In silico studies of nucleic acid complexes with proteins, and therapeutic small molecules.

In silico approaches to nucleic acid targeted drug discovery have been used in order to study duplex DNA, in complexes with proteins as well as more unusual form of G-rich DNA folded into higher-order structures termed as G-quadruplexes, in complexes with therapeutic small molecules. The overall aim of this work has been to provide insight into the stability, recognition, energetics of binding and dynamic behavior of these DNAs in complexes with the STAT3βtc homodimer:DNA complex and with therapeutic small molecules in G-quadruplex/pyridostatin and G-quadruplex/fragment complexes by means of combined in silico approaches. The techniques of explicit solvent molecular dynamics (MD) simulations, and subsequent calculations of the free energies of binding, molecular docking, and 3D-pharmacophore modeling have been applied to study STAT3 and G-quadruplex DNA, promising targets for anticancer therapeutic intervention. Analysis of the data obtained from multiple 50-ns MD simulations of the STAT3-DNA complexes has suggested how the transcription factor STAT3 interacts with duplex DNA, the nature of the conformational changes, and ways in which func- tion may be affected. A majority of known pathologic mutations affecting the DNA-biding region of the STAT3 have been found at the protein-DNA interface, and they have been mapped in detail. The STAT3 conformations obtained from these MD simulations have been subsequently used as a basis for a comparative multiple-target molecular docking study with an in-house library of potential STAT3 inhibitors, providing a rational of their binding in the absence of structural data. A novel “dynamic docking” approach (robust platform of numerous MD simulations) has been developed to address the G-quadruplex receptor and ligand flexibility issue, and subsequent conformational change upon binding. The strength of binding at different regions and both sites of the G-quadruplex were then closely examined. An in silico study of a fragment-based approach towards G-quadruplex stabilizing ligands has also been explored, in parallel with experimental studies, to assess whether this could provide a reliable rapid approach to finding hit fragments in the case of the c-MYC promoter quadruplex

Increasing flood exposure in the Netherlands: implications for risk financing

The effectiveness of disaster risk management and financing mechanisms depends on an accurate assessment of current and future hazard exposure. The increasing availability of detailed data offers policy makers and the insurance sector new opportunities to understand trends in risk, and to make informed decisions on ways to deal with these trends. In this paper we show how comprehensive property level information can be used for the assessment of exposure to flooding on a national scale, and how this information provides valuable input to discussions on possible risk financing practices. The case study used is the Netherlands, which is one of the countries most exposed to flooding globally, and which is currently undergoing a debate on strategies for the compensation of potential losses. Our results show that flood exposure has increased rapidly between 1960 and 2012, and that the growth of the building stock and its economic value in flood-prone areas has been higher than in non-flood-prone areas. We also find that property values in flood-prone areas are lower than those in non-flood-prone areas. We argue that the increase in the share of economic value located in potential flood-prone areas can have a negative effect on the feasibility of private insurance schemes in the Netherlands. The methodologies and results presented in this study are relevant for many regions around the world where the effects of rising flood exposure create a challenge for risk financing

Assortative mating in an ecological context:Effects of mate choice errors and relative species abundance on the frequency and asymmetry of hybridization

The frequency and asymmetry of mixed-species mating set the initial stage for the ecological and evolutionary implications of hybridization. How such patterns of mixed-species mating, in turn, are influenced by the combination of mate choice errors and relative species abundance remains largely unknown. We develop a mathematical model that generates predictions for how relative species abundances and mate choice errors affect hybridization patterns. When mate choice errors are small (5%), the highest hybridization frequency occurs when species occur in equal proportions. Furthermore, females of the less abundant species are overrepresented in mixed-species matings. We compare our theoretical predictions with empirical data on naturally hybridizing Ficedula flycatchers and find that hybridization is highest when the two species occur in equal abundance, implying rather high mate choice errors. We discuss ecological and evolutionary implications of our findings and encourage future work on hybrid zone dynamics that take demographic aspects, such as relative species abundance, into account

Comparative support for the expensive tissue hypothesis: Big brains are correlated with smaller gut and greater parental investment in Lake Tanganyika cichlids

This is the final version of the article. Available from the publisher via the DOI in this record.The brain is one of the most energetically expensive organs in the vertebrate body. Consequently, the energetic requirements of encephalization are suggested to impose considerable constraints on brain size evolution. Three main hypotheses concerning how energetic constraints might affect brain evolution predict covariation between brain investment and (1) investment into other costly tissues, (2) overall metabolic rate, and (3) reproductive investment. To date, these hypotheses have mainly been tested in homeothermic animals and the existing data are inconclusive. However, there are good reasons to believe that energetic limitations might play a role in large-scale patterns of brain size evolution also in ectothermic vertebrates. Here, we test these hypotheses in a group of ectothermic vertebrates, the Lake Tanganyika cichlid fishes. After controlling for the effect of shared ancestry and confounding ecological variables, we find a negative association between brain size and gut size. Furthermore, we find that the evolution of a larger brain is accompanied by increased reproductive investment into egg size and parental care. Our results indicate that the energetic costs of encephalization may be an important general factor involved in the evolution of brain size also in ectothermic vertebrates.The authors thank the staff of the Department of Fisheries of the Ministry of Agriculture and Cooperatives at Mpulungu, Zambia, for their cooperation during fieldwork, especially for collecting fishes from the deeper levels. They also thank H. Tanaka for collecting fish samples for us. This study was funded through the student exchange support program (scholarship for long-term study abroad) from the Japanese Student Services Organization (JASSO) to MT, the Zoologiska foundation to MT and AK, a Davis Expedition Fund grant, Helge Axelsson Johnson grant, and a Stiftelsen Hierta-Retzius stipendiefond grant to AH, the Austrian Science Fund (J 3304-B24) to AK, and a Swedish Research Council grant to NK. The authors have no conflict of interest to declare

Non‐random sampling along rural‐urban gradients may reduce reliability of multispecies farmland bird indicators and their trends

The continued global biodiversity crisis necessitates the continuation and development of new well-designed monitoring strategies and action plans with particular focus on under-represented countries and regions. However, limited resources in terms of budget and availability of qualified field personnel can restrict the geographical coverage of monitoring efforts. Focusing monitoring efforts on a representative subset of species and locations can improve cost-efficiency. Optimal performance of multi-species indicators derived from such an approach requires objective methods for species selection and a sampling design that reduces inherent sampling bias caused by regional differences in habitat availability or accessibility. To explore the performance of a multi-species indicator across different regions within a nation, we developed a multi-species indicator (MSI) for farmland birds in Norway using objective niche-based selection of species. We compare the performance of this indicator at national and regional scales (Central and East regions) in Norway, and between urban and rural sites within regions. The seven-species indicator obtained from the species selection provided similar indicator values and trends for Norway and the Central and East regions, as well as for rural sites within the combined Central + East region. All trends were defined as showing moderate decline from 2007–2016. Urban sites within the combined Central + East region provided trend estimates that showed stronger decline than rural areas in the same region during the time span. Our results emphasize the need to control for sampling bias when structuring monitoring programmes such as a Breeding Bird Survey (BBS). This is especially important if limited resources restrict the geographical coverage of the monitoring scheme. We recommend that monitoring schemes follow a stratified random sampling design that represents both the availability of different land cover types and their distribution with regard to proximity to highly populated areas. If that is not possible, statistically weighting data from different regions or landscapes is likely to be necessary

The intensity of physical activity influences bone mineral accrual in childhood:the childhood health, activity and motor performance school (the CHAMPS) study, Denmark

BACKGROUND: Studies indicate genetic and lifestyle factors can contribute to optimal bone development. In particular, the intensity level of physical activity may have an impact on bone health. This study aims to assess the relationship between physical activity at different intensities and Bone Mineral Content (BMC), Bone Mineral Density (BMD) and Bone Area (BA) accretion. METHODS: This longitudinal study is a part of The CHAMPS study-DK. Whole-body DXA scans were performed at baseline and after two years follows up. BMC, BMD, and BA were measured. The total body less head (TBLH) values were used. Physical activity (PA) was recorded by accelerometers (ActiGraph, model GT3X). Percentages of different PA intensity levels were calculated and log odds of two intensity levels of activity relative to the third level were calculated. Multilevel regression analyses were used to assess the relationship between the categories of physical activity and bone traits. RESULTS: Of 800 invited children, 742 (93%) accepted to participate. Of these, 682/742 (92%) participated at follow up. Complete datasets were obtained in 602/742 (81%) children. Mean (range) of age was 11.5 years (9.7-13.9). PA at different intensity levels was for boys and girls respectively, sedentary 62% and 64%, low 29% for both genders and moderate to high 9% and 7% of the total time. Mean (range) BMC, BMD, and BA was 1179 g (563–2326), 0.84 g/cm(2) (0.64-1.15) and 1393 cm(2) (851–2164), respectively. Valid accelerometer data were obtained for a mean of 6.1 days, 13 hours per day. CONCLUSIONS: There 7was a positive relationship between the log odds of moderate to high-level PA versus low level activity and BMC, BMD and BA. Children with an increased proportion of time in moderate to high-level activity as opposed to sedentary and low-level activity achieved positive effects on BMC, BMD and BA

Therapeutic affordances of online support group use in women with endometriosis

Background: The Internet has provided women living with endometriosis new opportunities to seek support online. Online support groups may provide a range of therapeutic affordances which may benefit these women. Objective: To examine the presence of therapeutic affordances as perceived by women who use endometriosis online support groups. Methods: Sixty-nine women (aged 19 to 50 years; Mean = 34.2; 65.2% UK; 21.7% USA) participated in an online interview exploring online support group use. Participants had been using online support groups on average 2 years and 4 months (Range = 1 month to 14 years, 9 months). Responses were analysed using inductive thematic analysis. Results: The analysis revealed 4 therapeutic affordances related to online support group use; i) “connection” i.e. the ability to connect in order to support each other, exchange advice, and to try to overcome feelings of loneliness; ii) “exploration” i.e. the ability to look for information, learn and bolster their knowledge; iii) “narration” i.e. the ability to share their experiences, as well as read about the experiences of others; and iv) “self-presentation” i.e. the ability to manage how they present themselves online. The associated outcomes of use were predominantly positive, such as reassurance and improved coping. However, a number of negative aspects were revealed including: concerns about the accuracy of information, arguments between members, over-reliance on the group, becoming upset by negative experiences or good news items and confidentiality of personal information. Conclusions: Our findings support the SCENA model (Self-presentation, Connection, Exploration, Narration and Adaptation) proposed by Merolli et al., (2014) and reveal a range of positive aspects that may benefit members, particularly in relation to reassurance and coping. However, negative aspects need to be addressed in order to maximise the potential benefit of support groups. Some of these can be addressed relatively easily through making privacy policies clearer, including health professionals to moderate content and structuring forums to encourage the sharing of positive stories

Assessment of the inherent allergenic potential of proteins in mice.

There is considerable interest in the design of approaches that will permit the accurate identification and characterization of proteins that have the inherent potential to induce sensitization and cause food allergy. Among the methods used currently as part of such assessments are consideration of structural similarity to, or amino acid sequence homology with, known human allergens; whether there exists immunologic cross-reactivity with known allergens; and measurement of resistance to proteolytic digestion in a simulated gastric fluid. Although such approaches provide information that will contribute to a safety assessment, they do not--either individually or collectively--provide a direct evaluation of the ability of a novel protein to cause allergic sensitization. For this reason, work is in progress to design and evaluate suitable animal models that will provide a more holistic assessment of allergenic potential. In this laboratory, the approach we have taken has been to examine the characteristics of immune responses induced in mice following parenteral (intraperitoneal) exposure to test proteins. The basis of this method is to determine simultaneously the overall immunogenic potential of proteins [measured as a function of immunoglobulin (Ig) G antibody responses] and to compare this with their ability to provoke IgE antibody production, IgE being the antibody that effects allergic sensitization. Although this approach has not yet been evaluated fully, the results available to date suggest that it will be possible to distinguish proteins that have the inherent potential to induce allergic sensitization from those that do not. In this article we summarize progress to date in the context of the scientific background against which such methods are being developed