Does the Canadian economy suffer from Dutch disease?

We argue that the failure to disentangle the evolution of the Canadian currency from the U.S. currency leads to potentially incorrect conclusions regarding the case of Dutch disease in Canada. We propose a new approach that is aimed at extracting both currency components and energy- and commodity-price components from observed exchange rates and prices. We first analyze the separate influence of commodity prices on the Canadian and the U.S. currency components. We then estimate the separate impact of the two currency components on the shares of manufacturing employment in Canada. We show that 42 per cent of the manufacturing employment loss that was due to exchange rate developments between 2002 and 2007 is related to the Dutch disease phenomenon. The remaining 58 per cent of the employment loss can be ascribed to the weakness of the U.S. currency

G019 Cholesterol depletion enhances Kv1.5-encoded K+ current by increasing Rab11-mediated recycling

Membrane lipid composition is a major determinant of protein organisation in the cell membrane. In a previous study, we reported that depletion of membrane cholesterol by methyl-fÒ-cyclodextrin (MCD) causes a marked increase in Kv1.5-current (Ikur) in neonatal cardiac myocytes. Here, we examined the mechanisms of the cholesterol effects on potassium current in adult rat cardiomyocytes (ARC). GFP-tagged Kv1.5 channels were transduced in ARC using adenoviral vectors and patch clamp experiments were performed to record whole-cell currents and single channel activity. Fluorescence recovery after photobleaching (FRAP) technique was used to investigate GFP-Kv1.5 channels mobility; 3D-epifluorescence microscopy was conducted to follow Kv1.5 channels trafficking.In both freshly isolated and cultured ARC over-expressing GFP-Kv1.5 channels, MCD induced a rapid (< 7min) increase in Ikur but not Ito. On the contrary, incubation with the cholesterol donor LDL reduced Ikur. Single channel experiments revealed that MCD application caused a progressive and drastic increase of the number of active channels. Moreover, FRAP experiments showed that MCD reduced both mobility and recovery of GFP-Kv1.5. Several steps of the trafficking process of ion channels were studied. Blocking SNARE-mediated exocytosis with N-ethylmaleimide prevented the MCD-effect on Ikur. While disruption of Golgi complex/secretion pathway with brefeldine-A had no effect, manipulation of GTP-ases activity with GTP-f×-S suppressed the MCD effect. Transfection with a dominant negative (DN) form of Rab11 effect but not Rab4 DN prevented the MCD. Moreover, Kv1.5 channels co-immunoprecipitated with Rab11 which is stringly expressed in myocardium and ARC (qPCR and western blot). Finally, 3D-microscopy evidenced that Kv1.5 channels association with Rab11-positive recycling endosomes observed in control condition disappeared following cholesterol depletion.ConclusionLowering cholesterol rapidly induces the insertion of Kv1.5 channels by a process that involves vesicle fusion and trafficking processes, particularly the Rab11-associated slow recycling pathway. Given the role of Kv1.5 channel in normal and pathological atrial electrical properties, this study opens news perspectives for therapeutic modulation of cardiac myocytes excitability

Origin, burial and preservation of late Pleistocene-age glacier ice in Arctic permafrost (Bylot Island, NU, Canada)

Over the past decades, observations of buried glacier ice exposed in coastal bluffs and headwalls of retrogressive thaw slumps of the Arctic have indicated that considerable amounts of late Pleistocene glacier ice survived the deglaciation and are still preserved in permafrost. In exposures, relict glacier ice and intrasedimental ice often coexist and look alike but their genesis is strikingly different. This paper aims to present a detailed description and infer the origin of a massive ice body preserved in the permafrost of Bylot Island (Nunavut). The massive ice exposure and core samples were described according to the cryostratigraphic approach, combining the analysis of permafrost cryofacies and cryostructures, ice crystallography, stable O-H isotopes and cation contents. The ice was clear to whitish in appearance with large crystals (cm) and small gas inclusions (mm) at crystal intersections, similar to observations of englacial ice facies commonly found on contemporary glaciers and ice sheets. However, the δ18O composition (-34.0±0.4&thinsp;‰) of the massive ice was markedly lower than contemporary glacier ice and was consistent with the late Pleistocene age ice in the Barnes Ice Cap. This ice predates the aggradation of the surrounding permafrost and can be used as an archive to infer palaeo-environmental conditions at the study site. As most of the glaciated Arctic landscapes are still strongly determined by their glacial legacy, the melting of these large ice bodies could lead to extensive slope failures and settlement of the ground surface, with significant impact on permafrost geosystem landscape dynamics, terrestrial and aquatic ecosystems and infrastructure.</p

PIP degron proteins, substrates of CRL4Cdt2, and not PIP boxes, interfere with DNA polymerase η and κ focus formation on UV damage

International audienceProliferating cell nuclear antigen (PCNA) is a well-known scaffold for many DNA replication and repair proteins, but how the switch between partners is regulated is currently unclear. Interaction with PCNA occurs via a domain known as a PCNA-Interacting Protein motif (PIP box). More recently, an additional specialized PIP box has been described, the « PIP degron », that targets PCNA-interacting proteins for proteasomal degradation via the E3 ubiquitin ligase CRL4(Cdt2). Here we provide evidence that CRL4(Cdt2)-dependent degradation of PIP degron proteins plays a role in the switch of PCNA partners during the DNA damage response by facilitating accumulation of translesion synthesis DNA polymerases into nuclear foci. We show that expression of a nondegradable PIP degron (Cdt1) impairs both Pol η and Pol κ focus formation on ultraviolet irradiation and reduces cell viability, while canonical PIP box-containing proteins have no effect. Furthermore, we identify PIP degron-containing peptides from several substrates of CRL4(Cdt2) as efficient inhibitors of Pol η foci formation. By site-directed mutagenesis we show that inhibition depends on a conserved threonine residue that confers high affinity for PCNA-binding. Altogether these findings reveal an important regulative role for the CRL4(Cdt2) pathway in the switch of PCNA partners on DNA damage

Feasibility of nanofluid-based optical filters

In this article we report recent modeling and design work indicating that mixtures of nanoparticles in liquids can be used as an alternative to conventional optical filters. The major motivation for creating liquid optical filters is that they can be pumped in and out of a system to meet transient needs in an application. To demonstrate the versatility of this new class of filters, we present the design of nanofluids for use as long-pass, short-pass, and bandpass optical filters using a simple Monte Carlo optimization procedure. With relatively simple mixtures, we achieve filters with &lt;15% mean-squared deviation in transmittance from conventional filters. We also discuss the current commercial feasibility of nanofluid-based optical filters by including an estimation of today&#039;s off-the-shelf cost of the materials. While the limited availability of quality commercial nanoparticles makes it hard to compete with conventional filters, new synthesis methods and economies of scale could enable nanofluid-based optical filters in the near future. As such, this study lays the groundwork for creating a new class of selective optical filters for a wide range of applications, namely communications, electronics, optical sensors, lighting, photography, medicine, and many more

Response of the Hepatic Transcriptome to Aflatoxin B1 in Domestic Turkey (Meleagris gallopavo)

Dietary exposure to aflatoxin B1 (AFB1) is detrimental to avian health and leads to major economic losses for the poultry industry. AFB1 is especially hepatotoxic in domestic turkeys (Meleagris gallopavo), since these birds are unable to detoxify AFB1 by glutathione-conjugation. The impacts of AFB1 on the turkey hepatic transcriptome and the potential protection from pretreatment with a Lactobacillus-based probiotic mixture were investigated through RNA-sequencing. Animals were divided into four treatment groups and RNA was subsequently recovered from liver samples. Four pooled RNA-seq libraries were sequenced to produce over 322 M reads totaling 13.8 Gb of sequence. Approximately 170,000 predicted transcripts were de novo assembled, of which 803 had significant differential expression in at least one pair-wise comparison between treatment groups. Functional analysis linked many of the transcripts significantly affected by AFB1 exposure to cancer, apoptosis, the cell cycle or lipid regulation. Most notable were transcripts from the genes encoding E3 ubiquitin-protein ligase Mdm2, osteopontin, S-adenosylmethionine synthase isoform type-2, and lipoprotein lipase. Expression was modulated by the probiotics, but treatment did not completely mitigate the effects of AFB1. Genes identified through transcriptome analysis provide candidates for further study of AFB1 toxicity and targets for efforts to improve the health of domestic turkeys exposed to AFB1.published_or_final_versio

Adaptation of clinical guidelines: literature review and proposition for a framework and procedure

Purpose. The development and updating of high-quality clinical practice guidelines require substantial resources. Many guideline programmes throughout the world are using similar strategies to achieve similar goals, resulting in many guidelines on the same topic. One method of using resources more efficiently and avoiding unnecessary duplication of effort would be to adapt existing guidelines. The aim was to review the literature on adaptation of guidelines and to propose a systematic approach for adaptation of guidelines. Data sources. We selected and reviewed reports describing the methods and results of adaptation of guidelines from those found by searching Medline, Internet, and reference lists of relevant papers. On the basis of this review and our experience in guideline development, we proposed a conceptual framework and procedure for adaptation of guidelines. Results. Adaptation of guidelines is performed either as an alternative to de novo guideline development or to improve guideline implementation through local tailoring of an international or national guideline. However, no validated process for the adaptation of guidelines produced in one cultural and organizational setting for use in another (i.e. trans-contextual adaptation) was found in the literature. The proposed procedure is a stepwise approach to trans-contextual adaptation, including searching for existing guidelines, quality appraisal, detailed analysis of the coherence between the evidence and the recommendations, and adaptation of the recommendations to the target context of use, taking into account the organization of the health care system and cultural context. Conclusions. Trans-contextual adaptation of guidelines is increasingly being considered as an alternative to de novo guideline development. The proposed approach should be validated and evaluated to determine if it can reduce duplication of effort and inefficient use of resources, although guaranteeing a high-quality product, compared with de novo developmen

292. Towards Large-Scale Manufacturing of Adeno-Associated Virus by Transient Transfection of HEK293 Suspension Cells in a Stirred Tank Bioreactor Using Serum-Free Medium

Adeno-Associated Virus (AAV) vectors showing safety profile in phase I clinical trials and its ability to transduce gene expression in various tissues have made it a vector of choice for gene delivery. There are different modes of AAV vector production and each has advantages and disadvantages. Here we demonstrated that the production of AAV by transient transfection in a serum-free medium using NRC's patented cGMP compliant human embryonic kidney HEK293 cell line (clone HEK293SF-3F6) adapted for growth in suspension can be readily scaled-up in stirred tank bioreactors. We employed triple-plasmid / polyethylenimine (PEI) based transient transfection technique. As a proof of concept, we demonstrated that nine serotypes of AAV (AAV-1 to AAV-9) encoding GFP can be produced by our cell line HEK293SF with yields of about 1E+13 genome-containing particles per liter (Vg/L). Depending on the serotypes 4-30% of AAV is present in the supernatant of the cell culture at 48hpt. The presence of plasmids and plasmid polyplexes that were not taken up by the cells or were not brought into the cell nucleus were removed by Iodixanol-ultracentrifugation method and Benzonase treatment before analyzing by real-time PCR. About 25% loss in genome containing viral particle counts were observed by Iodixanol purification method based on infectivity assay. Productions of AAV2 and AAV6 encoding GFP were demonstrated in 3L stirred tank bioreactors. Purification scheme was based on column chromatography - a scalable process. Different chromatography media, such as cation exchanger, anion exchanger and hydrophobic interaction chromatography, were tested with each AAV serotypes for their ability to adsorb and elute efficiently. The purification scheme was then adopted by integrating best chromatography medium and sequence dependent upon the AAV serotype in use. We demonstrated the purification scheme for AAV2 based on ion-exchange and hydrophobic interaction chromatography steps. The SDS-PAGE showed the purity of the final product and the presence of three capsid proteins VP1, VP2 and VP3 on Western blot corresponding to the only three bands present in the final product on SDS-PAGE. To extend the storage life of AAV we explored lyophilization technique to study the stability of AAV2 and AAV6 under lyophilized conditions. The AAV2 and AAV6 were stable for over 40 weeks based on infectivity assay. We demonstrated the scalability of the process up to 45L. Productions tested in 20 and 500 mL cultures in shake flasks were scaled up in 2 and 45L cultures (in 3- and 60-L stirred tank bioreactors, respectively). The volumetric yields and purification recoveries were comparable at all of these production scale levels demonstrating scalability of transient transfection at even larger scale is possible to generate material necessary for dosages required for gene therapy application

Study of the wettability of coke by different pitches and their blends

The properties of coal tar pitch, which is used as the binder material for carbon anode production, strongly affect the anode properties. Pitches have significant differences in their chemical compositions depending on their origin. In this study, four different coal tar pitches and their blends were studied with the aim of understanding the wettability of a calcined petroleum coke by pitch using the sessile-drop test. In this test, contact angle, which is an indication of wettability, is measured. Contact angles decrease with increasing time, and smaller contact angle means better wettability. The chemical properties of pitches and coke were studied using XPS to investigate their interactions and, consequently, the wetting mechanism. The results showed that blending different pitches influences the wettability. The presence of acidic, basic, and heteroatom containing functional groups in pitch might cause acid–base/condensation reactions when they are blended and, thus, influence the wetting behavior of the pitch blend