Department of Cell Biology and Physiology

www.med.unc.edu/cellbiophysio

PATRICK BRENNWALD, Interim Co-Chair

CAROL A. OTEY, Interim Co-Chair

The Department of Cell Biology and Physiology offers two Ph.D. degree programs, one in Cell and Developmental Biology and one in Cell and Molecular Physiology.


Cell and Developmental Biology Graduate Program

Professors

Patrick Brennwald (5) Cell Polarity, Tumor Suppressor, Vesicle Transport, Exocytosis, Rho GTPases

Keith W. T. Burridge (41) Cell Migration, Cell-Matrix and Cell-Cell Adhesion, Rho Family GTPases, Leukocyte Transendothelial Migration

Johnny L. Carson (6) Developmental Biology, Pathogenic Mechanisms Involving Mammalian Airways

M. Joseph Costello (50) Membrane Biophysics, Intercellular Junctions, Active Transport, Membrane Fusion, Electron Microscopy

Douglas M. Cyr (6) Cystic Fibrosis, Organelle Biogenesis, Protein Folding, Molecular Chaperones, Ubiquitin-Proteasome Pathway

Mohanish P. Deshmukh (3) Neuronal Apoptosis, Molecular Mechanism of Programmed Cell Death, Regulation of Caspase Activation

Kenneth A. Jacobson (39) Membrane Biology and Biophysics, Cell Migration, Video Image Analysis

Royce L. Montgomery (11) Invertebral Disc Lesions and Back Pain

Deborah A. O'Brien (51) Mammalian Spermatogenesis and Fertilization, Regulation of Sperm Motility, Genetics of Male Infertility

Michael G. O'Rand (38) Cell Biology, Immunology, Reproductive Biology

W. Cam Patterson (10) Cardiovascular

Peter Petrusz (13) Neurobiology, Reproductive Biology

Aldo Rustioni (15) Glutamate Receptors Expression and Regulation, Axonal Regeneration and the Cytoskeleton, Somatosensory Mechanisms

Kathleen K. Sulik (40) Developmental Toxicology, Embryology

Ellen R. Weiss (9) Regulatory Domains of G-Protein Coupled Receptors, Molecular Biology of Cellular Signaling Pathways

Associate Professors

James Bear (14) Cell Motility, Actin Cytoskeleton, Coronins, Live-Cell Microscopy

Cornelius J. Beckers (12) Signal Transduction, Cell Motility, Cytoskeleton, Infectious Diseases, Cell Biology

Jay E. Brenman (10) Drosophila and Mouse Genetics, Metabolic Signaling, Type 2 Diabetes Therapeutics

Scott Hammond (008) Biochemical Mechanism for RNA Interference

Assistant Professors

Kurt Gilliland (16) Intercellular Junctions, Human Cataract, Electron/Confocal Microscopy

Stephanie Gupton, Coordination of Actin Dynamics and Membrane Trafficking during Development and Cancer Metastasis, Live Cell Imaging, Cell Adhesion

Edward Kernick, Human Anatomy, Neuroanatomy, Central Nervous System

Ben Major, Proteomic Analysis of Signal Transduction and Cell Biology, Oxidative Stress, Functional Genomics, Mass Spectrometry

John Reader, Protein Translation Apparatus, Aminoacyl-tRNA Synthetases, tRNAs

Research Professors

Richard Weinberg (20) Quantitative Immunocytochemistry, Organization of Excitatory Synapses, Calcium Signaling in Dendritic Spines

Research Associate Professors

Shoji Osawa (16) Regulation of Signal Transduction Pathways by G Proteins

Julia Shackelford

Research Assistant Professors

James Alb

Oleg Alekseev

Elizabeth Benson

Alain Burette

Jr-Gang Cheng

Polina Danshina

Martina Gentzch

Gerald W. Gordon

Maryna Kapustina

Scott Parnell

Erika Wittchen

Instructor

Linda Levitch

Professors Emeriti

Noelle A. Granger

Charles R. Hackenbrock

O'Dell W. Henson Jr.

William E. Koch

Jean M. Lauder

Program of Study

The Department of Cell Biology and Physiology of the School of Medicine offers a program of study leading to the doctor of philosophy degree in Cell and Developmental Biology. The primary purpose of the graduate program is to train students to become biomedical scientists. The program provides training for students whose research/teaching career objectives are faculty positions in medical school basic sciences departments. However, the flexibility of the program also provides for the training of students who seek careers in basic science as well as clinical science departments of medical schools, in other professional schools such as dental schools, in liberal arts academic departments such as biology, or in state, federal, private, and industrial research laboratories. The program for the Ph.D. normally takes five to six years to complete. Persons interested in a combined M.D./Ph.D. program must be accepted into the School of Medicine and the departmental graduate program, whereupon the combined studies are scheduled in accordance with individual requirements.

Some of the department's areas of specialization are cell biology, developmental biology, neurobiology, reproductive biology, membrane biology, molecular biology, cell signaling, and parasitology. Ph.D. students take graduate level courses in their first year as well as conduct laboratory rotations. Students who join the departmental graduate program at the end of year one are examined for advancement to candidacy. Ph.D. candidacy is followed by a dissertation based on original research is conducted under the supervision of a faculty advisor. Additional information is available on the departmental Web site (www.cellbio.med.unc.edu/grad/depttest/welcome.htm).

Admission Requirements

Admission to the departmental graduate program is via the unified Biological and Biomedical Sciences Program (BBSP) at UNC. A B.A. or B.S. degree is required for admission. Applicants are expected to have a strong background in the biological sciences, chemistry, physics, and mathematics. Details of the application process are available at the BBSP Web site (www.med.unc.edu/bbsp) and The Graduate School Web site (gradschool.unc.edu/admissions/). Briefly, the application should include transcripts, Graduate Record Examination (GRE) scores, three letters of recommendation, and a personal statement outlining career goals.

Research Facilities

The department occupies 40,000 square feet of research and office space (in addition to teaching space), primarily in Taylor Hall and the Biomolecular Research Building in the School of Medicine. The department and its research laboratories are a biotechnological resource available for qualified scientists in the University, state, and region. The laboratories house instrumentation for transmission, scanning, and cryo electron microscopy, as well as equipment to prepare biological specimens for these techniques. The Electron Microscope Facility contains a multipurpose JOEL 820 scanning electron microscope and a high-resolution FEI-Philips Tecnai 12 transmission electron microscope. Ancillary facilities include fully equipped darkrooms and equipment for ultramicrotomy, critical point drying, rotary evaporation, sputter coating, and a state-of-the-art, high-resolution Reichert freeze fracture system. A world class facility is available for optical imaging of all kinds, including digitized video microscopy, confocal microscopy, and fluorescence lifetime imaging microscopy, two-photon confocal microscopy, nanovid microscopy, and fluorescence recovery after photobleaching.

Assistantships and Other Student Aid

Students are supported by a stipend of $27,500 annually plus tuition, fees, and medical insurance.

Courses for Graduate and Advanced Undergraduate Students

CBIO

423 Developmental Toxicology and Teratology (TOXC 423) (3). Emphasizes topics of current research interest relative to the genesis of environmentally caused and genetically based birth defects. One two-hour session per week (evening).

607 Gross Anatomy (2–4). Permission of the instructor. Primarily for graduate students. Enrollment by availability of space and material.

627 Regional Anatomy (3). Permission of the instructor. For students of oral surgery, surgical residents, and graduate students.

643 Cell Structure, Function, and Growth Control I (BIOC 643, MCRO 643, PHCO 643, PHYI 643) (3). Required preparation, undergraduate cell biology or biochemistry or permission of the instructor. Comprehensive introduction to cell structure, function, and transformation.

644 Cell Structure, Function, and Growth Control II (BIOC 644, MCRO 644, PHCO 644, PHYI 644) (3). Required preparation, undergraduate cell biology or biochemistry or permission of the instructor. Comprehensive introduction to cell structure, function, and transformation.

Courses for Graduate Students

CBIO

741 Introduction to Human Anatomy (3). A general course for persons preparing for careers as dental hygienists. Two lectures and two laboratory hours a week.

750 Applied Biostatistics (PATH 750, PHCO 750) (1). See course description for PHCO 750.

791 Gross Anatomy for Physical Therapists (4). Prerequisites, BIOL 276 and 276L. Permission of the instructor. Fundamental principles and concepts of human gross anatomy for physical therapists taught by lectures and cadaver dissection. Emphasis on functional anatomy. Three lecture hours and six laboratory hours a week.

793 Functional Neuroanatomy (3). Prerequisites, CBIO 607 and 791. Permission of the instructor. Study of basic structure of the brain and spinal cord, including both lecture and laboratory. Primarily for physical therapy students. Four hours a week.

805 Gross Anatomy (4). Systematic approach to gross anatomy emphasizing a regional approach stressing head and neck anatomy. Primarily for dental students.

890 Advanced Topics in Cell and Developmental Biology (1–21). Permission of the instructor. Seminar/discussion course dealing with advanced topics in modern cell biology and/or developmental biology. Based mainly on discussion of current literature.

891A Contemporary Problems (3). Permission of the instructor. Analysis of grant proposals dealing with advanced topics in modern cell biology and/or developmental biology.

892B Contemporary Problems (3). Permission of the instructor. Analysis of grant proposals dealing with advanced topics in modern cell biology and/or developmental biology.

893 Cell Biology I (4). Permission of the instructor. Graduate students only. Discussion based course that covers key elements of cell, molecular, and developmental biology, and genetics. Students present and discuss breakthrough primary research papers under the direction of faculty members across the department. Minimal instructor lecturing is included.

894 Cell Biology II (4). Permission of the instructor. Graduate students only. Continuation of CBIO 893. Further topics are covered including cell structure, developmental biology, and cell cycle.

899 Electron Microscopy Principles and Applications (3). Permission of the instructor. Lectures on scanning, transmission, high voltage, freeze fracture, analytical and immunoelectron microscopy. Laboratory training in preparation of biological specimens, operation of scanning and transmission microscopes, and darkroom procedures. Three lecture hours and twelve laboratory hours per week.

910 Research (2–21). Credit to be arranged in individual cases.

915 Research Laboratory Apprenticeship (2). Enrollment in the cell biology and anatomy graduate program required. A course for first- and second-year graduate students in cell biology and anatomy, consisting of a research project of limited scope pursued under the supervision of a faculty member.

993 Master's Thesis (3).

994 Doctoral Dissertation (3).


Cell and Molecular Physiology Graduate Program

Professors

Eva Anton (76) Molecular Analysis of Neuronal Migration and Development of the Cerebral Cortex

William J. Arendshorst (25) Cell and Integrative Biology of Vascular and Nephron Function, Interactions of Endothelial and Vascular Smooth Muscle Cells, Receptors and Signal Transduction, Regulation of Cytosolic Calcium Concentration, Pathogenic Mechanisms of Hypertension

Richard E. Cheney (69) Motor Proteins, Cytoskeleton, Neuronal Cell Biology

James E. Faber (49) Vascular Physiology, Signal Transduction of Vascular Smooth Muscle and Fibroblast Cells, Atherosclerosis, Adrenergic Receptors

Michael F. Goy (60) Biochemistry and Physiology of Excitable Cells, Second Messenger Mechanisms in Signal Transduction, Epithelial Biology, Natriuretic Peptides

Susan J. Henning (98), Intestinal Stem CellsóBiological Properties and Potential for Therapeutic Application

Pauline K. Lund (50) Growth Factors, Cytokines, Gastrointestinal Growth, Molecular Biology, Signal Transduction, Aging and Memory Loss

Paul Manis (81) Cellular Mechanisms of Auditory Information Processing, Synaptic Plasticity, Ion Channels

Gerhard W. D. Meissner (26) Mechanisms in Excitation-Contraction Coupling in Muscle, Ion Channels

Roy C. Orlando (99) Ion Transport and Barrier Function as Mucosal Defense in Esophageal and Barrett's Epithelium; Mechanisms by Which Acid/Pepsin Injures Squamous Epithelium Leading to Esophagitis and Alters Barrett's Epithelium, Promoting Dysplasia and Malignancy

Carol A. Otey (72) Mechanisms of Cell Adhesion, Cell Migration and Cytoskeletal Organization, and Neuronal Cell Biology

Daniel N. Pomp (89) Genetics of Growth, Obesity, and Body Weight Regulation in Animal Models

Lola M. Reid (67) Hepatic Stem Cell and Maturational Lineage Biology, Synergies between Extracellular Matrix and Hormones in the Regulation of Gene Expression

Aldo Rustioni (30) Somatosensory System; Connections, Neurotransmitters, and Interneuronal Integration

Robert Sealock (32) Cell Biology and Biochemistry of the Neuromuscular Junction, Proteins Involved in Duchenne Muscular Dystrophy

William Snider (74) Developmental Regulation by Neuronal Growth Factors

Barry L. Whitsel (23) Neuronal Mechanisms of Somatic Sensation

Associate Professors

Kathleen Caron (80) Gene Targeted Models of Human Disease, Reproductive Biology, Cardiovascular Biology, G-Protein Coupled Receptor Signaling

Benjamin Philpot (82) Mechanisms of Experience-Dependent Synaptic Plasticity in Visual Cortex

Scott Randell (75) Airway Epithelial Cell Biology-Stem Cells, Host Defense and Response to Injury

Nobuyuki Takahashi (84) Mechanism of Hypertension, Diabetic Complications, and Obesity Using Genetically Engineered Animals

Robert Tarran (87) Regulation of Airway Epithelial Ion and Mucus Transport

Eleni Tzima (88) Mechanisms of Vascular Endothelial Cell Signaling and Angiogenesis in Response to Hemodynamic Stimuli

Mark J. Zylka (90) Molecules and Mechanisms for Pain

Assistant Professors

Andrew C. Dudley (103) Tumor Microenvironment, Tumor Angiogenesis, Vascular Stem Cells

Flavio Frohlich (106) Cortical Neurophysiology, Computational Neuroscience, Brain Stimulation, Epilepsy

Spencer Smith (105) Neuroscience and Neuroengineering

Research Professor

C. William Davis (51) Airway Epithelial Cell Physiology

Research Associate Professor

Nicholas G. Moss (94) Biological Signal Transduction

Research Assistant Professors

Scott Magness (104) Stem Cells/Bioengineered Tissue Scaffolds

Andrea AzcŠrate Peril (102) Defining Fundamental Mechanisms of Probiosis

Sarah Street (107) Molecules and Mechanisms for Pain

Hua Zhang (108) Collateral Vascular Biology: Effects of Aging on Collaterals, Assessing Collateral Endothelial Phenotype, Role of Primary Cilia

Professors Emeriti

Robert G. Faust

Paul B. Farel

Enid R. Kafer

Alan Light

David L. McIlwain

Edward R. Perl

Ann E. Stuart

Lloyd R. Yonce

Physiology is the study of the biological, chemical, and physical processes that underlie the functions of living cells and organs. Research in physiology uses tools from chemistry, mathematics, molecular biology, and physics to identify regulatory mechanisms that operate at levels of complexity ranging from the subcellular to the organismic.

Curriculum

The Department of Cell Biology and Physiology offers a program of study in Cell and Molecular Physiology leading to the Ph.D. or M.D./Ph.D. degree. The M.S. degree is offered only under special circumstances. Research opportunities cover molecular, cellular, and systems physiology with an emphasis on mechanisms of disease. Faculty specialties include neurophysiology, endocrinology, and gastrointestinal, cardiovascular, and renal physiology. The Ph.D. program typically requires four to five years of study. The first two years of graduate study include core and elective course work, laboratory rotations, seminar courses, and research. The curriculum is individualized to develop the analytical, research, and communication skills necessary to carry out successful dissertation research. All students typically take the following courses: a foundational course in physiology (PHYI 702, 703), a presentation skills class (PHYI 705, 706), and electives in year two. Requirements may be waived for students with previous graduate-level course work.

Journal clubs, a class in oral and written communication, the seminar program, and a research-in-progress series provide mechanisms for students to develop research and analytical skills. Teaching experience is available in preprofessional courses, graduate school, and medical school courses. The qualifying examination is scheduled during the second year. Students submit the dissertation proposal in year three and complete research and writing in years four and five.

Research Facilities

The department is located in the Medical Biomolecular Research Building and the adjoining Neuroscience Research Building. Faculty laboratories are equipped for research and training in all methods of biological research, including biophysics, molecular biology, biochemistry, immunochemistry, and whole-animal studies. UNC–Chapel Hill has outstanding centers for the development and breeding of transgenic and gene-knockout mice for molecular biology/recombinant DNA-related research, cardiovascular biology, and cystic fibrosis and pulmonary medicine as well as resources such as the microbiome core and the zebrafish acquaculture core facilities. Researchers in the department routinely collaborate with members of other School of Medicine departments and centers, with laboratories at Duke University, and with researchers at NIEHS in nearby Research Triangle Park.

Financial Aid

All students in good academic standing receive a stipend, tuition scholarship, and health insurance. Many students compete successfully for individual predoctoral fellowships from the AHA, NIH, and NSF, and for competitive awards from The Graduate School. Interdisciplinary training grants in vascular biology, nutrition, cell and molecular biology, and integrative medicine support students across the campus. In addition, the department and individual labs provide funds for students to attend national and international research meetings and specialty courses on- and off-campus.

Placement of Graduates

Recent graduates are working as postdoctoral fellows and faculty members at colleges and universities, as bench scientists in the biotechnology and pharmaceutical sectors, and as scientific advisers in both clinical and basic research settings.

Requirements for Admission

Applications for all 12 School of Medicine basic science graduate programs are processed through the Biomedical and Biological Sciences Program (BBSP), and students spend their first year in that program before transferring to a degree program. Majors in cell and molecular physiology typically have an undergraduate record that includes course work in organic chemistry and biochemistry, two semesters of calculus and physics, and appropriate course work in the biological sciences, typically including zoology, genetics, cell biology, and molecular biology. All applicants are required to submit scores on the GRE aptitude test, a written statement, transcripts, and a minimum of three letters of recommendation. Application details can be found on the BBSP Web site at www.med.unc.edu/bbsp and The Graduate School Web site at gradschool.unc.edu/admissions.

Courses for Graduate and Advanced Undergraduate Students

PHYI

643 Cell Structure, Function, and Growth Control I (BIOC 643, CBIO 643, MCRO 643, PHCO 643) (3). See CBIO 643 for description.

644 Cell Structure, Function, and Growth Control II (BIOC 644, CBIO 644, MCRO 644, PHCO 644) (3). See CBIO 644 for description.

Courses for Graduate Students

PHYI

701 Physiology Laboratory Rotation (1–6). Permission of the director of graduate studies. Rotations in faculty laboratories introduce methods and techniques in physiology. Individual projects provide an opportunity to explore potential dissertation topics.

702 Experimental Physiology of Human Health and Disease (4). Principles of cell, organ, and systems physiology and pathophysiology required to identify important areas of biomedical research, using model systems, common disease examples (schizophrenia, hypertension, diabetes), and current research opportunities.

703 Experimental Physiology of Human Health and Disease (4). Permission of the instructor. Molecular and cellular basis of organ system function; integration of systems to maintain the normal state. Understanding of normal physiology is amplified by examples from human disease and mouse models. Principles of cell, organ, and integrative physiology and how these principles apply to translational research.

705 Communicating Scientific Results (1). Practice in oral and written communication evaluated by peers and faculty. Includes delivery of coached presentations on topics in physiology and preparation of writing assignments typically encountered in scientific life.

706 Communicating Scientific Results (1). Practice in oral and written communication evaluated by peers and faculty. Includes delivery of coached presentations on topics in physiology and preparation of writing assignments typically encountered in scientific life.

710 Medical Neurobiology (NBIO 710) (1–3). Permission of the instructor. A special section (for physiology graduate students only) of the neurobiology course for medical students. Structural and functional organization is analyzed at the level of the cell membrane, the neuron, and integrated neuronal systems.

712A Special Topics in Physiology (NBIO 891) (1–5). Permission of the instructor. Individually arranged in-depth programs of study of selected topics such as membrane function, transport physiology, renal physiology, etc.

712B Special Topics in Physiology (NBIO 892) (1–5). See NBIO 892 for description.

712C Organ System Physiology in Health and Disease: Respiratory Physiology (1). The course begins with the basic physiology of respiration and gas transport, then applies that understanding to in-depth discussions of common respiratory diseases. Format is lecture plus journal club.

714 Physiology (DENT 114) (4). This basic physiology course introduces students to the functions of and interactions between the various systems of the body. Particular emphasis is placed on those concepts of specific relevance for students and practitioners of dentistry. The course also provides students with a solid physiological background for subsequent courses within the dentistry curriculum.

720 Human Physiology (1–5). Permission of the instructor. A special section (for physiology graduate students only) of the course for medical students. The course provides a general consideration of cell function and systemic physiology. Six lecture hours per week.

721 Stem Cells and Maturational Lineage Biology (4). Prerequisites, BIOL 111; CHEM 101, 102, and 241. All tissues are organized with stem cell compartments giving rise to maturational cell lines with lineage-dependent phenotypic characteristics. Investigators discuss research in stem cell biology and regenerative medicine.

722 Cellular and Molecular Neurobiology I (PHCO 722) (2–6). See PHCO 722 for description.

722A Cellular and Molecular Neurobiology: Introduction and Electrical Signaling (BIOC 722A, NBIO 722A, PHCO 722A) (2). See NBIO 722A for description.

722B Cellular and Molecular Neurobiology: Postsynaptic Mechanisms-Receptors (BIOC 722B, NBIO 722B, PHCO 722B) (2). See NBIO 722B for description.

722C Cellular and Molecular Neurobiology: Synaptic Mechanisms & Intracellular Signaling (BIOC 722C, NBIO 722C, PHCO 722C) (2). See NBIO 722C for description.

723 Cellular and Molecular Neurobiology II (PHCO 723) (2–6). Lecture/discussion course on the physiology, pharmacology, biochemistry, and molecular biology of the nervous system. Topics include function and structure of ion channels, neurotransmitter biosynthesis and release mechanisms, neurotransmitter receptors and intracellular signaling pathways.

723A Cellular and Molecular Neurobiology: Development of the Nervous System (BIOC 723A, NBIO 723A, PHCO 723A) (2). See NBIO 723A for description.

723B Cellular and Molecular Neurobiology: Anatomy and Function of Sensory and Motor Systems (BIOC 723B, NBIO 723B, PHCO 723B) (2). See NBIO 723B for description.

724 Developmental Neurobiology (NBIO 724) (3). Prerequisite, NBIO 722. Permission of the instructor. A survey of nervous system development emphasizing detailed analysis of selected research topics such as neuronal induction, neural crest development, neuronal differentiation, synapse formation, neurotrophic factors, glial development, and the effects of experience.

751 Seminar in Physiology (1). Permission of the director of graduate studies.

752 Seminar in Physiology (1). Permission of the director of graduate studies.

800 Teaching Physiology (1–3). Permission of the instructor. Introduces the principles of teaching physiology. Provides students the opportunity to plan instruction and to teach with increasing degrees of responsibility. The teaching internship is under the direct supervision of a faculty mentor

832 Respiratory Physiology: Defense Mechanisms in the Airways (1–4). Prerequisite, PHYI 703. The integrated defense mechanisms that protect the airways and lung from inhaled allergens, irritants, particulates, and pathogens. Topics include transepithelial ion transport, mucociliary clearance, and innate immune responses.

833 Gastrointestinal Physiology: Growth, Cancer, Inflammation, and the Microbiome (1–3). Prerequisite, PHYI 703. Roles of growth factor and cytokine signaling, and the intestinal microbiome in normal intestinal growth, inflammation, or colon cancer. Molecular, cellular, genomic, model organisms and translational medicine approaches.

834 Pain and Somatic Sensation (NBIO 824) (1–21). Prerequisite, PHYI 720. Permission of the instructor. Consideration of peripheral and central neural mechanisms for somatic sensation with particular emphasis on pain.

835 CNS Organization (1). Primary literature explores how the nervous system is organized, integrates information, and adapts.

836 Excitable Membranes, Receptors, Channels and Synapses (1–4). Basic neurophysiology of excitable membranes, channels, and synapse as the basis of neuronal communication.

839 Endothelial Cells in Health and Disease (1). Prerequisite, PHYI 703. Literature-based survey of endothelial cell biology including development, angiogenesis, environmental influences, and disease models.

840 Renal/Cardiovascular Systems (1–4). Prerequisite, PHYI 703. Permission of the instructor. Blood pressure control in normal, diseased, and genetically modified animals. Physiology and pathophysiology of the renal and cardiovascular systems.

850 Seminar in Neurobiology (BIOL 850, NBIO 850, PHCO 850) (3). See NBIO 850 for description.

901 Research in Physiology (3–10).

902 Research in Physiology (3–10).

903 Research in Physiology (3–10).

951 Research in Neurobiology (BIOL 951, NBIO 951, PHCO 951) (3–12). See NBIO 951 for description.

993 Master's Thesis (3–21).

994 Doctoral Dissertation (3–21).