Given a context passage, generate a question from the passage such that its answer is shortest continous span from the passage.

Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin
Which human disease is associated with mutated UBQLN2

Ian Lafferty (Josh Zuckerman) is an 18-year-old recent high school graduate. He searches for a girl online making it seem as if he is attractive and strong, although he's sweet and unassuming. He soon meets "Ms. Tasty" (Katrina Bowden) and agrees to meet her in person. She lives in Knoxville, Tennessee, while he lives in Chicago, Illinois. With his best friends Lance Nesbitt (Clark Duke) and Felicia Alpine (Amanda Crew), he goes to Knoxville in a 1969 Pontiac GTO Judge borrowed without permission from Ian's arrogant homophobic older brother Rex (James Marsden). On the way to Knoxville, they come across a hitchhiker (David Koechner), as the radiator in the Judge overheats. They attempt urinating in the radiator, which only works briefly as they try to leave the hitchhiker in the dust. The hitchhiker, frustrated at Ian's lack of concern for his well being, leaves, but not before urinating on the car window. As Ian and Felicia wander to find help, Lance is waiting with the car as Ezekiel (Seth Green) happens to pass by in his horse-drawn buggy. Ezekiel and his Amish buddies repair the car while they join a Rumspringa party where Fall Out Boy are playing a concert, and at which Lance meets an attractive Amish girl, Mary (Alice Greczyn). The three promise to come again on the way back to do some work in return for fixing the car. They go to jail due to Ian throwing a tire iron into a state trooper car, due to his increasing frustration after trying to put a possum he hit out of its misery, and are released after Mary pays the bail. Upon arriving at Knoxville, they find a hotel that sports a wide variety of role playing rooms. Rex, who has discovered the Judge gone missing, arrives angrily and insists that they go back and that Ian cannot visit Ms. Tasty. After Ian pretends to be gay, Rex allows him to see Ms. Tasty, hoping this encounter will change Ian's mind. Ian finally meets Ms. Tasty. However, when he tells her about Felicia, her seduction for Ian to take off his clothes becomes a threat as her psychotic boyfriend Bobby Jo (Dave Sheridan) puts a gun to Ian's head. It becomes apparent that they work at a chop shop and attempt to steal the Judge. Lance and Mary arrive after having sex, as well as a redneck named Rick (Michael Cudlitz) whose girlfriend Brandy (Andrea Anders) slept with Lance earlier. Felicia, however, is hiding in the car when Bobby Jo tries to steal it. Soon, a green car that has been continuously drag-racing with the Judge throughout the movie arrives. Ian manages to save Felicia, who then is able to run off and report to the police. Ms. Tasty tries to escape, but is stopped by the green car, whose drivers turn out to be Andy and Randy (Charlie McDermott and Mark L. Young), two dim-witted self-declared "womanizers" from Ian's school, who Ms. Tasty tried to manipulate into giving her the car. Bobby Jo is treated after being shot by Ian in self-defense. Felicia tells the police about the chop shop location and the couple is arrested. Upon finding out that if Mary leaves the Amish community, she will be shunned, Lance refuses to come back home and stays behind to marry Mary, while Ian and Felicia realize their love for each other. Ian and Felicia drive to a tree where Ian throws his shoes up into the tree. A few weeks later Ian is Felicia's date to her cousin's wedding. At Thanksgiving dinner, Rex tells his family that he's gay. On New Year's Eve Ian and Felicia finally have sex, in Ian's basement under a blanket on the sofa. In the final frame of the film, a picture is shown of Lance and Mary getting married, accompanied by Ian. Lance is shown sporting a beard exactly like Ezekiel's. During the credits, a short scene is shown of Ezekiel and Fall Out Boy arguing over the fact that the
Who does Ian shoot?

Activating point mutations in the K-Ras oncogene are among the most common genetic alterations in pancreatic cancer, occurring early in the progression of the disease. However, the function of mutant K-Ras activity in tumor angiogenesis remains poorly understood. Using human pancreatic duct epithelial (HPDE) and K-Ras4B(G12V)-transformed HPDE (HPDE-KRas) cells, we show that activated K-Ras significantly enhanced the production of angiogenic factors including CXC chemokines and vascular endothelial growth factor (VEGF). Western blot analysis revealed that K-Ras activation promoted the phosphorylation of Raf/mitogen-activated protein kinase kinase-1/2 (MEK1/2) and expression of c-Jun. MEK1/2 inhibitors, U0126 and PD98059, significantly inhibited the secretion of both CXC chemokines and VEGF, whereas the c-Jun NH(2)-terminal kinase inhibitor SP600125 abrogated only CXC chemokine production. To further elucidate the biological functions of oncogenic K-Ras in promoting angiogenesis, we did in vitro invasion and tube formation assays using human umbilical vein endothelial cells (HUVEC). HUVEC cocultured with HPDE-KRas showed significantly enhanced invasiveness and tube formation as compared with either control (without coculture) or coculture with HPDE. Moreover, SB225002 (a CXCR2 inhibitor) and 2C3 (an anti-VEGF monoclonal antibody) either alone or in a cooperative manner significantly reduced the degree of both Ras-dependent HUVEC invasiveness and tube formation. Similar results were obtained using another pair of immortalized human pancreatic duct-derived cells, E6/E7/st and its oncogenic K-Ras variant, E6/E7/Ras/st. Taken together, our results suggest that angiogenesis is initiated by paracrine epithelial secretion of CXC chemokines and VEGF downstream of activated oncogenic K-Ras, and that this vascular maturation is in part dependent on MEK1/2 and c-Jun signaling.

Which is the molecular mechanism underlying K-ras alterations in carcinomas?

