Experimental evolution of drug resistance in human fungal pathogens.

Experimental evolution in vitro is a powerful tool to uncover the factors that contribute to resistance evolution and understand the genetic basis of adaptation. Here, we discuss recent experimental evolution studies from human fungal pathogens. We synthesize the results to highlight the common threads that influence resistance acquisition. The picture that emerges is that drug resistance consistently appears readily and rapidly. Mutations are often found in an overlapping set of genes and genetic pathways known to be involved in drug resistance, including whole or partial chromosomal aneuploidy. The likelihood of acquiring resistance and cross-resistance between drugs seems to be influenced by the specific drug (not just drug class), level of drug, and strain genetic background. We discuss open questions, such as the potential for increases in drug tolerance to evolve in static drugs. We highlight opportunities to use this framework to probe how different factors influence the rate and nature of adaptation to antifungal drugs in fungal microbes through a call for increased reporting on all replicates that were evolved, not just those that acquired resistance.

Automated morphometric analysis with SMorph software reveals plasticity induced by antidepressant therapy in hippocampal astrocytes.

Nervous system development and plasticity involve changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyze the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by principal component analysis (PCA). SMorph was tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with the antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes in mice. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.

Relevance of antifungal penetration in biofilm-associated resistance of Candida albicans and non-albicans Candida species.

The role of penetration limitation in Candida biofilm-associated antifungal resistance remains unclear. Most of the previous work has been done on Candida albicans, although non-albicans (NAC) species are also implicated in invasive candidiasis and the biofilm matrix has been shown to vary amongst different species. Only a few studies have evaluated clinical isolates. This study aimed to determine the relevance of penetration limitation in the antifungal resistance of biofilms formed by C. albicans and NAC clinical isolates, using an agar disk diffusion assay. The penetration of posaconazole and amphotericin B through the biofilms was significantly reduced. Fluconazole, voriconazole and caspofungin showed a superior penetration capacity in C. albicans, Candida tropicalis and Candida parapsilosis biofilms, but exhibited inter-species and strain/isolate variation. Candida krusei biofilms were the most resilient to antifungal permeation. All of the antifungal drugs failed to kill the biofilm cells, independent of penetration, suggesting that the other factors contribute markedly to the recalcitrance of the biofilms.