progressive fragmentation of ejected material produced on a very short time-scale at the time of the initial outburst, with fragmentation time-scales decreasing from tfrag ~ 2 × 103 to ~1 × 103 s over our observing period. Analysis of the expansion of 17P's coma reveals a velocity gradient suggesting that the outer coma was dominated by material ejected in an instantaneous, explosive manner. We find an expansion velocity at the edge of the dust coma of vexp = 0.55 +/- 0.02 kms -1 and a likely outburst date of t0 = 2007 October 23.3 +/- 0.3, consistent with our finding that the comet remained below SuperWASP's detection limit of mV ~ 15mag until at least 2007 October 23.3. Modelling of 17P's gas coma indicates that its outer edge, which was observed to extend past the outer dust coma, is best explained with a single pulse of gas production, consistent with our conclusions concerning the production of the outer dust coma.

P2Y(1) antagonists: Combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoring

P2Y(1) is an ADP-activated G protein-coupled receptor (GPCR). Its antagonists impede platelet aggregation in vivo and are potential antithrombotic agents. Combining ligand and structure-based modeling we generated a consensus model (LIST-CM) correlating antagonist structures with their potencies. We docked 45 antagonists into our rhodopsin-based human P2Y(1) homology model and calculated docking scores and free binding energies with the Linear Interaction Energy (LIE) method in continuum-solvent. The resulting alignment was also used to build QSAR based on CoMFA, CoMSIA, and molecular descriptors. To benefit from the strength of each technique and compensate for their limitations, we generated our LIST-CM with a PLS regression based on the predictions of each methodology. A test set featuring untested substituents was synthesized and assayed in inhibition of 2-MeSADP-stimulated PLC activity and in radioligand binding. LIST-CM outperformed internal and external predictivity of any individual model to predict accurately the potency of 75% of the test set.

Functional expression of KCNQ (Kv7) channels in guinea-pig bladder smooth muscle and their contribution to spontaneous activity

Background and Purpose: The aim of the study was to determine whether KCNQ channels are functionally expressed in bladder smooth muscle cells (SMC) and to investigate their physiological significance in bladder contractility. 

Experimental Approach: KCNQ channels were examined at the genetic, protein, cellular and tissue level in guinea pig bladder smooth muscle using RT-PCR, immunofluorescence, patch-clamp electrophysiology, calcium imaging, detrusor strip myography, and a panel of KCNQ activators and inhibitors. 

Key Results: KCNQ subtypes 1-5 are expressed in bladder detrusor smooth muscle. Detrusor strips typically displayed TTX-insensitive myogenic spontaneous contractions that were increased in amplitude by the KCNQ channel inhibitors XE991, linopirdine or chromanol 293B. Contractility was inhibited by the KCNQ channel activators flupirtine or meclofenamic acid (MFA). The frequency of Ca2+-oscillations in SMC contained within bladder tissue sheets was increased by XE991. Outward currents in dispersed bladder SMC, recorded under conditions where BK and KATP currents were minimal, were significantly reduced by XE991, linopirdine, or chromanol, and enhanced by flupirtine or MFA. XE991 depolarized the cell membrane and could evoke transient depolarizations in quiescent cells. Flupirtine (20M) hyperpolarized the cell membrane with a simultaneous cessation of any spontaneous electrical activity. 

Conclusions and Implications: These novel findings reveal the role of KCNQ currents in the regulation of the resting membrane potential of detrusor SMC and their important physiological function in the control of spontaneous contractility in the guinea pig bladder.