Phenotypic heterogeneity in fungi: importance and methodology

Phenotypic heterogeneity describes the variation that exists between individual cells, spores or other biological entities within genetically-uniform populations of fungi or other organisms. Studies over the last 10-15 years have successfully used laboratory- and modelling-based approaches to demonstrate the prevalence of phenotypic heterogeneity and characterise the molecular bases of the phenomenon (primarily centred around heterogeneous gene expression). In contrast to progress in these areas, the relevance of phenotypic heterogeneity for the competitive success of organisms in different natural scenarios, although widely speculated upon, has only recently begun to be investigated. This focus review addresses this latter question as tackled in recent studies with yeasts and filamentous fungi. We concentrate on the relevance to fungal activities such as survival against environmental stressors, pathogenesis, and spoilage. We also discuss methodologies for interrogating phenotypic heterogeneity in fungi. The emerging prevalence and apparent importance of fungal phenotypic heterogeneity provides a timely reminder that certain, potentially core aspects of fungal biology still remain widely under-explored

Bet Hedging in Yeast by Heterogeneous, Age-Correlated Expression of a Stress Protectant

A new experimental approach reveals a bet-hedging strategy in unstressed, clonal yeast cells, whereby they adopt a range of growth states that correlate with expression of a trehalose-synthesis regulator and predict resistance to future stress

Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

Strohnutzung von Sauen in Bewegungsbuchten

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BLENDED RETIREMENT SYSTEM OPT-IN DECISIONS: A BEHAVIORAL ECONOMICS ANALYSIS

Modernization of the military retirement system, beginning in 2018, left many Marines with an important decision to make about their futures. They were allowed 12 months to choose whether it was in their best interest to opt into the new Blended Retirement System (BRS), or to remain under the legacy High-3 retirement plan. By analyzing their choices through the lens of behavioral economics, the primary goal of my research is to determine if Marines made rational or irrational retirement savings decisions. By the end of 2018, 49 percent of eligible Marines opted into the BRS, 28 percent opted out of the BRS, and 23 percent failed to register a decision via Marine Online, making a passive choice for the status quo. I find significant variation in the timing of Marines’ opt-in decisions, and those with lower years of service, who are younger, and more cognitively able are more likely to have opted in. Using a Linear Probability Model, I also find life events such as a change in the number of dependents, promotion, and re-enlistment to be significant determinants of their choices. Lastly, I provide summary statistics on their Thrift Savings Plan contribution percentages. Through analysis of this information, I find some evidence that Marines may have demonstrated irrational behavior with regard to their retirement decision making, suggesting that some pundits’ predictions prior to the opt-in period were overly optimistic.http://archive.org/details/blendedretiremen1094562233Captain, United States Marine CorpsApproved for public release; distribution is unlimited

The History Of The National Socialist German Student League.

PhDHistoryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/179942/2/7104776.pd