Rhinovirus infection significantly alters the expression of many genes associated with the immune response, including chemokines and antivirals. The data obtained provide insights into the host response to rhinovirus infection and identify potential novel targets for further evaluation.
A relatively small subset (11.9%) of the immune response genes analyzed by array was transiently activated in response to biofilm overgrowth, suggesting a degree of specificity in the transcriptome-expression response. The fact that this same subset demonstrates a reversal in expression patterns during clinical resolution implicates these genes as being critical for maintaining tissue homeostasis at the biofilm-gingival interface. In addition to the immune response pathway as the dominant response theme, new candidate genes and pathways were identified as being selectively modulated in experimental gingivitis, including neural processes, epithelial defenses, angiogenesis, and wound healing.
Zinc pyrithione (ZPT) is an antimicrobial material with widespread use in antidandruff shampoos and antifouling paints. Despite decades of commercial use, there is little understanding of its antimicrobial mechanism of action. We used a combination of genome-wide approaches (yeast deletion mutants and microarrays) and traditional methods (gene constructs and atomic emission) to characterize the activity of ZPT against a model yeast, Saccharomyces cerevisiae. ZPT acts through an increase in cellular copper levels that leads to loss of activity of iron-sulfur cluster-containing proteins. ZPT was also found to mediate growth inhibition through an increase in copper in the scalp fungus Malassezia globosa. A model is presented in which pyrithione acts as a copper ionophore, enabling copper to enter cells and distribute across intracellular membranes. This is the first report of a metalligand complex that inhibits fungal growth by increasing the cellular level of a different metal.Fungi have an essential role in causing dandruff, a scalp disease affecting Ͼ40% of the world's adult population (36). Zinc pyrithione (ZPT) is an antimicrobial compound that has been used since the 1960s in antidandruff shampoos (36) and in antifouling paints (37). In dandruff subjects, ZPT treatment reduces the amount of fungus on the scalp and stops dandruff flaking (6). Despite billions of human scalp treatments for over 4 decades, little is known of the mechanism by which ZPT inhibits fungal growth.Malassezia globosa and M. restricta are the two most common fungi on scalp (15). Despite a recent description of the genome sequences of these two species (42), study of Malassezia is challenging due to the absence of transformation methods and available mutants. Several attempts have been made to characterize the mode of action of ZPT against model fungi. ZPT has been reported to inhibit transport by membrane depolarization (5, 11). However, efficacy was reported only with doses of at least 100 M, whereas microbial growth inhibition is observed at much lower ZPT doses. Pyrithione is a well-known zinc ionophore that causes increased zinc levels within mammalian cells (1,18,27). High intracellular zinc levels can inhibit microbial growth, likely due to zinc binding to intracellular proteins and resulting in mismetallation (31). Yasokawa et al. (43) recently used transcriptional analysis of ZPT-treated Saccharomyces cerevisiae to suggest that ZPT causes iron starvation. They further showed that an iron salt lowered the antiyeast activity of ZPT, suggesting that iron starvation is a key component of ZPT's mechanism of action.In this communication, we confirm the observation by Yasokawa et al. (43) that ZPT increases transcription of the iron regulon: however, we ascribe that increase not to a transcriptional response to low iron concentrations but rather to a decrease in the activity of iron-sulfur (Fe-S) cluster-containing proteins. We show that ZPT-mediated growth inhibition is due to increased copper uptake and that copper inactivates key F...
Starting at weaning (22 d), Sprague-Dawley rats were fed either a control diet high in protein (CT, 24% protein) or an isocaloric low protein diet (LPT, 4% protein) to determine how protein malnutrition alters the rate and timing of limb bone growth. Length and width measurements were taken from longitudinal radiographs to provide complete growth trajectories of both treatments. Data collection continued until rats reached adult size, which varied among diet-sex groups. The rats were then killed and five muscles and eight organs were weighed. A nonlinear Gompertz model was then fit to each trajectory for 13 skeletal measurements, producing parameters that described the rate and timing of growth for each rat, the unit of analysis. Parameter differences due to diet, sex and litter were tested by using a mixed-model, three-way ANOVA. For most measurements, the LPT rats were not significantly smaller than the CT rats, for the model's prediction of final size. Bone length was significantly less affected than width. The instantaneous initial growth rate, maximum rate of growth and rate of growth decay were significantly higher in the control rats for all measurements. The rats fed the low protein diet grew for significantly longer periods of time. For all muscles and most organs relative to body size, there was no difference between rats fed the two diets. The exceptions, eyes and brains, were proportionally larger in the LPT rats, suggesting that these organs receive nutritional priority during growth. For the systems in this study, structures that grow or have the potential for extended growth are less affected by the nutritional insult.
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