In-vitro toxoplasmacidal activity of cationic electron carriers

Exposing murine macrophages infected th the protozoan parasite Toxoplasma gondii to micromolar concentrations of some cationic electron carriers (dyes), resulted in complete killing of the intracellular parasites at concentrations at which these compounds did not seem toxic for the macrophages. The 50% inhibitory concentrations (with 95% confidence limits) were calculated as 0·26 (0·18-0·37), 1·35 (1-2·25), 0·45 (0·13-1·50), and 1·52 (0·91-2·53) μM for crystal violet, phenazine methosulphate, methylene blue and brilliant cresyl blue, respectively. The effects of these electron carriers did not appear to be the result of an enhancement of the natural antitoxoplasmic activity of the macrophages. None of the tested compounds was active against extracellular Tox. gondii as measured by ability to reinfect murine macrophages; thus, these dyes seem to act primarily on actively metabolizing, intracellular, Tox. gondii. Our data also suggest that the killing effect of the electron carriers was not related to the generation of reactive oxygen intermediates as judged by the inability of scavengers of these intermediates to block the activity against intracellular Tox. gondii. Further studies with related redox compounds would have an interesting chemotherapeutic perspective for treating toxoplasma infection

Activity of roxithromycin against Toxoplasma gondii in murine models

Investigations into the activity of roxithromycin against murine toxoplasma infections are reviewed. Roxithromycin is an active drug against murine toxoplasmosis after intraperitoneal challenge with the RH strain of Toxoplasma gondii. Roxithromycin protected 100% of mice after five daily doses of 540 mg per kg administered by gavage. The cure rate after treatment of peritoneal infections seemed to be related to the length of the therapy. Roxithromycin also decreased the number of toxoplasma cysts, after intracerebral infection with the C56 strain and showed synergistic activity when combined with gamma interferon. Thus, roxithromycin could be a worthwhile alternative to current therapy against toxoplasma infections. Clinical studies on its activity and safety, especially in pregnancy, are warrante

Activity of spiramycin against Toxoplasma gondii in vitro, in experimental infections and in human infection

The in-vitro, experimental and clinical activities of spiramycin against Toxoplasma gondii have been reviewed. In mammalian cells infected by T. gondii as in various experimental models, spiramycin definitively exerts an inhibitory antitoxoplasmic effect which, clinically, seems useful for preventing congenital toxoplasma infection during pregnancy or for reducing the inflammation in toxoplasmic chorioretinitis. However, spiramycin does not kill the parasite efficiently, and cannot be recommended for eradicating the most severe forms of toxoplasmosi

Effects of ampicillin, ceftriaxone, chloramphenicol, pefloxacin and trimethoprim-sulphamethoxazole on Salmonella typhi within human monocyte-derived macrophages

The killing effect of various antimicrobial agents used in the therapy of Salmonella typhi infection was tested against Salm. typhi strain Ty2 after phagocytosis by human monocyte-derived macrophages. The macrophages, cultured in 96-well microtitre plates, were infected for 1 h at 37°C by opsonized Salm. typhi Ty2 at a bacteria-cell ratio of 9:1. When added to the infected macrophage monolayers, at one and ten times the MIC, ampicillin, ceftriaxone and pefloxacin appeared to be highly bactericidal (< 0.25 logl0 cfu/well after 20 h, against 4 log10 cfu/well in antibiotic-free controls). Trimethoprim-sulphamethoxazole was bactericidal at ten times the MIC, but not at the MIC. Chloramphenicol was mostly bacteriostatic at the concentrations tested. As a control, gentamicin (10mg/l) did not exhibit any significant antibacterial effect, indicating that most or all the bacteria recovered from lyied cells were intracellular. Other controls for phagocytosis were also performed with heat-killed Candida albicans. Our results seem to correlate with the known clinical effect of some antimicrobials in human Salm. typhi infection. The in-vitro assay described here may be useful for assessing the activity of antimicrobial agents against Salm. typhi infectio

Activity of A-56268 (TE-031), a new macrolide, against Toxoplasma gondii in mice

The activity of A-56268 (TE-031), a new macrolide, was tested in a murine model of acute toxoplasmosis. All control animals died in 8 ± 1 days, while all mice treated with nine daily doses of A-56268 at 300 mg/kg, administered by gavage, survived. Moreover, 41.6% of the surviving mice were free from cerebral infection with Toxoplasma gondii, as assessed by brain subpassage. A-56268 is active against T. gondii in vivo, but further studies are needed to determine its usefulness in the treatment of human toxoplasmosi

Activity of minocycline against Toxoplasma gondii infection in mice

The chemotherapeutic activity of minocycline, a semi-synthetic tetracycline analogue, was evaluated in a murine model of toxoplasmosis. A lethal acute toxoplas-mosis was produced by injecting 105 tachyzoites of the RH strain of Toxoplasma gondii into the peritoneal cavities of Swiss-Webster mice. When infected mice were treated once daily for 12 days, starting 2 h after challenge, the survival and cure rates were 100% and 40% respectively after minocycline alone (100 mg/kg per day), 0% and 0% after pyrimethamine alone (8.5 mg/kg per day), and 100% and 50% after combination of the two drugs at the same dosages. Absolute survival and cure with minocycline were observed when mice were treated with two daily doses of 100 mg/kg for 12 days. Mice chronically infected with a low virulent strain of T. gondii (Me49) showed a significant reduction in the number of brain cysts after three weeks of treatment with 50 mg/kg per day of minocycline. Minocycline serum levels after a single oral administration of 50 mg/kg or 100 mg/kg to normal mice, peaked at 1.8 mg/1 and 10 mg/1 after 1 h, respectively, and showed an extended half-lif

Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure

Mitochondrial dysfunction and metabolic remodelling are pivotal in the development of cardiomyopathy. Here, we show that myocardial COUP-TFII overexpression causes heart failure in mice, suggesting a causal effect of elevated COUP-TFII levels on development of dilated cardiomyopathy. COUP-TFII represses genes critical for mitochondrial electron transport chain enzyme activity, oxidative stress detoxification and mitochondrial dynamics, resulting in increased levels of reactive oxygen species and lower rates of oxygen consumption in mitochondria. COUP-TFII also suppresses the metabolic regulator PGC-1 network and decreases the expression of key glucose and lipid utilization genes, leading to a reduction in both glucose and oleate oxidation in the hearts. These data suggest that COUP-TFII affects mitochondrial function, impairs metabolic remodelling and has a key role in dilated cardiomyopathy. Last, COUP-TFII haploinsufficiency attenuates the progression of cardiac dilation and improves survival in a calcineurin transgenic mouse model, indicating that COUP-TFII may serve as a therapeutic target for the treatment of dilated cardiomyopathy

Collusion through Joint R&D: An Empirical Assessment

This paper tests whether upstream R&D cooperation leads to downstream collusion. We consider an oligopolistic setting where firms enter in research joint ventures (RJVs) to lower production costs or coordinate on collusion in the product market. We show that a sufficient condition for identifying collusive behavior is a decline in the market share of RJV-participating firms, which is also necessary and sufficient for a decrease in consumer welfare. Using information from the US National Cooperation Research Act, we estimate a market share equation correcting for the endogeneity of RJV participation and R&D expenditures. We find robust evidence that large networks between direct competitors – created through firms being members in several RJVs at the same time – are conducive to collusive outcomes in the product market which reduce consumer welfare. By contrast, RJVs among non-competitors are efficiency enhancing

Single-Cell Census of Mechanosensitive Channels in Living Bacteria

Bacteria are subjected to a host of different environmental stresses. One such insult occurs when cells encounter changes in the osmolarity of the surrounding media resulting in an osmotic shock. In recent years, a great deal has been learned about mechanosensitive (MS) channels which are thought to provide osmoprotection in these circumstances by opening emergency release valves in response to membrane tension. However, even the most elementary physiological parameters such as the number of MS channels per cell, how MS channel expression levels influence the physiological response of the cells, and how this mean number of channels varies from cell to cell remain unanswered. In this paper, we make a detailed quantitative study of the expression of the mechanosensitive channel of large conductance (MscL) in different media and at various stages in the growth history of bacterial cultures. Using both quantitative fluorescence microscopy and quantitative Western blots our study complements earlier electrophysiology-based estimates and results in the following key insights: i) the mean number of channels per cell is much higher than previously estimated, ii) measurement of the single-cell distributions of such channels reveals marked variability from cell to cell and iii) the mean number of channels varies under different environmental conditions. The regulation of MscL expression displays rich behaviors that depend strongly on culturing conditions and stress factors, which may give clues to the physiological role of MscL. The number of stress-induced MscL channels and the associated variability have far reaching implications for the in vivo response of the channels and for modeling of this response. As shown by numerous biophysical models, both the number of such channels and their variability can impact many physiological processes including osmoprotection, channel gating probability, and channel clustering

Morphological Plant Modeling: Unleashing Geometric and Topological Potential within the Plant Sciences

The geometries and topologies of leaves, flowers, roots, shoots, and their arrangements have fascinated plant biologists and mathematicians alike. As such, plant morphology is inherently mathematical in that it describes plant form and architecture with geometrical and topological techniques. Gaining an understanding of how to modify plant morphology, through molecular biology and breeding, aided by a mathematical perspective, is critical to improving agriculture, and the monitoring of ecosystems is vital to modeling a future with fewer natural resources. In this white paper, we begin with an overview in quantifying the form of plants and mathematical models of patterning in plants. We then explore the fundamental challenges that remain unanswered concerning plant morphology, from the barriers preventing the prediction of phenotype from genotype to modeling the movement of leaves in air streams. We end with a discussion concerning the education of plant morphology synthesizing biological and mathematical approaches and ways to facilitate research advances through outreach, cross-disciplinary training, and open science. Unleashing the potential of geometric and topological approaches in the plant sciences promises to transform our understanding of both plants and mathematics