Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function

Following inducible expression in HEK293 cells, the human orexin-1 receptor was targeted to the cell surface but became internalized following exposure to the peptide agonist orexin A. By contrast, constitutive expression of the human cannabinoid CB1 receptor resulted in a predominantly punctate, intracellular distribution pattern consistent with spontaneous, agonistindependent internalization. Expression of the orexin-1 receptor in the presence of the CB1 receptor resulted in both receptors displaying the spontaneous internalization phenotype. Single cell fluorescence resonance energy transfer imaging indicated the two receptors were present as heterodimers/oligomers in intracellular vesicles. Addition of the CB1 receptor antagonist SR-141716A to cells expressing only the CB1 receptor resulted in re-localization of the receptor to the cell surface. Although SR-141716A has no significant affinity for the orexin-1 receptor, in cells co-expressing the CB1 receptor, the orexin-1 receptor was also re-localized to the cell surface by treatment with SR-141716A. Treatment of cells co-expressing the orexin-1 and CB1 receptors with the orexin-1 receptor antagonist SB-674042 also resulted in re-localization of both receptors to the cell surface. Treatment with SR-141716A resulted in decreased potency of orexin A to activate the mitogen-activated protein kinases ERK1/2 only in cells co-expressing the two receptors. Treatment with SB-674042 also reduced the potency of a CB1 receptor agonist to phosphorylate ERK1/2 only when the two receptors were co-expressed. These studies introduce an entirely novel pharmacological paradigm, whereby ligands modulate the function of receptors for which they have no significant inherent affinity by acting as regulators of receptor heterodimers

We Could, but Should We? Ethical Considerations for Providing Access to GeoCities and Other Historical Digital Collections

We live in an era in which the ways that we can make sense of our past are evolving as more artifacts from that past become digital. At the same time, the responsibilities of traditional gatekeepers who have negotiated the ethics of historical data collection and use, such as librarians and archivists, are increasingly being sidelined by the system builders who decide whether and how to provide access to historical digital collections, often without sufficient reflection on the ethical issues at hand. It is our aim to better prepare system builders to grapple with these issues. This paper focuses discussions around one such digital collection from the dawn of the web, asking what sorts of analyses can and should be conducted on archival copies of the GeoCities web hosting platform that dates to 1994.This research was supported by the Natural Sciences and Engineering Research Council of Canada, the Social Sciences and Humanities Research Council of Canada, the US National Science Foundation (grants 1618695 and 1704369), the Andrew W. Mellon Foundation, Start Smart Labs, and Compute Canada

RHESSI and SOHO/CDS Observations of Explosive Chromospheric Evaporation

Simultaneous observations of explosive chromospheric evaporation are presented using data from the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) and the Coronal Diagnostic Spectrometer (CDS) onboard SOHO. For the first time, co-spatial imaging and spectroscopy have been used to observe explosive evaporation within a hard X-ray emitting region. RHESSI X-ray images and spectra were used to determine the flux of non-thermal electrons accelerated during the impulsive phase of an M2.2 flare. Assuming a thick-target model, the injected electron spectrum was found to have a spectral index of ~7.3, a low energy cut-off of ~20 keV, and a resulting flux of >4x10^10 ergs cm^-2 s^-1. The dynamic response of the atmosphere was determined using CDS spectra, finding a mean upflow velocity of 230+/-38 km s^-1 in Fe XIX (592.23A), and associated downflows of 36+/-16 km s^-1 and 43+/-22 km s^-1 at chromospheric and transition region temperatures, respectively, relative to an averaged quiet-Sun spectra. The errors represent a 1 sigma dispersion. The properties of the accelerated electron spectrum and the corresponding evaporative velocities were found to be consistent with the predictions of theory.Comment: 5 pages, 4 figures, ApJL (In Press

HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain

BACKGROUND: To examine the role of inflammatory mediators in neuropathic pain, we used a replication-defective genomic herpes simplex virus (HSV)-based vector containing the coding sequence for the anti-inflammatory peptide interleukin (IL)-4 under the transcriptional control of the HSV ICP4 immediate early promoter, vector S4IL4, to express IL-4 in dorsal root ganglion (DRG) neurons in vivo. RESULTS: Subcutaneous inoculation of S4IL4 in the foot transduced lumbar DRG to produce IL-4. Transgene-mediated expression of IL-4 did not alter thermal latency or tactile threshold in normal animals, but inoculation of S4IL4 1 week after spinal nerve ligation (SNL) reduced mechanical allodynia and reversed thermal hyperalgesia resulting from SNL. Inoculation of S4IL4 1 week before SNL delayed the development of thermal hyperalgesia and tactile allodynia, but did not prevent the ultimate development of these manifestations of neuropathic pain. S4IL4 inoculation suppressed non-noxious-induced expression of c-Fos immunoreactivity in dorsal horn of spinal cord and reversed the upregulation of spinal IL-1β, PGE2, and phosphorylated-p38 MAP kinase, characteristic of neuropathic pain. CONCLUSION: HSV-mediated expression of IL-4 effectively reduces the behavioral manifestations of neuropathic pain, and reverses some of the biochemical and histologic correlates of neuropathic pain at the spinal level

A grounded theory approach to physical activity and advanced cancer:a qualitative study protocol

Background: Physical activity has demonstrated benefits in cancer-related fatigue and physical functioning in early-stage cancer patients; however, the role of physical activity at the end stage of cancer has not been established. To challenge positivist–empiricist assumptions, I am seeking to develop a new theoretical framework that is grounded in the advanced cancer patient’s experience of activity. Aim: To gain an in-depth understanding of the experience of activity and quality of life in advanced cancer patients. Objectives: (1) To explore the meaning of activity for advanced cancer patients in the context of their day-to-day life, (2) to elicit advanced cancer patients’ perceptions of activity with respect to their quality of life, and (3) to elicit advanced cancer patients’ views of barriers and facilitators to activity in the context of their day-to-day life. Study Design: A two-phase, crosssectional, qualitative study will be conducted through the postpositivist lens of subtle realism and informed by the principles of grounded theory methods. Study Methods: Advanced cancer patients will be recruited through the outpatient department of a tertiary cancer center. For Phase 1, participants will wear an activPAL™ activity monitor and fill out a daily record sheet for 7-day duration. For Phase 2, the activity monitor output and daily record sheets will be used as qualitative probes for face-to-face, semistructured interviews. Concurrent coding, constant comparative analysis, and theoretical sampling will continue with the aim of achieving as close as possible to theoretical saturation. Ethics and Discussion: Ethical and scientific approval will be obtained by all local institutional review boards prior to study commencement. The findings will generate new mid-level theory about the experience of activity and quality of life in advanced cancer patients and aid in the development of a new theoretical framework for designing interventions for this population

Disentangling habitat concepts for demersal marine fish management

Fishing and other anthropogenic impacts have led to declines in many fish stocks and modification of the seabed. As a result, efforts to restore marine ecosystems have become increasingly focused on spatially explicit management methods to protect fish and the habitats they require for survival. This has led to a proliferation of investigations trying to map ‘habitats’ vulnerable to anthropogenic impacts and identify fish resource requirements in order to meet conservation and management needs. A wide range of habitat-related concepts, with different uses and understandings of the word ‘habitat’ itself has arisen as a consequence. Inconsistencies in terminology can cause confusion between studies, making it difficult to investigate and understand the ecology of fish and the factors that affect their survival. Ultimately, the inability to discern the relationships between fish and their environment clearly can hinder conservation and management measures for fish populations. This review identifies and addresses the present ambiguity surrounding definitions of ‘habitat’ and habitat-related concepts currently used in spatial management of demersal marine fish populations. The role of spatial and temporal scales is considered, in addition to examples of how to assess fish habitat for conservation and management purposes

JEDI II: Jobs and Economic Development Impacts from Coal, Naural Gas and Wind Power

Poster for WindPower 2006 held June 4-7, 2006, in Pittsburgh, PA, describing how JEDI II calculates economic impacts from wind projects

Economic Development Impacts of Wind Power: A Comparative Analysis of Impacts within the Western Governors' Association States; Preprint

This paper uses NREL's newest Jobs and Economic Development Impacts (JEDI II) model to assess economic impacts from alternative power technologies, with a focus on wind energy, for a variety of states

User-Friendly Tool to Calculate Economic Impacts from Coal, Natural Gas, and Wind: The Expanded Jobs and Economic Development Impact Model (JEDI II); Preprint

In this paper we examine the impacts of building new coal, gas, or wind plants in three states: Colorado, Michigan, and Virginia. Our findings indicate that local/state economic impacts are directly related to the availability and utilization of local industries and services to build and operate the power plant. For gas and coal plants, the economic benefit depends significantly on whether the fuel is obtained from within the state, out of state, or some combination. We also find that the taxes generated by power plants can have a significant impact on local economies via increased expenditures on public goods

Economic Development Impacts from Wind Power in the Western Governors' Association States (Poster)

The Western Governors' Association created the Clean and Diversified Energy Advisory Committee (CDEAC) "to utilize the region's diverse resources to produce affordable, sustainable, and environmentally reponsible energy." This conference poster, prepared for WINDPOWER 2007 in Los Angeles, outlines the economic impact to the Western United States from new wind energy projects