Protein-protein interactions in GnRH receptor signalling

Many signal transduction pathways in eukaryotic cells are controlled by the reversible assembly of proteins into signalling complexes that integrate and transmit signals from cell surface receptors to the cytoplasm and nucleus. Protein phosphorylation on serine, threonine and tyrosine residues plays a key role in these events by creating binding sites for modular protein-interaction domains to allow proteins to associate with one another, and regulating the activity of many enzymes and transcription factors.The extracellular signal regulated kinase (ERK) cascade is one of the most intensively studied signalling pathways in mammalian cells. ERK 1 and 2 have been shown to regulate gene expression programmes in response to extracellular signals, including gonadotrophin releasing hormone (GnRH), which binds to a G-protein coupled receptor (GPCR). However, many questions remain to be answered regarding the proximal events that lead to the activation of the ERK cascade by GnRH.A HEK 293 cell line, stably expressing the rat GnRH receptor, was used to investigate the mechanism of ERK activation by GnRH. ERK activation was found to be dependent on cell adhesion to the extracellular matrix, and required an intact actin cytoskeleton. Through the use of specific pharmacological inhibitors and by expression of dominant negative cDNA constructs, ERK activation was found to be mediated by the Rho family GTPase Racl, and the non-receptor tyrosine kinases focal adhesion kinase (FAK) and Src. FAK was found to function as a tyrosine phosphorylated scaffold upon which key components of the ERK cascade assembled.Having established a role for Src in the activation of ERK, a proteomics study was undertaken to identify novel Src binding proteins that may be involved in the regulation of GnRH receptor signalling. Through a combination of immune precipitation, twodimensional gel electrophoresis and matrix assisted laser desorption ionisation-time of flight (MALDI-ToF) mass spectrometry, Src was found to associate with the lipid kinase diacylglycerol kinase ζ, (DGKζ. This interaction was found to be required for GnRH to stimulate DGKζ enzyme activity. By phosphorylating the second messenger molecule diacylglycerol to produce phosphatidic acid, DGKζ may play an important role in regulating GnRH receptor signalling.In this thesis, a potential mechanism of ERK activation is described for the GnRH receptor, with Src playing a key role in this pathway. In addition, Src was found to be involved in the activation of DGKζ, and is therefore implicated in the regulation of diacylglycerol signalling. This is the first report of an interaction between Src and DGKζ

The effects of surgical operations on the physiology of respiration: a review of present knowledge

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ENGAGEMENT AND PHILOSOPHY

This article explores these two keywords through the approach of placing “school” on a continuum between the two extremes of a transactional, instrumental organisation and a transformational community. The variety of stakeholder groups are redefined to include personification of abstract concepts and the model of community is considered including these stakeholders. School is looked at here as a verb rather than a noun and the extent to which school must by definition be, or have the form of, an organisation, is seen as a manifestation of the will of the community, with the levers of transaction pulled by the Head on behalf of the community. The 1994 UNESCO international conference on education provides a framework for discussion about culture and the purpose of education, which is reconciled with the evolving model described and envisioned in this short paper

North American Blastomycosis in Rhodesia

A CAJM article on the prevalence of American blastomycosis in Zimbabwe (formerly Rhodesia.)The clinical and pathological features of North American Blastomycosis in the United States of America have been well documented by Abernathy (1959) and by Witorsch & Utz (1968) who showed that blastomycosis is a chronic mycosis generally believed to begin in the lungs and which then spreads to other organs giving rise to secondary lesions, especially in the skin and bones

Testing a Reconfiguration of FAST at the Blaine POE

In prior articles we have described problems with efficacy of the Free and Secure Trade (FAST) trusted-shipper program at the Blaine, Washington, port-of-entry (POE). At Blaine, state and provincial transportation agencies invested in the construction of highway lanes dedicated to FAST trucks, but there has been relatively light usage of those lanes. In a 2009 field study we found that 23 percent of southbound trucks and just 2 percent of northbound trucks used the FAST lanes. Of the southbound FAST traffic, 73 percent of the trucks were empty. Southbound, the FAST lane seems primarily to be a rapid path by which a FAST carrier and driver can travel empty across the border—i.e., rather than expediting the cross-border flow of goods, FAST expedites empty backhauls and therefore serves as an incentive to inefficient freight transport, from an environmental point of view. Meanwhile, long delays are a frequent occurrence in the standard truck lanes

Pilot Project: Using RFID to Reduce Border Queues

Since 9/11, about $500 million has been spent on border infrastructure in the Cascade Gateway region, including new port facilities, improvements to approaching highways, and deployments of technologies such as wait-time systems. Yet there frequently are queues in excess of 60 minutes for the many travelers who are not enrolled in NEXUS (a program that provides trusted travelers with access to a dedicated highway lane). While regional stakeholders know that queues would be far worse in the absence of past investments, efforts are continually underway to improve border mobility. Greater usage of RFID-enabled documents is a proven method of bolstering mobility, because such documents can improve throughput at each inspection booth

Principal Bimodules of Nest Algebras

AbstractWe classify thewot-closed bimodules over a pair of nest algebras which are singly generated as algebraic and as norm-closed bimodules. The obstructions relate to the finite rank atoms. In particular, if both nest algebras have infinite multiplicity, then every wot-closed bimodule is (algebraically) principal. Another important special case is the ideal of strictly upper triangular operators, which is always principal; and the generator is a sum of commutators. In general, every countably generated wot-closed bimodule is singly generated, and we obtain explicit bounds on the number and norms of the terms in a factorization through the generator

Cross-Border Freight Flows at the Two Land Borders

This article provides an overview of the flow of goods between the U.S. and its two NAFTA neighbors, Canada and Mexico. It is the job of border agencies to facilitate these flows, and this article seeks to explain some aspects of the scope of the job. There is much regional variation in the volume and composition of freight flows, and this variety inevitably has implications for border management policies

Additional Powers of Search and Seizure at and near the Border

In normal practice, the Fourth Amendment of the U.S. Constitution requires individualized suspicion together with procurement of a warrant prior to a government search and/or seizure. Federal courts have recognized some exceptions, however, with the most common one pertaining at the nation’s borders, where most stops and searches are exempt from the usual requirements. That exception is justified by the understanding that a sovereign nation has the power to control who and what comes within its borders. This article describes practices related to searches and seizures at and near the border. A lengthy discussion of U.S. practices is followed by a brief discussion of Canadian practices