Space-time thermodynamics and subsystem observables in a kinetically constrained model of glassy systems

In a recent article [M. Merolle et al., Proc. Natl. Acad. Sci. USA 102, 10837 (2005)] it was argued that dynamic heterogeneity in $d$-dimensional glass formers is a manifestation of an order-disorder phenomenon in the $d+1$ dimensions of spacetime. By considering a dynamical analogue of the free energy, evidence was found for phase coexistence between active and inactive regions of spacetime, and it was suggested that this phenomenon underlies the glass transition. Here we develop these ideas further by investigating in detail the one-dimensional Fredrickson-Andersen (FA) model in which the active and inactive phases originate in the reducibility of the dynamics. We illustrate the phase coexistence by considering the distributions of mesoscopic spacetime observables. We show how the analogy with phase coexistence can be strengthened by breaking microscopic reversibility in the FA model, leading to a non-equilibrium theory in the directed percolation universality class.Comment: 12 pages, 11 figures, final version with minor change

Candida Urinary Tract Infection: Pathogenesis

Candida species are unusual causes of urinary tract infection (UTI) in healthy individuals, but common in the hospital setting or among patients with predisposing diseases and structural abnormalities of the kidney and collecting system. The urinary tract may be invaded in either an antegrade fashion from the bloodstream or retrograde via the urethra and bladder. Candida species employ a repertoire of virulence factors, including phenotypic switching, dimorphism, galvano - and thigmotropism, and hydrolytic enzymes, to colonize and then invade the urinary tract. Antegrade infection occurs primarily among patients predisposed to candidemia. The process of adherence to and invasion of the glomerulus, renal blood vessels, and renal tubules by Candida species was elegantly described in early histopathologic studies. Armed with modern molecular biologic techniques, the various virulence factors involved in bloodborne infection of the kidney are gradually being elucidated. Disturbances of urine flow, whether congenital or acquired, instrumentation of the urinary tract, diabetes mellitus, antimicrobial therapy, and immunosuppression underlie most instances of retrograde Candida UTI. In addition, bacterial UTIs caused by Enterobacteriaceae may facilitate the initial step in the process. Ascending infections generally do not result in candidemia in the absence of obstruction

Candida Urinary Tract Infection: Pathogenesis

Candida species are unusual causes of urinary tract infection (UTI) in healthy individuals, but common in the hospital setting or among patients with predisposing diseases and structural abnormalities of the kidney and collecting system. The urinary tract may be invaded in either an antegrade fashion from the bloodstream or retrograde via the urethra and bladder. Candida species employ a repertoire of virulence factors, including phenotypic switching, dimorphism, galvano - and thigmotropism, and hydrolytic enzymes, to colonize and then invade the urinary tract. Antegrade infection occurs primarily among patients predisposed to candidemia. The process of adherence to and invasion of the glomerulus, renal blood vessels, and renal tubules by Candida species was elegantly described in early histopathologic studies. Armed with modern molecular biologic techniques, the various virulence factors involved in bloodborne infection of the kidney are gradually being elucidated. Disturbances of urine flow, whether congenital or acquired, instrumentation of the urinary tract, diabetes mellitus, antimicrobial therapy, and immunosuppression underlie most instances of retrograde Candida UTI. In addition, bacterial UTIs caused by Enterobacteriaceae may facilitate the initial step in the process. Ascending infections generally do not result in candidemia in the absence of obstruction

Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid

<p>Abstract</p> <p>Background</p> <p>Due to the global occurrence of multi-drug-resistant malarial parasites (<it>Plasmodium falciparum</it>), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood (<it>Artemisia annua</it>). However, artemisinin is in short supply and unaffordable to most malaria patients. Artemisinin can be semi-synthesized from its precursor artemisinic acid, which can be synthesized from simple sugars using microorganisms genetically engineered with genes from <it>A. annua</it>. In order to develop an industrially competent yeast strain, detailed analyses of microbial physiology and development of gene expression strategies are required.</p> <p>Results</p> <p>Three plant genes coding for amorphadiene synthase, amorphadiene oxidase (<it>AMO </it>or <it>CYP71AV1</it>), and cytochrome P450 reductase, which in concert divert carbon flux from farnesyl diphosphate to artemisinic acid, were expressed from a single plasmid. The artemisinic acid production in the engineered yeast reached 250 μg mL^-1in shake-flask cultures and 1 g L^-1in bio-reactors with the use of <it>Leu2d </it>selection marker and appropriate medium formulation. When plasmid stability was measured, the yeast strain synthesizing amorphadiene alone maintained the plasmid in 84% of the cells, whereas the yeast strain synthesizing artemisinic acid showed poor plasmid stability. Inactivation of AMO by a point-mutation restored the high plasmid stability, indicating that the low plasmid stability is not caused by production of the AMO protein but by artemisinic acid synthesis or accumulation. Semi-quantitative reverse-transcriptase (RT)-PCR and quantitative real time-PCR consistently showed that pleiotropic drug resistance (<it>PDR</it>) genes, belonging to the family of ATP-Binding Cassette (ABC) transporter, were massively induced in the yeast strain producing artemisinic acid, relative to the yeast strain producing the hydrocarbon amorphadiene alone. Global transcriptional analysis by yeast microarray further demonstrated that the induction of drug-resistant genes such as ABC transporters and major facilitator superfamily (MSF) genes is the primary cellular stress-response; in addition, oxidative and osmotic stress responses were observed in the engineered yeast.</p> <p>Conclusion</p> <p>The data presented here suggest that the engineered yeast producing artemisinic acid suffers oxidative and drug-associated stresses. The use of plant-derived transporters and optimizing AMO activity may improve the yield of artemisinic acid production in the engineered yeast.</p

Flight Test Results from Real-Time Relative Global Positioning System Flight Experiment on STS-69

A real-time global positioning system (GPS) Kalman filter has been developed to support automated rendezvous with the International Space Station (ISS). The filter is integrated with existing Shuttle rendezvous software running on a 486 laptop computer under Windows. In this work, we present real-time and postflight results achieved with the filter on STS-69. The experiment used GPS data from an Osborne/Jet propulsion Laboratory TurboRouge receiver carried on the Wake Shield Facility (WSF) free flyer and a Rockwell Collins 3M receiver carried on the Orbiter. Real time filter results, processed onboard the Shuttle and replayed in near-time on the ground, are based on single vehicle mode operation and on 5 to 20 minute snapshots of telemetry provided by WSF for dual-vehicle mode operation. The Orbiter and WSF state vectors calculated using our filter compare favorably with precise reference orbits determined by the University of Texas Center for Space Research. The lessons learned from this experiment will be used in conjunction with future experiments to mitigate the technology risk posed by automated rendezvous and docking to the ISS

High-Level Production of Amorpha-4,11-Diene, a Precursor of the Antimalarial Agent Artemisinin, in Escherichia coli

BACKGROUND: Artemisinin derivatives are the key active ingredients in Artemisinin combination therapies (ACTs), the most effective therapies available for treatment of malaria. Because the raw material is extracted from plants with long growing seasons, artemisinin is often in short supply, and fermentation would be an attractive alternative production method to supplement the plant source. Previous work showed that high levels of amorpha-4,11-diene, an artemisinin precursor, can be made in Escherichia coli using a heterologous mevalonate pathway derived from yeast (Saccharomyces cerevisiae), though the reconstructed mevalonate pathway was limited at a particular enzymatic step. METHODOLOGY/ PRINCIPAL FINDINGS: By combining improvements in the heterologous mevalonate pathway with a superior fermentation process, commercially relevant titers were achieved in fed-batch fermentations. Yeast genes for HMG-CoA synthase and HMG-CoA reductase (the second and third enzymes in the pathway) were replaced with equivalent genes from Staphylococcus aureus, more than doubling production. Amorpha-4,11-diene titers were further increased by optimizing nitrogen delivery in the fermentation process. Successful cultivation of the improved strain under carbon and nitrogen restriction consistently yielded 90 g/L dry cell weight and an average titer of 27.4 g/L amorpha-4,11-diene. CONCLUSIONS/ SIGNIFICANCE: Production of >25 g/L amorpha-4,11-diene by fermentation followed by chemical conversion to artemisinin may allow for development of a process to provide an alternative source of artemisinin to be incorporated into ACTs

Dopamine transporter genotype is associated with a lateralized resistance to distraction during attention selection

Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional versus response selection. A sample of nonclinical adult humans (N = 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1; SLC6A3), which are argued to influence the level of available synaptic dopamine and confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and spatial cueing but not flanker tasks. Specifically, compared with individuals carrying one or two copies of the 10-repeat DAT1 allele, individuals without this allele demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None of these significant effects could be explained by speed–accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield

Political strategies of external support for democratization

Political strategies of external support to democratization are contrasted and critically examined in respect of the United States and European Union. The analysis begins by defining its terms of reference and addresses the question of what it means to have a strategy. The account briefly notes the goals lying behind democratization support and their relationship with the wider foreign policy process, before considering what a successful strategy would look like and how that relates to the selection of candidates. The literature's attempts to identify strategy and its recommendations for better strategies are compared and assessed. Overall, the article argues that the question of political strategies of external support for democratization raises several distinct but related issues including the who?, what?, why?, and how? On one level, strategic choices can be expected to echo the comparative advantage of the "supporter." On a different level, the strategies cannot be divorced from the larger foreign policy framework. While it is correct to say that any sound strategy for support should be grounded in a theoretical understanding of democratization, the literature on strategies reveals something even more fundamental: divergent views about the nature of politics itself. The recommendations there certainly pinpoint weaknesses in the actual strategies of the United States and Europe but they have their own limitations too. In particular, in a world of increasing multi-level governance strategies for supporting democratization should go beyond preoccupation with just an "outside-in" approach

Fluctuations in the coarsening dynamics of the O(N) model: are they similar to those in glassy systems?

We study spatio-temporal fluctuations in the non-equilibrium dynamics of the d dimensional O(N) in the large N limit. We analyse the invariance of the dynamic equations for the global correlation and response in the slow ageing regime under transformations of time. We find that these equations are invariant under scale transformations. We extend this study to the action in the dynamic generating functional finding similar results. This model therefore falls into a different category from glassy problems in which full time-reparametrisation invariance, a larger symmetry that emcompasses time scale invariance, is expected to be realised asymptotically. Consequently, the spatio-temporal fluctuations of the large N O(N) model should follow a different pattern from that of glassy systems. We compute the fluctuations of local, as well as spatially separated, two-field composite operators and responses, and we confront our results with the ones found numerically for the 3d Edwards-Anderson model and kinetically constrained lattice gases. We analyse the dependence of the fluctuations of the composite operators on the growing domain length and we compare to what has been found in super-cooled liquids and glasses. Finally, we show that the development of time-reparametrisation invariance in glassy systems is intimately related to a well-defined and finite effective temperature, specified from the modification of the fluctuation-dissipation theorem out of equilibrium. We then conjecture that the global asymptotic time-reparametrisation invariance is broken down to time scale invariance in all coarsening systems.Comment: 57 pages, 5 figure

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures