Intergenerational Metabolomic Analysis of Mothers with a History of Gestational Diabetes Mellitus and Their Offspring

Shared metabolomic patterns at delivery have been suggested to underlie the mother-to-child transmission of adverse metabolic health. This study aimed to investigate whether mothers with gestational diabetes mellitus (GDM) and their offspring show similar metabolomic patterns several years postpartum. Targeted metabolomics (including 137 metabolites) was performed in plasma samples obtained during an oral glucose tolerance test from 48 mothers with GDM and their offspring at a cross-sectional study visit 8 years after delivery. Partial Pearson’s correlations between the area under the curve (AUC) of maternal and offspring metabolites were calculated, yielding so-called Gaussian graphical models. Spearman’s correlations were applied to investigate correlations of body mass index (BMI), Matsuda insulin sensitivity index (ISI-M), dietary intake, and physical activity between generations, and correlations of metabolite AUCs with lifestyle variables. This study revealed that BMI, ISI-M, and the AUC of six metabolites (carnitine, taurine, proline, SM(-OH) C14:1, creatinine, and PC ae C34:3) were significantly correlated between mothers and offspring several years postpartum. Intergenerational metabolite correlations were independent of shared BMI, ISI-M, age, sex, and all other metabolites. Furthermore, creatinine was correlated with physical activity in mothers. This study suggests that there is long-term metabolic programming in the offspring of mothers with GDM and informs us about targets that could be addressed by future intervention studies.     

Glial development in the Drosophila CNS requires concomitant activation of glial and repression of neuronal differentiation genes

Two classes of glial cells are found in the embryonic Drosophila CNS, midline glial cells and lateral glial cells. Midline glial development is triggered by EGF-receptor signalling, whereas lateral glial development is controlled by the gcm gene. Subsequent glial cell differentiation depends partly on the pointed gene. Here we describe a novel component required for all CNS glia development. The tramtrack gene encodes two zinc-finger proteins, one of which, ttkp69, is expressed in all non-neuronal CNS cells. We show that ttkp69 is downstream of gcm and can repress neuronal differentiation. Double mutant analysis and coexpression experiments indicate that glial cell differentiation may depend on a dual process, requiring the activation of glial differentiation by pointed and the concomitant repression of neuronal development by tramtrack.     

The roles of conserved carboxylate residues in IMP dehydrogenase and identification of a transition state analog

IMP dehydrogenase (IMPDH) catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD+; the enzyme is activated by K+. This reaction is the rate-limiting step in de novo guanine nucleotide biosynthesis. In order to identify functionally important residues in IMPDH, including those involved in substrate and K+ binding, we have mutated 11 conserved Asp and Glu residues to Ala in Escherichia coli IMPDH. The values of kcat, Km, and Ki for GMP, XMP, mizoribine 5'-monophosphate (MMP), and beta-methylene-tiazofurin adenine dinucleotide (TAD) were determined. Five of these mutations caused a significant change (>/=10-fold) in one of these parameters. The Asp248 --> Ala mutation caused 100-fold decrease in the value of kcat and a 25-fold increase in the value of Kii for TAD; these observations suggest that Asp248 is in the NAD+ binding site. The Asp338 --> Ala mutation caused a 600-fold decrease in the value of kcat, but only a 5-10-fold increase in the values of Km for IMP and Kis for IMP analogs, suggesting that Asp338 may be involved in acid-base catalysis as well as IMP binding. The remaining three residues, Asp13, Asp50, and Glu469, appear to be involved in K+ activation; these residues may be ligands at one or more K+ binding sites. Interestingly, changes in the values of Ki for MMP correlate with changes in kcat/KmKm of IMPDH, while no such correlation is observed for GMP, XMP, and TAD. This observation indicates that MMP is a transition state analog for the IMPDH reaction.     

Relationship between the genomic organization and the overlapping embryonic expression patterns of the zebrafish dlx genes

To understand the relationship between the expression and the genomic organization of the zebrafish dlx genes, we have determined the genomic structure of the dlx2 and dlx4 loci. This led to the identification of the zebrafish dlx1 and dlx6 genes, which are closely linked to dlx2 and dlx4, respectively. Therefore, the inverted convergent configuration of Dlx genes is conserved among vertebrates. Analysis of the expression patterns of dlx1 and dlx6 showed striking similarities to those of dlx2 and dlx4, respectively, the genes to which they are linked. Furthermore, the expression patterns of dlx3 and dlx7, which likely constitute a third pair of convergently transcribed genes, are indistinguishable. Thus, the overlapping expression patterns of linked Dlx genes during embryonic development suggest that they share cis-acting sequences that control their spatiotemporal expression. The evolutionary conservation of the genomic organization and combinatorial expression of Dlx genes in distantly related vertebrates suggest tight control mechanisms that are essential for their function during development.     

A case of paraquat poisoning and subsequent fatality presenting to an emergency department

Paraquat (1,1'-dimethyl-4,4'-dipyridylium) is an herbicide associated with both accidental and intentional ingestion, leading to severe and often fatal toxicity. Prognosis is largely dependent on the amount of paraquat absorbed. Rapid identification of the symptoms of paraquat toxicity (burns or ulceration at the site of ingestion or injection, acute respiratory distress, and renal failure) can facilitate early treatment intervention to limit absorption. We report a case of a 71-year-old man with a suicidal ingestion of paraquat 2 days prior to presentation. Serum paraquat levels, time elapsed since ingestion, and clinical symptoms all indicated poor prognosis. The patient developed severe respiratory distress and progressive renal failure, and died 6 days after admission to the hospital.     

Tyrosine kinases: modular signaling enzymes with tunable specificities

Cytoplasmic tyrosine kinases are composed of modular domains; one (SH1) has catalytic activity, the other two (SH2 and SH3) do not. Kinase specificity is largely determined by the binding preferences of the SH2 domain. Attaching the SH1 domain to a new SH2 domain, via protein-protein association or mutation, can thus dramatically change kinase function.     

COPD: using nutrition to prevent respiratory function decline

Close to three-fourths of patients with chronic obstructive pulmonary disease (COPD) suffer from weight loss. Identifying a single cause for this is difficult, as several factors-including chronic mouth breathing, dyspnea, aerophagia, certain medications, and depression-often act in concert. Malnutrition can exacerbate symptoms of COPD by decreasing ventilatory muscle strength, exercise tolerance, and immunocompetence, and by increasing the risk of depression and anxiety. Goals of nutrition intervention are to prevent or reverse malnutrition without worsening the disease process and to improve respiratory function, thereby reducing morbidity and delaying mortality. Recommendations for intake of fats, carbohydrates, protein, and water must be individualized.     

The number and biodiversity of the parasites from small mammals in the evacuation area of the Chernobyl Nuclear Power Station

The study of the micromammalian parasite complexes in the Belorussian part of the evacuation zone of the Chernobyl nuclear station revealed 13 species of Coccidia and 30 species of ectoparasitic Arthropoda. Total increase of abundance and biodiversity of both parasites and their hosts was observed. The part of ectoparasites being epidemically hazardous was significantly increased. An analysis of a long-term dynamics of parasite abundance reveals their adaptation to new conditions in the Belorussia.     

Combination calculi for uncertainty reasoning: representing uncertainty using distributions

There are many different methods for incorporating notions of uncertainty in evidential reasoning. A common component to these methods is the use of additional values, other than conditional probabilities, to assert current degrees of belief and certainties in propositions. Beginning with the viewpoint that these values can be associated with statistics of multiple opinions in an evidential reasoning system, we categorize the choices that are available in updating and tracking these multiple opinions. In this way, we develop a matrix of different uncertainty calculi, some of which are standard, and others are new. The main contribution is to formalize a framework under which different methods for reasoning with uncertainty can be evaluated. As examples, we see that both the “Kalman filtering” approach and the “Dempster–Shafer” approach to reasoning with uncertainty can be interpreted within this framework of representing uncertainty by the statistics of multiple opinions. This revised version was published online in June 2006 with corrections to the Cover Date.