Excited state properties of deoxyguanosine, and the electrostatic interactions in DNA

The photophysical properties of deoxyguanosine, dG, have been studied in aqueous solution as well as in organic solvents of varying polarity. The fluorescence quantum yield, q, is found to increase as the solvent polarity is decreased: in diethyl ether, the solvent of lowest polarity used in the present study, q has been found to increase by a factor of 35 relative to the value of q in aqueous buffer. This suggests that hydrophobic interactions reduce considerably the rate constant of the radiationless process of internal conversion. On the other hand, upon increasing the viscosity, η (through addition of sucrose), q has been found to increase by a factor of 1.7 for η = 14 cP and by a factor of 7.4 for η = 149 cP. These results suggest that the increase in the rigidity of dG and of the hydrophobic nature of its environment, which occur when dG becomes part of DNA, are not responsible for the very small value of q in DNA * 0.8 x 10-5 as compared to that of 0.8 x 10-4 for free dG m water. An attractive alternative is provided by differences in the hydration network between free dG and dG in DNA. Support for this proposal was obtained from an experiment with an 8% water/butanol mixture which suggested that the hydration network affects profoundly the photophysical properties of free dG. Measurements in this water/butanol mixture were pursued further Surprisingly, it was found that the results depended on the sequence of the steps used in preparing the solution. This is consistent with the reported very large, about - 20 kcal/mol, solvation free energy of guanine We measured the fluorescence of dG at room temperature after the solution was incubated for 10 minutes at a number of temperatures ranging from 23 to 40 °C. An Arrhenius plot yielded ΔH ≈ - 6 kcal/mol and ΔS ≈ 48 cal/mol K. A potential implication of these findings is that intermolecular hydrogen bonds in DNA, once broken by thermal fluctuations, would tend to remain broken; consequently, the helix would appear to contain a number of GC open or unzipped base pairs. Because of the known coupling between base pair opening and bending, it would take relatively little energy for the DNA to bend at GC open sites. We have also employed the theoretical analysis of Jarque and Buckingham, for two ions of the same charge embedded in a polarizable medium, to calculate the contribution which is made by the polarization effects to the electrostatic interaction between the negatively-charged phosphate groups in DNA. It is found that many-body, non-additive polarization interactions greatly diminish the effect of the repulsive Coulomb interactions between phosphates both across the DNA minor groove (but not across the major groove) and along the same DNA strand. This reduction is found to be dramatic for groove widths in the range of about 3.5-5 Å for a nearest neighbor distance β of about 3.5 Å. This value of β appears to be realistic for DNA. Thus, variations in the minor groove width caused by sequence effects or by thermal fluctuations induce local anisotropic interactions with concomitant local DNA bending toward the groove with the smaller width. Other values of &beta ranging from 3.2 to 5 Å have also been used. From the derivative of the effective potential with respect to the groove width, the overall force F was calculated and its magnitude and direction were found to be strongly dependent on the value of β for small groove widths F is negative, i e attractive for β ≤ 4 Å, and positive for larger β values. Thus, the conformation of DNA exerts a profound effect on the ability of DNA to control its dynamics. Based on the fact that the A-tracts have a narrow groove width of about 3.5 Å, the present findings suggest that they would tend to bend toward that groove. This prediction is in agreement with the results of electrophoresis studies. Because of the known coupling between DNA bending and opening of its base pairs, the present findings suggest that base pair opening is a process that does not appear to be very infrequent and is driven by both sequence effects (of static origin) and by thermal fluctuations (of dynamic origin). Such a process may contribute to the creation of the intercalation cavity during drug-DNA interaction. This analysis also offers an explanation for the wrapping of DNA around the histone octamer in nucleosomes: because the A-tracts in DNA are known to bind with their minor grooves facing in toward the histone octamer, the DNA in those regions would bend toward those tracts. Because of the known gradual decrease of the width of the grooves of these tracts from 5\u27 to 3\u27 and the large increase of the strength of the polarization interaction that occurs with this groove width decrease, the DNA wrapping would be done with considerable force. The present analysis brings into question the validity of the continuum dielectric screening model currently being used in the literature to calculate electrostatic interactions

Protocol for a longitudinal qualitative interview study: maintaining psychological well-being in advanced cancer - what can we learn from patients' and carers' own coping strategies?

IntroductionPeople with advanced cancer and their carers experience stress and uncertainty which affects the quality of life and physical and mental health. This study aims to understand how patients and carers recover or maintain psychological well-being by exploring the strategies employed to self-manage stress and uncertainty.Methods and analysisA longitudinal qualitative interview approach with 30 patients with advanced cancer and 30 associated family or informal carers allows the exploration of contexts, mechanisms and outcomes at an individual level. Two interviews, 4–12?weeks apart, will not only enable the exploration of individuals’ evolving coping strategies in response to changing contexts but also how patients’ and carers’ strategies inter-relate. Patient and Carer focus groups will then consider how the findings may be used in developing an intervention. Recruiting through two major tertiary cancer centres in the North West and using deliberately broad and inclusive criteria will enable the sample to capture demographic and experiential breadth.Ethics and disseminationThe research team will draw on their considerable experience to ensure that the study is sensitive to a patient and carer group, which may be considered vulnerable but still values being able to contribute its views. Public and patient involvement (PPI) is integral to the design and is evidenced by: a research advisory group incorporating patient and carers, prestudy consultations with the PPI group at one of the study sites and a user as the named applicant. The study team will use multiple methods to disseminate the findings to clinical, policy and academic audiences. A key element will be engaging health professionals in patient and carer ideas for promoting self-management of psychological well-being. The study has ethical approval from the North West Research Ethics Committee and the appropriate NHS governance clearance.RegistrationNational Institute for Health Research (NIHR) Clinical Studies Portfolio, UK Clinical Research Network (UKCRN) Study number 11725

Long time, no see. Australians with mental illnesses wait too long before independent review of detention

Imagine that you found yourself arrested in a New South Wales country town; Dubbo, for example. The local constabulary tell you that you are guilty of some offence and that you are now looking at several weeks inside. You know you are innocent. If you know the law, you are anxious, certainly, but you are not dismayed. You know that in New South Wales the police must ‘as soon as is reasonably practicable, take [you] … before an authorised officer to be dealt with according to law’.1 This will be a magistrate, or another independent person, who will review your arrest. You also know that in New South Wales ‘as soon as is reasonably practicable’ is normally interpreted as being within 24 hours, 365 days of the year. All Australians who find themselves detained against their will have a right to be brought before a court or other independent body to ensure that the terms of their detention are lawful. This ancient right is protected in the civil law through the writ of habeas corpus and in the legislative rules requiring prompt review of criminal detention in each state and territory. Timely independent review of restrictions on liberty is also applied in the medico-legal context. For example, while the Guardianship Act 1987 (NSW) allows a person responsible or guardian to consent to medical treatment for a patient who lacks capacity, if that patient objects to the treatment, the Act stipulates that a quasi-judicial body — the Guardianship Tribunal — must authorise this consent, to check that this deprivation of freedom is justified.2 The Tribunal is available to hear urgent matters around the clock and urgent orders are usually made within a week.3 At the time of writing, New South Wales law demands a similar timely independent review of measures that restrict the liberty of people with mental illnesses. The Mental Health Act 2007 (NSW) stipulates that people who are deemed ‘mentally ill persons’ must be taken before a magistrate ‘as soon as practicable’ after two doctors decide they warrant detention.4 Currently, and since 1958,5 ‘as soon as practicable’ is interpreted as meaning within a week or so. Again the short timeframe is intended to protect the civil rights of the person detained.6 If, however, changes proposed to the operation of the Mental Health Act are allowed to proceed, people living with mental illnesses in New South Wales may have lost a substantial degree of this human rights protection by the time this article is published

Family visits to libraries and bookshops: observations and implications for digital libraries

This paper explores how families select books for leisure reading. We recruited 17 families (adults and children) for this study, and spent time with each in both bookshops and public libraries. Our research aims to add to understanding of how families interact with books and bookshelves in these places, and how digital libraries might best support the shared needs of these inter-generational users. Much of our understanding of how an eBook should look and feel comes from generalizations about books and assumptions about the needs of those individuals who read them. We explore how children and adults search and browse for books together, with specific focus on the type of information seeking tasks that families undertake and on the families’ shared search and browsing strategies. We further explore the implications of this study for the development of digital libraries for children and families

SUMSS: A Wide-Field Radio Imaging Survey of the Southern Sky. I. Science goals, survey design and instrumentation

The Molonglo Observatory Synthesis Telescope, operating at 843 MHz with a 5 square degree field of view, is carrying out a radio imaging survey of the sky south of declination -30 deg. This survey (the Sydney University Molonglo Sky Survey, or SUMSS) produces images with a resolution of 43" x 43" cosec(Dec.) and an rms noise level of about 1 mJy/beam. SUMSS is therefore similar in sensitivity and resolution to the northern NRAO VLA Sky Survey (NVSS; Condon et al. 1998). The survey is progressing at a rate of about 1000 square degrees per year, yielding individual and statistical data for many thousands of weak radio sources. This paper describes the main characteristics of the survey, and presents sample images from the first year of observation.Comment: 27 pages, 12 figures (figures 2, 8, 10 in jpg format); AJ, in pres

A Terraced Scanning Superconducting Quantum Interference Device Susceptometer with Sub-Micron Pickup Loops

Superconducting Quantum Interference Devices (SQUIDs) can have excellent spin sensitivity depending on their magnetic flux noise, pick-up loop diameter, and distance from the sample. We report a family of scanning SQUID susceptometers with terraced tips that position the pick-up loops 300 nm from the sample. The 600 nm - 2 um pickup loops, defined by focused ion beam, are integrated into a 12-layer optical lithography process allowing flux-locked feedback, in situ background subtraction and optimized flux noise. These features enable a sensitivity of ~70 electron spins per root Hertz at 4K.Comment: See http://stanford.edu/group/moler/publications.html for an auxiliary document containing additional fabrication details and discussio

Constriction size distributions of granular filters: a numerical study

The retention capability of granular filters is controlled by the narrow constrictions connecting the voids within the filter. The theoretical justification for empirical filter rules used in practice includes consideration of an idealised soil fabric in which constrictions form between co-planar combinations of spherical filter particles. This idealised fabric has not been confirmed by experimental or numerical observations of real constrictions. This paper reports the results of direct, particle-scale measurement of the constriction size distribution (CSD) within virtual samples of granular filters created using the discrete-element method (DEM). A previously proposed analytical method that predicts the full CSD using inscribed circles to estimate constriction sizes is found to poorly predict the CSD for widely graded filters due to an over-idealisation of the soil fabric. The DEM data generated are used to explore quantitatively the influence of the coefficient of uniformity, particle size distribution and relative density of the filter on the CSD. For a given relative density CSDs form a narrow band of similarly shaped curves when normalised by characteristic filter diameters. This lends support to the practical use of characteristic diameters to assess filter retention capability

Effects of D-amino acid oxidase inhibition on memory performance and long-term potentiation in vivo

N-methyl-d-aspartate receptor (NMDAR) activation can initiate changes in synaptic strength, evident as long-term potentiation (LTP), and is a key molecular correlate of memory formation. Inhibition of d-amino acid oxidase (DAAO) may increase NMDAR activity by regulating d-serine concentrations, but which neuronal and behavioral effects are influenced by DAAO inhibition remain elusive. In anesthetized rats, extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded before and after a theta frequency burst stimulation (TBS) of the Schaffer collateral pathway of the CA1 region in the hippocampus. Memory performance was assessed after training with tests of contextual fear conditioning (FC, mice) and novel object recognition (NOR, rats). Oral administration of 3, 10, and 30 mg/kg 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) produced dose-related and steady increases of cerebellum d-serine in rats and mice, indicative of lasting inhibition of central DAAO. SUN administered 2 h prior to training improved contextual fear conditioning in mice and novel object recognition memory in rats when tested 24 h after training. In anesthetized rats, LTP was established proportional to the number of TBS trains. d-cycloserine (DCS) was used to identify a submaximal level of LTP (5× TBS) that responded to NMDA receptor activation; SUN administered at 10 mg/kg 3–4 h prior to testing similarly increased in vivo LTP levels compared to vehicle control animals. Interestingly, in vivo administration of DCS also increased brain d-serine concentrations. These results indicate that DAAO inhibition increased NMDAR-related synaptic plasticity during phases of post training memory consolidation to improve memory performance in hippocampal-dependent behavioral tests