Papillomavirus E1 helicase assembly maintains an asymmetric state in the absence of DNA and nucleotide cofactors.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Concerted, stochastic and sequential mechanisms of action have been proposed for different hexameric AAA+ molecular motors. Here we report the crystal structure of the E1 helicase from bovine papillomavirus, where asymmetric assembly is for the first time observed in the absence of nucleotide cofactors and DNA. Surprisingly, the ATP-binding sites adopt specific conformations linked to positional changes in the DNA-binding hairpins, which follow a wave-like trajectory, as observed previously in the E1/DNA/ADP complex. The protein's assembly thus maintains such an asymmetric state in the absence of DNA and nucleotide cofactors, allowing consideration of the E1 helicase action as the propagation of a conformational wave around the protein ring. The data imply that the wave's propagation within the AAA+ domains is not necessarily coupled with a strictly sequential hydrolysis of ATP. Since a single ATP hydrolysis event would affect the whole hexamer, such events may simply serve to rectify the direction of the wave's motion.Wellcome TrustYorkshire Cancer ResearchBBSRCEPSRCMR

The Berkeley Contact Lens Extended Wear Study. Part I : Study design and conduct.

ObjectiveThe primary aim of the Berkeley Contact Lens Extended Wear Study (CLEWS) was to test the hypotheses that extended wear of rigid gas-permeable (RGP) contact lenses with greater oxygen permeability (Dk) reduces the incidence of contact lens-associated keratopathy (CLAK) and increases the survival rate in RGP extended wear (EW). In this article we describe the clinical trial design in detail, present the results of subject recruitment and retention, and provide the baseline demographic and ocular characteristics of the CLEWS subjects, whose data will be analyzed to address the study aims in a companion article.DesignA randomized, concurrently controlled clinical trial.InterventionSubjects were fitted with day wear (DW) high-Dk RGP lenses and then adapted to EW. Subjects who adapted to EW were then randomly assigned to either high- or medium-Dk RGP lenses for 12 months of 6-nights/week EW.Main outcome measuresSlit-lamp assessment and grading of 17 possible keratopathies, measurement of refractive error and corneal curvature, and symptoms. Follow-up data were collected every 3 months.ResultsFrom 545 subjects entering the DW adaptation phase, 201 adapted to EW and were randomly assigned to medium- or high-Dk lenses for 12 months of EW. The baseline characteristics of the two study groups were similar and did not differ from the 344 DW subjects who failed to adapt to EW. The distributions of oxygen transmissibility for the two study groups were disjoint, indicating that each group received distinctly different levels of hypoxia.ConclusionsWe show that CLEWS was appropriately designed to address the study hypotheses, was conducted with regard for the safety of the subjects, and adhered to rigorous protocols designed to control for bias and ensure the integrity of study data. We establish the internal validity of between-group statistical comparisons and characterize our study population to permit informed evaluation of the applicability of our results to the contact lens-wearing population in general

The Berkeley Contact Lens Extended Wear Study. Part II : Clinical results.

ObjectiveTo describe the principal clinical outcomes associated with 12 months use of rigid gas-permeable (RGP) extended wear contact lenses and address two primary study questions: (1) does extended wear (EW) of high oxygen transmissibility (Dk/t) RGP lenses reduce the incidence of ocular complications, and (2) does the wearing of high-Dk/t lenses reduce the rate of failure to maintain 6-night RGPEW over 12 months?DesignA randomized, concurrently controlled clinical trial.InterventionSubjects who adapted to EW with high Dk (oxygen permeability) RGP lenses were randomized to either high Dk or medium-Dk RGP lenses for 12 months of 6-night EW.Main outcome measuresContact lens-associated keratopathies (CLAK), changes in refractive error and corneal curvature, and survival in EW.ResultsTwo hundred one subjects were randomized to medium or high-Dk lenses for 12 months of EW. Sixty-two percent of the subjects in each group completed 12 months of EW; however, the probability of failure was significantly greater for the medium-Dk group. Although the risk of complications was similar for the two groups, the number of CLAK events that led to termination were 16 versus 5 for the medium-Dk and high-Dk groups, respectively. This suggests that the type of adverse response or the inability to reverse an adverse event was different for the group being exposed to the lower oxygen dose.ConclusionsThe level of oxygen available to the cornea has a significant impact on maintaining successful RGP extended contact lens wear, but not on the initial onset of CLAK. The number of clinical events leading to termination was substantially higher for the medium Dk group, which suggests that corneal hypoxia is an important factor in the development of CLAK. Although overnight contact lens wear should be recommended with caution and carefully monitored for early detection of ocular complications, it appears that high-Dk RGP lenses can be a safe and effective treatment for correction of refractive error for most individuals who can adapt to EW

Parenting and child behaviour as predictors of toothbrushing difficulties in young children

Background: Oral disease is one of the most prevalent chronic health conditions affecting children. Twice-daily toothbrushing is recommended to promote good oral health; however, a large proportion of Australian families are not meeting this recommendation. Aim: This study aimed to identify important barriers to regular toothbrushing for young children. Design: In this study, 239 parents of 0- to 4-year-old children completed an online survey that investigated child, family, and parent factors associated with child toothbrushing. Hierarchical linear regression was used to identify predictors of toothbrushing frequency in children and perceived difficulty of the task by parents. Results: We found that parent factors, specifically oral health knowledge, were the most significant predictors of toothbrushing frequency. Conversely, parent factors did not contribute significantly to the prediction of perceived difficulty of toothbrushing once family and child factors were taken into account. Oral health knowledge and use of routines were identified as the most important predictors of toothbrushing frequency, whereas resistant child behaviour and household organisation were found to be the most important predictors of perceived difficulty of regular toothbrushing. Conclusions: The findings of the study have implications for behavioural interventions to support parents, as well as directions for future research

A runaway collision in a young star cluster as the origin of the brightest supernova

Supernova 2006gy in the galaxy NGC 1260 is the most luminous one recorded \cite{2006CBET..644....1Q, 2006CBET..647....1H, 2006CBET..648....1P, 2006CBET..695....1F}. Its progenitor might have been a very massive ($>100$ \msun) star \cite{2006astro.ph.12617S}, but that is incompatible with hydrogen in the spectrum of the supernova, because stars $>40$ \msun are believed to have shed their hydrogen envelopes several hundred thousand years before the explosion \cite{2005A&A...429..581M}. Alternatively, the progenitor might have arisen from the merger of two massive stars \cite{2007ApJ...659L..13O}. Here we show that the collision frequency of massive stars in a dense and young cluster (of the kind to be expected near the center of a galaxy) is sufficient to provide a reasonable chance that SN 2006gy resulted from such a bombardment. If this is the correct explanation, then we predict that when the supernova fades (in a year or so) a dense cluster of massive stars becomes visible at the site of the explosion

Modified Newtonian Dynamics as an Alternative to Dark Matter

Modified Newtonian dynamics (MOND) is an empirically motivated modification of Newtonian gravity or inertia suggested by Milgrom as an alternative to cosmic dark matter. The basic idea is that at accelerations below a0 ~ 10^{-8} cm/s^2 ~ cH0/6 the effective gravitational attraction approaches sqrt{gN*a0} where gN is the usual Newtonian acceleration. This simple algorithm yields flat rotation curves for spiral galaxies and a mass-rotation velocity relation of the form M ~ V^4 that forms the basis for the observed luminosity-rotation velocity relation-- the Tully-Fisher law. We review the phenomenological success of MOND on scales ranging from dwarf spheroidal galaxies to superclusters, and demonstrate that the evidence for dark matter can be equally well interpreted as evidence for MOND. We discuss the possible physical basis for an acceleration-based modification of Newtonian dynamics as well as the extension of MOND to cosmology and structure formation.Comment: To be published in volume 40 of Annual Reviews of Astronomy & Astrophysics. 36 pages plus 12 figures and 1 tabl

A massive reservoir of low-excitation molecular gas at high redshift

Molecular hydrogen is an important component of galaxies because it fuels star formation and accretion onto AGN, the two processes that generate the large infrared luminosities of gas-rich galaxies. Observations of spectral-line emission from the tracer molecule CO are used to probe the properties of this gas. But the lines that have been studied in the local Universe, mostly the lower rotational transitions of J = 1-0 and J = 2-1, have hitherto been unobservable in high-redshift galaxies. Instead, higher transitions have been used, although the densities and temperatures required to excite these higher transitions may not be reached by much of the gas. As a result, past observations may have underestimated the total amount of molecular gas by a substantial amount. Here we report the discovery of large amounts of low-excitation molecular gas around the infrared-luminous quasar, APM 08279+5255 at z = 3.91, using the two lowest excitation lines of 12CO (J = 1-0 and J = 2-1). The maps confirm the presence of hot and dense gas near the nucleus, and reveal an extended reservoir of molecular gas with low excitation that is 10 to 100 times more massive than the gas traced by higher-excitation observations. This raises the possibility that significant amounts of low-excitation molecular gas may lurk in the environments of high-redshift (z > 3) galaxies.Comment: To appear as a Letter to Nature, 4th January 200

A Suborbital Payload for Soft X-ray Spectroscopy of Extended Sources

We present a suborbital rocket payload capable of performing soft X-ray spectroscopy on extended sources. The payload can reach resolutions of ~100(lambda/dlambda) over sources as large as 3.25 degrees in diameter in the 17-107 angstrom bandpass. This permits analysis of the overall energy balance of nearby supernova remnants and the detailed nature of the diffuse soft X-ray background. The main components of the instrument are: wire grid collimators, off-plane grating arrays and gaseous electron multiplier detectors. This payload is adaptable to longer duration orbital rockets given its comparatively simple pointing and telemetry requirements and an abundance of potential science targets.Comment: Accepted to Experimental Astronomy, 12 pages plus 1 table and 17 figure

SuperCLASS - II. Photometric redshifts and characteristics of spatially resolved mu Jy radio sources

We present optical and near-infrared imaging covering a ∼1.53 deg2 region in the Super-Cluster Assisted Shear Survey (SuperCLASS) field, which aims to make the first robust weak lensing measurement at radio wavelengths. We derive photometric redshifts for ≈176 000 sources down to i′AB∼24 and present photometric redshifts for 1.4 GHz expanded Multi-Element Radio Linked Interferometer Network (e-MERLIN) and Karl G. Jansky Very Large Array (VLA) detected radio sources found in the central 0.26 deg2. We compile an initial catalogue of 149 radio sources brighter than S1.4 > 75 μJy and find their photometric redshifts span 0 7σ in the density map and we confirm the photometric redshifts are consistent with previously measured spectra from a few galaxies at the cluster centres

Hepatitis C infection: eligibility for antiviral therapies

peer reviewedBackground Current treatments of chronic hepatitis C virus (HCV) are effective, but expensive and susceptible to induce significant side effects. Objectives To evaluate the proportion of HCV patients who are eligible for a treatment. Methods In a database comprising 1726 viraemic HCV patients, the files of 299 patients who presented to the same hepatologist for an initial appointment between 1996 and 2003 were reviewed. Results Patients' characteristics were age 43.1 +/- 15.6 years, 53% male and 92% Caucasian. The main risk factors were transfusion (43%) and drug use (22%). Genotypes were mostly genotype 1 (66%), genotype 3 (12%) and genotype 2 (10%). These characteristics were not different from those of the whole series of 1726 patients. A total of 176 patients (59%) were not treated, the reasons for non-treatment being medical contraindications (34%), non-compliance (25%) and normal transaminases (24%). In addition, 17% of patients declined therapy despite being considered as eligible, mainly due to fear of adverse events. Medical contraindications were psychiatric (27%), age (22%), end-stage liver disease (15%), willingness for pregnancy (13%), cardiac contraindication (7%) and others (16%). Only 123 patients (41%) were treated. A sustained viral response was observed in 41%. The treatment was interrupted in 16% for adverse events. Conclusions The majority of HCV patients are not eligible for treatment. This implies that, with current therapies, only 17% of patients referred for chronic HCV become sustained responders. Some modifications of guidelines could extend the rate of treatment (patients with normal transaminases), but an important barrier remains the patients' and the doctors' fear of adverse events