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: After ingestion of phosphatidylcholine, l-carnitine or betaine, trimethylamine-N-oxide (TMAO) is formed by gut microbiota and liver enzymes. Elevated TMAO plasma levels were associated with increased cardiovascular risk and other diseases. Also betaine and choline itself were recently associated with increased cardiovascular risk.', 'A newly developed LC-HRMS method was applied to measure the plasma concentrations of TMAO, betaine and choline in a cohort of 339 patients undergoing coronary angiography for the evaluation of suspected coronary artery disease.', "Betaine concentrations in males were significantly higher than in females (42.0 vs. 35.9mol/L; p<0.001). Plasma concentrations of TMAO but not of betaine or choline were higher in patients with diabetes compared to euglycemic patients (2.39 vs. 0.980mol/L; p=0.001) as well as in patients with metabolic syndrome as compared to patients without metabolic syndrome (2.37 vs. 1.43mol/L; p=0.002). Plasma concentrations of TMAO or choline increased significantly with decreasing renal function (Spearman's rho:-0.281; p<0.001). However, plasma levels of TMAO or betaine were associated with neither a history of myocardial infarction nor the angiographically assessed presence of coronary heart disease, nor incident cardiovascular events during 8 years of follow-up. Plasma levels of choline were significantly lower in patients with a history of acute myocardial infarction as compared to those without such history (10.0 vs. 10.8mol/L; p=0.045).
Answer: Plasma levels of TMAO are confounded by impaired kidney function and poor metabolic control but are not associated with the history, presence or incidence of symptoms or events of coronary heart disease.

SOLUTION: Are plasma levels of trimethylamine-N-oxide confounded by impaired kidney function and poor metabolic control?

PROBLEM: Context: Excessive infant crying, or infantile colic, is a common and often stress-inducing problem for parents that can ultimately result in child abuse. From previous research it is known that maternal depression is related to excessive crying, but so far little is known about the influence of paternal depression.', "In a prospective, population-based study, we obtained information on both maternal and paternal depressive symptoms at 20 weeks of pregnancy by using the Brief Symptom Inventory. Parental depressive symptoms were related to excessive crying in 4426 two-month-old infants. The definition of excessive crying was based on the widely used Wessel's criteria (ie, crying >3 hours for >3 days in the past week).", 'After adjustment for depressive symptoms of the mother and relevant confounders, we found a 1.29 (95% confidence interval: 1.09-1.52) higher risk of excessive infant crying per SD of paternal depressive symptoms.
Answer: Our findings indicate that paternal depressive symptoms during pregnancy might be a risk factor for excessive infant crying. This finding could be related to genetic transmission, interaction of a father with lasting depressive symptoms with the infant, or related indirectly through contextual stressors such as marital, familial, or economic distress.

SOLUTION:
Are paternal depressive symptoms during pregnancy related to excessive infant crying?