Sequence variation in ligand binding sites in proteins

BACKGROUND: The recent explosion in the availability of complete genome sequences has led to the cataloging of tens of thousands of new proteins and putative proteins. Many of these proteins can be structurally or functionally categorized from sequence conservation alone. In contrast, little attention has been given to the meaning of poorly-conserved sites in families of proteins, which are typically assumed to be of little structural or functional importance. RESULTS: Recently, using statistical free energy analysis of tetratricopeptide repeat (TPR) domains, we observed that positions in contact with peptide ligands are more variable than surface positions in general. Here we show that statistical analysis of TPRs, ankyrin repeats, Cys(2)His(2 )zinc fingers and PDZ domains accurately identifies specificity-determining positions by their sequence variation. Sequence variation is measured as deviation from a neutral reference state, and we present probabilistic and information theory formalisms that improve upon recently suggested methods such as statistical free energies and sequence entropies. CONCLUSION: Sequence variation has been used to identify functionally-important residues in four selected protein families. With TPRs and ankyrin repeats, protein families that bind highly diverse ligands, the effect is so pronounced that sequence "hypervariation" alone can be used to predict ligand binding sites

Model Checking CTL is Almost Always Inherently Sequential

The model checking problem for CTL is known to be P-complete (Clarke, Emerson, and Sistla (1986), see Schnoebelen (2002)). We consider fragments of CTL obtained by restricting the use of temporal modalities or the use of negations---restrictions already studied for LTL by Sistla and Clarke (1985) and Markey (2004). For all these fragments, except for the trivial case without any temporal operator, we systematically prove model checking to be either inherently sequential (P-complete) or very efficiently parallelizable (LOGCFL-complete). For most fragments, however, model checking for CTL is already P-complete. Hence our results indicate that, in cases where the combined complexity is of relevance, approaching CTL model checking by parallelism cannot be expected to result in any significant speedup. We also completely determine the complexity of the model checking problem for all fragments of the extensions ECTL, CTL+, and ECTL+

The IBER study: a feasibility randomised controlled trial of imagery based emotion regulation for the treatment of anxiety in bipolar disorder

BACKGROUND: Intrusive mental imagery is associated with anxiety and mood instability within bipolar disorder and therefore represents a novel treatment target. Imagery Based Emotion Regulation (IBER) is a brief structured psychological intervention developed to enable people to use the skills required to regulate the emotional impact of these images. METHODS: Participants aged 18 and over with a diagnosis of bipolar disorder and at least a mild level of anxiety were randomly assigned (1:1) to receive IBER plus treatment as usual (IBER + TAU) or treatment as usual alone (TAU). IBER was delivered in up to 12 sessions overs 16 weeks. Clinical and health economic data were collected at baseline, end of treatment and 16-weeks follow-up. Objectives were to inform the recruitment process, timeline and sample size estimate for a definitive trial and to refine trial procedures. We also explored the impact on participant outcomes of anxiety, depression, mania, and mood stability at 16-weeks and 32-weeks follow-up. RESULTS: Fifty-seven (28: IBER + TAU, 27: TAU) participants from two sites were randomised, with 50 being recruited within the first 12 months. Forty-seven (82%) participants provided outcome data at 16 and 32-weeks follow-up. Thirty-five participants engaged in daily mood monitoring at the 32-week follow-up stage. Retention in IBER treatment was high with 27 (96%) attending ≥ 7 sessions. No study participants experienced a serious adverse event. DISCUSSION: The feasibility criteria of recruitment, outcome completion, and intervention retention were broadly achieved, indicating that imagery-focused interventions for bipolar disorder are worthy of further investigation

Warm Dust and Spatially Variable PAH Emission in the Dwarf Starburst Galaxy NGC 1705

We present Spitzer observations of the dwarf starburst galaxy NGC 1705 obtained as part of SINGS. The galaxy morphology is very different shortward and longward of ~5 microns: short-wavelength imaging shows an underlying red stellar population, with the central super star cluster (SSC) dominating the luminosity; longer-wavelength data reveals warm dust emission arising from two off-nuclear regions offset by ~250 pc from the SSC. These regions show little extinction at optical wavelengths. The galaxy has a relatively low global dust mass (~2E5 solar masses, implying a global dust-to-gas mass ratio ~2--4 times lower than the Milky Way average). The off-nuclear dust emission appears to be powered by photons from the same stellar population responsible for the excitation of the observed H Alpha emission; these photons are unassociated with the SSC (though a contribution from embedded sources to the IR luminosity of the off-nuclear regions cannot be ruled out). Low-resolution IRS spectroscopy shows moderate-strength PAH emission in the 11.3 micron band in the eastern peak; no PAH emission is detected in the SSC or the western dust emission complex. There is significant diffuse 8 micron emission after scaling and subtracting shorter wavelength data; the spatially variable PAH emission strengths revealed by the IRS data suggest caution in the interpretation of diffuse 8 micron emission as arising from PAH carriers alone. The metallicity of NGC 1705 falls at the transition level of 35% solar found by Engelbracht and collaborators; the fact that a system at this metallicity shows spatially variable PAH emission demonstrates the complexity of interpreting diffuse 8 micron emission. A radio continuum non-detection, NGC 1705 deviates significantly from the canonical far-IR vs. radio correlation. (Abridged)Comment: ApJ, in press; please retrieve full-resolution version from http://www.astro.wesleyan.edu/~cannon/pubs.htm

Lifetime determination of excited states in Cd-106

Two separate experiments using the Differential Decay Curve Method have been performed to extract mean lifetimes of excited states in 106 Cd. The inedium-spin states of interest were populated by the Mo-98(C-12, 4n) Cd-106 reaction performed at the Wright Nuclear Structure Lab., Yale University. From this experiment, two isomeric state mean lifetimes have been deduced. The low-lying states were populated by the Mo-96(C-13, 3n)Cd-106 reaction performed at the Institut fur Kernphysik, Universitat zu Koln. The mean lifetime of the I-pi = 2(1)(+) state was deduced, tentatively, as 16.4(9) ps. This value differs from the previously accepted literature value from Coulomb excitation of 10.43(9) ps

A genome-wide CRISPR/Cas9 screen reveals the requirement of host sphingomyelin synthase 1 for infection with Pseudorabies virus mutant gD–Pass

Herpesviruses are large DNA viruses, which encode up to 300 different proteins including enzymes enabling efficient replication. Nevertheless, they depend on a multitude of host cell proteins for successful propagation. To uncover cellular host factors important for replication of pseudorabies virus (PrV), an alphaherpesvirus of swine, we performed an unbiased genome-wide CRISPR/Cas9 forward screen. To this end, a porcine CRISPR-knockout sgRNA library (SsCRISPRko.v1) targeting 20,598 genes was generated and used to transduce porcine kidney cells. Cells were then infected with either wildtype PrV (PrV-Ka) or a PrV mutant (PrV-gD–Pass) lacking the receptor-binding protein gD, which regained infectivity after serial passaging in cell culture. While no cells survived infection with PrV-Ka, resistant cell colonies were observed after infection with PrV-gD–Pass. In these cells, sphingomyelin synthase 1 (SMS1) was identified as the top hit candidate. Infection efficiency was reduced by up to 90% for PrV-gD–Pass in rabbit RK13-sgms1KO cells compared to wildtype cells accompanied by lower viral progeny titers. Exogenous expression of SMS1 partly reverted the entry defect of PrV-gD–Pass. In contrast, infectivity of PrV-Ka was reduced by 50% on the knockout cells, which could not be restored by exogenous expression of SMS1. These data suggest that SMS1 plays a pivotal role for PrV infection, when the gD-mediated entry pathway is blocked

Detectors for the James Webb Space Telescope Near-Infrared Spectrograph I: Readout Mode, Noise Model, and Calibration Considerations

We describe how the James Webb Space Telescope (JWST) Near-Infrared Spectrograph's (NIRSpec's) detectors will be read out, and present a model of how noise scales with the number of multiple non-destructive reads sampling-up-the-ramp. We believe that this noise model, which is validated using real and simulated test data, is applicable to most astronomical near-infrared instruments. We describe some non-ideal behaviors that have been observed in engineering grade NIRSpec detectors, and demonstrate that they are unlikely to affect NIRSpec sensitivity, operations, or calibration. These include a HAWAII-2RG reset anomaly and random telegraph noise (RTN). Using real test data, we show that the reset anomaly is: (1) very nearly noiseless and (2) can be easily calibrated out. Likewise, we show that large-amplitude RTN affects only a small and fixed population of pixels. It can therefore be tracked using standard pixel operability maps.Comment: 55 pages, 10 figure