Combining Acoustic Trapping with Plane Wave Imaging for Localized Microbubble Accumulation in Large Vessels

The capability of accumulating microbubbles using ultrasound, could be beneficial for enhancing targeted drug delivery. When microbubbles are used to deliver a therapeutic payload, there is a need to track them, for a localized release of the payload. In this study, a method for localizing microbubble accumulation with fast image guidance is presented. A linear array transducer performed trapping of microbubble populations interleaved with plane wave imaging, through the use of a composite pulse sequence. The acoustic trap in the pressure field was created parallel with the direction of flow in a model of a vessel section. The acoustic trapping force resultant from the large gradients in the acoustic field was engendered to directly oppose the flowing microbubbles. This was demonstrated numerically with field simulations, and experimentally using an Ultrasound Array Research Platform II (UARP II). SonoVue microbubbles at clinically relevant concentrations were pumped through a tissue-mimicking flow phantom and exposed to either the acoustic trap or a control ultrasonic field composed of a single-peak acoustic radiation force beam. Under the flow condition at a shear rate of 433 s-1, the use of the acoustic trap led to lower speed estimations (p< 0.05) in the center of the acoustic field, and an enhancement of 71 ± 28% (p< 0.05) in microbubble image brightness

The Ministry of Works and the Development of Souvenir Guides from 1955

The first formal guidebooks for historic sites placed in state guardianship in the United Kingdom appeared in 1917. There was an expansion of the series in the 1930s and 1950s. However, from the late 1950s the Ministry of Works, and later the Ministry of Public Buildings and Works, started to produce an additional series of illustrated souvenir guides. One distinct group covered Royal Palaces: the Tower of London, Hampton Court Palace, Queen Victoria's residence of Osborne House on the Isle of Wight, and Holyroodhouse in Edin-burgh. This was followed by guides for archaeological sites such as Stone-henge and Avebury, the Neolithic flint mines at Grime's Graves, the Roman villa at Lullingstone, and Hadrian's Wall. In 1961, a series of guides, with covers designed by Kyffin Williams, was produced for the English castles constructed in North Wales. These illustrated guides, some with colour, prepared the way for the fully designed guides now produced by English Heritage, Cadw, and Historic Environment Scotland

Review of battery powered embedded systems design for mission-critical low-power applications

The applications and uses of embedded systems is increasingly pervasive. Mission and safety critical systems relying on embedded systems pose specific challenges. Embedded systems is a multi-disciplinary domain, involving both hardware and software. Systems need to be designed in a holistic manner so that they are able to provide the desired reliability and minimise unnecessary complexity. The large problem landscape means that there is no one solution that fits all applications of embedded systems. With the primary focus of these mission and safety critical systems being functionality and reliability, there can be conflicts with business needs, and this can introduce pressures to reduce cost at the expense of reliability and functionality. This paper examines the challenges faced by battery powered systems, and then explores at more general problems, and several real-world embedded systems

A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine

Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisininbased combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nucleasebased gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance. Using heme fractionation assays, we demonstrate that PPQ causes a buildup of reactive free heme and inhibits the formation of chemically inert hemozoin crystals. Our data evoke inhibition of heme detoxification in the parasite’s acidic digestive vacuole as the primary mode of both the bisaminoquinoline PPQ and the related 4-aminoquinoline CQ. Both drugs also inhibit hemoglobin proteolysis at elevated concentrations, suggesting an additional mode of action. Isogenic lines differing in their pfmdr1 copy number showed equivalent PPQ susceptibilities. We propose that mutations in PfCRT could contribute to a multifactorial basis of PPQ resistance in field isolates

A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine

Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance. Using heme fractionation assays, we demonstrate that PPQ causes a buildup of reactive free heme and inhibits the formation of chemically inert hemozoin crystals. Our data evoke inhibition of heme detoxification in the parasite’s acidic digestive vacuole as the primary mode of both the bis-aminoquinoline PPQ and the related 4-aminoquinoline CQ. Both drugs also inhibit hemoglobin proteolysis at elevated concentrations, suggesting an additional mode of action. Isogenic lines differing in their pfmdr1 copy number showed equivalent PPQ susceptibilities. We propose that mutations in PfCRT could contribute to a multifactorial basis of PPQ resistance in field isolates

A metallic additively manufactured metamaterial for enhanced monitoring of acoustic cavitation‐based therapeutic ultrasound

The combination of ultrasound and microbubbles allows treatment of indications that would be impossible or too risk adverse with conventional surgery. During treatment, subharmonic and ultraharmonic components that can only be generated from microbubbles are of great interest for intraoperative monitoring. However, the microbubble emissions are several orders of magnitude lower in power compared to that of the fundamental frequency component from the ultrasound applicator, resulting in a low signal‐to‐noise ratio (SNR) for monitoring. A 3D acoustic metamaterial (AMM) immersed in water is proposed for suppressing unwanted ultrasound waves, which allows the improved sensitivity for detecting weak microbubble emissions. Numerically, the importance of shear waves on the AMM transfer properties is highlighted, though only longitudinal ultrasound waves are transmitted through water. Experimentally, the design is implemented in titanium using additive manufacturing, with an attenuation level of 40 dB at the fundamental frequency. Consequently, the application of the AMM efficiently improves the SNR for subharmonic and ultraharmonic microbubble emissions by 11.8 and 11.9 dB, respectively. The subharmonic components originally overwhelmed by noise are recovered. This is the first time that AMMs have been applied to passive acoustic monitoring and this work stands to improve treatment outcomes from cavitation‐mediated focused ultrasound therapy

LRRK2 secretion in exosomes is regulated by 14-3-3

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 in the endocytic pathway. Here, we show that LRRK2 is released in extracellular microvesicles (i.e. exosomes) from cells that natively express LRRK2. LRRK2 localizes to collecting duct epithelial cells in the kidney that actively secrete exosomes into urine. Purified urinary exosomes contain LRRK2 protein that is both dimerized and phosphorylated. We provide a quantitative proteomic profile of 1673 proteins in urinary exosomes and find that known LRRK2 interactors including 14-3-3 are some of the most abundant exosome proteins. Disruption of the 14-3-3 LRRK2 interaction with a 14-3-3 inhibitor or through acute LRRK2 kinase inhibition potently blocks LRRK2 release in exosomes, but familial mutations in LRRK2 had no effect on secretion. LRRK2 levels were overall comparable but highly variable in urinary exosomes derived from PD cases and age-matched controls, although very high LRRK2 levels were detected in some PD affected cases. We further characterized LRRK2 exosome release in neurons and macrophages in culture, and found that LRRK2-positive exosomes circulate in cerebral spinal fluid (CSF). Together, these results define a pathway for LRRK2 extracellular release, clarify one function of the LRRK2 14-3-3 interaction and provide a foundation for utilization of LRRK2 as a biomarker in clinical trial

<i>Gaia</i> Data Release 1. Summary of the astrometric, photometric, and survey properties

Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims. A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods. The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results. Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the HIPPARCOS and Tycho-2 catalogues – a realisation of the Tycho-Gaia Astrometric Solution (TGAS) – and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of ∼3000 Cepheid and RR-Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr−1 for the proper motions. A systematic component of ∼0.3 mas should be added to the parallax uncertainties. For the subset of ∼94 000 HIPPARCOS stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr−1. For the secondary astrometric data set, the typical uncertainty of the positions is ∼10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to ∼0.03 mag over the magnitude range 5 to 20.7. Conclusions. Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data

The Effect of the Earned Income Tax Credit in the District of Columbia on Poverty and Income Dynamics

Using unique longitudinal administrative tax panel data for the District of Columbia (DC), we assess the combined effect of the DC supplemental earned income tax credit (EITC) and the federal EITC on poverty and income dynamics within Washington, DC, from 2001 to 2011. The EITC in DC merits investigation, as the DC supplement to the federal credit is the largest in the nation. The supplemental DC EITC was enacted in 2000, and has been expanded from 10 percent of the federal credit in 2001 to 40 percent as of 2009. To implement the study, we estimate least squares models with 0/1 dependent variables to estimate the likelihood of net-EITC income above poverty and near-poverty thresholds. We also estimate the likelihood of earnings growth and income stabilization from the EITC. To identify the effect of the EITC, we exploit variation in the EITC subsidy rate from 2008 to 2009, when an additional EITC bracket of 45 percent was added for workers with three or more dependent children, up from 40 percent in the previous year for workers with two or more children. We also estimate a model examining the impact of city-level changes to the EITC. The structure and richness of our data enable us to control for tax filer fixed effects, an important innovation from many previous EITC studies. Overall, we find that the combined EITC raises the likelihood of net-EITC income above poverty and near poverty by as much as 9 percent, with the largest consistent effects accruing to single-parent families