Electrically monitoring DNA repair by photolyase

Cyclobutane pyrimidine dimers are the major DNA photoproducts produced upon exposure to UV radiation. If left unrepaired, these lesions can lead to replication errors, mutation, and cell death. Photolyase is a light-activated flavoenzyme that binds to pyrimidine dimers in DNA and repairs them in a reaction triggered by electron transfer from the photoexcited flavin cofactor to the dimer. Using gold electrodes modified with DNA duplexes containing a cyclobutane thymine dimer (T T), here we probe the electrochemistry of the flavin cofactor in Escherichia coli photolyase. Cyclic and square-wave voltammograms of photolyase deposited on these electrodes show a redox signal at 40 mV versus normal hydrogen electrode, consistent with electron transfer to and from the flavin in the DNA-bound protein. This signal is dramatically attenuated on surfaces where the pi-stacking of the DNA bases is perturbed by the presence of an abasic site below the T T, an indication that the redox pathway is DNA-mediated. DNA repair can, moreover, be monitored electrically. Exposure of photolyase on T T-damaged DNA films to near-UV/blue light leads to changes in the flavin signal consistent with repair, as confirmed by parallel HPLC experiments. These results demonstrate the exquisite sensitivity of DNA electrochemistry to perturbations in base pair stacking and the applicability of this chemistry to probe reactions of proteins with DNA

Lack of Z-DNA Conformation in Mitomycin-Modified Polynucleotides Having Inverted Circular Dichroism

Poly(dG-dC)· poly(dG-dC) and Micrococcus lysodeikticus DNA were modified by exposure to reductively activated mitomycin C, an antitumor antibiotic. The resulting covalent drug-polynucleotide complexes displayed varying degrees of CD inversions, which are strikingly similar to the inverted spectrum observed with Z-DNA. The following criteria have been used to establish, however, that the inverted CD pattern seen in mitomycin C-polynucleotide complexes does not reflect a Z-DNA conformation. (i) The ethanol-induced transition of poly(dG-dC)· poly(dG-dC) from B to Z conformation is not facilitated but rather is inhibited by mitomycin C modification. This may be due to the presence of crosslinks. (ii) Radioimmunoassay indicated no competition for Z-DNA-specific antibody by any of the mitomycin C-modified polynucleotides. (iii) 31P NMR of the complexes yielded a single relatively narrow resonance, which is inconsistent with the dinucleotide repeat characteristic of Z-DNA. Alternative explanations for the inverted CD pattern include a drug-induced left-handed but non-Z conformational change or the superposition of an induced CD onto the CD of B-DNA due to drug-base electronic interactions. These results illustrate the need for caution in interpreting CD changes alone as an indication of Z-DNA conformation

The evolution of strong reproductive isolation

Felsenstein distinguished two ways by which selection can directly strengthen isolation. First, a modifier that strengthens prezygotic isolation can be favored everywhere. This fits with the traditional view of reinforcement as an adaptation to reduce deleterious hybridization by strengthening assortative mating. Second, selection can favor association between different incompatibilities, despite recombination. We generalize this “two allele” model to follow associations among any number of incompatibilities, which may include both assortment and hybrid inviability. Our key argument is that this process, of coupling between incompatibilities, may be quite different from the usual view of reinforcement: strong isolation can evolve through the coupling of any kind of incompatibility, whether prezygotic or postzygotic. Single locus incompatibilities become coupled because associations between them increase the variance in compatibility, which in turn increases mean fitness if there is positive epistasis. Multiple incompatibilities, each maintained by epistasis, can become coupled in the same way. In contrast, a single-locus incompatibility can become coupled with loci that reduce the viability of haploid hybrids because this reduces harmful recombination. We obtain simple approximations for the limits of tight linkage, and strong assortment, and show how assortment alleles can invade through associations with other components of reproductive isolation

Unplanned pregnancy and subsequent psychological distress in partnered women: a cross-sectional study of the role of relationship quality and wider social support

Background: Research into the impact of unintended pregnancy on the wellbeing of women tends to focus on pregnancies ending in either termination or lone motherhood. Unintended pregnancy is common in partnered women, but little is known about the association between unintended pregnancy and postpartum affective disorders, such as depression and anxiety in this group. Poor relationship quality and lack of social support are considered risk factors for psychological distress (PD). We examined the association between unplanned motherhood and subsequent PD in partnered women, for whom evidence is sparse, accounting for the role of relationship quality and social support. Methods: Data for 12,462 partnered mothers were drawn from the first survey of Millennium Cohort Study, completed at 9 months postpartum. Women reported whether their baby was planned, and how they felt when they discovered that they were pregnant. Pregnancy intention is categorised as “planned”, “unplanned/happy”, “unplanned/ambivalent” and “unplanned/unhappy”. PD was assessed using the modified 9-item Rutter Malaise Inventory. Social support was measured by a composite score for perceived support, and a measure of actual support from friends and family. Relationship quality was assessed using a modified Golombok-Rust Inventory of Marital State. The effect of pregnancy intention on the odds of PD at 9 months was estimated, adjusting for potential confounding factors. All analyses were weighted for response and design effects. Results: In total 32.8%(weighted) (4343/ 12462) of mothers reported an unplanned pregnancy: 23.3wt% (3087) of mothers felt happy, 3.5wt% (475) ambivalent, and 6.0wt% (781) unhappy upon discovery. Unplanned pregnancy was associated with a significantly increased odds of PD compared to planned (OR 1.73 (95%CI: 1.53, 1.95)). This was more pronounced among women who reported negative or ambivalent feelings in early pregnancy (OR 2.72 (95%CI:2.17, 3.41) and 2.56 (95%CI:1.95, 3.34), respectively), than those who reported positive feelings (OR 1.39 (95%CI:1.21, 1.60)). Adjustment for relationship quality, in particular, reduced odds of PD after unplanned pregnancy (e.g. from 2.19 (95%C: 1.74, 2.74) to 1.63 (95% CI: 1.29, 2.07 in the unplanned, unhappy group compared to the planned). Conclusions: A third of partnered mothers reported that their pregnancy was unintended, yet this group is under-researched. Unplanned motherhood was associated with increased risk of PD at 9 months postpartum, particularly among women who felt unhappy or ambivalent at the start. The roles of relationship quality and social support require further investigation, as possible means to intervene and improve maternal wellbeing

The extended mixture distribution survival tree based analysis for clustering and patient pathway prognostication in a stroke care unit

In our previous work we proposed a special class of survival distribution called Mixture distribution survival trees, which are constructed by approximating different nodes in the tree by distinct types of mixture distributions to achieve more improvement in the likelihood function and thus the improved within node homogeneity. We proposed its applications in modelling hospital length of stay and clustering patients into clinically meaningful patient groups, where partitioning was based on covariates representing patient characteristics such as gender, age at the time of admission, and primary diagnosis code. This paper proposes extended Mixture distribution survival trees and demonstrates its applications to patient pathway prognostication and to examine the relationship between hospital length of stay and/or treatment outcome. 5 year retrospective data of patients admitted to Belfast City Hospital with a diagnosis of stroke is used to illustrate the approach.peer-reviewe

Seal carrion is a predictable resource for coastal ecosystems

The timing, magnitude, and spatial distribution of resource inputs can have large effects on dependent organisms. Few studies have examined the predictability of such resources and no standard ecological measure of predictability exists. We examined the potential predictability of carrion resources provided by one of the UK's largest grey seal (Halichoerus grypus) colonies, on the Isle of May, Scotland. We used aerial (11 years) and ground surveys (3 years) to quantify the variability in time, space, quantity (kg), and quality (MJ) of seal carrion during the seal pupping season. We then compared the potential predictability of seal carrion to other periodic changes in food availability in nature. An average of 6893 kg of carrion ∙yr−1 corresponding to 110.5 × 103 MJ yr−1 was released for potential scavengers as placentae and dead animals. A fifth of the total biomass from dead seals was consumed by the end of the pupping season, mostly by avian scavengers. The spatial distribution of carcasses was similar across years, and 28% of the area containing >10 carcasses ha−1 was shared among all years. Relative standard errors (RSE) in space, time, quantity, and quality of carrion were all below 34%. This is similar to other allochthonous-dependent ecosystems, such as those affected by migratory salmon, and indicates high predictability of seal carrion as a resource. Our study illustrates how to quantify predictability in carrion, which is of general relevance to ecosystems that are dependent on this resource. We also highlight the importance of carrion to marine coastal ecosystems, where it sustains avian scavengers thus affecting ecosystem structure and function. © 2018 Elsevier Masson SAS. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Philip Barton" is provided in this record*

Costing hospital resources for stroke patients using phase-type models

Optimising resources in healthcare facilities is essential for departments to cope with the growing population’s requirements. An aspect of such performance modelling involves investigating length of stay, which is a key performance indicator. Stroke disease costs the United Kingdom economy seven billion pounds a year and stroke patients are known to occupy long periods of time in acute and long term beds in hospital as well as requiring support from social services. This may be viewed as an inefficient use of resources. Thrombolysis is a therapy which uses a clot-dispersing drug which is known to decrease the institutionalisation of eligible stroke patients if administered 3 h after incident but it is costly to administer to patients. In this paper we model the cost of treating stroke patients within a healthcare facility using a mixture of Coxian phase type model with multiple absorbing states. We also discuss the potential benefits of increasing the usage of thrombolysis and if these benefits balance the expense of administering the drug.peer-reviewe

Is it beneficial to increase the provision of thrombolysis? - a discrete-event simulation model

Background: Although Thrombolysis has been licensed in the UK since 2003, it is still administered only to a small percentage of eligible patients. Aim: We consider the impact of investing the impact of thrombolysis on important acute stroke services, and the effect on quality of life. The concept is illustrated using data from the Northern Ireland Stroke Service. Design: Retrospective study. Methods: We first present results of survival analysis utilizing length of stay (LOS) for discharge destinations, based on data from the Belfast City Hospital (BCH). None of these patients actually received thrombolysis but from those who would have been eligible, we created two initial groups, the first representing a scenario where they received thrombolysis and the second comprising those who do not receive thrombolysis. On the basis of the survival analysis, we created several subgroups based on discharge destination. We then developed a discrete event simulation (DES) model, where each group is a patient pathway within the simulation. Coxian phase type distributions were used to model the group LOS. Various scenarios were explored focusing on cost-effectiveness across hospital, community and social services had thrombolysis been administered to these patients, and the possible improvement in quality of life, should the proportion of patients who are administered thrombolysis be increased. Our aim in simulating various scenarios for this historical group of patients is to assess what the cost-effectiveness of thrombolysis would have been under different scenarios; from this we can infer the likely cost-effectiveness of future policies. Results: The cost of thrombolysis is offset by reduction in hospital, community rehabilitation and institutional care costs, with a corresponding improvement in quality of life. Conclusion: Our model suggests that provision of thrombolysis would produce moderate overall improvement to the service assuming current levels of funding.peer-reviewe

The interpretation of selection coefficients

Evolutionary biologists have an array of powerful theoretical techniques that can accurately predict changes in the genetic composition of populations. Changes in gene frequencies and genetic associations between loci can be tracked as they respond to a wide variety of evolutionary forces. However, it is often less clear how to decompose these various forces into components that accurately reflect the underlying biology. Here, we present several issues that arise in the definition and interpretation of selection and selection coefficients, focusing on insights gained through the examination of selection coefficients in multilocus notation. Using this notation, we discuss how its flexibility-which allows different biological units to be identified as targets of selection-is reflected in the interpretation of the coefficients that the notation generates. In many situations, it can be difficult to agree on whether loci can be considered to be under "direct" versus "indirect" selection, or to quantify this selection. We present arguments for what the terms direct and indirect selection might best encompass, considering a range of issues, from viability and sexual selection to kin selection. We show how multilocus notation can discriminate between direct and indirect selection, and describe when it can do so