The intrinsically disordered distal face of nucleoplasmin recognizes distinct oligomerization states of histones

The role of Nucleoplasmin (NP) as a H2A-H2B histone chaperone has been extensively characterized. To understand its putative interaction with other histone ligands, we have characterized its ability to bind H3-H4 and histone octamers. We find that the chaperone forms distinct complexes with histones, which differ in the number of molecules that build the assembly and in their spatial distribution. When complexed with H3-H4 tetramers or histone octamers, two NP pentamers form an ellipsoidal particle with the histones located at the center of the assembly, in stark contrast with the NP/H2A-H2B complex that contains up to five histone dimers bound to one chaperone pentamer. This particular assembly relies on the ability of H3-H4 to form tetramers either in solution or as part of the octamer, and it is not observed when a variant of H3 (H3C110E), unable to form stable tetramers, is used instead of the wild-type protein. Our data also suggest that the distal face of the chaperone is involved in the interaction with distinct types of histones, as supported by electron microscopy analysis of the different NP/histone complexes. The use of the same structural region to accommodate all type of histones could favor histone exchange and nucleosome dynamics

Integrating modes of policy analysis and strategic management practice : requisite elements and dilemmas

There is a need to bring methods to bear on public problems that are inclusive, analytic, and quick. This paper describes the efforts of three pairs of academics working from three different though complementary theoretical foundations and intervention backgrounds (i.e., ways of working) who set out together to meet this challenge. Each of the three pairs had conducted dozens of interventions that had been regarded as successful or very successful by the client groups in dealing with complex policy and strategic problems. One approach focused on leadership issues and stakeholders, another on negotiating competitive strategic intent with attention to stakeholder responses, and the third on analysis of feedback ramifications in developing policies. This paper describes the 10 year longitudinal research project designed to address the above challenge. The important outcomes are reported: the requisite elements of a general integrated approach and the enduring puzzles and tensions that arose from seeking to design a wide-ranging multi-method approach

Conformal Symmetry for General Black Holes

We show that the warp factor of a generic asymptotically flat black hole in five dimensions can be adjusted such that a conformal symmetry emerges. The construction preserves all near horizon properties of the black holes, such as the thermodynamic potentials and the entropy. We interpret the geometry with modified asymptotic behavior as the "bare" black hole, with the ambient flat space removed. Our warp factor subtraction generalizes hidden conformal symmetry and applies whether or not rotation is significant. We also find a relation to standard AdS/CFT correspondence by embedding the black holes in six dimensions. The asymptotic conformal symmetry guarantees a dual CFT description of the general rotating black holes.Comment: 26 page

Feasibility and safety of combining repetitive transcranial magnetic stimulation and quadriceps strengthening exercise for chronic pain in knee osteoarthritis: A study protocol for a pilot randomised controlled trial

Introduction Knee osteoarthritis is a leading cause of disability, resulting in pain and reduced quality of life. Exercise is the cornerstone of conservative management but effects are, at best, moderate. Early evidence suggests that repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor cortex (M1) may improve the effect of exercise in knee osteoarthritis. This pilot study aims to (1) determine the feasibility, safety and participant-rated response to an intervention adding M1 rTMS to exercise in knee osteoarthritis; (2) elucidate physiological mechanisms in response to the intervention; (3) provide data to conduct a sample size calculation for a fully powered trial. Methods and analysis This is a pilot randomised, assessor-blind, therapist-blind and participant-blind, sham-controlled trial. Thirty individuals with painful knee osteoarthritis will be recruited and randomly allocated to receive either: (1) active rTMS+exercise or (2) sham rTMS+exercise intervention. Participants will receive 15 min of either active or sham rTMS immediately prior to 30 min of supervised muscle strengthening exercise (2×/week, 6 weeks) and complete unsupervised home exercises. Outcome measures of feasibility, safety, pain, function and physiological mechanisms will be assessed before and/or after the intervention. Feasibility and safety will be analysed using descriptive analysis. Within-group and between-group comparisons of pain and function will be conducted to examine trends of efficacy. Ethics and dissemination This study has been approved by the University of New South Wales Human Research Ethics Committee (HC210954). All participants will provide written informed consent. The study results will be submitted for peer-reviewed publication. Trial registration number ACTRN12621001712897p

Conformal Symmetry for Black Holes in Four Dimensions

We show that the asymptotic boundary conditions of general asymptotically flat black holes in four dimensions can be modified such that a conformal symmetry emerges. The black holes with the asymptotic geometry removed in this manner satisfy the equations of motion of minimal supergravity in five dimensions. We develop evidence that a two dimensional CFT dual of general black holes in four dimensions account for their black hole entropy.Comment: 24 pages, minor correction

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning

The experience of linking Victorian emergency medical service trauma data

<p>Abstract</p> <p>Background</p> <p>The linking of a large Emergency Medical Service (EMS) dataset with the Victorian Department of Human Services (DHS) hospital datasets and Victorian State Trauma Outcome Registry and Monitoring (VSTORM) dataset to determine patient outcomes has not previously been undertaken in Victoria. The objective of this study was to identify the linkage rate of a large EMS trauma dataset with the Department of Human Services hospital datasets and VSTORM dataset.</p> <p>Methods</p> <p>The linking of an EMS trauma dataset to the hospital datasets utilised deterministic and probabilistic matching. The linking of three EMS trauma datasets to the VSTORM dataset utilised deterministic, probabilistic and manual matching.</p> <p>Results</p> <p>There were 66.7% of patients from the EMS dataset located in the VEMD. There were 96% of patients located in the VAED who were defined in the VEMD as being admitted to hospital. 3.7% of patients located in the VAED could not be found in the VEMD due to hospitals not reporting to the VEMD. For the EMS datasets, there was a 146% increase in successful links with the trauma profile dataset, a 221% increase in successful links with the mechanism of injury only dataset, and a 46% increase with sudden deterioration dataset, to VSTORM when using manual compared to deterministic matching.</p> <p>Conclusion</p> <p>This study has demonstrated that EMS data can be successfully linked to other health related datasets using deterministic and probabilistic matching with varying levels of success. The quality of EMS data needs to be improved to ensure better linkage success rates with other health related datasets.</p