Qualitative Analysis of Universes with Varying Alpha

Assuming a Friedmann universe which evolves with a power-law scale factor, $a=t^{n}$, we analyse the phase space of the system of equations that describes a time-varying fine structure 'constant', $\alpha$, in the Bekenstein-Sandvik-Barrow-Magueijo generalisation of general relativity. We have classified all the possible behaviours of $\alpha (t)$ in ever-expanding universes with different $n$ and find new exact solutions for $\alpha (t)$. We find the attractors points in the phase space for all $n$. In general, $\alpha$ will be a non-decreasing function of time that increases logarithmically in time during a period when the expansion is dust dominated ($n=2/3$), but becomes constant when $n>2/3$. This includes the case of negative-curvature domination ($n=1$). $\alpha$ also tends rapidly to a constant when the expansion scale factor increases exponentially. A general set of conditions is established for $\alpha$ to become asymptotically constant at late times in an expanding universe.Comment: 26 pages, 6 figure

Is it e or is it c? Experimental Tests of Varying Alpha

Is the recent evidence for a time-varying fine structure 'constant' $\alpha$ to be interpreted as a varying $e$, $c$, $\hbar$, or a combination thereof? We consider the simplest varying electric charge and varying speed of light theories (VSL) and prove that for the same type of dark matter they predict opposite senses of variation in $\alpha$ over cosmological times. We also show that unlike varying $e$ theories, VSL theories do not predict violations of the weak equivalence principle (WEP). Varying $e$ theories which explain astronomical inferences of varying $\alpha$ predict WEP violations only an order of magnitude smaller than existing E\"otv\"os experiment limits but could be decisively tested by STEP. We finally exhibit a set of atomic-clock and related experiments for which {\it all} (hyperbolic) varying $\alpha$ theories predict non-null results. They provide independent tests of the recent astronomical evidence

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Effect of Foregrounds on the CMBR Multipole Alignment

We analyze the effect of foregrounds on the observed alignment of CMBR quadrupole and octopole. The alignment between these multipoles is studied by using a symmetry based approach which assigns a principal eigenvector (PEV) or an axis with each multipole. We determine the significance of alignment between these multipoles by using the Internal Linear Combination (ILC) 5 and 7 year map s and also the maps obtained by using the Internal Power Spectrum Estimation (IPSE) procedure. The effect of foreground cleaning is studied in detail within the framework of the IPSE method both analytically and numerically. By using simulated CMBR data, we study how the PEVs of the pure simulated CMB map differ from those of the final cleaned map. We find that, in general, the shift in the PEVs is relatively small and in random directions. Due to the random nature of the shift we conclude that it can only lead to misalignment rather than alignment of multipoles. We also directly estimate the significance of alignment by using simulated cleaned maps. We find that the results in this case are identical to those obtained by simple analytic estimate or by using simulated pure CMB maps.Comment: 27 pages, 8 figure

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. P. falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics

Direct observation of DNA threading in flap endonuclease complexes

Maintenance of genome integrity requires that branched nucleic acid molecules are accurately processed to produce double-helical DNA. Flap endonucleases are essential enzymes that trim such branched molecules generated by Okazaki fragment synthesis during replication. Here, we report crystal structures of bacteriophage T5 flap endonuclease in complexes with intact DNA substrates, and products, at resolutions of 1.9–2.2 Å. They reveal single-stranded DNA threading through a hole in the enzyme enclosed by an inverted Vshaped helical arch straddling the active site. Residues lining the hole induce an unusual barb-like conformation in the DNA substrate juxtaposing the scissile phosphate and essential catalytic metal ions. A series of complexes and biochemical analyses show how the substrate’s single-stranded branch approaches, threads through, and finally emerges on the far side of the enzyme. Our studies suggest that substrate recognition involves an unusual “flycasting, thread, bend and barb” mechanis

Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne

The post-translational modification of proteins with polyubiquitin regulates virtually all aspects of cell biology. Eight distinct chain linkage types in polyubiquitin co-exist and are independently regulated in cells. This ‘ubiquitin code’ determines the fate of the modified protein1. Deubiquitinating enzymes of the Ovarian Tumour (OTU) family regulate cellular signalling by targeting distinct linkage types within polyubiquitin2, and understanding their mechanisms of linkage specificity gives fundamental insights into the ubiquitin system. We here reveal how the deubiquitinase Cezanne/OTUD7B specifically targets Lys11-linked polyubiquitin. Crystal structures of Cezanne alone and in complex with mono- and Lys11-linked diubiquitin, in combination with hydrogen-deuterium exchange mass spectrometry, enable reconstruction of the enzymatic cycle in exquisite detail. An intricate mechanism of ubiquitin-assisted conformational changes activate the enzyme, and while all chain types interact with the enzymatic S1 site, only Lys11-linked chains can bind productively across the active site and stimulate catalytic turnover. Our work highlights the fascinating plasticity of deubiquitinases, and indicates that new conformational states can occur when a true substrate, such as diubiquitin, is bound at the active site

Primary health care delivery models in rural and remote Australia – a systematic review

© 2008 Wakerman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background One third of all Australians live outside of its major cities. Access to health services and health outcomes are generally poorer in rural and remote areas relative to metropolitan areas. In order to improve access to services, many new programs and models of service delivery have been trialled since the first National Rural Health Strategy in 1994. Inadequate evaluation of these initiatives has resulted in failure to garner knowledge, which would facilitate the establishment of evidence-based service models, sustain and systematise them over time and facilitate transfer of successful programs. This is the first study to systematically review the available published literature describing innovative models of comprehensive primary health care (PHC) in rural and remote Australia since the development of the first National Rural Health Strategy (1993–2006). The study aimed to describe what health service models were reported to work, where they worked and why. Methods A reference group of experts in rural health assisted in the development and implementation of the study. Peer-reviewed publications were identified from the relevant electronic databases. 'Grey' literature was identified pragmatically from works known to the researchers, reference lists and from relevant websites. Data were extracted and synthesised from papers meeting inclusion criteria. Results A total of 5391 abstracts were reviewed. Data were extracted finally from 76 'rural' and 17 'remote' papers. Synthesis of extracted data resulted in a typology of models with five broad groupings: discrete services, integrated services, comprehensive PHC, outreach models and virtual outreach models. Different model types assume prominence with increasing remoteness and decreasing population density. Whilst different models suit different locations, a number of 'environmental enablers' and 'essential service requirements' are common across all model types. Conclusion Synthesised data suggest that, moving away from Australian coastal population centres, sustainable models are able to address diseconomies of scale which result from large distances and small dispersed populations. Based on the service requirements and enablers derived from analysis of reported successful PHC service models, we have developed a conceptual framework that is particularly useful in underpinning the development of sustainable PHC models in rural and remote communities

The Accelerated Acceleration of the Universe

We present a simple mechanism which can mimic dark energy with an equation of state w < -1 as deduced from the supernova data. We imagine that the universe is accelerating under the control of a quintessence field, which is moving up a very gently sloping potential. As a result, the potential energy and hence the acceleration increases at lower redshifts. Fitting this behavior with a dark energy model with constant w would require w<-1. In fact we find that the choice of parameters which improves the fit to the SNe mimics w = -1.4 at low redshifts. Running up the potential in fact provides the best fit to the SN data for a generic quintessence model. However, unlike models with phantoms, our model does not have negative energies or negative norm states. Future searches for supernovae at low redshifts 0.1 < z < 0.5 and at high redshifts z>1 may be a useful probe of our proposal.Comment: 14 pages, 5 figure