Corey Nislow completed his doctor of philosophy in University of Colorado. He was an American Cancer Society fellow, group leader in three biotechnology companies and senior genome scientist at Stanford University. Before joining UBC, Dr. Nislow was a Genome Scientist at Stanford University, and associate professor at the University of Toronto. In the UBC Faculty of Pharmacy he is an Associate Professor, Director of the UBC Sequencing Centre and a Tier 1 Canada Research Chair. His work on drug-gene and drug-environment interactions is broad in scope, ranging from yeast to human and, as part of an ongoing collaboration with NASA and Duke University, he has flown experiments on 4 missions to the International Space Station. Nislow is Principal Investigator for the ‘Genomics for Precision Drug Therapy in Community Pharmacy’ project, which demonstrated that pharmacists are well positioned to convey pharmacogenomics information to their patients and their healthcare team. He has 175 peer-reviewed publications and 8 issued patents.
To examine the role of nucleosome occupancy in the evolution of gene expression, we measured the ... more To examine the role of nucleosome occupancy in the evolution of gene expression, we measured the genome-wide nucleosome profiles of four yeast species, three belonging to the Saccharomyces sensu stricto lineage and the more distantly related Candida glabrata. Nucleosomes and associated promoter elements at C. glabrata genes are typically shifted upstream by20 bp, compared to their orthologs from sensu stricto species. Nonetheless, all species display the same global organization features first described for Saccharomyces cerevisiae: a stereotypical nucleosome organization along genes and a division of promoters into those that contain or lack a pronounced nucleosome-depleted region (NDR), with the latter displaying a more dynamic pattern of gene expression. Despite this global similarity, however, nucleosome occupancy at specific genes diverged extensively between sensu stricto and C. glabrata orthologs (50 million years). Orthologs with dynamic expression patterns tend to maintain ...
Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of severa... more Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds (DMF and 4NQO) and several of their metabolites. A collection of 4800 non-essential homozygous diploid yeast deletion strains were screened in parallel and the strain abundance was quantified by barcode sequencing. These data were used to rank deletion strains representing genes required for resistance to the compounds to delineate affected cellular pathways and to visualize the global cellular effects of these toxins in an easy-to-use searchable database. Our analysis of the N-nitrosamine screens uncovered genes (via their corresponding homozygous deletion mutants) involved in several evolutionarily conserved pathways, including: arginine biosynthesis, mitochondrial genome integrity, vacuolar protein sorting and DNA damage repair. To investigate why NDMA, NDEA and DMF caused fitnes...
The experimental evolution of microorganisms exposed to extreme conditions can provide insight in... more The experimental evolution of microorganisms exposed to extreme conditions can provide insight into cellular adaptation to stress. Typically, stress-sensitive species are exposed to stress over many generations and then examined for improvements in their stress tolerance. In contrast, when starting with an already stress-tolerant progenitor there may be less room for further improvement, it may still be able to tweak its cellular machinery to increase extremotolerance, perhaps at the cost of poorer performance under non-extreme conditions. To investigate these possibilities, a strain of extremely halotolerant black yeast Hortaea werneckii was grown for over seven years through at least 800 generations in a medium containing 4.3 M NaCl. Although this salinity is well above the optimum (0.8–1.7 M) for the species, the growth rate of the evolved H. werneckii did not change in the absence of salt or at high concentrations of NaCl, KCl, sorbitol, or glycerol. Other phenotypic traits did ...
The experimental evolution of microorganisms exposed to extreme conditions can provide insight in... more The experimental evolution of microorganisms exposed to extreme conditions can provide insight into cellular adaptation to stress. Typically, stress-sensitive species are exposed to stress over many generations and then examined for improvements in their stress tolerance. In contrast, when starting with an already stress-tolerant progenitor there may be less room for further improvement, it may still be able to tweak its cellular machinery to increase extremotolerance, perhaps at the cost of poorer performance under non-extreme conditions. To investigate these possibilities, a strain of extremely halotolerant black yeast Hortaea werneckii was grown for over seven years through at least 800 generations in a medium containing 4.3 M NaCl. Although this salinity is well above the optimum (0.8–1.7 M) for the species, the growth rate of the evolved H. werneckii did not change in the absence of salt or at high concentrations of NaCl, KCl, sorbitol, or glycerol. Other phenotypic traits did ...
The combination of model organisms and comprehensive genome-wide screens has provided a wealth of... more The combination of model organisms and comprehensive genome-wide screens has provided a wealth of data into the structure and regulation of the genome, gene-environment interactions, and more recently, into the mechanism of action of human therapeutics. The success of these studies relies, in part, on the ability to quantify the combined effects of multifactorial biological interactions. In this review, we explore the history and rationale behind genetic and chemical-genetic interactions with an emphasis on the phenomena of drug synergy and then briefly describe the theoretical models that we can leverage to investigate the synergy between compounds. In addition to reviewing the literature, we also provide a reference list including many of the most important studies in this field. The concept of chemical genetics interactions derives from classical studies of synthetic lethality and functional genomics. These techniques have recently graduated from the research lab to the clinic, and a better understanding of the basic principles can help accelerate this translation.
In this study 180 patients were consented and enrolled for pharmacogenomic testing based on curre... more In this study 180 patients were consented and enrolled for pharmacogenomic testing based on current antidepressant/antipsychotic usage. Samples from patients were genotyped by PCR, MassArray, and targeted next generation sequencing. We also conducted a quantitative, frequency-based analysis of participants’ perceptions using simple surveys. Pharmacogenomic information, including medication changes and altered dosing recommendations were returned to the pharmacists and used to direct patient therapy. Overwhelmingly, patients perceived pharmacists/pharmacies as an appropriate healthcare provider to deliver pharmacogenomic services. In total, 81 medication changes in 33 unique patients, representing 22% of all genotyped participants were recorded. We performed a simple drug cost analysis and found that medication adjustments and dosing changes across the entire cohort added $24.15CAD per patient per year for those that required an adjustment. Comparing different platforms, we uncovered...
New technologies have powered rapid advances in cellular imaging, genomics and phenotypic analysi... more New technologies have powered rapid advances in cellular imaging, genomics and phenotypic analysis in life sciences. However, most of these methods operate at sample population levels and provide statistical averages of aggregated data that fail to capture single-cell heterogeneity, complicating drug discovery and development. Here we demonstrate a new single-cell approach based on convex lens-induced confinement (CLiC) microscopy. We validated CLiC on yeast cells, demonstrating subcellular localization with an enhanced signal-to-noise and fluorescent signal detection sensitivity compared with traditional imaging. In the live-cell CLiC assay, cellular proliferation times were consistent with flask culture. Using methotrexate, we provide drug response data showing a fivefold cell size increase following drug exposure. Taken together, CLiC enables high-quality imaging of single-cell drug response and proliferation for extended observation periods.
Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and ... more Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and lowering risk of serious adverse events. As of June 2019, there are 132 pharmacogenomic dosing guidelines for 99 drugs and pharmacogenomic information is included in 309 medication labels. Recently, the technology for identifying individual-specific genetic variants (genotyping) has become more accessible. Next generation sequencing (NGS) is a cost-effective option for genotyping patients at many pharmacogenomic loci simultaneously, and guidelines for implementation of these data are available from organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). NGS and related technologies are increasing knowledge in the research sphere, yet rates of genomic literacy remain low, resulting in a widening gap in knowledge translation to the patient. Multidisciplinary teams—including physicians, nurses, genetic counsel...
Persons living with human immunodeficiency virus (PLWH) face an increased burden of chronic obstr... more Persons living with human immunodeficiency virus (PLWH) face an increased burden of chronic obstructive pulmonary disease (COPD). Repeated pulmonary infections, antibiotic exposures, and immunosuppression may contribute to an altered small airway epithelium (SAE) microbiome. SAE cells were collected from 28 PLWH and 48 HIV- controls through bronchoscopic cytologic brushings. DNA extracted from SAE cells was subjected to 16S rRNA amplification and sequencing. Comparisons of alpha and beta diversity between HIV+ and HIV- groups were performed and key operational taxonomic units (OTUs) distinguishing the two groups were identified using the Boruta feature selection after Random Forest Analysis. PLWH demonstrated significantly reduced Shannon diversity compared with HIV- volunteers (1.82 ± 0.10 vs. 2.20 ± 0.073, p = 0.0024). This was primarily driven by a reduction in bacterial richness (23.29 ± 2.75 for PLWH and 46.04 ± 3.716 for HIV-, p < 0.0001). Phyla distribution was significant...
American journal of respiratory and critical care medicine, Jan 30, 2018
Lung dysbiosis promotes airway inflammation and decreased local immunity, potentially playing a r... more Lung dysbiosis promotes airway inflammation and decreased local immunity, potentially playing a role in the pathogenesis of acute exacerbations of COPD (AECOPD). We determined the relationship between sputum microbiome at the time of AECOPD hospitalization and 1-year mortality in a COPD cohort. We used sputum samples from 102 patients hospitalized due to AECOPD. All subjects were followed for one year after discharge. The microbiome profile was assessed through sequencing of 16S rRNA gene. Microbiome analyses were performed according to 1-year mortality status. To investigate the effect of alpha diversity measures and taxa features on time to death, we applied Cox proportional-hazards regression models and obtained hazard ratios (HR) associated with these variables. We observed significantly lower values of alpha diversity (Richness, Shannon Index, Evenness, and Faith's Phylogenetic Diversity) among non-survivors (n=19, 18.6%) compared to survivors (n=83, 81.4%). Beta diversity ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Mar 9, 2017
Excess circulating insulin is associated with obesity in humans and in animal models. However, th... more Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor (Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circul...
Streptomyces spp. have the ability to produce a wide variety of secondary metabolites that intera... more Streptomyces spp. have the ability to produce a wide variety of secondary metabolites that interact with the environment. This study aimed to discover antifungal volatiles from the genus Streptomyces and to determine the mechanisms of inhibition. Volatiles identified from Streptomyces spp. included three major terpenes, geosmin, caryolan-1-ol and an unknown sesquiterpene. antiSMASH and KEGG predicted that the volatile terpene synthase gene clusters occur in the Streptomyces genome. Growth inhibition was observed when fungi were exposed to the volatiles. Biological activity of caryolan-1-ol has previously not been investigated. Fungal growth was inhibited in a dose-dependent manner by a mixture of the main volatiles, caryolan-1-ol and the unknown sesquiterpene, from Streptomyces sp. S4–7. Furthermore, synthesized caryolan-1-ol showed similar antifungal activity. Results of chemical-genomics profiling assays showed that caryolan-1-ol affected the endomembrane system by disrupting sphi...
The causal relationships between insulin levels, insulin resistance, and longevity are not fully ... more The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2(+/-) mice to Ins2(+/+) littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2(+/-) mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates t...
Extremophilic organisms demonstrate the flexibility and adaptability of basic biological processe... more Extremophilic organisms demonstrate the flexibility and adaptability of basic biological processes by highlighting how cell physiology adapts to environmental extremes. Few eukaryotic extremophiles have been well studied and only a small number are amenable to laboratory cultivation and manipulation. A detailed characterisation of the genome architecture of such organisms is important to illuminate how they adapt to environmental stresses. One excellent example of a fungal extremophile is the halophile Hortaea werneckii (Pezizomycotina; Dothideomycetes, Capnodiales), a yeast-like fungus able to thrive at near-saturating concentrations of sodium chloride and which is also tolerant to both UV irradiation and desiccation. Given its unique lifestyle and its remarkably recent whole genome duplication, H. werneckii provides opportunities for testing the role of genome duplications and adaptability to extreme environments. We previously assembled the genome of H. werneckii using short-read...
The Yeast Knockout Collection is a complete set of gene deletion strains for the budding yeast, S... more The Yeast Knockout Collection is a complete set of gene deletion strains for the budding yeast, Saccharomyces cerevisiae In each strain, one of approximately 6000 open-reading frames is replaced with a dominant selectable marker flanked by two DNA barcodes. These barcodes, which are unique to each gene, allow the growth of thousands of strains to be individually measured from a single pooled culture. The collection, and other resources that followed, has ushered in a new era in chemical biology, enabling unbiased and systematic identification of chemical-genetic interactions (CGIs) with remarkable ease. CGIs link bioactive compounds to biological processes, and hence can reveal the mechanism of action of growth-inhibitory compounds in vivo, including those of antifungal, antibiotic, and anticancer drugs. The chemogenomic profiling method described here measures the sensitivity induced in yeast heterozygous and homozygous deletion strains in the presence of a chemical inhibitor of gr...
The development of new antimalarial compounds remains a pivotal part of the strategy for malaria ... more The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.
To examine the role of nucleosome occupancy in the evolution of gene expression, we measured the ... more To examine the role of nucleosome occupancy in the evolution of gene expression, we measured the genome-wide nucleosome profiles of four yeast species, three belonging to the Saccharomyces sensu stricto lineage and the more distantly related Candida glabrata. Nucleosomes and associated promoter elements at C. glabrata genes are typically shifted upstream by20 bp, compared to their orthologs from sensu stricto species. Nonetheless, all species display the same global organization features first described for Saccharomyces cerevisiae: a stereotypical nucleosome organization along genes and a division of promoters into those that contain or lack a pronounced nucleosome-depleted region (NDR), with the latter displaying a more dynamic pattern of gene expression. Despite this global similarity, however, nucleosome occupancy at specific genes diverged extensively between sensu stricto and C. glabrata orthologs (50 million years). Orthologs with dynamic expression patterns tend to maintain ...
Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of severa... more Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds (DMF and 4NQO) and several of their metabolites. A collection of 4800 non-essential homozygous diploid yeast deletion strains were screened in parallel and the strain abundance was quantified by barcode sequencing. These data were used to rank deletion strains representing genes required for resistance to the compounds to delineate affected cellular pathways and to visualize the global cellular effects of these toxins in an easy-to-use searchable database. Our analysis of the N-nitrosamine screens uncovered genes (via their corresponding homozygous deletion mutants) involved in several evolutionarily conserved pathways, including: arginine biosynthesis, mitochondrial genome integrity, vacuolar protein sorting and DNA damage repair. To investigate why NDMA, NDEA and DMF caused fitnes...
The experimental evolution of microorganisms exposed to extreme conditions can provide insight in... more The experimental evolution of microorganisms exposed to extreme conditions can provide insight into cellular adaptation to stress. Typically, stress-sensitive species are exposed to stress over many generations and then examined for improvements in their stress tolerance. In contrast, when starting with an already stress-tolerant progenitor there may be less room for further improvement, it may still be able to tweak its cellular machinery to increase extremotolerance, perhaps at the cost of poorer performance under non-extreme conditions. To investigate these possibilities, a strain of extremely halotolerant black yeast Hortaea werneckii was grown for over seven years through at least 800 generations in a medium containing 4.3 M NaCl. Although this salinity is well above the optimum (0.8–1.7 M) for the species, the growth rate of the evolved H. werneckii did not change in the absence of salt or at high concentrations of NaCl, KCl, sorbitol, or glycerol. Other phenotypic traits did ...
The experimental evolution of microorganisms exposed to extreme conditions can provide insight in... more The experimental evolution of microorganisms exposed to extreme conditions can provide insight into cellular adaptation to stress. Typically, stress-sensitive species are exposed to stress over many generations and then examined for improvements in their stress tolerance. In contrast, when starting with an already stress-tolerant progenitor there may be less room for further improvement, it may still be able to tweak its cellular machinery to increase extremotolerance, perhaps at the cost of poorer performance under non-extreme conditions. To investigate these possibilities, a strain of extremely halotolerant black yeast Hortaea werneckii was grown for over seven years through at least 800 generations in a medium containing 4.3 M NaCl. Although this salinity is well above the optimum (0.8–1.7 M) for the species, the growth rate of the evolved H. werneckii did not change in the absence of salt or at high concentrations of NaCl, KCl, sorbitol, or glycerol. Other phenotypic traits did ...
The combination of model organisms and comprehensive genome-wide screens has provided a wealth of... more The combination of model organisms and comprehensive genome-wide screens has provided a wealth of data into the structure and regulation of the genome, gene-environment interactions, and more recently, into the mechanism of action of human therapeutics. The success of these studies relies, in part, on the ability to quantify the combined effects of multifactorial biological interactions. In this review, we explore the history and rationale behind genetic and chemical-genetic interactions with an emphasis on the phenomena of drug synergy and then briefly describe the theoretical models that we can leverage to investigate the synergy between compounds. In addition to reviewing the literature, we also provide a reference list including many of the most important studies in this field. The concept of chemical genetics interactions derives from classical studies of synthetic lethality and functional genomics. These techniques have recently graduated from the research lab to the clinic, and a better understanding of the basic principles can help accelerate this translation.
In this study 180 patients were consented and enrolled for pharmacogenomic testing based on curre... more In this study 180 patients were consented and enrolled for pharmacogenomic testing based on current antidepressant/antipsychotic usage. Samples from patients were genotyped by PCR, MassArray, and targeted next generation sequencing. We also conducted a quantitative, frequency-based analysis of participants’ perceptions using simple surveys. Pharmacogenomic information, including medication changes and altered dosing recommendations were returned to the pharmacists and used to direct patient therapy. Overwhelmingly, patients perceived pharmacists/pharmacies as an appropriate healthcare provider to deliver pharmacogenomic services. In total, 81 medication changes in 33 unique patients, representing 22% of all genotyped participants were recorded. We performed a simple drug cost analysis and found that medication adjustments and dosing changes across the entire cohort added $24.15CAD per patient per year for those that required an adjustment. Comparing different platforms, we uncovered...
New technologies have powered rapid advances in cellular imaging, genomics and phenotypic analysi... more New technologies have powered rapid advances in cellular imaging, genomics and phenotypic analysis in life sciences. However, most of these methods operate at sample population levels and provide statistical averages of aggregated data that fail to capture single-cell heterogeneity, complicating drug discovery and development. Here we demonstrate a new single-cell approach based on convex lens-induced confinement (CLiC) microscopy. We validated CLiC on yeast cells, demonstrating subcellular localization with an enhanced signal-to-noise and fluorescent signal detection sensitivity compared with traditional imaging. In the live-cell CLiC assay, cellular proliferation times were consistent with flask culture. Using methotrexate, we provide drug response data showing a fivefold cell size increase following drug exposure. Taken together, CLiC enables high-quality imaging of single-cell drug response and proliferation for extended observation periods.
Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and ... more Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and lowering risk of serious adverse events. As of June 2019, there are 132 pharmacogenomic dosing guidelines for 99 drugs and pharmacogenomic information is included in 309 medication labels. Recently, the technology for identifying individual-specific genetic variants (genotyping) has become more accessible. Next generation sequencing (NGS) is a cost-effective option for genotyping patients at many pharmacogenomic loci simultaneously, and guidelines for implementation of these data are available from organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). NGS and related technologies are increasing knowledge in the research sphere, yet rates of genomic literacy remain low, resulting in a widening gap in knowledge translation to the patient. Multidisciplinary teams—including physicians, nurses, genetic counsel...
Persons living with human immunodeficiency virus (PLWH) face an increased burden of chronic obstr... more Persons living with human immunodeficiency virus (PLWH) face an increased burden of chronic obstructive pulmonary disease (COPD). Repeated pulmonary infections, antibiotic exposures, and immunosuppression may contribute to an altered small airway epithelium (SAE) microbiome. SAE cells were collected from 28 PLWH and 48 HIV- controls through bronchoscopic cytologic brushings. DNA extracted from SAE cells was subjected to 16S rRNA amplification and sequencing. Comparisons of alpha and beta diversity between HIV+ and HIV- groups were performed and key operational taxonomic units (OTUs) distinguishing the two groups were identified using the Boruta feature selection after Random Forest Analysis. PLWH demonstrated significantly reduced Shannon diversity compared with HIV- volunteers (1.82 ± 0.10 vs. 2.20 ± 0.073, p = 0.0024). This was primarily driven by a reduction in bacterial richness (23.29 ± 2.75 for PLWH and 46.04 ± 3.716 for HIV-, p < 0.0001). Phyla distribution was significant...
American journal of respiratory and critical care medicine, Jan 30, 2018
Lung dysbiosis promotes airway inflammation and decreased local immunity, potentially playing a r... more Lung dysbiosis promotes airway inflammation and decreased local immunity, potentially playing a role in the pathogenesis of acute exacerbations of COPD (AECOPD). We determined the relationship between sputum microbiome at the time of AECOPD hospitalization and 1-year mortality in a COPD cohort. We used sputum samples from 102 patients hospitalized due to AECOPD. All subjects were followed for one year after discharge. The microbiome profile was assessed through sequencing of 16S rRNA gene. Microbiome analyses were performed according to 1-year mortality status. To investigate the effect of alpha diversity measures and taxa features on time to death, we applied Cox proportional-hazards regression models and obtained hazard ratios (HR) associated with these variables. We observed significantly lower values of alpha diversity (Richness, Shannon Index, Evenness, and Faith's Phylogenetic Diversity) among non-survivors (n=19, 18.6%) compared to survivors (n=83, 81.4%). Beta diversity ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Mar 9, 2017
Excess circulating insulin is associated with obesity in humans and in animal models. However, th... more Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor (Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circul...
Streptomyces spp. have the ability to produce a wide variety of secondary metabolites that intera... more Streptomyces spp. have the ability to produce a wide variety of secondary metabolites that interact with the environment. This study aimed to discover antifungal volatiles from the genus Streptomyces and to determine the mechanisms of inhibition. Volatiles identified from Streptomyces spp. included three major terpenes, geosmin, caryolan-1-ol and an unknown sesquiterpene. antiSMASH and KEGG predicted that the volatile terpene synthase gene clusters occur in the Streptomyces genome. Growth inhibition was observed when fungi were exposed to the volatiles. Biological activity of caryolan-1-ol has previously not been investigated. Fungal growth was inhibited in a dose-dependent manner by a mixture of the main volatiles, caryolan-1-ol and the unknown sesquiterpene, from Streptomyces sp. S4–7. Furthermore, synthesized caryolan-1-ol showed similar antifungal activity. Results of chemical-genomics profiling assays showed that caryolan-1-ol affected the endomembrane system by disrupting sphi...
The causal relationships between insulin levels, insulin resistance, and longevity are not fully ... more The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2(+/-) mice to Ins2(+/+) littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2(+/-) mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates t...
Extremophilic organisms demonstrate the flexibility and adaptability of basic biological processe... more Extremophilic organisms demonstrate the flexibility and adaptability of basic biological processes by highlighting how cell physiology adapts to environmental extremes. Few eukaryotic extremophiles have been well studied and only a small number are amenable to laboratory cultivation and manipulation. A detailed characterisation of the genome architecture of such organisms is important to illuminate how they adapt to environmental stresses. One excellent example of a fungal extremophile is the halophile Hortaea werneckii (Pezizomycotina; Dothideomycetes, Capnodiales), a yeast-like fungus able to thrive at near-saturating concentrations of sodium chloride and which is also tolerant to both UV irradiation and desiccation. Given its unique lifestyle and its remarkably recent whole genome duplication, H. werneckii provides opportunities for testing the role of genome duplications and adaptability to extreme environments. We previously assembled the genome of H. werneckii using short-read...
The Yeast Knockout Collection is a complete set of gene deletion strains for the budding yeast, S... more The Yeast Knockout Collection is a complete set of gene deletion strains for the budding yeast, Saccharomyces cerevisiae In each strain, one of approximately 6000 open-reading frames is replaced with a dominant selectable marker flanked by two DNA barcodes. These barcodes, which are unique to each gene, allow the growth of thousands of strains to be individually measured from a single pooled culture. The collection, and other resources that followed, has ushered in a new era in chemical biology, enabling unbiased and systematic identification of chemical-genetic interactions (CGIs) with remarkable ease. CGIs link bioactive compounds to biological processes, and hence can reveal the mechanism of action of growth-inhibitory compounds in vivo, including those of antifungal, antibiotic, and anticancer drugs. The chemogenomic profiling method described here measures the sensitivity induced in yeast heterozygous and homozygous deletion strains in the presence of a chemical inhibitor of gr...
The development of new antimalarial compounds remains a pivotal part of the strategy for malaria ... more The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.
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Papers by Corey Nislow