TASK DEFINITION: Given a context passage, generate a question from the passage such that its answer is shortest continous span from the passage.
PROBLEM: The War of the Spanish Succession was a European conflict of the early 18th century, triggered by the death of the childless Charles II of Spain in November 1700. His closest heirs were members of the Austrian Habsburg and French Bourbon families; acquisition of an undivided Spanish Empire or Monarchy by either threatened the European balance of power. Charles left his throne to Louis XIV's grandson Philip who was proclaimed King of Spain on 16 November 1700. Disputes over the separation of the Spanish and French crowns, division of territories and commercial rights led to war in 1701 between the Bourbons of France and Spain and the Grand Alliance, whose candidate was Archduke Charles, younger son of Habsburg Emperor Leopold. By 1710, fighting was deadlocked; Allied victories in Italy and the Low Countries had driven the French back to their borders but they could not achieve a decisive breakthrough while Philip was secure in Spain. When Archduke Charles succeeded his brother Joseph I as Emperor in 1711, Britain effectively withdrew, forcing its Allies to make peace and leading to the 1713 Treaty of Utrecht, followed in 1714 with Rastatt and Baden. Philip was confirmed as King of Spain and renounced the French throne; Spain retained the bulk of its pre-war territories outside Europe with their European territories divided between Austria, Britain and Savoy. Longer term impacts included Britain's emergence as the leading maritime and commercial power, the beginning of the decline of the Dutch Republic, the creation of a centralised Spanish state and the acceleration of the break-up of the Holy Roman Empire.

SOLUTION: Who was Emperor first, Archduke Charles or his brother Joseph I?

PROBLEM: Rigel Pharmaceuticals Inc is developing fostamatinib, a prodrug of the spleen tyrosine kinase (Syk) inhibitor R-406, for the potential treatment of autoimmune diseases such as rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and B-cell lymphomas. Syk is a key mediator of Fc and B-cell receptor signaling in inflammatory cells, such as B-cells, mast cells, macrophages and neutrophils. Preclinical studies of R-406 or fostamatinib demonstrated a significant reduction in major inflammatory mediators such as TNFalpha, IL-1, IL-6 and IL-18, leading to reduced inflammation and bone degradation in models of RA. In a phase II clinical trial, fostamatinib treatment effectively improved American College of Rheumatology response rates in patients with RA. Preclinical studies and phase II trials also suggested the potential of using fostamatinib for the treatment of ITP and B-cell lymphomas, by increasing platelet counts and inducing response rates, respectively. Fostamatinib is orally bioavailable and was well tolerated in phase I and II trials, with the most common side effect being gastrointestinal symptoms. At the time of publication, phase II trials for fostamatinib were ongoing in patients with RA, ITP and B-cell lymphomas. The Syk inhibitor appears to be a promising therapeutic for immunological diseases, but further data are required to establish the efficacy and long-term safety of the drug in humans.

SOLUTION: Which enzyme is inhibited by a drug fostamatinib?

PROBLEM: Osteoporosis and several other bone disorders occur when there is an imbalance between the resorption and formation components of bone remodeling activity. Therapies available for some of these conditions modulate the activity of osteoclasts and/or osteoblasts. The recent discoveries of receptor activator of NF-kappaB ligand (RANKL), an endogenous activator of osteoclastogenenesis and osteoclast activity and its inhibitor, osteoprotegerin (OPG) as pivotal regulatory factors in the pathogenesis of bone diseases like osteoporosis provide unique targets for therapeutic agents. In laboratory animals and now in humans, administering forms of OPG markedly inhibits osteoclast activity and improves bone strength, documenting that the strategy of inhibiting RANKL activity has therapeutic promise. A highly specific, fully human antibody against RANKL has been produced (denosumab) that in early studies in humans reduces bone turnover and improves bone density. Attributes of denosumab in these clinical studies include a very rapid onset of action, sustained effects for several months after a single injection, and good tolerability. These results provide the basis for studies evaluating the effectiveness of denosumab in several clinical conditions characterized by increased osteoclastic activity.

SOLUTION:
To the ligand of which receptors does Denosumab (Prolia) bind?