Computer simulation of protein systems

Ligand binding to dihydrofolate reductase (DHFR) is discussed. This is an extremely important enzyme, as it is the target of several drugs (inhibitors) which are used clinically as antibacterials, antiprotozoals and in cancer chemotherapy. DHFR catalyzes the NADPH (reduced nicotinamide adenine dinucleotide phosphate) dependent reduction of dihydrofolate to tetrahydrofolate, which is used in several pathways of purine and pyrimidine iosynthesis, including that of thymidylate. Since DNA synthesis is dependent on a continuing supply of thymidylate, a blockade of DHFR resulting in a depletion of thymidylate can lead to the cessation of growth of a rapidly proliferating cell line. DHFR exhibits a significant species to species variability in its sensitivity to various inhibitors. For example, trimethoprim, an inhibitor of DHFR, binds to bacterial DHFR's 5 orders of magnitude greater than to vertebrate DHFR's. The structural mechanics, dynamics and energetics of a family of dihydrofolate reductases are studied to rationalize the basis for the inhibitor of these enyzmes and to understand the molecular basis of the difference in the binding constants between the species. This involves investigating the conformational changes induced in the protein on binding the ligand, the internal strain imposed by the enzyme on the ligand, the restriction of fluctuations in atom positions due to binding and the consequent change in entropy

Gluon flux-tube distribution and linear confinement in baryons

We have observed the formation of gluon flux-tubes within baryons using lattice QCD techniques. A high-statistics approach, based on translational and rotational symmetries of the four-dimensional lattice, enables us to observe correlations between vacuum action density and quark positions in a completely gauge independent manner. This contrasts with earlier studies which used gauge-dependent smoothing techniques. We used 200 O(a^2) improved quenched QCD gauge-field configurations on a 16^3x32 lattice with a lattice spacing of 0.123 fm. In the presence of static quarks flux tubes representing the suppression of gluon-field fluctuations are observed. We have analyzed 11 L-shapes and 8 T and Y shapes of varying sizes in order to explore a variety of flux-tube topologies, including the ground state. At large separations, Y-shape flux-tube formation is observed. T-shaped paths are observed to relax towards a Y-shaped topology, whereas L-shaped paths give rise to a large potential energy. We do not find any evidence for the formation of a Delta-shaped flux-tube (empty triangle) distribution. However, at small quark separations, we observe an expulsion of gluon-field fluctuations in the shape of a filled triangle with maximal expulsion at the centre of the triangle. Having identified the precise geometry of the flux distribution, we are able to perform quantitative comparison between the length of the flux-tube and the associated static quark potential. For every source configuration considered we find a universal string tension, and conclude that, for large quark separations, the ground state potential is that which minimizes the length of the flux-tube. The flux tube radius of the baryonic ground state potential is found to be 0.38 \pm 0.03 fm, with vacuum fluctuations suppressed by 7.2 \pm 0.6 %.Comment: 16 pages, final version as accepted for publication in Physical review D1. Abstract, text, references and some figures have been revise

Linoleic acid participates in the response to ischemic brain injury through oxidized metabolites that regulate neurotransmission.

Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO2-induced ischemia and that LA-derived 13-hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemia-related conditions such as stroke

Improving older people's care in one acute hospital setting: a realist evaluation of a KT intervention

Background: Older people make up an increasingly large group using acute care facilities yet the nature of the care is often not conducive to their personal needs, wellbeing and recovery. This research explored how a structured intervention (called the KT Toolkit) could help frontline clinical staff improve the care for older people going through one acute hospital setting in South Australia. Methods/Design: The case study approach used draws on the overarching framework of realist evaluation, a methodology designed to test, refine and explain what is happening in complex situations. Seven parallel teams within the organisation selected one discrete clinical area each for improvement through the introduction of evidence based practice guidelines. Each improvement team’s progress was recorded using multiple data sources including ethnographic observations, semi structured interviews, document reviews and other routinely collected data on nursing care. Each of the seven journeys was analysed and synthesised according to the principles of realist evaluation where the role of the researchers (and stakeholders) is to elucidate what things work for which teams in what particular circumstances thus arriving at a set of explanatory statements. Results: Four broad mechanisms appeared to be affecting the way improvements were being introduced into the clinical areas by the seven different teams: building on existing structures and support; optimising existing human potential; focus on the older person and on-going support through facilitation. Within these mechanisms a range of different actions and behaviours were noted but collectively the teams were able to show how these mechanisms enabled them to make progress in improving discrete aspects of care for their older patients. Conclusions: The use of realist evaluation as the overarching methodological framework enabled the research team to document and interpret the complex interactions happening at the level of everyday practice. Such interpretations enabled the research team to engage the clinical teams and work with them on on-going improvements. We found that even trying to improve the so-called simplest of aspects of care (e.g. weighing patients as part of nutritional care) was fraught with challenges. Also, our use of the realist method raised a number of theoretical and methodological questions that need further refining and in particular how realist evaluation relates to knowledge translation (KT) conceptual frameworks.Alison Kitson, Rick Wiechula, Kathryn Zeitz, Danni Marcoionni, Tammy Page and Heidi Silversto

Fluorescent dyes as a probe for the localized field of coupled surface plasmon-related resonances

M. Kreiter, T. Neumann, S. Mittler, W. Knoll, and J. Roy Sambles, Physical Review B, Vol. 64, article 075406 (2001). "Copyright © 2001 by the American Physical Society."The fluorescence light of Cy5 dye molecules in the vicinity of a metal grating is studied for varying directions of both the exciting and the emitted light. A different angular dependence of the intensity of the emitted light is observed for different directions of excitation. Model calculations that take into account the localization of the electrical field of grating-coupled surface plasmon-related resonances are in good agreement with the experimental observations. In addition, the spatially inhomogenous photobleaching of the dye in the field of the coupled resonances is experimentally observed. These results can be viewed both as a way to use chromophores as molecular probes for the localized electrical near field of coupled surface plasmon-related resonances and as a way to manipulate dye molecules on a submicron scale

A study protocol for applying the co-creating knowledge translation framework to a population health study

BACKGROUND: Population health research can generate significant outcomes for communities, while Knowledge Translation (KT) aims to expressly maximize the outcomes of knowledge producing activity. Yet the two approaches are seldom explicitly combined as part of the research process. A population health study in Port Lincoln, South Australia offered the opportunity to develop and apply the co-KT Framework to the entire research process. This is a new framework to facilitate knowledge formation collaboratively between researchers and communities throughout a research to intervention implementation process. DESIGN: This study employs a five step framework (the co-KT Framework) that is formulated from engaged scholarship and action research principles. By following the steps a knowledge base will be cumulatively co-created with the study population that is useful to the research aims. Step 1 is the initiating of contact between the researcher and the study contexts, and the framing of the research issue, achieved through a systematic data collection tool. Step 2 refines the research issue and the knowledge base by building into it context specific details and conducting knowledge exchange events. Step 3 involves interpreting and analysing the knowledge base, and integrating evidence to inform intervention development. In Step 4 the intervention will be piloted and evaluated. Step 5 is the completion of the research process where outcomes for improvement will be instituted as regular practice with the facilitation of the community. In summary, the model uses an iterative knowledge construction mechanism that is complemented by external evidence to design interventions to address health priorities within the community. DISCUSSION: This is a systematic approach that operationalises the translational cycle using a framework for KT practice. It begins with the local context as its foundation for knowledge creation and ends with the development of contextually applicable interventions. It will be of interest to those involved in KT research, participatory action research, population health research and health care systems studies. The co-KT Framework is a method for embedding the principles of KT into all stages of a community-based research process, in which research questions are framed by emergent data from each previous stage.Kathryn Powell, Alison Kitson, Elizabeth Hoon, Jonathan Newbury, Anne Wilson and Justin Beilb

Translating clinical training into practice in complex mental health systems: Toward opening the 'Black Box' of implementation

<p>Abstract</p> <p>Background</p> <p>Implementing clinical training in a complex health care system is challenging. This report describes two successive trainings programs in one Veterans Affairs healthcare network and the lessons we drew from their success and failures. The first training experience led us to appreciate the value of careful implementation planning while the second suggested that use of an external facilitator might be an especially effective implementation component. We also describe a third training intervention in which we expect to more rigorously test our hypothesis regarding the value of external facilitation.</p> <p>Results</p> <p>Our experiences appear to be consonant with the implementation model proposed by Fixsen. In this paper we offer a modified version of the Fixsen model with separate components related to training and implementation.</p> <p>Conclusion</p> <p>This report further reinforces what others have noted, namely that educational interventions intended to change clinical practice should employ a multilevel approach if patients are to truly benefit from new skills gained by clinicians. We utilize an implementation research model to illustrate how the aims of the second intervention were realized and sustained over the 12-month follow-up period, and to suggest directions for future implementation research. The present report attests to the validity of, and contributes to, the emerging literature on implementation research.</p

Single photon emitters based on Ni/Si related defects in single crystalline diamond

We present investigations on single Ni/Si related color centers produced via ion implantation into single crystalline type IIa CVD diamond. Testing different ion dose combinations we show that there is an upper limit for both the Ni and the Si dose 10^12/cm^2 and 10^10/cm^2 resp.) due to creation of excess fluorescent background. We demonstrate creation of Ni/Si related centers showing emission in the spectral range between 767nm and 775nm and narrow line-widths of 2nm FWHM at room temperature. Measurements of the intensity auto-correlation functions prove single-photon emission. The investigated color centers can be coarsely divided into two groups: Drawing from photon statistics and the degree of polarization in excitation and emission we find that some color centers behave as two-level, single-dipole systems whereas other centers exhibit three levels and contributions from two orthogonal dipoles. In addition, some color centers feature stable and bright emission with saturation count rates up to 78kcounts/s whereas others show fluctuating count rates and three-level blinking.Comment: 7 pages, submitted to Applied Physics B, revised versio

Light scattering from disordered overlayers of metallic nanoparticles

We develop a theory for light scattering from a disordered layer of metal nanoparticles resting on a sample. Averaging over different disorder realizations is done by a coherent potential approximation. The calculational scheme takes into account effects of retardation, multipole excitations, and interactions with the sample. We apply the theory to a system similar to the one studied experimentally by Stuart and Hall [Phys. Rev. Lett. {\bf 80}, 5663 (1998)] who used a layered Si/SiO$_2$/Si sample. The calculated results agree rather well with the experimental ones. In particular we find conspicuous maxima in the scattering intensity at long wavelengths (much longer than those corresponding to plasmon resonances in the particles). We show that these maxima have their origin in interference phenomena in the layered sample.Comment: 19 pages, 12 figure