PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells

A phosphatidylinositol (PI) kinase activity associated with certain protein tyrosine kinases important in cell proliferation phosphorylates the 3' hydroxyl position of PI to produce phosphatidylinositol-3-phosphate (PI-3-P). Here we report that, in addition to PI-3' kinase activity, anti-phosphotyrosine (alpha-P-tyr) immunoprecipitates from platelet-derived growth factor (PDGF)-stimulated smooth muscle cells (SMC) contain lipid kinase activities that utilize the substrates phosphatidylinositol-4-phosphate (PI-4-P) and phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2). These activities are absent in alpha-P-tyr immunoprecipitates from quiescent SMC. The product of PI-4-P phosphorylation appears to be phosphatidylinositol-3,4-bisphosphate (PI-3,4-P2), a lipid not previously reported. The product of PI-4,5-P2 phosphorylation is phosphatidylinositol-trisphosphate (PIP3). PI-3-P was detected in quiescent SMC and increased only slightly in response to PDGF. PIP3 and the putative PI-3,4-P2 appeared only after the addition of mitogen. Both the temporal production of these novel phospholipids after PDGF stimulation and the observation of the enzymatic activities that produce them in alpha-P-tyr immunoprecipitates suggest that these phospholipids are excellent candidates for mediators of the PDGF mitogenic response.     

L’Inhibine B sérique, marqueur sensible de la production spermatique chez l’homme

Several recent papers indicate that the blood concentration of inhibin B measured by the dimeric assay is a marker of human spermatogenesis. The aim of the present study was to validate the dimeric assay in our hospital. For this purpose, we studied a population of 106 patients attending our infertility clinic. We found that serum inhibin B levels were positively correlated with the level of sperm production as reflected by the sperm concentration and negatively correlated with serum FSH levels. Serum inhibin B concentrations were found to be superior to FSH levels for discriminating between subgroups of patients with different levels of sperm production. For example, the differences in the inhibin B levels in severe oligozoospermia (< 5×106 sperm/ml) compared to non-obstructive azoospermia were more pronounced than the differences in FSH (p=0.0002 vs p=0.007, respectively). Overall, the results obtained in the present study were similar to those reported in other studies based on the same assay. Serum inhibin B levels in patients with non obstructive azoospermia were ten times lower than in patients with normal sperm concentrations. From a practical point of view, the measurement of serum inhibin B opens up new possibilities for the diagnosis and prognosis of many testicular disorders. Firstly, serum inhibin B determination should be performed whenever reproductive hormones are prescribed. In the particular case of azoospermia, serum inhibin B concentrations appear to be particularly useful to distinguish between obstructive and non-obstructive situations. Finally, according to a recent publication, a serum inhibin B cut-off value (> 40 pg/mL) could predict the success of testicular sperm extraction in patients with non-obstructive azoospermia. Serum inhibin B could therefore represent a unique non-invasive marker of focal hypospermatogenesis in men with non-obstructive azoospermia, who are candidates for intracytoplasmic sperm injection (ICSI) and a useful early marker to monitor possible recovery of spermatogenesis after chemotherapy or radiotherapy.     

Theoretical Study of Cardiac Transient Conduction Blocks on Reentries Induction. Applications to Antiarrhythmic Drugs

Limitations of antiarrhythmic drugs on cardiac sudden death prevention appeared since the early 80's. The "Cardiac Arrhythmia Suppression Trial"(CAST) showed more recently that mortality was significantly higher inpatients treated with some particular antiarrhythmic drugs than in non-treated patients. In this field, our group recently demonstrated that a bolus of a Class 1B antiarrhythmic drug was able to trigger a ventricular fibrillation due to transient blocks induction. The aim of the present work was to systematically study, by use of the van Capelle and Durrer (VCD) model which allows to simulate ventricular activation wave propagation, the link between arrhythmogenic effects and the ability of transient blocks to possibly degenerate in severe arrhythmias. A fragment of the ventricular wall is represented by an array of 16384elements electrically coupled. Effects of induction of one or several transient blocks, as the effects of their size and duration on possible induction of reentries have been studied. Results obtained show that various combinations between these different parameters may trigger reentries, ventricular tachycardia and/or more complex patterns assimilable to ventricular fibrillation. These results clearly evidence the fact that possible induction of transient blocks may directly be related to risk factor associated to arrhythmogenic effects of antiarrhythmic drugs. This revised version was published online in June 2006 with corrections to the Cover Date.     

Synthesis of an analogue of the lipoglycopeptide membrane intermediate I of peptidoglycan biosynthesis

Summary α-Dihydroheptaprenyl-pyrophosphoryl-N-acetylmuramoyl-L-Ala-γ-D-Glu-meso-diaminopimeloyl(N ^∈-dansyl)-D-Ala-D-Ala (1), an analogue of lipid I of peptidoglycan biosynthesis, was synthesized from natural UDP-N-acetylmuramoyl-pentapeptide in three steps. Compound1 was shown to be a substrate for the MurG transferase fromEscherichia coli, even in the absence of membranes. When membranes were present, dansylated peptidoglycan was also formed.     

Effects of asymmetric dispersal and environmental gradients on the stability of host–parasitoid systems

We consider host–parasitoid systems spatially distributed on a row of patches connected by dispersal. We analyze the effects of dispersal frequency, dispersal asymmetry, number of patches and environmental gradients on the stability of the host–parasitoid interactions. To take into account dispersal frequency, the hosts and parasitoids are allowed to move from one patch to a neighboring patch a certain number of times within a generation. When this number is high, aggregation methods can be used to simplify the proposed initial model into an aggregated model describing the dynamics of both the total host and parasitoid populations. We show that as the number of patches increases less asymmetric parasitoid dispersal rates are required for stability. We found that the 'CV²>1 rule' is a valid approximation for stability if host growth rate is low, otherwise the general condition of stability we establish should be preferred. Environmental variability along the row of patches is introduced as gradients on host growth rate and parasitoid searching efficiency. We show that stability is more likely when parasitoids move preferentially towards patches where they have high searching efficiency or when hosts go mainly to patches where they have a low growth rate.     

Factors affecting ambulatory dispersal in the predaceous mite Neoseiulus californicus (Acari: Phytoseiidae)

Experiments conducted in the laboratory showed that different biotic and abiotic factors affected the ambulatory dispersal behaviour of Neoseiulus californicus. The experimental set-up comprised dwarf alfalfa (Medicago polymorpha) infested or unifested by Tetranychus urticae. Temperatures were measured with thermocouples. Trials were performed at three temperatures, three prey densities, three light intensities, two relative humidities (RHs) and two vegetative states of alfalfa plants, turgid and withered. Deutonymphs were the most dispersive followed by young ovipositional females. High temperatures (35°C), high light intensities (40 000 lux) and drought-stressed alfalfa increased the dispersal of N. californicus. The availability of food in the environment and high moisture (80% RH) slowed down dispersion. The main factors which seem to elicit dispersal behaviour are the deprivation of food and high temperatures which result in an increase in the walking speed of the mite. In addition, other factors tested either increase or reduce the ambulatory dispersal of N. californicus. According to our results, individuals could move from ground cover into apple trees before spring. © Rapid Science Ltd. 1998     

Determination of the MurD mechanism through crystallographic analysis of enzyme complexes.

UDP -N- acetylmuramoyl- L -alanine: D -glutamate (MurD) ligase catalyses the addition of d -glutamate to the nucleotide precursor UDP -N- acetylmuramoyl- L -alanine (UMA). The crystal structures of three complexes of Escherichia coli MurD with a variety of substrates and products have been determined to high resolution. These include (1) the quaternary complex of MurD, the substrate UMA, the product ADP, and Mg2+, (2) the quaternary complex of MurD, the substrate UMA, the product ADP, and Mn2+, and (3) the binary complex of MurD with the product UDP - N- acetylmuramoyl- L -alanine- D -glutamate (UMAG). The reaction mechanism supported by these structures proceeds by the phosphorylation of the C-terminal carboxylate group of UMA by the gamma-phosphate group of ATP to form an acyl-phosphate intermediate, followed by the nucleophilic attack by the amino group of D-glutamate to produce UMAG. A key feature in the reaction intermediate is the presence of two magnesium ions bridging negatively charged groups.     

Focus: Rare Disease: Necrotizing Fasciitis: Association with Pregnancy-related Risk Factors Early in Life

Background: Pregnancy-related risk factors for necrotizing fasciitis are poorly understood. We investigated pregnancy-related characteristics associated with the long-term risk of developing necrotizing fasciitis, a rare life-threatening infectious disease. Methods: We analyzed a longitudinal cohort of 1,344,996 parous women in Quebec, Canada between 1989 and 2020. The main exposure measures included complications of pregnancy such as gestational diabetes, preterm delivery, metabolic disorder, and other maternal characteristics. We followed the women over time to identify future hospitalizations for necrotizing fasciitis up to three decades after delivery. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association of pregnancy characteristics with risk of necrotizing fasciitis in time-varying Cox proportional hazards regression models. Results: A total of 420 women were hospitalized for necrotizing fasciitis during follow-up, including 83 (19.8%) with diabetes-related necrotizing fasciitis. The incidence of necrotizing fasciitis was elevated for women with gestational diabetes (2.9 per 100,000 person-years), preterm delivery (3.2 per 100,000 person-years), and metabolic disorders (5.4 per 100,000 person-years), compared with no pregnancy complication (1.1 per 100,000 person-years). Compared with no pregnancy complication, gestational diabetes was associated with 1.87 times the risk (95% CI 1.38-2.53), preterm delivery with 2.10 times the risk (95% CI 1.65-2.66), and metabolic disorder with 3.72 times the risk (95% CI 2.92-4.74) of developing necrotizing fasciitis over time. Pregnancy complications were more strongly associated with the risk of necrotizing fasciitis 5 years or more after delivery. Conclusions: Complications of pregnancy may be associated with the long-term risk of necrotizing fasciitis in women.