TASK DEFINITION: Given a context passage, generate a question from the passage such that its answer is shortest continous span from the passage.
PROBLEM: Throughout 1476, supporters of Joanna from the nobility continued to submit to Isabella and Ferdinand, particularly those from the Pacheco-Giron lineage: Juan Tellez-Giron and his brother Rodrigo; Luis de Portocarrero; and, in September, the Marquis of Villena. In November 1476, Isabella's troops captured the castle of Toro. In the following months, they took control of the last bordering localities controlled by the Portuguese and dealt with their adversaries in Extremadura. In July 1477, Isabella arrived in Seville, the most populous city of Castile, with the objective of asserting her power over the nobility of Andalusia. In April 1476, Isabella and Ferdinand gave their first exculpation to the Marquis of Cadiz. He had been regaining power while his rival, the Duke of Medina Sidonia, initially the main Isabella supporter in Andalusia, had been falling into dishonour. Through skilful negotiations, the Queen managed to take control of the main strongholds of Seville occupied by the Marquis and the Duke and, instead of returning them to their legitimate owners, named others as their heads. She prohibited both nobles from entering the city of Seville, under the pretext that their simultaneous presence there would risk violent conflicts. In this way the Duke's political dominance over Seville disappeared, and the city passed into the control of the Crown. One of the few nobles that refused to submit to the monarchs was Marshall Fernan Arias de Saavedra. Isabella's troops laid siege to his fortress at Utrera, and conquered it by assault in March 1478. The defeated suffered harsh repression. The first son of the monarchs, John of Aragon and Castile, was born in Seville on June 30, 1478, which opened new possibilities for dynastic stability of the Isabellian side.

SOLUTION: What event happened first, Isabella arriving in Seville or Isabella and Ferdinand giving their first exculpation to the Marquis of Cadiz?

PROBLEM: Freshwater below Earths surface is called groundwater. The water infiltrates, or seeps down into, the ground from the surface. How does this happen? And where does the water go? Water infiltrates the ground because soil and rock are porous. Between the grains are pores, or tiny holes. Since water can move through this rock it is permeable. Eventually, the water reaches a layer of rock that is not porous and so is impermeable. Water stops moving downward when it reaches this layer of rock. Look at the diagram in Figure 13.11. It shows two layers of porous rock. The top layer is not saturated; it is not full of water. The next layer is saturated. The water in this layer has nowhere else to go. It cannot seep any deeper into the ground because the rock below it is impermeable. The top of the saturated rock layer in Figure 13.11 is called the water table. The water table isnt like a real table. It doesnt remain firmly in one place. Instead, it rises or falls, depending on how much water seeps down from the surface. The water table is higher when there is a lot of rain and lower when the weather is dry. An underground layer of rock that is saturated with groundwater is called an aquifer. A diagram of an aquifer is shown in Figure 13.12. Aquifers are generally found in porous rock, such as sandstone. Water infiltrates the aquifer from the surface. The water that enters the aquifer is called recharge. Most land areas have aquifers beneath them. Many aquifers are used by people for freshwater. The closer to the surface an aquifer is, the easier it is to get the water. However, an aquifer close to the surface is also more likely to become polluted. Pollutants can seep down through porous rock in recharge water. An aquifer that is used by people may not be recharged as quickly as its water is removed. The water table may lower and the aquifer may even run dry. If this happens, the ground above the aquifer may sink. This is likely to damage any homes or other structures built above the aquifer. One of the biggest aquifers in the world is the Ogallala aquifer. As you can see from Figure 13.13, this aquifer lies beneath parts of eight U.S. states. It covers a total area of 451,000 square kilometers (174,000 square miles). In some places, it is less than a meter deep. In other places, it is hundreds of meters deep. The Ogallala aquifer is an important source of freshwater in the American Midwest. This is a major farming area, and much of the water is used to irrigate crops. The water in this aquifer is being used up ten times faster than it is recharged. If this continues, what might happen to the Ogallala aquifer? The top of an aquifer may be high enough in some places to meet the surface of the ground. This often happens on a slope. The water flows out of the ground and creates a spring. A spring may be just a tiny trickle, or it may be a big gush of water. One of the largest springs in the world is Big Spring in Missouri, seen in Figure 13.14. Water flowing out of the ground at a spring may flow downhill and enter a stream. Thats what happens to the water that flows out of Big Spring in Missouri. If the water from a spring cant flow downhill, it may spread out to form a pond or lake instead. Lake George in New York State, which is pictured in Figure 13.15, is a spring-fed lake. The lake basin was carved by a glacier. Some springs have water that contains minerals. Groundwater dissolves minerals out of the rock as it seeps through the pores. The water in some springs is hot because it is heated by hot magma. Many hot springs are also mineral springs. Thats because hot water can dissolve more minerals than cold water. Grand Prismatic Spring, shown in Figure 13.16, is a hot mineral spring. Dissolved minerals give its water a bright blue color. The edge of the spring is

SOLUTION: top of an underground rock layer that is saturated with water

PROBLEM: Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in patients with sLOXL2 concentrations in the 75th percentile or higher. Treatment duration was event-driven, and interim analyses were planned and conducted after approximately 120 and 200 progression-free survival events, respectively, occurred. We compared treatment groups with the stratified log-rank test. This study is registered with ClinicalTrials.gov, number NCT01769196. Patients with IPF were recruited between Jan 31, 2013, and June 1, 2015. The intention-to-treat population included 544 randomly assigned patients (272 patients in both groups), and the safety population included 543 randomly assigned patients who received at least one dose of study medication. The study was terminated when the second interim analysis met the prespecified futility stopping criteria in the intention-to-treat population. We noted no difference in progression-free survival between simtuzumab and placebo in the intention-to-treat population (median progression free survival times of 126 months and 154 months for simtuzumab and placebo, respectively; stratified HR 113, 95% CI 088-145; p=0329) and in patients with baseline sLOXL2 in the 50th percentile or higher (median progression-free survival 117 months and 143 months for simtuzumab and placebo, respectively; stratified HR 103, 95% CI 074-143; p=0851), or in the 75th percentile or higher (median progression-free survival 116 months and 169 months for simtuzumab and placebo, respectively; stratified HR 120, 95% CI 072-200; p=0475). The incidence of adverse events and serious adverse events was similar between treatment groups. The most common adverse events in both the simtuzumab and placebo groups were dyspnoea, cough, upper respiratory tract infection, and worsening of IPF; and the most common grade 3 or 4 adverse events were worsening of IPF, dyspnoea, and pneumonia. Simtuzumab did not improve progression-free survival in a well-defined population of patients with IPF. Our data do not support the use of simtuzumab for patients with IPF. Gilead Sciences Inc.

SOLUTION:
What is the drug target for Simtuzumab?