Phenotypic Switching

Phenotypic Switching: Implications in Biology and Medicine provides a comprehensive examination of phenotypic switching across biological systems, including underlying mechanisms, evolutionary significance, and its role in biomedical science. Contributions from international leaders discuss conceptual and theoretical aspects of phenotypic plasticity, its influence over biological development, differentiation, biodiversity, and potential applications in cancer therapy, regenerative medicine and stem cell therapy, among other treatments. Chapters discuss fundamental mechanisms of phenotypic switching, including transition states, cell fate decisions, epigenetic factors, stochasticity, protein-based inheritance, specific areas of human development and disease relevance, phenotypic plasticity in melanoma, prostate cancer, breast cancer, non-genetic heterogeneity in cancer, hepatitis C, and more. This book is essential for active researchers, basic and translational scientists, clinicians, postgraduates and students in genetics, human genomics, pathology, bioinformatics, developmental biology, evolutionary biology and adaptive opportunities in yeast. Thoroughly addresses the conceptual, experimental and translational aspects that underlie phenotypic plasticity Emphasizes quantitative approaches, nonlinear dynamics, mechanistic insights and key methodologies to advance phenotypic plasticity studies Features a diverse range of chapter contributions from international leaders in the field

Candida albicans is a major fungal pathogen of humans. It is a harmless commensal in healthy individuals, but it can cause serious infections in immune-compromised hosts. C. albicans undergoes a meta-stable and reversible switch between two distinct cell types known as white and opaque. The role of white-opaque switching in the biology of C. albicans was originally not well understood. We discovered an unexpected relationship between white-opaque switching and the sexual cycle of C. albicans . The mating type locus of C. albicans (MTL) encodes transcriptional regulatory proteins that regulate mating. We demonstrated that two MTL -encoded homeodomain proteins, a 1 and alpha2, work together to repress white-opaque switching in C. albicans . The observations that the MTL locus controlled both mating and white-opaque switching led us to hypothesize that opaque cells played a role in mating. Indeed, we found that opaque cells mate one million times more efficiently than do white cells. Additionally, opaque cells, but not white cells, developed specialized mating projections when exposed to mating pheromone. Thus, opaque cells are a specialized mating form of C. albicans . As white cells are generally more robust in a mammalian host than opaque cells, this strategy allows the organism to survive the rigors of life within a mammalian host, while generating a small population of mating-competent cells. The mechanism that controls white-opaque switching is not well understood. To better understand the mechanism, we investigated the regulation of white-opaque switching by a 1-alpha2. We demonstrated that a 1-alpha2 regulates white-opaque switching by destabilizing opaque cells, and we monitored gene expression during the transition from opaque to white using DNA microarrays. We used a candidate approach to identify additional regulators of white-opaque switching among genes enriched for their expression in the opaque phase. We identified two potent positive regulators of white-opaque switching: the opaque-specific transcriptional regulatory proteins Czf1 and Naf1. We also further investigated the role of Efg1, a previously identified regulator of white-opaque switching, and found that efg1/efg1 mutants were unable to bypass a 1-alpha2 repression of switching. Finally, we determined the epistatic and regulatory relationships between Efg1, Czf1 and Naf1.

In order to determine the host signals and fungal signaling pathways that control the white-GUT switch and drive commensalism, we developed an in vitro system to induce switching behavior and screened a library of C. albicans signaling mutants. We identified three fungal signaling pathways (Hog1, Rim101, and PKA), previously associated with other morphological transitions, which promote GUT cell formation. Together these studies help to understand how C. albicans' phenotypic plasticity influences its interactions with the mammalian host.

Gene expression is a stochastic biological processes that controls the different phenotypes of an organism depending on the environment. High-resolution single cell measurements show that genetically identical cells can be different from each other even in a homogeneous environment, leading a spectrum of phenotypes with different cellular fitnesses that can reversibly switch between phenotypes. How population-level properties emerge from single cell behavior and how mutants emerge and spread in such populations is unclear. In this thesis, we developed mathematical models to study (i) the effect of time-delay needed for a mutation in a regulator gene influence an effector protein and the long term population fitness, (ii) how optimum population fitness behaves as a function of the growth rates of the various phenotypes for different durations in fluctuating environments. Our work shows a paradoxical outcome of evolution where mutations in a regulator gene interact with gene network dynamics and evolutionary dynamics, giving rise to permanent decrease in population fitness. In the other scenario of fluctuating environments, a previously predicted optimum exists for wider parameter regime if the environmental durations are long and narrow regime for short environmental durations. We also find that a mutant, which randomly evolved to match its phenotypic switching rates with environmental switching rates, can sweep the population if the predicted optimum matches with the assumed one, but not otherwise.

This text gives an overview of the fundamental aspects of molecular fungal development in one comprehensive volume, highlighting different elements in the maturational and reproductive cycles of selected fungal taxa.

The process of Epithelial-Mesenchymal-Transition (EMT) is known to result in a phenotype change in cells from a proliferative state to a more invasive state. EMT has been reported to drive the metastatic spread of various cancers and has also been associated with drug resistance to cytotoxics and targeted therapeutics. Recently phenotype switching akin to EMT has been reported in non-epithelial cancers such as metastatic melanoma. This process involves changes in EMT-Transcription Factors (EMT-TFs), suggesting that phenotype-switching may be common to several tumour types. It remains unclear as to whether the presence of both Epilthelial-like and Mesenchymal-like cells are a pre-requisite for phenotype switching within a tumour, how this heterogeneity is regulated, and if alteration of cell phenotype is sufficient to mediate migratory changes, or whether drivers of cell migration result in an associated phenotype switch in cancer cells. Similarly it has yet to be clarified if cells in an altered phenotype can be refractory to drug therapy or whether mediators of drug resistance induce a concurrent phenotypic change. Little is known today about the underlying genetic, epigenetic and transient changes that accompany this phenotypic switch and about the role for the tumor micro-environment in influencing it. Hence this is currently an area of speculation and keen interest in the Oncology field with wide-ranging translational implications. In this Frontiers Research Topic, we discuss our current understanding of these concepts in various cancer types including breast cancer, colorectal cancer and metastatic melanoma. This topic covers how these processes of cellular and phenotypic plasticity are regulated and how they relate to cancer initiation, progression, dormancy, metastases and response to cytotoxics or targeted therapies.

The first textbook of mycology ever to focus on the management of patients with fungal infections, CLINICAL MYCOLOGY represents an expert, authoritative examination of clinical problem-solving approaches to diagnosis and management. It offers specific recommendations for understanding, controlling, and preventing fungal infections based on underlying principles of epidemiology and infection control policy, pathogenesis, immunology, histopathology, and laboratory diagnosis and antifungal therapy. The book also covers etiologic agents of disease, fungal infections in special hosts such as pediatric patients and patients with cancer or HIV, infections of the organ systems, and more. Extensive illustrations, tables, and photographs throughout the book highlight its clinical context and enhance the reader's understanding of the subject. Complete and authoritative, yet practical, discussion makes this book an ideal one-stop source for diagnosis, management, and prevention of fungal infections. Editors and authors are recognized experts in their field, offering consistently high standard-of-care approaches. Excellent photographs and drawings illustrate specific concepts and conditions. Tables present summaries of key points to help the reader quickly access information on a subject. Clear, definitive recommendations for diagnosis and management of fungal infections are outlined and related to clinical practice.

Brings together the papers presented at this important 1993 workshop. Addressed is a wide array of issues of interest to the dental practitioner and researcher, from oral lesions to periodontal concerns to provision of care and infection control practices. [editor].

Proceedings of a workshop held at the U. of Florida Health Center in Gainesville, February 1989. Surveys and evaluates the status of research in the related fields of bacteriology, mycology, immunology, and host-parasite relationships. The five sections address bacterial factors; fungal factors; bacterial factors in sexually transmitted diseases; biologic factors; and antibiotic resistance. Members price, $41. Annotation copyrighted by Book News, Inc., Portland, OR

A comprehensive and critical review of the medical and scientific literature on Candida infections by a leading authority in the field. Covers all aspects of the subject, including epidemiology, pathogensis and treatment, as well as the properties of the fungi that cause infections.