TASK DEFINITION: Given a context passage, generate a question from the passage such that its answer is shortest continous span from the passage.
PROBLEM: Transcription factors of the NFAT (nuclear factor of activated T cells) family are expressed in most immune system cells and in a range of other cell types. Signaling through NFAT is implicated in the regulation of transcription for the immune response and other processes, including differentiation and apoptosis. NFAT normally resides in the cytoplasm, and a key aspect of the NFAT activation pathway is the regulation of its nuclear import by the Ca(2+)/calmodulin-dependent phosphatase calcineurin. In a cell line stably expressing green fluorescent protein (GFP)-NFAT, this import can be triggered by elevation of intracellular calcium and visualized in live cells. Here we show that the inducible nuclear import of GFP-NFAT is efficiently blocked at early stages of herpes simplex virus (HSV) infection. This is a specific effect, since we observed abundant nuclear accumulation of a test viral protein and no impediment to general nuclear localization signal-dependent nuclear import and retention in infected cells. We show that virus binding at the cell surface is not itself sufficient to inhibit the signaling that induces NFAT nuclear translocation. Since the block occurs following infection in the presence of phosphonoacetic acid but not cycloheximide, we infer that the entry of the virion and early gene transcription are required but the effect is independent of DNA replication or late virus gene expression. A consequence of the block to GFP-NFAT import is a reduction in NFAT-dependent transcriptional activation from the interleukin-2 promoter in infected cells. This HSV-mediated repression of the NFAT pathway may constitute an immune evasion strategy or subversion of other NFAT-dependent cellular processes to promote viral replication.

SOLUTION: Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?

PROBLEM: The SWR1 complex (SWR1C) in yeast catalyzes the replacement of nucleosomal H2A with the H2AZ variant, which ensures full activation of underlying genes. We compared the phenotype of mutants in the homologs of SWR1C components in Arabidopsis thaliana. Mutations in Arabidopsis SWC6 (AtSWC6), SUPPRESSOR OF FRIGIDA 3 (SUF3) and PHOTOPERIOD-INDEPENDENT EARLY FLOWERING 1 (PIE1), homologs of SWC6, ARP6 and SWR1, respectively, caused similar developmental defects, including leaf serration, weak apical dominance, flowers with extra petals and early flowering by reduction in expression of FLOWERING LOCUS C (FLC), a strong floral repressor. Chromatin immunoprecipitation assays showed that AtSWC6 and SUF3 bind to the proximal region of the FLC promoter, and protoplast transfection assays showed that AtSWC6 colocalizes with SUF3. Protein interaction analyses suggested the formation of a complex between PIE1, SUF3, AtSWC6 and AtSWC2. In addition, H2AZ, a substrate of SWR1C, interacts with both PIE1 and AtSWC2. Finally, knockdown of the H2AZ genes by RNA interference or artificial microRNA caused a phenotype similar to that of atswc6 or suf3. Our results strongly support the presence of an SWR1C-like complex in Arabidopsis that ensures proper development, including floral repression through full activation of FLC.

SOLUTION: Which protein mediates the replacement of H2A by H2A.Z in the yeast Saccharomyces cerevisiae?

PROBLEM: Increased expression of nerve growth factor in injured or inflamed tissue is associated with increased pain. This proof-of-concept study was designed to investigate the safety and analgesic efficacy of tanezumab, a humanized monoclonal antibody that binds and inhibits nerve growth factor. We randomly assigned 450 patients with osteoarthritis of the knee to receive tanezumab (administered at a dose of 10, 25, 50, 100, or 200 g per kilogram of body weight) or placebo on days 1 and 56. The primary efficacy measures were knee pain while walking and the patient's global assessment of response to therapy. We also assessed pain, stiffness, and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); the rate of response using the criteria of the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI); and safety. When averaged over weeks 1 through 16, the mean reductions from baseline in knee pain while walking ranged from 45 to 62% with various doses of tanezumab, as compared with 22% with placebo (P<0.001). Tanezumab, as compared with placebo, was also associated with significantly greater improvements in the response to therapy as assessed with the use of the patients' global assessment measure (mean increases in score of 29 to 47% with various doses of tanezumab, as compared with 19% with placebo; P0.001). The rate of response according to the OMERACT-OARSI criteria ranged from 74 to 93% with tanezumab treatment, as compared with 44% with placebo (P<0.001). The rates of adverse events were 68% and 55% in the tanezumab and placebo groups, respectively. The most common adverse events among tanezumab-treated patients were headache (9% of the patients), upper respiratory tract infection (7%), and paresthesia (7%). In this proof-of-concept study, treatment with tanezumab was associated with a reduction in joint pain and improvement in function, with mild and moderate adverse events, among patients with moderate-to-severe osteoarthritis of the knee. (Funded by Rinat Neuroscience; ClinicalTrials.gov number, NCT00394563.).

SOLUTION:
What is the target of tanezumab?