High-pressure phases of FeTiO3 from first principles

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Controversies in the management of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) remains a rare but significant disease, which affects mainly young males in association with inflammatory bowel disease. There have been few advances in the understanding of the pathogenesis of the condition and no therapeutics with proven mortality benefit aside from liver transplantation. There remain areas of controversy in the management of PSC which include the differentiation from other cholangiopathies, in particular immunoglobulin G4 related sclerosing cholangitis, the management of dominant biliary strictures, and the role of ursodeoxycholic acid. In addition, the timing of liver transplantation in PSC remains difficult to predict with standard liver severity scores. In this review, we address these controversies and highlight the latest evidence base in the management of PSC

Policy insights and modelling challenges: The case of passenger car powertrain technology transition in the European Union

Purpose: We are interested in what policy insights can be transferred from EU countries that have been most successful in introducing EVs to those that are debating policy options. As we use a model to explore this, we are also interested in the application of modelling, seeking to understand if real world policies and results can be replicated in a model and, more generally, the challenges to the use of modelling in policy appraisal. Methods: We use the EC-JRC Powertrain Technology Transition Market Agent Model (PTTMAM), a system dynamics model based around the interactions of conceptual market agent groups in the EU. We perform iterative scenario tests to replicate the policies carried out in the Netherlands and the UK in recent years in an attempt to achieve similar results in EV sales. We then transfer the policy scenarios to other EU member states and assess the transferability of the policies. Results: Reasonable approximations of the Netherlands and UK EV policies and sales were achieved and implemented in other EU member states. Conclusion: We find that the PTTMAM is fit-for-purpose and can replicate successful policies to a certain degree. Policy success is sensitive to country specific conditions, and a system dynamics model like the PTTMAM can help identify which conditions react to which policy stimulus. There are challenges to modelling in policy appraisal, such as the subjectivity of the modeller and flexibility to specific conditions, which must be kept transparent for the model to be a relevant tool for policy making

Fluid and Diffusion Limits for Bike Sharing Systems

Bike sharing systems have rapidly developed around the world, and they are served as a promising strategy to improve urban traffic congestion and to decrease polluting gas emissions. So far performance analysis of bike sharing systems always exists many difficulties and challenges under some more general factors. In this paper, a more general large-scale bike sharing system is discussed by means of heavy traffic approximation of multiclass closed queueing networks with non-exponential factors. Based on this, the fluid scaled equations and the diffusion scaled equations are established by means of the numbers of bikes both at the stations and on the roads, respectively. Furthermore, the scaling processes for the numbers of bikes both at the stations and on the roads are proved to converge in distribution to a semimartingale reflecting Brownian motion (SRBM) in a $N^{2}$-dimensional box, and also the fluid and diffusion limit theorems are obtained. Furthermore, performance analysis of the bike sharing system is provided. Thus the results and methodology of this paper provide new highlight in the study of more general large-scale bike sharing systems.Comment: 34 pages, 1 figure

Live to cheat another day: bacterial dormancy facilitates the social exploitation of beta-lactamases

The breakdown of antibiotics by β-lactamases may be cooperative, since resistant cells can detoxify their environment and facilitate the growth of susceptible neighbours. However, previous studies of this phenomenon have used artificial bacterial vectors or engineered bacteria to increase the secretion of β-lactamases from cells. Here, we investigated whether a broad-spectrum β-lactamase gene carried by a naturally occurring plasmid (pCT) is cooperative under a range of conditions. In ordinary batch culture on solid media, there was little or no evidence that resistant bacteria could protect susceptible cells from ampicillin, although resistant colonies could locally detoxify this growth medium. However, when susceptible cells were inoculated at high densities, late-appearing phenotypically susceptible bacteria grew in the vicinity of resistant colonies. We infer that persisters, cells that have survived antibiotics by undergoing a period of dormancy, founded these satellite colonies. The number of persister colonies was positively correlated with the density of resistant colonies and increased as antibiotic concentrations decreased. We argue that detoxification can be cooperative under a limited range of conditions: if the toxins are bacteriostatic rather than bacteridical; or if susceptible cells invade communities after resistant bacteria; or if dormancy allows susceptible cells to avoid bactericides. Resistance and tolerance were previously thought to be independent solutions for surviving antibiotics. Here, we show that these are interacting strategies: the presence of bacteria adopting one solution can have substantial effects on the fitness of their neighbours

Frequency tuning of the efferent effect on cochlear gain in humans

Cochlear gain reduction via efferent feedback from the medial olivocochlear bundle is frequency specific (Guinan, Curr Opin Otolaryngol Head Neck Surg 18:447-453, 2010). The present study with humans used the Fixed Duration Masking Curve psychoacoustical method (Yasin et al., J Acoust Soc Am 133:4145-4155, 2013a; Yasin et al., Basic aspects of hearing: physiology and perception, pp 39-46, 2013b; Yasin et al., J Neurosci 34:15319-15326, 2014) to estimate the frequency specificity of the efferent effect at the cochlear level. The combined duration of the masker-plus-signal stimulus was 25 ms, within the efferent onset delay of about 31-43 ms (James et al., Clin Otolaryngol 27:106-112, 2002). Masker level (4.0 or 1.8 kHz) at threshold was obtained for a 4-kHz signal in the absence or presence of an ipsilateral 60 dB SPL, 160-ms precursor (200-Hz bandwidth) centred at frequencies between 2.5 and 5.5 kHz. Efferent-mediated cochlear gain reduction was greatest for precursors with frequencies the same as, or close to that of, the signal (gain was reduced by about 20 dB), and least for precursors with frequencies well removed from that of the signal (gain remained at around 40 dB). The tuning of the efferent effect filter (tuning extending 0.5-0.7 octaves above and below the signal frequency) is within the range obtained in humans using otoacoustic emissions (Lilaonitkul and Guinan, J Assoc Res Otolaryngol 10:459-470, 2009; Zhao and Dhar, J Neurophysiol 108:25-30, 2012). The 10 dB bandwidth of the efferent-effect filter at 4000 Hz was about 1300 Hz (Q10 of 3.1). The FDMC method can be used to provide an unbiased measure of the bandwidth of the efferent effect filter using ipsilateral efferent stimulation

The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans

What traits are carried on mobile genetic elements, and why?

Although similar to any other organism, prokaryotes can transfer genes vertically from mother cell to daughter cell, they can also exchange certain genes horizontally. Genes can move within and between genomes at fast rates because of mobile genetic elements (MGEs). Although mobile elements are fundamentally self-interested entities, and thus replicate for their own gain, they frequently carry genes beneficial for their hosts and/or the neighbours of their hosts. Many genes that are carried by mobile elements code for traits that are expressed outside of the cell. Such traits are involved in bacterial sociality, such as the production of public goods, which benefit a cell's neighbours, or the production of bacteriocins, which harm a cell's neighbours. In this study we review the patterns that are emerging in the types of genes carried by mobile elements, and discuss the evolutionary and ecological conditions under which mobile elements evolve to carry their peculiar mix of parasitic, beneficial and cooperative genes

cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission.

Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites

Global environmental controls of wildfire burnt area, size and intensity.

Fire is an important influence on the global patterns of vegetation structure and composition. Wildfire is included as a distinct process in many dynamic global vegetation models but limited current understanding of fire regimes restricts these models' ability to reproduce more than the broadest geographic patterns. Here we present a statistical analysis of the global controls of remotely sensed burnt area (BA), fire size (FS), and a derived metric related to fire intensity (FI). Separate generalized linear models were fitted to observed monthly fractional BA from the Global Fire Emissions Database (GFEDv4), median FS from the Global Fire Atlas, and median fire radiative power from the MCD14ML dataset normalized by the square root of median FS. The three models were initially constructed from a common set of 16 predictors; only the strongest predictors for each model were retained in the final models. It is shown that BA is primarily driven by fuel availability and dryness; FS by conditions promoting fire spread; and FI by fractional tree cover and road density. Both BA and FS are constrained by landscape fragmentation, whereas FI is constrained by fuel moisture. Ignition sources (lightning and human population) were positively related to BA (after accounting for road density), but negatively to FI. These findings imply that the different controls on BA, FS and FI need to be considered in process-based models. They highlight the need to include measures of landscape fragmentation as well as fuel load and dryness, and to pay close attention to the controls of fire spread