Carbohydrate metabolism.

<p>(A) Heatmap depicting the log basis 2 fold changes in metabolite (rows) concentration determined in liver tissues between matched pairs (columns) of homozygous (G/G, <i>Bcs1l</i>^G/G) and littermate control (A/A, <i>Bcs1l</i>^A/A) mice. Columns (i.e. matched pairs) are reordered by hierarchical clustering (HCA, Ward aggregation method) using the age group (14, 24 and more than 30 days, >30) to label the tree leaves. Metabolites are grouped according to chemical classification. (B) Explicit fold changes with their corresponding 95% confidence intervals for all the carbohydrate intermediates measured in the three age groups. Significance levels: +, q<0.2; **, q<0.01 and ***, q<0.001. DHAP+3-PGA: mixture of dihydroxyacetonephosphate and 3-phosphoglyceraldehyde. (C) Periodic acid-Schiff staining of liver sections showing progressive glycogen depletion from 24 to 34 days old homozygotes.</p

Amino acids and biogenic amines.

<p>(A) Log₂ fold changes of amino acids and biogenic amines found significant at false discovery rate <0.1 in the three age groups (14, 24 and >30 days) between matched pairs of homozygous and control mice. Sick homozygotes (indicated as >30 days) have significantly elevated levels of the two metabolite groups, especially the cell signalling amine putrescine.</p

Hypothetic diagram of metabolic changes in hepatocytes in relation to disease progression in <i>Bcs1l</i>^G/G mice.

<p>(A) With decreasing incorporation of Rieske iron sulphur protein (RISP) in complex CIII (CIII), the activity decreases and symptoms appear; at less than 50% incorporation growth failure starts. (B) Metabolomic changes in association with decreased CIII activity and respiratory chain dysfunction are depicted in red. Initial metabolic changes are elevated levels of succinate, aspartate and glutamate. Glycogen depletion leads to lack of glucose and lactate and induces beta-oxidation and protein breakdown resulting in accumulation of fatty acids and acylcarnitines as well as of the biogenic amines putrescine and spermidine. PDH. Pyruvate dehydrogenase complex, CPT1/2: Carnitine palmitoyl transferases 1 and 2. GAP, glyceraldehyde- 3 phosphate, DHAP, Dihydroxy acetone phosphate.</p

Acylcarnitines and lipid accumulation.

<p>(A) Log₂ fold changes of the acylcarnitines found significant at a false discovery rate <0.1 in the three age groups (14, 24 and >30 days) between matched pairs of homozygous (G/G, <i>Bcs1l</i>^G/G) and control (A/A, <i>Bcs1l</i>^A/A) mice. Metabolites are presented in the increasing order of their molecular weight. Significance levels are defined as: +, q<0.2; *, q<0.05; **, q<0.01 and ***, q<0.001. (B) Oil-Red-O staining showing microvesicular lipid accumulation in hepatocytes of sick animal (34d), only.</p

Respirometry and H₂O₂ production in mitochondria with RISP depleted CIII (A-C), and signs of oxidative stress in liver tissue (D, E).

<p>(A) Blue Native PAGE and Western blot showing decreased Rieske iron sulphur protein (RISP) incorporation in CIII in mitochondria from two representative <i>Bcs1l</i>^G/G (G/G₁, G/G₂) mice compared to wild type (A/A₁, A/A₂) aged >30 d. (B) Respiratory chain oxygen consumption under convergent substrate input in CI and CII is impaired in G/G₁. (C) Similar H₂O₂ production was detected with Amplex Red in isolated mitochondria of G/G₁ and A/A₁ mice. (D) In liver tissue homogenates of three age group animals, metabolomic analyses showed that log₂ fold changes of the oxidative stress markers were significantly increased in sick animals only (>30 days). (E) Antioxidant defence in liver tissue measured with quantitative PCR in 14 days old and sick (>30 d) homozygotes expressed as relation to β-actin. In sick animals manganese superoxide dismutase (MnSOD) and catalase (Cat) were decreased, whereas glutathione peroxidase 3 (GPx-3) was increased.</p

Perinatal outcomes of treated, confirmed asthma by ATC-groups compared to controls for singleton live and stillbirths.

<p>Perinatal outcomes of treated, confirmed asthma by ATC-groups compared to controls for singleton live and stillbirths.</p

Perinatal outcomes in mothers with confirmed, treated or untreated asthma for singleton live and stillbirths.

<p>Perinatal outcomes in mothers with confirmed, treated or untreated asthma for singleton live and stillbirths.</p