Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74

The receptor for calcitonin gene-related peptide (CGRP) has been the target for the development of novel small molecule antagonists for the treatment of migraine. Two such antagonists, BIBN4096BS and MK-0974, have shown great promise in clinical trials and hence a deeper understanding of the mechanism of their interaction with the receptor is now required. The structure of the CGRP receptor is unusual since it is comprised of a hetero-oligomeric complex between the calcitonin receptor-like receptor (CRL) and an accessory protein (RAMP1). Both the CLR and RAMP1 components have extracellular domains which interact with each other and together form part of the peptide-binding site. It seems likely that the antagonist binding site will also be located on the extracellular domains and indeed Trp-74 of RAMP1 has been shown to form part of the binding site for BIBN4096BS. However, despite a chimeric study demonstrating the role of the N-terminal domain of CLR in antagonist binding, no specific residues have been identified. Here we carry out a mutagenic screen of the extreme N-terminal domain of CLR (residues 23-63) and identify a mutant, Met-42-Ala, which displays 48-fold lower affinity for BIBN4096BS and almost 900-fold lower affinity for MK-0974. In addition, we confirm that the Trp-74-Lys mutation at human RAMP1 reduces BIBN4096BS affinity by over 300-fold and show for the first time a similar effect for MK-0974 affinity. The data suggest that the non-peptide antagonists occupy a binding site close to the interface of the N-terminal domains of CLR and RAMP1

Warm Molecular Hydrogen Emission in Normal Edge-On Galaxies NGC 4565 and NGC 5907

We have observed warm molecular hydrogen in two nearby edge-on disk galaxies, NGC 4565 and NGC 5907, using the Spitzer high-resolution infrared spectrograph. The 0-0 S(0) 28.2 micron and 0-0 S(1) 17.0 micron pure rotational lines were detected out to 10 kpc from the center of each galaxy on both sides of the major axis, and in NGC 4565 the S(0) line was detected at r = 15 kpc on one side. This location lies beyond a steep drop in the radio continuum emission from cosmic rays in the disk. Despite indications that star formation activity decreases with radius, the H2 excitation temperature and the ratio of the H2 line and the far-IR luminosity surface densities, Sigma_L(H2}/Sigma_L(TIR}, change very little as a function of radius, even into the diffuse outer region of the disk of NGC 4565. This suggests that the source of excitation of the H2 operates over a large range of radii, and is broadly independent of the strength and relative location of UV emission from young stars. Although excitation in photodissociation regions is the most common explanation for the widespread H2 emission, cosmic ray heating or shocks cannot be ruled out. The inferred mass surface densities of warm molecular hydrogen in both edge-on galaxies differ substantially, being 4(-60) M_solar/pc^2 and 3(-50) M_solar/pc^2 at r = 10 kpc for NGC 4565 and NGC 5907, respectively. The higher values represent very unlikely point-source upper limits. The point source case is not supported by the observed emission distribution in the spectral slits. These mass surface densities cannot support the observed rotation velocities in excess of 200 km/s. Therefore, warm molecular hydrogen cannot account for dark matter in these disk galaxies, contrary to what was implied by a previous ISO study of the nearby edge-on galaxy NGC 891.Comment: Accepted for publication in the Astronomical Journal (20 pages, 17 figures, 7 tables

Beluga whales in the western Beaufort Sea : current state of knowledge on timing, distribution, habitat use and environmental drivers

ECG was supported by a National Research Council-National Academy of Sciences Postdoctoral Fellowship.The seasonal and geographic patterns in the distribution, residency, and density of two populations (Chukchi and Beaufort) of beluga whales (Delphinapterus leucas) were examined using data from aerial surveys, passive acoustic recordings, and satellite telemetry to better understand this arctic species in the oceanographically complex and changing western Beaufort Sea. An aerial survey data-based model of beluga density highlights the Beaufort Sea slope as important habitat for belugas, with westerly regions becoming more important as summer progresses into fall. The Barrow Canyon region always had the highest relative densities of belugas from July-October. Passive acoustic data showed that beluga whales occupied the Beaufort slope and Beaufort Sea from early April until early November and passed each hydrophone location in three broad pulses during this time. These pulses likely represent the migrations of the two beluga populations: the first pulse in spring being from Beaufort animals, the second spring pulse Chukchi belugas, with the third, fall pulse a combination of both populations. Core-use and home range analyses of satellite-tagged belugas showed similar use of habitats as the aerial survey data, but also showed that it is predominantly the Chukchi population of belugas that uses the western Beaufort, with the exception of September when both populations overlap. Finally, an examination of these beluga datasets in the context of wind-driven changes in the local currents and water masses suggests that belugas are highly capable of adapting to oceanographic changes that may drive the distribution of their prey.PostprintPeer reviewe

Defining the genetic susceptibility to cervical neoplasia - a genome-wide association study

Funding: MAB was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. Support was also received from the Australian Cancer Research Foundation. JL holds a Tier 1 Canada Research Chair in Human Genome Epidemiology. The Seattle study was supported by the following grants: NIH, National Cancer Institute grants P01CA042792 and R01CA112512. Cervical Health Study (from which the NSW component was obtained) was funded by NHMRC Grant 387701, and CCNSW core grant. The Montreal study was funded by the Canadian Institutes of Health Research (grant MOP-42532) and sample processing was funded by the Reseau FRQS SIDA-MI. The Swedish Research Council, the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg and Umeå, the Lundberg Foundation, the Torsten and Ragnar Soderberg’s Foundation, the Novo Nordisk Foundation, and the European Commission grant HEALTH-F2-2008-201865-GEFOS, BBMRI.se, the Swedish Society of Medicine, the KempeFoundation (JCK-1021), the Medical Faculty of Umeå University, the County Council of Vasterbotten (Spjutspetsanslag VLL:159:33-2007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptPeer reviewedPublisher PDFPublisher PD

Survey of information technology in Intensive Care Units in Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>The Intensive Care Unit (ICU) is a data-rich environment where information technology (IT) may enhance patient care. We surveyed ICUs in the province of Ontario, Canada, to determine the availability, implementation and variability of information systems.</p> <p>Methods</p> <p>A self-administered internet-based survey was completed by ICU directors between May and October 2006. We measured the spectrum of ICU clinical data accessible electronically, the availability of decision support tools, the availability of electronic imaging systems for radiology, the use of electronic order entry and medication administration systems, and the availability of hardware and wireless or mobile systems. We used Fisher's Exact tests to compare IT availability and Classification and Regression Trees (CART) to estimate the optimal cut-point for the number of computers per ICU bed.</p> <p>Results</p> <p>We obtained responses from 50 hospitals (68.5% of institutions with level 3 ICUs), of which 21 (42%) were university-affiliated. The majority electronically accessed laboratory data and imaging reports (92%) and used picture archiving and communication systems (PACS) (76%). Other computing functions were less prevalent (medication administration records 46%, physician or nursing notes 26%; medication order entry 22%). No association was noted between IT availability and ICU size or university affiliation. Sites used clinical information systems from15 different vendors and 8 different PACS systems were in use. Half of the respondents described the number of computers available as insufficient. Wireless networks and mobile computing systems were used in 23 ICUs (46%).</p> <p>Conclusion</p> <p>Ontario ICUs demontrate a high prevalence of the use of basic information technology systems. However, implementation of the more complex and potentially more beneficial applications is low. The wide variation in vendors utilized may impair information exchange, interoperability and uniform data collection.</p

Dynamic scaling for 2D superconductors, Josephson junction arrays and superfluids

The value of the dynamic critical exponent $z$ is studied for two-dimensional superconducting, superfluid, and Josephson Junction array systems in zero magnetic field via the Fisher-Fisher-Huse dynamic scaling. We find $z\simeq5.6\pm0.3$, a relatively large value indicative of non-diffusive dynamics. Universality of the scaling function is tested and confirmed for the thinnest samples. We discuss the validity of the dynamic scaling analysis as well as the previous studies of the Kosterlitz-Thouless-Berezinskii transition in these systems, the results of which seem to be consistent with simple diffusion ($z=2$). Further studies are discussed and encouraged.Comment: 19 pages in two-column RevTex, 8 embedded EPS figure

Software-sorted geographies.

This paper explores the central role of computerized code in shaping the social and geographical politics of inequality in advanced societies. The central argument is that, while such processes are necessarily multifaceted, multiscaled, complex and ambivalent, a great variety of ‘software-sorting’ techniques is now being widely applied in efforts to try to separate privileged and marginalized groups and places across a wide range of sectors and domains. This paper’s central demonstration is that the overwhelming bulk of software-sorting applications is closely associated with broader transformations from Keynesian to neoliberal service regimes. To illustrate such processes of software-sorting, the paper analyses recent research addressing three examples of software-sorting in practice. These address physical and electronic mobility systems, online geographical information systems (GIS), and face-recognition closed circuit television (CCTV) systems covering city streets. The paper finishes by identifying theoretical, research and policy implications of the diffusion of software-sorted geographies within which computerized code continually orchestrates inequalities through technological systems embedded within urban environments

Review of research to inform California's climate scoping plan: Agriculture and working lands

Agriculture in California contributes 8% of the state's greenhouse gas (GHG) emissions. To inform the state's policy and program strategy to meet climate targets, we review recent research on practices that can reduce emissions, sequester carbon and provide other co-benefits to producers and the environment across agriculture and rangeland systems. Importantly, the research reviewed here was conducted in California and addresses practices in our specific agricultural, socioeconomic and biophysical environment. Farmland conversion and the dairy and intensive livestock sector are the largest contributors to GHG emissions and offer the greatest opportunities for avoided emissions. We also identify a range of other opportunities including soil and nutrient management, integrated and diversified farming systems, rangeland management, and biomass-based energy generation. Additional research to replicate and quantify the emissions reduction or carbon sequestration potential of these practices will strengthen the evidence base for California climate policy

Criminology or Zemiology? Yes, please! on the refusal of choice between false alternatives

Buried deep within the zemiological movement and its supportive literature is the implicit assumption that the word zemia, the organising concept around which zemiology is built, simply represents ‘the Greek word for harm’. This interpretation has supported numerous drives to ‘move beyond criminology’ and erect strict borders between the study of crime and harm. However, a deeper, albeit still rather brief, exploration of zemia reveals that it possesses a broader range of meaning than that commonly afforded to it. By beginning to unpick zemia’s semantic genealogy, it appears that the conventional use of the word to support the imposition of false alternatives between criminology and zemiology is untenable. Accordingly, this chapter attempts to foreground a more integrated approach to the study of crime and harm

Finite-Size Effects and Dynamical Scaling in Two-Dimensional Josephson Junction Arrays

In recent years many groups have used Fisher, Fisher, and Huse (FFH) dynamical scaling to investigate and demonstrate details of the superconducting phase transition. Some attention has been focused on two dimensions where the phase transition is of the Kosterlitz-Thouless-Berezinskii (KTB) type. Pierson et al. used FFH dynamical scaling almost exclusively to suggest that the dynamics of the two-dimensional superconducting phase transition may be other than KTB-like. In this work we investigate the ability of scaling behavior by itself to yield useful information on the nature of the transition. We simulate current-voltage (IV) curves for two-dimensional Josephson junction arrays with and without finite-size-induced resistive tails. We find that, for the finite-size effect data, the values of the scaling parameters, specifically the transition temperature and the dynamical scaling exponent z, depend critically on the magnitude of the contribution that the resistive tails make to the IV curves. In effect, the values of the scaling parameters depend on the noise floor of the measuring system.Comment: 24 pages, 8 figures; submitted to Physical Review