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D Slade

Publications and source records attributed to D Slade.

14 recordsLinked to original sources
PubMed2001

Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast.

Starvation for amino acids induces Gcn4p, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. In an effort to identify all genes regulated by Gcn4p during amino acid starvation, we performed cDNA microarray analysis. Data from 21 pairs of hybridization experiments using two different strains derived from S288c revealed that more than 1,000 genes were induced, and a similar number were repressed, by a factor of 2 or more in response to histidine starvation imposed by 3-aminotriazole (3AT). Profiling of a gcn4Delta strain and a constitutively induced mutant showed that Gcn4p is required for the full induction by 3AT of at least 539 genes, termed Gcn4p targets. Genes in every amino acid biosynthetic pathway except cysteine and genes encoding amino acid precursors, vitamin biosynthetic enzymes, peroxisomal components, mitochondrial carrier proteins, and autophagy proteins were all identified as Gcn4p targets. Unexpectedly, genes involved in amino acid biosynthesis represent only a quarter of the Gcn4p target genes. Gcn4p also activates genes involved in glycogen homeostasis, and mutant analysis showed that Gcn4p suppresses glycogen levels in amino acid-starved cells. Numerous genes encoding protein kinases and transcription factors were identified as targets, suggesting that Gcn4p is a master regulator of gene expression. Interestingly, expression profiles for 3AT and the alkylating agent methyl methanesulfonate (MMS) overlapped extensively, and MMS induced GCN4 translation. Thus, the broad transcriptional response evoked by Gcn4p is produced by diverse stress conditions. Finally, profiling of a gcn4Delta mutant uncovered an alternative induction pathway operating at many Gcn4p target genes in histidine-starved cells.

Amino Acids↗
PubMed2000

Functional discovery via a compendium of expression profiles.

Ascertaining the impact of uncharacterized perturbations on the cell is a fundamental problem in biology. Here, we describe how a single assay can be used to monitor hundreds of different cellular functions simultaneously. We constructed a reference database or "compendium" of expression profiles corresponding to 300 diverse mutations and chemical treatments in S. cerevisiae, and we show that the cellular pathways affected can be determined by pattern matching, even among very subtle profiles. The utility of this approach is validated by examining profiles caused by deletions of uncharacterized genes: we identify and experimentally confirm that eight uncharacterized open reading frames encode proteins required for sterol metabolism, cell wall function, mitochondrial respiration, or protein synthesis. We also show that the compendium can be used to characterize pharmacological perturbations by identifying a novel target of the commonly used drug dyclonine.

Cell Wall↗
PubMed2000

Widespread aneuploidy revealed by DNA microarray expression profiling.

Expression profiling using DNA microarrays holds great promise for a variety of research applications, including the systematic characterization of genes discovered by sequencing projects. To demonstrate the general usefulness of this approach, we recently obtained expression profiles for nearly 300 Saccharomyces cerevisiae deletion mutants. Approximately 8% of the mutants profiled exhibited chromosome-wide expression biases, leading to spurious correlations among profiles. Competitive hybridization of genomic DNA from the mutant strains and their isogenic parental wild-type strains showed they were aneuploid for whole chromosomes or chromosomal segments. Expression profile data published by several other laboratories also suggest the use of aneuploid strains. In five separate cases, the extra chromosome harboured a close homologue of the deleted gene; in two cases, a clear growth advantage for cells acquiring the extra chromosome was demonstrated. Our results have implications for interpreting whole-genome expression data, particularly from cells known to suffer genomic instability, such as malignant or immortalized cells.

Aneuploidy↗
PubMed2000

Gradual Hunterian ligation for infected prosthetic bypass.

OBJECTIVE: To review gradual snare occlusion for the management of complex or recurrent graft infection. PATIENTS AND METHODS: Medical records of patients treated with gradual snare occlusion following graft infection were reviewed for indication for operation, type of bypass and graft material used. In addition, infecting organism, grade of infection (Szilágyi) and outcome were recorded. RESULTS: Four femoropopliteal, two extra-anatomic (axillofemoral) and aortobifemoral bypasses were included in this study. All had chronic infection (Szilágyi grade III) with onset of 4 to 24 months and two of which were recurrent. The causative organisms were coagulase-negative staphylococci, Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus in three patients, with no organism isolated in the remaining cases. There was no loss of limb following gradual snare occlusion but there was only one death due to aortic stump rupture 2 weeks later. CONCLUSION: Gradual snare occlusion is an alternative for the management of chronic or recurrent graft infection.

Adult↗
PubMed1998

Drug target validation and identification of secondary drug target effects using DNA microarrays.

We describe here a method for drug target validation and identification of secondary drug target effects based on genome-wide gene expression patterns. The method is demonstrated by several experiments, including treatment of yeast mutant strains defective in calcineurin, immunophilins or other genes with the immunosuppressants cyclosporin A or FK506. Presence or absence of the characteristic drug 'signature' pattern of altered gene expression in drug-treated cells with a mutation in the gene encoding a putative target established whether that target was required to generate the drug signature. Drug dependent effects were seen in 'targetless' cells, showing that FK506 affects additional pathways independent of calcineurin and the immunophilins. The described method permits the direct confirmation of drug targets and recognition of drug-dependent changes in gene expression that are modulated through pathways distinct from the drug's intended target. Such a method may prove useful in improving the efficiency of drug development programs.

Calcineurin↗
PubMed1997

A collaborative approach to managing interstitial cystitis.

OBJECTIVES: To establish that conventional protocols often do not provide an adequate framework for managing interstitial cystitis, and to describe the special role of the urologic caregiver in developing a collaborative relationship with interstitial cystitis (IC) patients that can allay fears and provide hope that this devastating disease can be managed effectively. METHODS: Epidemiologic studies and a decade of experience of IC patients and their physicians are utilized in developing a rationale for a collaborative relationship between urologic caregivers and IC patients. RESULTS: The symptoms of interstitial cystitis-pain, urgency, and urinary frequency-can have a profoundly disruptive effect on patients' lives and present unique challenges to physicians as urologic caregivers. The impact of IC on patients' lives needs to be accounted for empathetically, and appropriate referrals for depression, sexuality, or relationship problems should be made. Pain should be managed aggressively, and patients who have had delayed diagnosis or who have not responded to the traditional treatments should be educated about the array of medical, complementary/alternative, and self-help modalities available. CONCLUSIONS: A successful treatment paradigm requires that physicians and patients be knowledgeable about the array of medical and complementary/alternative therapies and that these be applied in a systematic but creative way. Through empathic support, information, and a flexible treatment protocol, patients will learn to trust the medical process and take an active part in the management of IC.

Anxiety↗
PubMed1997

Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes.

OBJECTIVE: To determine the prevalence of concomitant disease in individuals with interstitial cystitis and to compare these results to the general population. METHODS: We used a questionnaire-based study evaluating 12 disease processes and a survey of interstitial cystitis characteristics. The population was 2,405 individuals with interstitial cystitis who responded to the initial survey and an additional 277 individuals who were randomly selected and individually contacted. RESULTS: Allergies, irritable bowel syndrome, and sensitive skin were the most common diseases in the interstitial cystitis population. In comparison to the general population, individuals with interstitial cystitis are 100 times more likely to have inflammatory bowel disease and 30 times more likely to have systemic lupus erythematosus. In addition, allergies, irritable bowel syndrome, sensitive skin, and fibromyalgia have an increased association with interstitial cystitis. CONCLUSIONS: Interstitial cystitis has, as yet, an unexplained association with certain other chronic disease and pain syndromes.

Adult↗
PubMed1994

Reengineering along departmental product flowlines.

This article describes how a medical records department responded to relocating, upgrading a departmental computer system, incorporating severity of illness abstracting, and implementing continuous quality improvement techniques by reengineering along department flowlines over a five-year period. Areas of the department that were restructured were storage and retrieval, record completion, and data collection and reporting functions.

Abstracting and Indexing↗
PubMed1994

Interstitial cystitis. A patient's perspective.

Interstitial cystitis is a debilitating bladder disorder that affects up to 450,000 people in the United States, 90% of whom are women. Confusion in defining and understanding interstitial cystitis has resulted in the failure to diagnose and treat thousands of afflicted patients, committing them to a life of intractable pain. Even with diagnosis, there are no uniformly effective treatments. It is extremely important that these patients have the understanding and support of the medical community, and they should develop a constructive and effective relationship with their physician and other urologic caregivers.

Cystitis↗