TASK DEFINITION: Given a passage with a context and an answer, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
PROBLEM: Context: BAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS). Here, we investigated the effects of BAF312 on isolated astrocyte and microglia cultures as well as in slice culture models of demyelination.', 'Mouse and human astrocytes were treated with S1PR modulators and changes in the levels of pERK, pAkt, and calcium signalling as well as S1PR1 internalization and cytokine levels was investigated using Western blotting, immunochemistry, ELISA and confocal microscopy. Organotypic slice cultures were prepared from the cerebellum of 10-day-old mice and treated with lysophosphatidylcholine (LPC), psychosine and/or S1PR modulators, and changes in myelination states were measured by fluorescence of myelin basic protein and neurofilament H.', 'BAF312 treatment of human and mouse astrocytes activated pERK, pAKT and Ca(2+) signalling as well as inducing S1PR1 internalization. Notably, activation of S1PR1 increased pERK and pAKT in mouse astrocytes while both S1PR1 and S1PR3 equally increased pERK and pAKT in human astrocytes, suggesting that the coupling of S1PR1 and S1PR3 to pERK and pAKT differ in mouse and human astrocytes. We also observed that BAF312 moderately attenuated lipopolysaccharide (LPS)- or TNF/IL17-induced levels of IL6 in both astrocyte and microglia cell cultures. In organotypic slice cultures, BAF312 reduced LPC-induced levels of IL6 and attenuated LPC-mediated demyelination. We have shown previously that the toxic lipid metabolite psychosine induces demyelination in organotypic slice cultures, without altering the levels of cytokines, such as IL6. Importantly, psychosine-induced demyelination was also attenuated by BAF312.
Answer: Overall, this study suggests that BAF312 can modulate glial cell function and attenuate demyelination, highlighting this drug as a further potential therapy in demyelinating disorders, beyond MS.

SOLUTION: Does the dual S1PR1/S1PR5 drug BAF312 ( Siponimod ) attenuate demyelination in organotypic slice cultures?

PROBLEM: Context: Surfactant protein (SP) D shares target cells with the proinflammatory cytokine TNF-alpha, an important autocrine stimulator of dendritic cells and macrophages in the airways.', 'We sought to study the mechanisms by which TNF-alpha and SP-D can affect cellular components of the pulmonary innate immune system.', 'Cytokine and SP-D protein and mRNA expression was assessed by means of ELISA, Western blotting, and real-time PCR, respectively, by using in vivo models of allergic airway sensitization. Macrophage and dendritic cell phenotypes were analyzed by means of FACS analysis. Maturation of bone marrow-derived dendritic cells was investigated in vitro.', 'TNF-alpha, elicited either by allergen exposure or pulmonary overexpression, induced SP-D, IL-13, and mononuclear cell influx in the lung. Recombinant IL-13 by itself was also capable of enhancing SP-D in vivo and in vitro, and the SP-D response to allergen challenge was impaired in IL-13-deficient mice. Allergen-induced increase of SP-D in the airways coincided with resolution of TNF-alpha release and cell influx. SP-D-deficient mice had constitutively high numbers of alveolar mononuclear cells expressing TNF-alpha, MHC class II, CD86, and CD11b, characteristics of proinflammatory, myeloid dendritic cells. Recombinant SP-D significantly suppressed all of these molecules in bone marrow-derived dendritic cell cultures.
Answer: TNF-alpha can contribute to enhanced SP-D production in the lung indirectly through inducing IL-13. SP-D, on the other hand, can antagonize the proinflammatory effects of TNF-alpha on macrophages and dendritic cells, at least partly, by inhibiting production of this cytokine.

SOLUTION: Does surfactant protein D inhibit TNF-alpha production by macrophages and dendritic cells in mice?

PROBLEM: Context: We quantitatively evaluated the collagen-to-smooth muscle tissue matrix ratio in ureteropelvic junction obstruction, and compared the ratio with the degree of obstruction, patient age and postoperative renal recovery.', "We analyzed histological sections from 65 patients with ureteropelvic junction obstruction and 6 normal controls. Morphological and functional grading systems were adapted to determine the degree of renal obstruction. To examine smooth muscle and collagen tissue, sections were stained using Masson's trichrome. Two distinct populations of collagen versus smooth muscle were identified and the tissue matrix ratio was calculated by color image analysis.", 'The mean tissue matrix ratio plus or minus standard deviation was 1.32+/-0.79 in all patients with ureteropelvic junction obstruction but only 0.30+/-0.10 in normal controls (p <0.0001). It appeared that the lower the tissue matrix ratio, the better the improvement in postoperative hydronephrosis (r = -0.50, p = 0.0001). Better recovery of renal function after pyeloplasty was observed with a decrease in the tissue matrix ratio (r = -0.43, p = 0.0004). We divided patients according to the tissue matrix ratio into groups 1--ratio 1 or less, 2--greater than 1 to 1.5 and 3--greater than 1.5 to determine a more detailed and clinically applicable correlation of tissue matrix ratio with postoperative renal functional changes. Better improvement in postoperative renal function was observed in group 1 than in group 3 (p = 0.002). Also, the tissue matrix ratio increased with patient age (r = 0.33, p = 0.007).
Answer: Since our data represent an objective and quantitative parameter associated with ureteropelvic junction obstruction, we believe that our findings may help to predict the prognosis after pyeloplasty.

SOLUTION:
Does collagen-to-smooth muscle ratio help prediction of prognosis after pyeloplasty?