The Golden Bull of 1356 was a decree issued by the Imperial Diet at Nuremberg and Metz headed by the Emperor Charles IV which fixed, for a period of more than four hundred years, important aspects of the constitutional structure of the Holy Roman Empire. It was named the Golden Bull for the golden seal. In June 2013 the Golden Bull was included in the UNESCO's Memory of the World Register. According to the written text of the Golden Bull of 1356: We have promulgated and recommended for ratification the subjoined laws for the purpose of cherishing unity among the Electors, of bringing about a unanimous election, of closing all approach to the aforesaid detestable discord and to the various dangers which arise from it. Though the election of the King of the Romans by the chief ecclesiastical and secular princes of the Holy Roman Empire was well established, disagreements about the process and papal involvement had resulted in controversies, most in 1314 when Louis of Bavaria and Frederick of Austria had been elected by opposing sets of electors.
Louis, who had subdued his rival's claim on the battlefield, made a first attempt to clarify the process in the Declaration of Rhense of 1338, which renounced any papal involvement and had restricted the right to choose a new king to the prince-electors. The Golden Bull, promulgated by Louis's successor and rival, Charles IV, was more precise in several ways. Firstly, the Bull explicitly named the seven Prince-electors who were to choose the King and defined the Reichserzämter, their offices at court: Secondly, the principle of majority voting was explicitly stated for the first time in the Empire; the Bull prescribed. Thirdly, the Electoral principalities were declared indivisible, succession to them was regulated to ensure that the votes would never be divided; the Bull cemented a number of privileges for the Electors, confirming their elevated role in the Empire. It is therefore a milestone in the establishment of independent states in the Empire, a process to be concluded only centuries notably with the Peace of Westphalia of 1648.
This codification of prince-electors, though based on precedence, was not uncontroversial in regard to the two chief rivals of the ruling House of Luxembourg: The House of Wittelsbach ruled the Duchy of Bavaria as well as the County Palatinate. Dynastic divisions had caused the two territories to devolve upon distinct branches of the house; the Treaty of Pavia, which in 1329 restored the Palatinate branch, stipulated that Bavaria and the Palatinate would alternate in future elections but the Golden Bull fixed the electoral vote upon the Palatinate and not upon Bavaria because Charles's predecessor and rival, Louis IV was of that branch. Louis IV's sons, Louis V and Stephen II of Bavaria, protested this omission, feeling that Bavaria, one of the original duchies of the realm and their family's chief territory for over 170 years, deserved primacy over the Palatinate; the omission of Bavaria from the list of prince-electors allowed Bavaria, which had only been reunited, to fall into dynastic fragmentation again.
Brandenburg was in the hands of the Bavarian Wittelsbachs in 1356, they lost the territory to the Luxemburgs in 1373, leaving the Bavarian branch without representation on the Electoral college until 1623. The House of Habsburg, long-time rivals of the Luxembourgs, were omitted from the list of prince-electors, leading to decreased political influence and dynastic fragmentation. In retaliation, Duke Rudolf IV, one of the dukes of fragmented Austria, had the Privilegium Maius forged, a document issued by Emperor Frederick Barbarossa; the document gave Austria – elevated to the position of an Archduchy – special privileges, including primogeniture. While ignored by the Emperor and other princes at the time, the document was ratified when Frederick of Austria himself became Emperor in the 15th century. Still, the Habsburgs remained without an electoral vote until they succeeded to the Kingdom of Bohemia in 1526; the bull regulated the whole election process in great detail, listing explicitly where and under which circumstances what should be done by whom, not only for the prince-electors but for the population of Frankfurt, where the elections were to be held, for the counts of the regions the prince-electors had to travel through to get there.
The decision to hold the elections in Frankfurt reflected a traditional feeling dating from East Frankish days that both election and coronation ought to take place on Frankish soil. However, the election location was not the only specified location; the elections were to be concluded within thirty days. But if they shall fail to do this within thirty days, counting continuously from the day when they took the aforesaid oath: when those thirty days are over
Susan R. McCouch is an American geneticist specializing in the genetics of rice, she is the Barbara McClintock Professor of Plant Breeding and Genetics at Cornell University, since 2018 a member of the National Academy of Sciences. In 2012, she was awarded the Chancellor's Award for Excellence in Scholarship and Creative Activities. McCouch completed her Bachelor of Arts in Hispanic Studies from Smiths College in 1975, she went on to receive her Masters of Science in Plant Pathology from the University of Massachusetts in 1982. McCouch completed her doctorate at Cornell under the supervision of Steven D. Tanksley. After receiving her PhD, McCouch worked with the International Rice Research Institute in the Philippines until 1995, she joined the Cornell faculty in the departments of Plant Breeding and Genetics, Plant biology, Biological Statistics, Computational Biology. Her research has included identifying the genetic mechanisms used by rice to survive long-term flooding, the development of a new cultivar of red rice.
Chancellor's Award for Excellence in Scholarship and Creative Activities Susan McCouch publications indexed by Google Scholar
Levodopa-induced dyskinesia is a form of dyskinesia associated with levodopa, used to treat Parkinson's disease. It involves hyperkinetic movements, including chorea and athetosis. In the context of Parkinson's disease, dyskinesia is the result of long-term dopamine therapy; these motor fluctuations occur in up to 80% of PD patients after 5–10 years of l-DOPA treatment, with the percentage of affected patients increasing over time. Based on the relationship with levodopa dosing, dyskinesia most occurs at the time of peak l-DOPA plasma concentrations and is thus referred to as peak-dose dyskinesia; as patients advance, they may present with symptoms of diphasic dyskinesia, which occurs when the drug concentration rises or falls. If dyskinesia becomes too severe or impairs the patient's quality of life, a reduction in l-Dopa might be necessary, however this may be accompanied by a worsening of motor performance. Therefore, once established, LID is difficult to treat. Amongst pharmacological treatments, N-methyl-D-aspartate antagonist, has been proven to be clinically effective in a small number of placebo controlled randomized controlled trials, while many others have only shown promise in animal models.
Attempts to moderate dyskinesia by the use of other treatments such as bromocriptine, a dopamine agonist, appears to be ineffective. In order to avoid dyskinesia, patients with the young-onset form of the disease or young-onset Parkinson's disease are hesitant to commence l-DOPA therapy until necessary for fear of suffering severe dyskinesia on. Alternatives include the use of DA agonists in lieu of early l-DOPA treatment which delays the use of l-DOPA. Additionally, a review shows that soluble l-DOPA prodrugs may be effective in avoiding the in vivo blood concentration swings that lead to motor fluctuations and dyskinesia. Levodopa-induced dyskinesia has long been thought to arise through pathological alterations in pre-synaptic and post-synaptic signal transduction in the nigrostriatal pathway, it is thought that the stage of illness, dosage of l-DOPA, frequency of l-DOPA treatment and the youth of the patient at the onset of symptoms. In experiments employing real-time electrophysiological recordings in awake and active animals, LIDs have been shown to be associated with cortical gamma-oscillations with accompanying Δc-fos overexpression, proposedly due to a dysregulation of dopamine signaling in the cortico-basal ganglia circuitry.
This was concluded from reduced tyrosine hydroxylase staining in the cortex - and the fact that a dopamine receptor 1 antagonist, delivered to the cortex, relieved the dyskinesia at its peak-time.ΔFosB overexpression in the dorsal striatum via viral vectors generates levodopa-induced dyskinesia in animal models of Parkinson's disease. Dorsal striatal ΔFosB is overexpressed in primates with dyskinesias. Levetiracetam, an antiepileptic drug, demonstrated to reduce the severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa. Although the signal transduction mechanism involved in this effect is unknown. Nicotine has been shown to improve Levodopa-induced dyskinesia and other PD symptoms. Patients with prominent dyskinesia resulting from high doses of antiparkinsonian medications may benefit from deep brain stimulation, which may benefit the patient in two ways: 1) DBS theoretically allows a reduction in l-DOPA dosage of 50–60%.
Mavoglurant is currently studied by Novartis for the treatment of this disease. On August 24, 2017 the FDA approved a drug to treat levodopa-induced dyskinesia for Parkinson's patients; the drug, Gocovri, is made by Adamas Pharmaceuticals. It is the first FDA approved treatment for this condition