Probing the interaction between huntingtin and NMDA receptors

Huntington's Disease (HD) is caused by an expansion (>35) of a polyglutamine (polyQ) tract, in the N-terminus of the protein, huntingtin (htt). Evidence suggests that the selective degeneration of striatal neurons seen in HD is, in part, caused by overactivation of N-methyl-D-aspartate (NMDA) type glutamate receptors (NMDARs). Previously, our lab has shown that co-expression of NMDARs and full-length htt (138Q), in HEK 293 cells, results in a significant increase in glutamate-evoked current amplitude for NR1/NR2B but not NRl/NR2A-type NMDARs. Since channel function and/or receptor distribution of NMDARs may be modulated by interactions with cytoskeletal proteins, we postulate that the polyQ expansion in mutant htt permits the indirect interaction of htt with NMDARs through cytoskeletal proteins, contributing to changes in NMDAR properties and resulting in overactivation of the receptors. We began by characterizing protein expression of htt, htt interacting proteins (i.e. HIP-1), PSD-95 family members and components of the actin cytoskeleton (actin and a-actinin) in HEK 293 cells and striatal, hippocampal and cortical tissue from wildtype and transgenic mice (18Q and 46Q). HEK 293 cells were shown to endogenously express HIP-1, a-actinin and actin. The wildtype and transgenic mice expressed all proteins of interest with relatively high expression of PSD-95 and SAP-102. In addition, NR2A vs. NR2B expression in the mouse striatal, hippocampal and cortical tissues was compared. Densitometric analysis revealed expression levels of NR2B in the striatum, relative to the cortex, is higher as compared to NR2A. The expression of a-actinin was further examined in both HEK cells and mouse tissues using antibodies specific for two isoforms of a-actinin, a-actinin-2 and a-actinin-4. Alpha-actinin-4 was present in HEK 293 cells and striatal, hippocampal and cortical tissue from both wildtype and transgenic mice. In contrast to a-actinin-4, no cc-actinin-2 was detected. Following completion of protein characterization we began to address our hypothesis by investigating a potential interaction between HIP-1 and a-actinin-4 in transfected HEK 293 cells. We have established that there is an interaction between HIP-1 and a-actinin-4. This interaction could prove to be a mechanism by which htt indirectly binds to NMDARs.Medicine, Faculty ofGraduat

Policy Forum: Establishing an Urban Reserve—Property Tax Challenges and Opportunities

Urban reserves offer a unique economic development tool for First Nation governments by providing access to markets and infrastructure unavailable on most reserve lands in Canada. Asimakiniseekan Askiy is Canada's first urban reserve established on land previously owned by a city. The urban reserve was established in Saskatoon by the Muskeg Lake Cree Nation in 1988. Asimakiniseekan Askiy provides an example of the economic potential of urban reserves for First Nations and their members, as well as municipal governments and their citizens. The urban reserve is currently home to 60 First Nation and non-First Nation businesses and their 700 employees. In 2020, the urban reserve contributed $465,662 to the city of Saskatoon in service fee payments. However, before this economic potential could be realized, property taxation presented a sizable barrier in the path of taking Asimakiniseekan Askiy from an innovative idea to a successful reality. Establishing an urban reserve has significant property tax implications, since the process requires the transfer of property from the taxing authority of a municipal jurisdiction to the tax jurisdiction of a First Nation government. Agreements providing for the transfer of tax authority also include negotiations relating to the continued provision of services to the urban reserve by the municipality. This article first provides a summary of the statutory environment surrounding the formation and taxation of an urban reserve. A case study of the establishment and 33 years of operation of Asimakiniseekan Askiy is then provided, to illustrate the property tax implications and municipal service agreement process necessary for Canadian communities to achieve the economic benefits of urban reserves. The authors identify property tax challenges inherent in the establishment of an urban reserve and offer recommendations to improve access to urban reserves as an innovative economic development tool.</jats:p

Inhibition of Transplant Vasculopathy in a Rat Aortic Allograft Model After Infusion of Anti-Inflammatory Viral Serpin

Background —Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. Methods and Results —Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth ( P &lt;0.002) and mononuclear cell invasion ( P &lt;0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage ( P &lt;0.0016) and nonspecific lymphocyte ( P &lt;0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells ( P &lt;0.0006). Conclusions —Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model. </jats:p

Composite polymeric-inorganic waveguide fabricated by injection molding for biosensing applications

Inorganic based optical transducers have demonstrated their suitability for labelled and label-free sensing of biomolecules but suffer from their relatively high cost. Photonic structures fabricated in polymer by molding techniques could drastically reduce the cost per test and pave the way for label-free screening in point-of care environment where the cost per test is an essential concern. In this paper we present the advances in the fabrication of waveguides with cyclo olefin copolymer (COC) cladding and TiO2 core with mass-production compatible injection molding and evaporation. We demonstrate the optical propagation in a slab waveguide supporting both transverse electric and magnetic modes and monitor the response of the phase difference between the two modes when a droplet of water is deposited on the chip

ICT BONE views on the network of the future: the role of optical networking

Part of the activities of the ICT EU Network of Excellence “Building the future Optical Network in Europe” (BONE) project is the development of the European Roadmap on Optical Networking in the context of the “Network of the Future”. This paper presents a summary of the views of the BONE consortium as they were developed in the framework of the Roadmap activity. The methodology followed in the development of the BONE Roadmap was firstly to identify and analyse the status of broadband access penetration as well as the availability of specific network and IT technologies in various European countries. The data collected were then processed and translated into the traffic volume (distributed across different European countries) that a Pan- European network would need to support. This information is then used as the basis of a WDM optical network dimensioning exercise performed with the aim of identifying the scale of the required optical network. In addition, based on estimations regarding the evolution of broadband access technologies and the degree of broadband penetration and network services and applications, extrapolations regarding the growth of traffic to be supported by the European Network of the Future were made in a systematic manner. These were also used to dimension and understand the requirements of the European Network of the Future. This paper presents the relevant results and also provides a discussion on the BONE consortium views on the Network of the Future from an architectural and technology perspective and an outlook of the relevant key research challenges and possible solutions