An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist, an inverse agonist causes an action opposite to that of the agonist. From the Greek αγωνιστής, contestant. A physiological agonist is a substance that creates the same bodily responses but does not bind to the same receptor. An endogenous agonist for a particular receptor is a compound produced by the body that binds to and activates that receptor. For example, the endogenous agonist for serotonin receptors is serotonin, the endogenous agonist for dopamine receptors is dopamine. Full agonists bind to and activate a receptor with the maximum response that an agonist can elicit at the receptor. One example of a drug that can act as a full agonist is isoproterenol, which mimics the action of adrenaline at β adrenoreceptors. Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the central nervous system.
However, a drug can act as a full agonist in some tissues and as a partial agonist in other tissues, depending upon the relative numbers of receptors and differences in receptor coupling. A co-agonist works with other co-agonists to produce the desired effect together. NMDA receptor activation requires the binding of both glycine and D-serine co-agonists. Calcium can act as a co-agonist at the IP3 receptor. A selective agonist is selective for a specific type of receptor. E.g. buspirone is a selective agonist for serotonin 5-HT1A. Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist at maximal receptor occupancy. Agents like buprenorphine are used to treat opiate dependence for this reason, as they produce milder effects on the opioid receptor with lower dependence and abuse potential. An inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor and inhibits the constitutive activity of the receptor.
Inverse agonists exert the opposite pharmacological effect of a receptor agonist, not an absence of the agonist effect as seen with an antagonist. An example is the cannabinoid inverse agonist rimonabant. A superagonist is a term used by some to identify a compound, capable of producing a greater response than the endogenous agonist for the target receptor, it might be argued that the endogenous agonist is a partial agonist in that tissue. An irreversible agonist is a type of agonist that binds permanently to a receptor through the formation of covalent bonds. A few of these have been described. New findings that broaden the conventional definition of pharmacology demonstrate that ligands can concurrently behave as agonist and antagonists at the same receptor, depending on effector pathways or tissue type. Terms that describe this phenomenon are "functional selectivity", "protean agonism", or selective receptor modulators. Potency is the amount of agonist needed to elicit a desired response; the potency of an agonist is inversely related to its EC50 value.
The EC50 can be measured for a given agonist by determining the concentration of agonist needed to elicit half of the maximum biological response of the agonist. The EC50 value is useful for comparing the potency of drugs with similar efficacies producing physiologically similar effects; the smaller the EC50 value, the greater the potency of the agonist, the lower the concentration of drug, required to elicit the maximum biological response. When a drug is used therapeutically, it is important to understand the margin of safety that exists between the dose needed for the desired effect and the dose that produces unwanted and dangerous side-effects; this relationship, termed the therapeutic index, is defined as the ratio TD50:ED50. In general, the narrower this margin, the more it is that the drug will produce unwanted effects; the therapeutic index emphasizes the importance of the margin of safety, as distinct from the potency, in determining the usefulness of a drug. Allosteric modulator Dose response curve Excitatory postsynaptic potential Functional selectivity Intrinsic activity Inverse agonist Mixed agonist/antagonist Receptor antagonist Receptor theory
Courts of Marine Inquiry and Boards of Marine Inquiry are tribunals established in common law countries to investigate matters relating to shipwrecks, casualties affecting ships, or charges of incompetency or misconduct on the part of the masters, mates or engineers of ships. Various tribunals are established in Australia to investigate the causes of shipwrecks and other matters pertaining to ships in Australian waters; as Australia is a federal jurisdiction, both the States of Australia and the National government have joint authority to make laws over navigation. Where navigation relates to overseas or interstate trade, the national government's law will take precedence in certain circumstances. At the national level, the Australian Government has established the Court of Marine Inquiry of Australia under the federal Navigation Act. At the state level, the following agencies have responsibility for the investigation of maritime incidents: In New South Wales a District Court may be authorised to sit as a Court of Marine Inquiry to hear and determine inquiries and references under the New South Wales Navigation Act 1901.
Decisions of such a Court are not subject to review courts of appeal. The NSW Maritime Authority has responsibility for marine incident investigation; the Authority investigates the causes of incidents involving shipping and commercial vessels and breaches of State or Commonwealth navigation laws. Incidents involving Sydney Ferries vessels are examined by the Office of Transport Safety Investigations, responsible for investigations into incidents involving publicly owned rail and bus transport; the Western Australian Government has established the Magistrates Court of Western Australia as a court of marine inquiry. The Victorian Government has established the Marine Board of Victoria to perform the functions of a court of marine inquiry. In Fiji, marine boards are established under the Marine Act to conduct enquiries. For a recent inquiry held in Fiji, see Marine Enquiry re the Sinking of the MV OVALAU II at http://www.paclii.org/fj/cases/FJHC/2005/369.html Magistrates Courts of Tonga are courts of marine inquiry under the Tongan Shipping Act.
New South Wales State Archives - https://web.archive.org/web/20061231155107/http://www.records.nsw.gov.au/cguide/c3/ctmar.htm Re Grounding of MV "TNT ALLTRANS" - 67 ALR 107 Public Records Office, Victoria - https://web.archive.org/web/20070908164006/http://www.access.prov.vic.gov.au/public/component/daPublicBaseContainer?component=daViewAgency&entityId=1424 Western Australian Government - http://www.parliament.wa.gov.au/hansard/hans35.nsf//19992511993876?opendocument
J&P Cycles, Inc. was founded by John and Jill Parham in 1979. It sells motorcycle components and gear for the American V-twin motorcycle rider. Owned by Motorcycle Aftermarket Group, the company has retail outlets in Ormond Beach, Anamosa and Sturgis, South Dakota. In 1975, John Parham began selling motorcycle parts and accessories via a small partnership in a motorcycle shop. In 1979, John and his wife Jill Parham founded "J. Parham Enterprises, Inc." The small motorcycle shop burned to the ground in 1984. Parham helped to create the National Motorcycle Museum in Anamosa, Iowa, he was the museum president and J&P Cycles is a donor. The company sells motorcycle parts and accessories such as tires, engine components, seats, as well as riding gear such as helmets and clothing via their website and in a retail environment. In October 2015, John Parham was inducted into the AMA Motorcycle Hall of Fame. In February 2012, Parham received the "Don J. Brown Lifetime Achievement Award", at the "Dealernews Top 100 Dealer Awards" in Indianapolis, Indiana.
Parham was recognized for his dedication to the motorcycle industry and through helping to set up the National Motorcycle Museum in Anamosa, Iowa. The award is presented to an individual recognized in the retailing community for furthering the sport, the business, the industry in general, over the course of his or her career, it is named in honor of Don J. Brown, a founding editor of Dealernews with a career that spanned over 50 years. Parham died in 2017; the National Motorcycle Museum, a non-profit entity, is located at 102 Chamber Drive, Iowa. The museum was founded in 1989 by motorcycle builders and riders, it aims to preserve the experience of biking in the past and demonstrate the present biking sport and lifestyle. The museum displays vintage bikes, it was named "Iowa Tourism Attraction" of the Year in 2001. J&P Express is the speed sports arm of J&P Cycles based at the National Motorcycle Museum in Iowa. In 2006 J&P Cycles established S/PG-1350 records of Kilo 180.4965, Mle 178.9485 with their modified 79 cubic inch Harley Sportster engine.
The museum will loan the streamliner motorcycle, which made land speed records at Bonneville, to other motorcycle historical sites and museums. J&P Cycles holds the land speed record in the S/PG-1350 CC class "Don J. Brown lifetime achievement award" Ranked #324 for online sales among all Internet retailers by Internet Retailer with $30 million and 11.1 percent growth in 2010 RightNow Technologies "Social Superstar Award" SilverPop "Social pop star award for best use of social media in email" Gartner, "1 to 1 Media silver awarded winner for social engagement" "Stella Service excellent award" J&P Cycles is a donor for the National Motorcycle Museum. In 2011, J&P Cycles sponsored two riders, Joe Kopp and Michael Beckin, in the "Vance and Hines XR1200 class" of the AMA Pro Racing Championship series. J&P Cycles has sponsored Camp Courageous and fundraised for AmVets in Anamosa. J&P Cycles was featured January 6, 2012 in two one-hour episodes of ABC's Extreme Makeover: Home Edition, J&P helped restore two vintage Kawasaki motorcycles for a disadvantaged Iowa family.
J&P Cycles appeared on "Two Wheel Tuesday" on the Speed Channel on a regular basis. J&P participated in a segment called "Corbin’s Ride On." J&P appeared in 10 episodes of the Speed Channel's American Thunder in 2006. J&P Cycles is referenced in several books on Harley-Davidson motorcycles, custom motorcycle building, choppers: The Complete Idiot's Guide to Motorcycles Eddie Paul's Extreme Chopper Building Biker's Handbook: Becoming Part of the Motorcycle Culture Choppers Field Guide Fundamentals of Marketing Ed Youngblood, an author of several books on the motorcycle industry and a member of the Motorcycle Hall of Fame, wrote Keeping the World on 2 Wheels. How J&P Cycles Changed the American Motorcycle Industry in 2008. Official website Company History Bikernet video interview: https://www.youtube.com/watch?v=B9wkM0elaFk