The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development.

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design

Optical tools for ocean monitoring and research

© 2009 The Authors. This article is distributed under the terms of the Creative Commons Attribution 3.0 License. The definitive version was published in Ocean Science 5 (2009): 661-684, doi: 10.5194/os-5-661-2009Requirements for understanding the relationships between ocean color and suspended and dissolved materials within the water column, and a rapidly emerging photonics and materials technology base for performing optical based analytical techniques have generated a diverse offering of commercial sensors and research prototypes that perform optical measurements in water. Through inversion, these tools are now being used to determine a diverse set of related biogeochemical and physical parameters. Techniques engaged include measurement of the solar radiance distribution, absorption, scattering, stimulated fluorescence, flow cytometry, and various spectroscopy methods. Selective membranes and other techniques for material isolation further enhance specificity, leading to sensors for measurement of dissolved oxygen, methane, carbon dioxide, common nutrients and a variety of other parameters. Scientists are using these measurements to infer information related to an increasing set of parameters and wide range of applications over relevant scales in space and time

The pain experiences of powered wheelchair users

Copyright © 2012 Informa UK, Ltd. This is the author's accepted manuscript. The final published article is available from the link below.Purpose: To explore the experience of pain and discomfort in users of electric-powered indoor/outdoor wheelchairs (EPIOCs) provided by a National Health Service. Methods: EPIOC users receiving their chair between February and November 2002 (N=74) were invited to participate in a telephone questionnaire/interview and 64 (aged 1081 years) agreed. Both specific and open-ended questions examined the presence of pain/discomfort, its severity, minimizing and aggravating factors, particularly in relation to the EPIOC and its use. Results: Most EPIOC users described experiences of pain with 17% reporting severe pain. Over half felt their pain was influenced by the wheelchair and few (25%) considered their chair eased their symptoms. The most common strategy for pain relief was taking medication. Other self-help strategies included changing position, exercise and complementary therapies. Respondents emphasized the provision of backrests, armrests, footrests and cushions which might alleviate or exacerbate pain, highlighting the importance of appropriate assessment for this high dependency group. Conclusions: Users related pain to their underlying medical condition, their wheelchair or a combination of the two. User feedback is essential to ensure that the EPIOC meets health needs with minimal pain. This becomes more important as the health condition of users changes over time

Spatial and temporal variability of absorption by dissolved material at a continental shelf

Optical properties of dissolved (colored dissolved organic material (CDOM)) and particulate matter and hydrographic measurements were obtained at the Mid-Atlantic Bight during the fall of 1996 and the spring of 1997 as part of the Coastal Mixing and Optics experiment. To assess the temporal and spatial variability, time series were obtained at one location and cross-shelf transects were carried out. On short timescales, variability in the vertical distribution of the dissolved fraction was mostly due to high-frequency internal waves. This variability was conservative, resulting in no changes on isopycnals. Over longer periods and episodically, CDOM variability was dominated by storms. The storms were associated with sediment resuspension evens and were accompanied by an increase in the absorption by the dissolved materials. Data from spatial transects show that near the bottom, over the shelf, and in both spring and fall, increased particulate absorption and increased CDOM absorption co-occur. These data support the hypothesis that bottom sediments can act as a source of dissolved organic carbon during sediment resuspension events

py4DSTEM: a software package for multimodal analysis of four-dimensional scanning transmission electron microscopy datasets

Scanning transmission electron microscopy (STEM) allows for imaging, diffraction, and spectroscopy of materials on length scales ranging from microns to atoms. By using a high-speed, direct electron detector, it is now possible to record a full 2D image of the diffracted electron beam at each probe position, typically a 2D grid of probe positions. These 4D-STEM datasets are rich in information, including signatures of the local structure, orientation, deformation, electromagnetic fields and other sample-dependent properties. However, extracting this information requires complex analysis pipelines, from data wrangling to calibration to analysis to visualization, all while maintaining robustness against imaging distortions and artifacts. In this paper, we present py4DSTEM, an analysis toolkit for measuring material properties from 4D-STEM datasets, written in the Python language and released with an open source license. We describe the algorithmic steps for dataset calibration and various 4D-STEM property measurements in detail, and present results from several experimental datasets. We have also implemented a simple and universal file format appropriate for electron microscopy data in py4DSTEM, which uses the open source HDF5 standard. We hope this tool will benefit the research community, helps to move the developing standards for data and computational methods in electron microscopy, and invite the community to contribute to this ongoing, fully open-source project

"Women's rights, the European Court and Supranational Constitutionalism"

This analysis examines supranational constitutionalism in the European Union. In particular, the study focuses on the role of the European Court of Justice in the creation of women’s rights. I examine the interaction between the Court and member state governments in legal integration, and also the integral role that women’s advocates – both individual activists and groups – have played in the development of EU social provisions. The findings suggest that this litigation dynamic can have the effect of fueling the integration process by creating new rights that may empower social actors and EU organizations, with the ultimate effect of diminishing member state government control over the scope and direction of EU law. This study focuses specifically on gender equality law, yet provides a general framework for examining the case law in subsequent legal domains, with the purpose of providing a more nuanced understanding of supranational governance and constitutionalism

Directional ballistic transport in the two-dimensional metal PdCoO2

This project was supported by the Max Planck Society and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (MiTopMat, grant agreement no. 715730). M.D.B. and P.H.M. acknowledge EPSRC for PhD studentship support through grant number EP/L015110/1. Research in Dresden benefits from the environment of the Excellence Cluster ct.qmat. A.S. acknowledges support from an ARCS Foundation Fellowship, a Ford Foundation Predoctoral Fellowship and a National Science Foundation Graduate Research Fellowship. A.S. would thanks Z. Gomez and E. Huang for helpful discussions and T. Devereaux for letting us use his group cluster. Computational work was performed on the Sherlock cluster at Stanford University and on resources of the National Energy Research Scientific Computing Center, supported by the DOE under contract DE_AC02-05CH11231. T.S. acknowledges support from the Emergent Phenomena in Quantum Systems initiative of the Gordon and Betty Moore Foundation, and from the Natural Sciences and Engineering Research Council of Canada (NSERC), in particular the Discovery Grant (RGPIN-2020-05842), Accelerator Supplement (RGPAS-2020-00060) and Discovery Launch Supplement (DGECR-2020-00222). T.S. contributed to this work prior to joining AWS. D.G.-G.’s and A.W.B.’s involvement in calculations was supported by the US Department of Energy, Office of Science, Basic Energy Sciences, Materials Sciences and Engineering Division under contract DE-AC02-76SF00515. E.Z. and M.M. thank the International Max Planck Research School for Chemistry and Physics of Quantum Materials (IMPRS-CPQM) for financial support. G.B. and D.A.B. acknowledge support from the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant RGPIN-2018-04280) and from the Canada First Research Excellence Fund.In an idealized infinite crystal, the material properties are constrained by the symmetries of the unit cell. The point-group symmetry is broken by the sample shape of any finite crystal, but this is commonly unobservable in macroscopic metals. To sense the shape-induced symmetry lowering in such metals, long-lived bulk states originating from an anisotropic Fermi surface are needed. Here we show how a strongly facetted Fermi surface and the long quasiparticle mean free path present in microstructures of PdCoO2 yield an in-plane resistivity anisotropy that is forbidden by symmetry on an infinite hexagonal lattice. We fabricate bar-shaped transport devices narrower than the mean free path from single crystals using focused ion beam milling, such that the ballistic charge carriers at low temperatures frequently collide with both of the side walls that define the channel. Two symmetry-forbidden transport signatures appear: the in-plane resistivity anisotropy exceeds a factor of 2, and a transverse voltage appears in zero magnetic field. Using ballistic Monte Carlo simulations and a numerical solution of the Boltzmann equation, we identify the orientation of the narrow channel as the source of symmetry breaking.Publisher PDFPeer reviewe

Hyperspectral temperature and salt dependencies of absorption by water and heavy water in the 400-750 nm spectral range

The temperature and salt dependencies of absorption by liquid water (H₂O) and heavy water (D₂O) were determined using a hyperspectral absorption and attenuation meter (WET Labs, AC-S). Sodium chloride (NaCl) was used as a proxy for seawater salts. There was no significant temperature (ψₜ) or salt (ψₛ) dependency of absorption at wavelengths 550 nm, ψₜ exhibited peaks at ~604, 662, and 740 nm. A small negative trough in ψₛ occurred at ~590 nm, followed by a small positive peak ~620 nm, a larger negative trough at ~720 nm, and a strong positive peak at ~755 nm. The salt dependency of absorption by heavy water, ψₛᴴ, exhibited a negative power-law shape with very low ψₛᴴ, at wavelengths >550 nm. Our experiments with NaCl, clean open ocean seawater, and artificial seawater support the hypothesis that salts modify the absorption spectra of seawater by modifying the molecular matrix and vibrations of pure water

Targeted inhibition of the serotonin 5HT 2A receptor improves coronary patency in an in vivo model of recurrent thrombosis

BACKGROUND: Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype. OBJECTIVE: To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina. METHODS: In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury+stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin. RESULTS: APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow-time area (index of coronary patency; normalized to baseline coronary flow) averaged 58-59% (P<0.01) following administration of APD791 vs. 21-28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation. CONCLUSION: 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model

Spectral particulate attenuation and particle size distribution in the bottom boundary layer of a continental shelf

Spectral attenuation and absorption coefficients of particulate matter and collocated hydrographic measurements were obtained in the Mid-Atlantic Bight during the fall of 1996 and the spring of 1997 as part of the Coastal Mixing and Optics experiment. Within the bottom boundary layer (BBL) the magnitude of the beam attenuation decreased and its spectral shape became steeper with distance from the bottom. Concurrently, the slope of the particulate size distribution (PSD) was found to increase with distance from the bottom. Changes in the PSD shape and the magnitude of the beam attenuation as functions of distance from the bottom in the BBL are consistent with particle resuspension and settling in the BBL, two processes that are dependent on particle size and density. For particles of similar density, resuspension and settling would result in a flattening of the PSD and an increase in the beam attenuation toward the bottom. In both fall and spring the magnitude of the particle attenuation coefficient correlates with its spectral shape, with a flatter shape associated with higher values of the attenuation. This observation is consistent with idealized optical theory for polydispersed nonabsorbing spheres. According to this theory, changes in the steepness of the particle size distribution (particle concentration as a function of size) will be associated with changes in the steepness of the attenuation spectra as a function of wavelength; a flatter particle size distribution will be associated with a flatter attenuation spectrum. In addition, the observed ranges of the beam attenuation spectral slope and PSD exponent are found to be consistent with this theory