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Search Results: 1 - 10 of 170504 matches for " Lawrence E Heisler "
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Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast
Elke Ericson,Marinella Gebbia,Lawrence E. Heisler,Jan Wildenhain,Mike Tyers,Guri Giaever,Corey Nislow
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000151
Abstract: To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril) had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol) and pimozide (Orap). Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes.
A comparative analysis of DNA barcode microarray feature size
Ron Ammar, Andrew M Smith, Lawrence E Heisler, Guri Giaever, Corey Nislow
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-471
Abstract: We demonstrate that barcode microarrays with smaller features are equally capable of detecting variation in DNA barcode intensity when compared to larger feature sizes within a specific microarray platform. The barcodes used in this study are the well-characterized set derived from the Yeast KnockOut (YKO) collection used for screens of pooled yeast (Saccharomyces cerevisiae) deletion mutants. We treated these pools with the glycosylation inhibitor tunicamycin as a test compound. Three generations of barcode microarrays at 30, 8 and 5 μm features sizes independently identified the primary target of tunicamycin to be ALG7.We show that the data obtained with 5 μm feature size is of comparable quality to the 30 μm size and propose that further shrinking of features could yield barcode microarrays with equal or greater resolving power and, more importantly, higher density.Genome-wide studies often measure changes in the abundance of all gene products over a period of time or under varying conditions. Microarrays have made these studies possible by enabling researchers to monitor all known genes of an organism simultaneously to detect patterns of gene activity [1], alternative splicing variants [2] the presence of single nucleotide polymorphisms [3], the presence of copy number variants and [4] DNA binding sites of diverse proteins [5], among others. One application of microarrays that our laboratory has focused on is the parallel identification of individual molecular barcoded gene deletion mutants grown competitively in pools [6,7]. Through the efforts of the Yeast Deletion Consortium, a Yeast KnockOut (YKO) collection was constructed consisting of approximately 6,000 heterozygous gene deletions (>96% of all annotated open reading frames), of which over 1,100 are known to be essential for growth [7]. The remaining ~5,000 genes are nonessential, created as homozygous deletions and MATαand MATα deletion collections. These collections were made by systematic replacement o
Multiple Means to the Same End: The Genetic Basis of Acquired Stress Resistance in Yeast
David B. Berry,Qiaoning Guan,James Hose,Suraiya Haroon,Marinella Gebbia,Lawrence E. Heisler,Corey Nislow,Guri Giaever,Audrey P. Gasch
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002353
Abstract: In nature, stressful environments often occur in combination or close succession, and thus the ability to prepare for impending stress likely provides a significant fitness advantage. Organisms exposed to a mild dose of stress can become tolerant to what would otherwise be a lethal dose of subsequent stress; however, the mechanism of this acquired stress tolerance is poorly understood. To explore this, we exposed the yeast gene-deletion libraries, which interrogate all essential and non-essential genes, to successive stress treatments and identified genes necessary for acquiring subsequent stress resistance. Cells were exposed to one of three different mild stress pretreatments (salt, DTT, or heat shock) and then challenged with a severe dose of hydrogen peroxide (H2O2). Surprisingly, there was little overlap in the genes required for acquisition of H2O2 tolerance after different mild-stress pretreatments, revealing distinct mechanisms of surviving H2O2 in each case. Integrative network analysis of these results with respect to protein–protein interactions, synthetic–genetic interactions, and functional annotations identified many processes not previously linked to H2O2 tolerance. We tested and present several models that explain the lack of overlap in genes required for H2O2 tolerance after each of the three pretreatments. Together, this work shows that acquired tolerance to the same severe stress occurs by different mechanisms depending on prior cellular experiences, underscoring the context-dependent nature of stress tolerance.
Identification of yeast genes that confer resistance to chitosan oligosaccharide (COS) using chemogenomics
Maria DLA Jaime, Luis V Lopez-Llorca, Ana Conesa, Anna Y Lee, Michael Proctor, Lawrence E Heisler, Marinella Gebbia, Guri Giaever, J Timothy Westwood, Corey Nislow
BMC Genomics , 2012, DOI: 10.1186/1471-2164-13-267
Abstract: Three different chemogenomic fitness assays, haploinsufficiency (HIP), homozygous deletion (HOP), and multicopy suppression (MSP) profiling were combined with a transcriptomic analysis to gain insight in to the mode of action and mechanisms of resistance to chitosan oligosaccharides. The fitness assays identified 39 yeast deletion strains sensitive to COS and 21 suppressors of COS sensitivity. The genes identified are involved in processes such as RNA biology (transcription, translation and regulatory mechanisms), membrane functions (e.g. signalling, transport and targeting), membrane structural components, cell division, and proteasome processes. The transcriptomes of control wild type and 5 suppressor strains overexpressing ARL1, BCK2, ERG24, MSG5, or RBA50, were analyzed in the presence and absence of COS. Some of the up-regulated transcripts in the suppressor overexpressing strains exposed to COS included genes involved in transcription, cell cycle, stress response and the Ras signal transduction pathway. Down-regulated transcripts included those encoding protein folding components and respiratory chain proteins. The COS-induced transcriptional response is distinct from previously described environmental stress responses (i.e. thermal, salt, osmotic and oxidative stress) and pre-treatment with these well characterized environmental stressors provided little or any resistance to COS.Overexpression of the ARL1 gene, a member of the Ras superfamily that regulates membrane trafficking, provides protection against COS-induced cell membrane permeability and damage. We found that the ARL1 COS-resistant over-expression strain was as sensitive to Amphotericin B, Fluconazole and Terbinafine as the wild type cells and that when COS and Fluconazole are used in combination they act in a synergistic fashion. The gene targets of COS identified in this study indicate that COS’s mechanism of action is different from other commonly studied fungicides that target membranes, sugges
Chemical–Genetic Profiling of Imidazo[1,2-a]pyridines and -Pyrimidines Reveals Target Pathways Conserved between Yeast and Human Cells
Lisa Yu equal contributor,Andres Lopez equal contributor,Abderrahmane Anaflous,Brahim El Bali,Abdellah Hamal,Elke Ericson,Lawrence E. Heisler,Angus McQuibban,Guri Giaever,Corey Nislow,Charles Boone,Grant W. Brown ,Mohammed Bellaoui
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000284
Abstract: Small molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, we discovered that two closely related compounds, an imidazo[1,2-a]pyridine and -pyrimidine that differ by a single atom, have distinctly different mechanisms of action in vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic to yeast strains with defects in electron transport and mitochondrial functions and caused mitochondrial fragmentation, suggesting that compound 13 acts by disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as a DNA poison, causing damage to the nuclear DNA and inducing mutagenesis. We compared compound 15 to known chemotherapeutics and found resistance required intact DNA repair pathways. Thus, subtle changes in the structure of imidazo-pyridines and -pyrimidines dramatically alter both the intracellular targeting of these compounds and their effects in vivo. Of particular interest, these different modes of action were evident in experiments on human cells, suggesting that chemical–genetic profiles obtained in yeast are recapitulated in cultured cells, indicating that our observations in yeast can: (1) be leveraged to determine mechanism of action in mammalian cells and (2) suggest novel structure–activity relationships.
A comprehensive platform for highly multiplexed mammalian functional genetic screens
Troy Ketela, Lawrence E Heisler, Kevin R Brown, Ron Ammar, Dahlia Kasimer, Anuradha Surendra, Elke Ericson, Kim Blakely, Dina Karamboulas, Andrew M Smith, Tanja Durbic, Anthony Arnoldo, Kahlin Cheung-Ong, Judice LY Koh, Shuba Gopal, Glenn S Cowley, Xiaoping Yang, Jennifer K Grenier, Guri Giaever, David E Root, Jason Moffat, Corey Nislow
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-213
Abstract: Experiments with specially constructed lentiviral-based plasmid pools containing ~78,000 shRNAs demonstrated that the GMAP is capable of deconvolving genome-wide shRNA "dropout" screens. Further experiments with a larger, ~90,000 shRNA pool demonstrate that equivalent results are obtained from plasmid pools and from genomic DNA derived from lentivirus infected cells. Parallel testing of large shRNA pools using GMAP and next-generation sequencing methods revealed that the two methods provide valid and complementary approaches to deconvolution of genome-wide shRNA screens. Additional experiments demonstrated that GMAP is equivalent to similar microarray-based products when used for deconvolution of open reading frame over-expression screens.Herein, we demonstrate four major applications for the GMAP resource, including deconvolution of pooled RNAi screens in cells with at least 90,000 distinct shRNAs. We also provide detailed methodologies for pooled shRNA screen readout using GMAP and compare next-generation sequencing to GMAP (i.e. microarray) based deconvolution methods.Beginning in the late 1990's, construction of a systematic, barcoded gene deletion strain collection in S. cerevisiae set the stage for high throughput functional screening in eukaryotes [1,2]. Researchers using that resource developed powerful functional genomics screening approaches, and significantly, introduced the concept of performing complex, pooled population screens to simultaneously interrogate an organism's entire genome to identify drug targets, synthetic genetic interactions and other phenomena [1,3-7]. Similarly, the contemporary development of large libraries of short hairpin RNAs (shRNAs) and open reading frame (ORF) collections has significantly expanded the research toolkit available for performing mammalian functional genetics in a comprehensive manner [8-11]. The development of such tools, combined with the years of lessons from yeast-based screens suggested that similar genome-w
Blow-Up Phenomena for a Class of Parabolic Systems with Time Dependent Coefficients  [PDF]
Lawrence E. Payne, Gérard A. Philippin
Applied Mathematics (AM) , 2012, DOI: 10.4236/am.2012.34049
Abstract: Blow-up phenomena for solutions of some nonlinear parabolic systems with time dependent coefficients are investigated. Both lower and upper bounds for the blow-up time are derived when blow-up occurs.
Interactions among Tamarix (Tamaricaceae), Opsius stactogalus (Cicadellidae), and Litter Fungi Limit Riparian Plant Establishment  [PDF]
Gibney M. Siemion, Lawrence E. Stevens
Advances in Entomology (AE) , 2015, DOI: 10.4236/ae.2015.32008
Abstract: One of the most significant plant invasions in the U.S. has been that of the Old World genus Tamarix. While Tamarix spp. is widely studied, surprisingly little is known about more complex trophically-linked community mechanisms influencing under-canopy succession. We investigated multi- trophic interactions among Tamarix spp., nonnative host-specific Opsius stactogalus leafhopper distribution and honeydew production, and the Tamarix spp. canopy floor fungal assemblage. We quantified leafhopper abundance and honeydew throughfall, and tested under-canopy seed viability and seedling mortality across a 1600 m elevation gradient in the lower Colorado River basin in 2007. We conducted field and laboratory experiments in 2007-08 to test the effects of Tamarix spp. litter fungi, synthetic honeydew, and the combination of those variables on germination and seedling survivorship of three common, co-occurring phreatophyte (riparian groundwater-dependent plant) species. Tamarix spp. litter and honeydew treatments reduced understory seed viability and recruitment of two native, woody riparian species (Populus fremontii and Baccharis salicina), as well as Tamarix spp. Four major patterns were detected. 1) Litter fungi alone and synthetic honeydew alone reduced seed viability and seedling survivorship of all three species by two- to four-fold. 2) Synthetic honeydew + litter reduced Tamarix spp. and P. fremontii seed and seedling viability by up to 10-fold. 3) Synthetic honeydew concentration and seedling mortality were positively related among all three plant species. 4) B. salicina was less susceptible to all treatments than Tamarix spp. and P. fremontii. These results indicate that complex interactions among nonnative Tamarix spp., nonnative Opsius leafhopper honeydew production, and soil fungi may influence riparian phreatophyte recruitment and succession.
Towards Ecological Civilization: Ideas from Azerbaijan  [PDF]
Urkhan Alakbarov, John E. S. Lawrence
Journal of Human Resource and Sustainability Studies (JHRSS) , 2015, DOI: 10.4236/jhrss.2015.33013
Abstract: This discussion/review article traces relationships between an innovative strategic, national approach to national human resources development and enhancing national capacity for a more ecologically knowledgeable, sensitive society in a former Soviet country. With stunning speed following independence, Azerbaijan managed its extractive industries (oil and natural gas) effectively, rising to the top globally in annual GDP growth. Its determination to translate “black gold to human gold (BGHG)” and to diversify its economy led to a broad decade-long effort to modernize linkages between education, training and livelihood preparation. A complex national strategy to achieve BGHG was put in place, involving among other components, national labor force surveys, accelerated skills development, and employment service reforms. Given the pressing need for cleanup of Soviet industrial detritus, as well as emerging awareness of environmental responsibility among all sectors, unique “eco-civil” initiatives were launched both in schools and in civil service training programs. The resulting mosaic of public and private sector cooperation in meeting the twin goals of BGHG and a more “eco-civil” society can serve as a model for the region and beyond.
Degree of adaptive response in urban tolerant birds shows influence of habitat-of-origin
Lawrence E. Conole
PeerJ , 2015, DOI: 10.7717/peerj.306
Abstract: Urban exploiters and adapters are often coalesced under a term of convenience as ‘urban tolerant’. This useful but simplistic characterisation masks a more nuanced interplay between and within assemblages of birds that are more or less well adapted to a range of urban habitats. I test the hypotheses that objectively-defined urban exploiter and suburban adapter assemblages within the broad urban tolerant grouping in Melbourne vary in their responses within the larger group to predictor variables, and that the most explanatory predictor variables vary between the two assemblages. A paired, partitioned analysis of exploiter and adapter preferences for points along the urban–rural gradient was undertaken to decompose the overall trend into diagnosable parts for each assemblage. In a similar way to that in which time since establishment has been found to be related to high urban densities of some bird species and biogeographic origin predictive of urban adaptation extent, habitat origins of members of bird assemblages influence the degree to which they become urban tolerant. Bird species that objectively classify as urban tolerant will further classify as either exploiters or adapters according to the degree of openness of their habitats-of-origin.
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