A model for transition of 5 '-nuclease domain of DNA polymerase I from inert to active modes

Bacteria contain DNA polymerase I (PolI), a single polypeptide chain consisting of similar to 930 residues, possessing DNA-dependent DNA polymerase, 3'-5' proofreading and 5'-3' exonuclease (also known as flap endonuclease) activities. PolI is particularly important in the processing of Okazaki fragments generated during lagging strand replication and must ultimately produce a double-stranded substrate with a nick suitable for DNA ligase to seal. PolI's activities must be highly coordinated both temporally and spatially otherwise uncontrolled 5'-nuclease activity could attack a nick and produce extended gaps leading to potentially lethal double-strand breaks. To investigate the mechanism of how PolI efficiently produces these nicks, we present theoretical studies on the dynamics of two possible scenarios or models. In one the flap DNA substrate can transit from the polymerase active site to the 5'-nuclease active site, with the relative position of the two active sites being kept fixed; while the other is that the 5'-nuclease domain can transit from the inactive mode, with the 5'-nuclease active site distant from the cleavage site on the DNA substrate, to the active mode, where the active site and substrate cleavage site are juxtaposed. The theoretical results based on the former scenario are inconsistent with the available experimental data that indicated that the majority of 5'-nucleolytic processing events are carried out by the same PolI molecule that has just extended the upstream primer terminus. By contrast, the theoretical results on the latter model, which is constructed based on available structural studies, are consistent with the experimental data. We thus conclude that the latter model rather than the former one is reasonable to describe the cooperation of the PolI's polymerase and 5'-3' exonuclease activities. Moreover, predicted results for the latter model are presented

Australian Aboriginal Birth Cohort study: follow-up processes at 20 years

Background: In 1987, a prospective study of an Australian Aboriginal Birth Cohort was established focusing on the relationships of fetal and childhood growth with the risk of chronic adult disease. However as the study is being conducted in a highly marginalized population it is also an important resource for cross-sectional descriptive and analytical studies. The aim of this paper is to describe the processes of the third follow up which was conducted 20 years after recruitment at birth. Methods: Progressive steps in a multiphase protocol were used for tracing, with modifications for the expected rural or urban location of the participants. Results: Of the original 686 cohort participants recruited 68 were untraced and 27 were known to have died. Of the 591 available for examination 122 were not examined; 11 of these were refusals and the remainder were not seen for logistical reasons relating to inclement weather, mobility of participants and single participants living in very remote locations. Conclusion: The high retention rate of this follow-up 20 years after birth recruitment is a testament to the development of successful multiphase protocols aimed at overcoming the challenges of tracing a cohort over a widespread remote area and also to the perseverance of the study personnel. We also interpret the high retention rate as a reflection of the good will of the wider Aboriginal community towards this study and that researchers interactions with the community were positive. The continued follow-up of this life course study now seems feasible and there are plans to trace and reexamine the cohort at age 25 years.Susan Sayers, Gurmeet Singh, Dorothy Mackerras, Megan Lawrance,Wendy Gunthorpe, Lisa Jamieson, Belinda Davison, Kobi Schutz and Joseph Fit

JointCalc: A web-based personalised patient decision support tool for joint replacement

Background and purpose Health information systems (HIS) are expected to be effective and efficient in improving healthcare services, but empirical observation of HIS reveals that most perform poorly in terms of these metrics. Theoretical factors of HIS performance are widely studied, and solutions to mitigate poor performance have been proposed. In this paper we implement effective methods to eliminate some common drawbacks of HIS design and demonstrate the synergy between the methods. JointCalc, the first comprehensive patient-facing web-based decision support tool for joint replacement, is used as a case study for this purpose. Methods and results User-centred design and thorough end-user involvement are employed throughout the design and development of JointCalc. This is supported by modern software production paradigms, including continuous integration/continuous development, agile and service-oriented architecture. The adopted methods result in a user-approved application delivered well within the scope of project. Conclusion This work supports the claims of high potential efficiency of HIS. The methods identified are shown to be applicable in the production of an effective HIS whilst aiding development efficiency

Morphology of Galaxy Clusters: A Cosmological Model-Independent Test of the Cosmic Distance-Duality Relation

Aiming at comparing different morphological models of galaxy clusters, we use two new methods to make a cosmological model-independent test of the distance-duality (DD) relation. The luminosity distances come from Union2 compilation of Supernovae Type Ia. The angular diameter distances are given by two cluster models (De Filippis et al. and Bonamente et al.). The advantage of our methods is that it can reduce statistical errors. Concerning the morphological hypotheses for cluster models, it is mainly focused on the comparison between elliptical $\beta$-model and spherical $\beta$-model. The spherical $\beta$-model is divided into two groups in terms of different reduction methods of angular diameter distances, i.e. conservative spherical $\beta$-model and corrected spherical $\beta$-model. Our results show that the DD relation is consistent with the elliptical $\beta$-model at $1\sigma$ confidence level (CL) for both methods, whereas for almost all spherical $\beta$-model parameterizations, the DD relation can only be accommodated at $3\sigma$ CL, particularly for the conservative spherical $\beta$-model. In order to minimize systematic uncertainties, we also apply the test to the overlap sample, i.e. the same set of clusters modeled by both De Filippis et al. and Bonamente et al.. It is found that the DD relation is compatible with the elliptically modeled overlap sample at $1\sigma$ CL, however for most of the parameterizations, the DD relation can not be accommodated even at $3\sigma$ CL for any of the two spherical $\beta$-models. Therefore it is reasonable that the marked triaxial ellipsoidal model is a better geometrical hypothesis describing the structure of the galaxy cluster compared with the spherical $\beta$-model if the DD relation is valid in cosmological observations.Comment: 12 pages, 9 figures, 3 tables, significantly improved compared with 1st version, accepted for publication in the Ap

Cow and herd-level risk factors associated with mobility scores in pasture-based dairy cows

peer-reviewedLameness in dairy cows is an area of concern from an economic, environmental and animal welfare point of view. While the potential risk factors associated with suboptimal mobility in non-pasture-based systems are evident throughout the literature, the same information is less abundant for pasture-based systems specifically those coupled with seasonal calving, like those in Ireland. Therefore, the objective of this study was to determine the potential risk factors associated with specific mobility scores (0 = good, 1 = imperfect, 2 = impaired, and 3 = severely impaired mobility) for pasture-based dairy cows. Various cow and herd-level potential risk factors from Irish pasture-based systems were collected and analyzed for their association with suboptimal mobility, whereby a mobility score of 0 refers to cows with optimal mobility and a mobility score ≥ 1 refers to a cow with some form of suboptimal mobility. Combined cow and herd-level statistical models were used to determine the increased or decreased risk for mobility score 1, 2, and 3 (any form of suboptimal mobility) compared to the risk for mobility score 0 (optimal mobility), as the outcome variable and the various potential risk factors at both the cow and herd-level were included as predictor type variables. Cow-level variables included body condition score, milk yield, genetic predicted transmitting ability for ‘lameness’, somatic cell score, calving month and cow breed. Herd-level variables included various environmental and management practices on farm. These analyses have identified several cow-level potential risk factors (including low body condition score, high milk yield, elevated somatic cell count, stage of lactation, calving month, and certain breed types), as well as various herd-level potential risk factors (including the amount of time taken to complete the milking process, claw trimmer training, farm layout factors and foot bathing practices) which are associated with suboptimal mobility. The results of this study should be considered by farm advisors when advising and implementing a cow/herd health program for dairy cows in pasture-based systems

Predictors of Objectively Measured Medication Nonadherence in Adults With Heart Failure

Background—Medication nonadherence rates are high. The factors predicting nonadherence in heart failure remain unclear. Methods and Results—A sample of 202 adults with heart failure was enrolled from the northeastern United States and followed for 6 months. Specific aims were to describe the types of objectively measured medication adherence (eg, taking, timing, dosing, drug holidays) and to identify contributors to nonadherence 6 months after enrollment. Latent growth mixture modeling was used to identify distinct trajectories of adherence. Indicators of the 5 World Health Organization dimensions of adherence (socioeconomic, condition, therapy, patient, and healthcare system) were tested to identify contributors to nonadherence. Two distinct trajectories were identified and labeled persistent adherence (77.8%) and steep decline (22.3%). Three contributors to the steep decline in adherence were identified. Participants with lapses in attention (adjusted OR, 2.65; P=0.023), those with excessive daytime sleepiness (OR, 2.51; P=0.037), and those with ≥2 medication dosings per day (OR, 2.59; P=0.016) were more likely to have a steep decline in adherence over time than to have persistent adherence. Conclusions—Two distinct patterns of adherence were identified. Three potentially modifiable contributors to nonadherence have been identified

The University of Minnesota Biocatalysis/Biodegradation Database: improving public access

The University of Minnesota Biocatalysis/Biodegradation Database (UM-BBD, http://umbbd.msi.umn.edu/) began in 1995 and now contains information on almost 1200 compounds, over 800 enzymes, almost 1300 reactions and almost 500 microorganism entries. Besides these data, it includes a Biochemical Periodic Table (UM-BPT) and a rule-based Pathway Prediction System (UM-PPS) (http://umbbd.msi.umn.edu/predict/) that predicts plausible pathways for microbial degradation of organic compounds. Currently, the UM-PPS contains 260 biotransformation rules derived from reactions found in the UM-BBD and scientific literature. Public access to UM-BBD data is increasing. UM-BBD compound data are now contributed to PubChem and ChemSpider, the public chemical databases. A new mirror website of the UM-BBD, UM-BPT and UM-PPS is being developed at ETH Zürich to improve speed and reliability of online access from anywhere in the world

Policies on bruises in premobile children: Why we need improved standards for policymaking

This review of the 91 English children's services departments with specific policies on bruising in premobile children found a major disjuncture between research evidence and its interpretation in guidance. Many policies require all premobile children found with a bruise to be seen urgently by a paediatrician, and in some, all bruised children are subject of a formal child protection investigation regardless of the explanations for the bruise or the views of front‐line practitioners. However, the research on bruises in premobile children on which these policies were based was found to be limited and contradictory and did not fully support the guidance given. National guidance given by the National Institute for Health and Care Excellence and many local policies state that bruising in premobile children is suggestive of physical abuse because accidental bruising is uncommon despite the only longitudinal study of bruising showing 27% of premobile children were bruised over an average of 7.6 weekly observations. The paper calls for an urgent review of these policies and guidance and improved standards for policymaking

Subdegree Sunyaev-Zel'dovich Signal from Multifrequency BOOMERanG observations

The Sunyaev-Zel'dovich (SZ) effect is the inverse Compton-scattering of cosmic microwave background (CMB) photons by hot electrons in the intervening gas throughout the universe. The effect has a distinct spectral signature that allows its separation from other signals in multifrequency CMB datasets. Using CMB anisotropies measured at three frequencies by the BOOMERanG 2003 flight we constrain SZ fluctuations in the 10 arcmin to 1 deg angular range. Propagating errors and potential systematic effects through simulations, we obtain an overall upper limit of 15.3 uK (2 sigma) for rms SZ fluctuations in a broad bin between multipoles of of 250 and 1200 at the Rayleigh-Jeans (RJ) end of the spectrum. When combined with other CMB anisotropy and SZ measurements, we find that the local universe normalization of the density perturbations is sigma-8(SZ) < 0.96 at the 95% confidence level, consistent with sigma-8 determined from primordial perturbations.Comment: accepted for publication in ApJ. Letter

Effect of feeding single-dam or pooled colostrum on maternally derived immunity in dairy calves

peer-reviewedThe role of colostrum management in providing adequate immunological protection to neonatal calves has been widely investigated, and thresholds for colostrum quality, as well as optimum volume and timing for colostrum feeding have been established. However, limited information is available on the effect of colostrum source (single dam or pooled) on passive immunity, as well as subsequent antibody survival in the calf. This study aimed to assess the effect of feeding single-dam colostrum (own and other dam) or pooled colostrum on transfer of passive immunity, and also investigate the rate of depletion of disease-specific antibodies among dairy calves. In total, 320 cows and 119 dairy heifer calves were enrolled in the study. Calves were blood-sampled immediately after birth and received either own-dam, other-dam, or pooled colostrum. Calves were blood-sampled at 24 h to assess serum IgG concentrations and at monthly intervals thereafter to document disease-specific antibody survival. Mean colostrum IgG concentration was higher for other-dam treatment group, whereas own-dam and pooled treatments were similar. For all treatment groups, the mean IgG concentration was >80 mg/mL, exceeding the quality threshold of 50 mg/mL. Mean calf serum IgG concentration was lower for calves fed pooled colostrum compared with those that received colostrum from a single cow. There was a negative association with 24-h serum IgG and calf birth bodyweight; calves <30 kg at birth had the highest 24-h serum IgG concentration. Survival of antibodies to bovine viral diarrhea, Salmonella infection, leptospirosis, bovine parainfluenza 3 virus, bovine respiratory syncytical virus, rotavirus, and coronavirus was not associated with colostrum source; however, antibodies to infectious bovine rhinotracheitis had a greater period of survival among calves fed own-dam colostrum. We found that feeding single-dam colostrum can thus improve calf immunity through increased serum IgG levels and antibody survival rates. Furthermore, we hypothesize that immune exclusion may occur with pooled colostrum; therefore, providing pooled colostrum may still be a good practice as long as it can be ensured that enough antibodies are absorbed into the blood stream to deal with pathogens calves may encounter because different dams may have antibodies against different strains of viruses and bacteria, yielding cross protection