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Energy production is a biological process required for life by all living organisms. However, this process exerts a major effect on aging as metabolism of nutritive energy at the mitochondria inevitably generates reactive oxygen species (ROS). ROS are by-products of cellular metabolism and have important physiological roles in cell signaling and homeostasis but can also harbor harmful effects. Because ROS readily react with other macromolecules, if ROS formation exceeds a physiological level and antioxidants are unable to balance out the damaging effects of ROS, a dangerous condition known as oxidative stress occurs. This accumulation of cellular damage severely compromises cell health and contributes to the onset of age-associated diseases. Many organisms have complex antioxidant systems to protect themselves and in Caenorhabditis elegans, SKN-1/Nrf2 and DAF-16/FOXO, promote the expression of stress resistance genes that aid in detoxifying ROS. Our lab has previously shown that transcription factors can influence the expression of phase II detoxifying genes, through SKN-1 activation, while phase I genes can be activated through DAF-16 which confer stress resistance. An RNAi screen against transcription factor ZTF-17 revealed thatSKN-1 target, gst-4p::gfpexpression, was enhanced. This suggested that ZTF-17 possessed repressor like functions during oxidative stress responses. I confirmed that ZTF-17 significantly reduced the activity of SKN-1 and DAF-16 on the skn-1cp and sod-3p target promoters indicating that ZTF-17 may interact directly and/or indirectly with the DNA to modulate transcription through repression. Analysis through various experiments using ztf-17(tm963) deletion mutants showed that genes related to oxidative stress, lifespan and longevity were enhanced to promote short-term oxidative stress resistance, but interestingly, mutants also had compromised heat shock survival. The stress regulatory network is extremely complex, and although detoxification processes exist, the molecular players involved in maintaining proper function under oxidative stress remains unclear. Thus, my investigation of ZTF-17s function along with characterizing its role as a potential negative regulator will help elucidate the mechanism to achieve stress resistance and the implications this has on lifespan and longevity.
Aging is a complex process influenced by the environment and genotype. Numerous conserved genetic pathways and factors have been identified as key mediators of lifespan and stress responses in the nematode C. elegans. Host cell factor-1 (HCF-1) is a longevity and stress response modulator in worms. Mammalian HCF-1 is a vital transcriptional regulator which scaffolds diverse transcriptional regulatory complexes and controls gene expression. In C. elegans, HCF-1 is a repressor of the critical longevity determinant DAF-16, the homolog of mammalian FOXO transcription factors. The molecular partners of HCF-1 and the mechanisms whereby it modulates lifespan and stress responses have not been fully elucidated. My work implicated HCF-1 as a critical player in the regulatory mechanism linking DAF-16 and its coactivator SIR-2.1 in worms. Genetic analyses revealed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response. Gene expression profiling uncovered a striking 80% overlap between the HCF-1- and SIR-2.1-regulated DAF16 target genes. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16mediated transcription important for aging and stress responses. My findings uncover a novel interaction between the key longevity determinants SIR-2.1 and HCF-1, and provide new insights into the complex regulation of DAF-16. SKN-1 transcription factor is an evolutionarily conserved protector against oxidative and xenobiotic stress and is a well-established pro-longevity factor. I demonstrated that SKN1 contributes to the enhanced oxidative stress resistance incurred by hcf-1 inactivation in a manner parallel to DAF-16. This functional interaction between HCF-1 and SKN-1 specifically occurs under excessive oxidant stress as SKN-1 is dispensable for the thermotolerance and long lifespan of hcf-1 mutants. HCF-1 represses the activation of SKN-1 to inhibit SKN-1 target genes involved in cellular detoxification pathways. To control SKN-1 activity, HCF-1 prevents nuclear accumulation of SKN-1 in response to oxidative stress. My findings reveal a new, context-specific regulatory relationship between the stress-response factors HCF-1 and SKN-1. Given that HCF-1, DAF-16, SIR-2.1, and SKN-1 are functionally conserved between C. elegans and mammals, my findings have important implications for the regulation of mammalian counterparts of these factors by HCF proteins.
Yeast Genetics: Methods and Protocols is a collection of methods to best study and manipulate Saccharomyces cerevisiae, a truly genetic powerhouse. The simple nature of a single cell eukaryotic organism, the relative ease of manipulating its genome and the ability to interchangeably exist in both haploid and diploid states have always made it an attractive model organism. Genes can be deleted, mutated, engineered and tagged at will. Saccharomyces cerevisiae has played a major role in the elucidation of multiple conserved cellular processes including MAP kinase signaling, splicing, transcription and many others. Written in the successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols and notes on troubleshooting and avoiding known pitfalls. Authoritative and easily accessible, Yeast Genetics: Methods and Protocols will provide a balanced blend of classic and more modern genetic methods relevant to a wide range of research areas and should be widely used as a reference in yeast labs.
Connects classical cellular descriptive studies with more recent work on the molecular and genetic aspects regarding germline development. Prominent scientists discuss research on a range of organisms including insects, worms, birds, fish, amphibia, mammals and green algae. Specification of germ cells, their migration to the gonads and subsequent interactions with the soma and evolutionary factors of their segregation are among the topics covered.
This second edition volume expands on the previous edition by exploring the latest advancements in high throughput screening (HTS) in toxicity studies by using in vitro, ex vivo, and in vivo models. This volume also covers the application of artificial intelligence (AI) and data science to curate, manage, and use HTS data. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and thorough, High Throughput Screening Assays in Modern Toxicology, Second Edition is a valuable resource for scientists pursuing chemical toxicology research. This book will aid scientists and researchers in translating new HTS techniques into standardized chemical toxicology assessment tools that can refine, reduce, and replace animal testing.
This book represents the proceedings from a conference that took place in Dallas in the spring of 1999 which was entitled "Pediatric Gender Assignment - A Critical Reappraisal". Some participants rightfully argued that the conference really focused on the issue of pediatric gender assignment, and that reassignment was not applied in most cases. Their comments were reflected in the title of this monograph. This multidisciplinary meeting was sponsored by a conference grant from the National Institutes of Health, and a broad inquiry into this complex topic took place from many points of view. Basic scientists offered insight into mechanisms of sexual differentiation of the gonads, physical phenotype and imprinting of the central nervous system. Endocrinologists reviewed their experience in diagnosis and management, surgeons described traditional as well as innovative approaches, and there was strong representation from the ethical and behavioral sciences. In putting together such a panel, it was essential that we identify a cast of speakers who could address their viewpoints with strong convictions, and yet not let their passions render the meeting counter productive. We were not disappointed. While many differing points of view were firmly expressed by the panelists and audience, all viewpoints were accorded the respect they deserved. The concept behind the meeting and this book really originated in 1997 shortly after Diamond and Sigmundson published their long term follow up study of the John/Joan case.