The evolution of drug resistance in clinical isolates of Candida albicans

Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.National Science Foundation (U.S.). Graduate Research Fellowship ProgramHoward Hughes Medical InstituteHelen Hay Whitney Foundation (Postdoctoral Fellowship)Alfred P. Sloan FoundationNational Institutes of Health (U.S.) (Grant 8DP1CA174427)National Institutes of Health (U.S.) (Grant 2R01CA119176-01

Estimating the current and future cancer burden in Canada: Methodological framework of the Canadian population attributable risk of cancer (ComPARe) study

Introduction The Canadian Population Attributable Risk of Cancer project aims to quantify the number and proportion of cancer cases incident in Canada, now and projected to 2042, that could be prevented through changes in the prevalence of modifiable exposures associated with cancer. The broad risk factor categories of interest include tobacco, diet, energy imbalance, infectious diseases, hormonal therapies and environmental factors such as air pollution and res

Y[subscript MAP]: a pipeline for visualization of copy number variation and loss of heterozygosity in eukaryotic pathogens

The design of effective antimicrobial therapies for serious eukaryotic pathogens requires a clear understanding of their highly variable genomes. To facilitate analysis of copy number variations, single nucleotide polymorphisms and loss of heterozygosity events in these pathogens, we developed a pipeline for analyzing diverse genome-scale datasets from microarray, deep sequencing, and restriction site associated DNA sequence experiments for clinical and laboratory strains of Candida albicans, the most prevalent human fungal pathogen. The Y[subscript MAP] pipeline (http://lovelace.cs.umn.edu/Ymap/) automatically illustrates genome-wide information in a single intuitive figure and is readily modified for the analysis of other pathogens with small genomes.Howard Hughes Medical InstituteBurroughs Wellcome Fund (Career Award at the Scientific Interface)National Institutes of Health (U.S.) (PIONEER Award)Alfred P. Sloan Foundation (Fellowship)National Institute of Allergy and Infectious Diseases (U.S.) (R01 AI-0624273

The \u27obligate diploid\u27 Candida albicans forms mating-competent haploids

Candida albicans, the most prevalent human fungal pathogen, is considered to be an obligate diploid that carries recessive lethal mutations throughout the genome. Here we demonstrate that C. albicans has a viable haploid state that can be derived from diploid cells under in vitro and in vivo conditions, and that seems to arise through a concerted chromosome loss mechanism. Haploids undergo morphogenetic changes like those of diploids, including the yeast-hyphal transition, chlamydospore formation and a white-opaque switch that facilitates mating. Haploid opaque cells of opposite mating type mate efficiently to regenerate the diploid form, restoring heterozygosity and fitness. Homozygous diploids arise spontaneously by auto-diploidization, and both haploids and auto-diploids show a similar reduction in fitness, in vitro and in vivo, relative to heterozygous diploids, indicating that homozygous cell types are transient in mixed populations. Finally, we constructed stable haploid strains with multiple auxotrophies that will facilitate molecular and genetic analyses of this important pathogen. © 2013 Macmillan Publishers Limited. All rights reserved

Corrigendum to “Estimates of the current and future burden of cancer attributable to low fruit and vegetable consumption in Canada” [Prev. Med. 122 (2019)20–30](S0091743519300891)(10.1016/j.ypmed.2019.03.013)

The authors regret that in Tables 5a and 5b, the column heading ‘All’ should be changed to ‘All Associated.’ In Table 1 (page 21)on the last row (Head and neck cancer), the intake level should be 135 g/day (it is currently 80 g/day), and the RR should be 0.89 (0.82–0.97)for both men and women. The footnote (j)should read “Estimates from Nagle and colleagues (Nagle et al., 2015)”. The authors would like to apologise for any inconvenience caused

Supplemental Material for Forche et al., 2018

Figure S1 provides detailed overview of experiment. Supplemental figure 2 shows <i>GAL1</i> LOH frequencies <br>Supplemental figure 3 shows examples of single and double aneuploidies<br>Supplemental figure 4 shows frequency of whole Chr LOH<br>Supplemental figure 5 shows a map with LOH breaks along Chr1<br>Supplemental figure 6 shows frequency of recurrent missegregation events <br><div>Table S1 contains strains, primers and plasmids for construction of strain YJB9318<br>Table S2 contains overview of ploidy and colony phenotypes<br>Table S3 provides summary of all detected events<br>Table S4 shows position and frequency of break regions<br>Table S5 shows frequency of recurrent missegregation events<br>Table S6 shows summary of multiple event frequency by mouse</div><div>File S1 is the custom R script<br></div

Estimates of the future burden of cancer attributable to infections in Canada

More than 7000 incident cancers diagnosed in Canada in 2015 were attributable to infections. The future infection-associated cancer burden can be lowered by reducing the prevalence of major cancer-causing infections; hepatitis B virus (HBV), hepatitis C virus (HCV), Helicobacter pylori (H. pylori) and human papillomavirus (HPV). We modeled the future impact of (1) 10%, 25%, and 50% relative reductions in the prevalence of HBV, HCV and H. pylori and (2) different school-based HPV vaccination coverage levels (lower, current, higher) on Canadian cancer incidence by the year 2042. We modeled counterfactual reductions in HBV, HCV and H. pylori prevalence in 2018, assuming a latenc

Estimates of the current and future burden of melanoma attributable to ultraviolet radiation in Canada

Exposure to ultraviolet radiation (UVR) is an established cause of cutaneous melanoma. The purpose of this study was to estimate the current attributable and future avoidable burden of melanoma related to exposure to UVR and modifiable UVR risk behaviors (sunburn, sunbathing, and indoor tanning). The population attributable ris