Preface Lehninger Teaching Hallmarks Students encountering biochemistry for the first time often have difficulty with two key aspects chemistry to help them understand biochem- istry.Those same students must also learn a challenges,we provide the following study aids: Focus on Chemical Logic nical Logi e organic chemistry with biochemistry. NEW chemical logic figures highlight the conservation of mechanism and pathways,including glycolysis (Fig.14-3) 16-7),and fatty acid Mechanism figures feature step-by-step the reaction pr s.These figures use +HD (chymotrypsin,pp.216-217). 。m Tryptophan synthase reaction
Lehninger Teaching Hallmarks Students encountering biochemistry for the first time often have difficulty with two key aspects of the course: approaching quantitative problems and drawing on what they learned in organic chemistry to help them understand biochemistry. Those same students must also learn a complex language, with conventions that are often unstated. To help students cope with these challenges, we provide the following study aids: Focus on Chemical Logic u Section 13.2, Chemical Logic and Common Biochemical Reactions, discusses the common biochemical reaction types that underlie all metabolic reactions, helping students to connect organic chemistry with biochemistry. u NEW chemical logic figures highlight the conservation of mechanism and illustrate patterns that make learning pathways easier. Chemical logic figures are provided for each of the central metabolic pathways, including glycolysis (Fig. 14–3), citric acid cycle (Fig. 16–7), and fatty acid oxidation (Fig. 17–9). u Mechanism figures feature step-by-step descriptions to help students understand the reaction process. These figures use a consistent set of conventions introduced and explained in detail with the first enzyme mechanism encountered (chymotrypsin, pp. 216–217). x Preface An aldol cleavage produces indole and glyceraldehyde 3-phosphate; PLP is not required. Dehydration of serine forms a PLP-aminoacrylate intermediate. Indole condenses with the aminoacrylate intermediate (2 steps). Imine linkage joining tryptophan to PLP is hydrolyzed. Indole traverses tunnel between a and b subunits. 1 Glyceraldehyde 3-phosphate Indole Quinonoid From serine Indole Tunnel CH3 O COO P NH NH NH H Glyceraldehyde 3-phosphate N H CH CH CH2 P Indole-3-glycerol phosphate O H C OH NH3 CH CH Indole N H COO C CH2 P O O C H O H CH2 PLP tryptophan synthase a subunits 2 3 4 tryptophan synthase b subunits Quinonoid intermediate CH3 COO P OH C N H CH2 C H B O H Indole H2C Aldimine with tryptophan CH2 N H N H H N H CH3 P OH C N H O CH2 H COO N H CH2 C H OH Serine (b) (a) NH3 CH COO CH2 H2O N H Tryptophan CH2 OH OH B HB PLP-aminoacrylate adduct PLP H2O Enzyme 5 aconitase fumarase aconitase malate dehydrogenase citrate synthase isocitrate dehydrogenase a-ketoglutarate dehydrogenase complex succinyl-CoA synthetase succinate dehydrogenase Oxaloacetate Acetyl-CoA Malate Citrate Isocitrate Succinyl-CoA Succinate Fumarate Citric acid cycle a-Ketoglutarate cis-Aconitate 1 3 4 5 6 7 8 CH3 C O S-CoA H2O CoA-SH CH2 COO HO H C O CoA-SH H2O COO C COO CH CH2 COO C O CH2 COO COO C COO CH2 COO C H HO C COO CH2 COO C COO H CH2 COO CH2 COO COO O COO CO2 C CH2 CH2 CH COO 2 COO COO HC HO COO COO CH CH2 CO2 S-CoA CoA-SH CH2 H2O H2O (3) NADH GTP (ATP) GDP (ADP) Pi FADH2 Claisen condensation: methyl group of acetyl-CoA converted to methylene in citrate. Dehydration/rehydration: —OH group of citrate repositioned in isocitrate to set up decarboxylation in next step. Oxidative decarboxylation: pyruvate-dehydrogenase-like mechanism; dependent on carbonyl on adjacent carbon. Substrate-level phosphorylation: energy of thioester conserved in phosphoanhydride bond of GTP or ATP. (Rehydration) Oxidative decarboxylation: —OH group oxidized to carbonyl, which in turn facilitates decarboxylation by stabilizing carbanion formed on adjacent carbon. Dehydrogenation: introduction of double bond initiates methylene oxidation sequence. Hydration: addition of water across double bond introduces —OH group for next oxidation step. Dehydrogenation: oxidation of —OH completes oxidation sequence; generates carbonyl positioned to facilitate Claisen condensation in next step. Reactions of the citric acid cycle Tryptophan synthase reaction FMTOC.indd Page x 19/10/12 1:36 PM user-F408 /Users/user-F408/Desktop
Preface Problem-Solving Tools In-text Worked Examples help students improve their quantitative problem-soving skills,taking them opportunity to practice what they have learned. University of Ma ssachu hey hav ly th from the erature Key Conventions Many of the conventions that are so necessary for understanding each biochemical topic and the biochem many assumptions and conventions that students are often expected to assimilate without being told (for are written from5'to 3end,left to right). Media and Supplements Vidall package of medaredoui i ch and goals of the sixth-edition textbook. *NEW*BiochemPortal e-Book(ebooks.bfwpub.com/lehninger6e) (courses.bfwpub.com/lehninger6e) student resources,instructor assignment and gradebook to support the text.The e-Book also provides useful functionality,and a new LeamingCurve quizzing tool. material for instructors. BiochemPortal includes the e-Book.with the full e-Book study tools include instant navigation to contents of the text,highlighting and note-taking any section or page of the book,bookmarks 1. nt mete the ability to assign any resource,as well as mehanisms,amimatodbiochenicalteciuques e-Bookrednisboa dposts,and their stru and Livina Graphs ceach described under"Student campus Course Management System. Resources"below) New biochemportal also includes lea Instructor features include the ability to add notes or files to any page and to share these notes tailored to students'target difficulty level and an with students.N may include text, eb lin the entire text or a custom version of the e-Book
Problem-Solving Tools u In-text Worked Examples help students improve their quantitative problem-solving skills, taking them through some of the most difficult equations. New worked examples appear in Chapters 1, 2, and 19. u More than 600 end-of-chapter problems (about 25 of them new) give students further opportunity to practice what they have learned. u Data Analysis Problems (one at the end of each chapter), contributed by Brian White of the University of Massachusetts–Boston, encourage students to synthesize what they have learned and apply their knowledge to the interpretation of data from the literature. Key Conventions Many of the conventions that are so necessary for understanding each biochemical topic and the biochemical literature are broken out of the text and highlighted. These Key Conventions include clear statements of many assumptions and conventions that students are often expected to assimilate without being told (for example, peptide sequences are written from amino- to carboxyl-terminal end, left to right; nucleotide sequences are written from 5 to 3 end, left to right). Preface xi Media and Supplements A full package of media resources and supplements provides instructors and students with innovative tools to support a variety of teaching and learning approaches. All these resources are fully integrated with the style and goals of the sixth-edition textbook. *NEW* BiochemPortal (courses.bfwpub.com/lehninger6e) This comprehensive and robust online teaching and learning tool incorporates the e-Book, all instructor and student resources, instructor assignment and gradebook functionality, and a new LearningCurve quizzing tool. u BiochemPortal includes the e-Book, with the full contents of the text, highlighting and note-taking tools, and links to important media assets (listed below). u In addition to all instructor resources (listed below), BiochemPortal provides instructors with the ability to assign any resource, as well as e-Book readings, discussion board posts, and their own materials. A gradebook tracks all student scores and can be easily exported to Excel or a campus Course Management System. u New BiochemPortal also includes LearningCurve, a self-paced adaptive quizzing tool. With questions tailored to students’ target difficulty level and an engaging scoring system, LearningCurve encourages students to incorporate content from the text into their study routine and provides them with a study plan on completion. u Students can access any of the student resources provided with the text (see below) through links in the e-Book or the handy Resources tab. e-Book (ebooks.bfwpub.com/lehninger6e) This online version of the textbook combines the contents of the printed book with electronic study tools and a full complement of student media specifically created to support the text. The e-Book also provides useful material for instructors. u e-Book study tools include instant navigation to any section or page of the book, bookmarks, highlighting, note-taking, instant search for any term, pop-up key-term definitions, and a spoken glossary. u The text-specific student media, fully integrated throughout the e-Book, include animated enzyme mechanisms, animated biochemical techniques, problem-solving videos, molecular structure tutorials in Jmol, Protein Data Bank IDs in Jmol, and Living Graphs (each described under “Student Resources” below). u Instructor features include the ability to add notes or files to any page and to share these notes with students. Notes may include text, Web links, animations, or photos. Instructors can also assign the entire text or a custom version of the e-Book. WORKED EXAMPLE 19–2 Stoichiometry of ATP Production: Effect of c Ring Size (a) If bovine mitochondria have 8 c subunits per c ring, what is the predicted ratio of ATP formed per NADH oxidized? (b) What is the predicted value for yeast mitochondria, with 10 c subunits? (c) What are the comparable values for electrons entering the respiratory chain from FADH2? Solution: (a) The question asks us to determine how many ATP are produced per NADH. This is another way of asking us to calculate the P/O ratio, or x in Equation 19–11. If the c ring has 8 c subunits, then one full rotation will transfer 8 protons to the matrix and produce 3 ATP molecules. But this synthesis also requires the transport of 3 Pi into the matrix, at a cost of 1 proton each, adding 3 more protons to the total number required. This brings the total cost to (11 protons)/(3 ATP) 5 3.7 protons/ATP. The consensus value for the number of protons pumped out per pair of electrons transferred from NADH is 10 (see Fig. 19–19). So, oxidizing 1 NADH produces (10 protons)/(3.7 protons/ ATP) 5 2.7 ATP. (b) If the c ring has 10 c subunits, then one full rotation will transfer 10 protons to the matrix and produce 3 ATP molecules. Adding in the 3 protons to transport the 3 Pi into the matrix brings the total cost to (13 protons)/ (3 ATP) 5 4.3 protons/ATP. Oxidizing 1 NADH produces (10 protons)/(4.3 protons/ATP) 5 2.3 ATP. (c) When electrons enter the respiratory chain from FADH2 (at ubiquinone), only 6 protons are available to drive ATP synthesis. This changes the calculation for bovine mitochondria to (6 protons)/(3.7protons/ ATP) 5 1.6 ATP per pair of electrons from FADH2. For yeast mitochondria, the calculation is (6 protons)/(4.3 protons/ATP) 5 1.4 ATP per pair of electrons from FADH2. These calculated values of x or the P/O ratio define a range that includes the experimental values of 2.5 ATP/NADH and 1.5 ATP/FADH2, and we therefore use these values throughout this book. c19OxidativePhosphorylationAndPhotophosphorylation.indd Page 757 21/09/12 8:33 AM user-F408 /Users/user-F408/Desktop FMTOC.indd Page xi 09/10/12 1:57 PM user-F408 /Users/user-F408/Desktop
xii Preface Instructor Resources Instructors are e set of representing a topic that students os,andndidaleachngstwesA traditionally struggle to master.Dr.Ensign first ture presentat d o ther the Instructor Resource DVD (ISBN 1-4641-0969-9) clear concise steps.Students can easily pause New clicker questions p ide instructors with wish until they daamiemitple-choicequestiornstobesedwn Working thr gh the Th in this way is designed tomake students better and tive e tin the cla and het e inform instructors on student misunderstandings Fully optimized JPEG files of every figure the Animated En photo,and table in the text feature enhand n students understand key and enlarged fonts.The mechanisms and techniques at their own pace e lecture hall to ensure structors and maximum clarity and visibility.The JPEGs are al chanter Anin a are available in Flash files and A list of Protein data bank ids fo the structures in the text are arranged by figure number.A new feature in this applet. equations from the textbook.show the graphic results of changing parameters. Protein Architecture Molecular Structure Tutoria A comprehensive Test Bank in PDF and editable Word formats in Molecular Structure Tutorials,using the Jmol the textbook.including Student Resource Protein Architectur Bacterorhodopsin Lac Repressor along with the PDB Structures and Living Graphs,are Nucleotides MHC Molecules the text indicate the availabilty of relevant animation Trimeric G proteins Living Graph.or Molecular Structure Tutorial. Oxygen-Binding Proteins Problem-Solving Videos,created by Scott Ensign Restriction Endonuclease of Utah State University.provide 24/7 online Hammerhead Ribozyme
Instructor Resources Instructors are provided with a comprehensive set of teaching tools, each developed to support the text, lecture presentations, and individual teaching styles. All instructor media are available for download on the book website (www.whfreeman.com/lehninger6e) and on the Instructor Resource DVD (ISBN 1-4641-0969-9). u New clicker questions provide instructors with dynamic multiple-choice questions to be used with iClicker or other classroom response systems. The clicker questions have been written specifically to foster active learning in the classroom and better inform instructors on student misunderstandings. u Fully optimized JPEG files of every figure, photo, and table in the text feature enhanced color, higher resolution, and enlarged fonts. The files have been reviewed by course instructors and tested in a large lecture hall to ensure maximum clarity and visibility. The JPEGs are also offered in separate files and in PowerPoint format for each chapter. u Animated Enzyme Mechanisms and Animated Biochemical Techniques are available in Flash files and preloaded into PowerPoint, in both PC and Macintosh formats, for lecture presentation. u A list of Protein Data Bank IDs for the structures in the text are arranged by figure number. A new feature in this edition is an index to all structures in the Jmol interactive Web browser applet. u Living Graphs, illustrating key equations from the textbook, show the graphic results of changing parameters. u A comprehensive Test Bank in PDF and editable Word formats includes 150 multiple-choice and short-answer problems per chapter, rated by level of difficulty. Student Resources Students are provided with media designed to enhance their understanding of biochemical principles and improve their problem-solving ability. All student media, along with the PDB Structures and Living Graphs, are also in the e-Book, and many are available on the book website (www.whfreeman.com/lehninger6e). Icons in the text indicate the availability of relevant animation, Living Graph, or Molecular Structure Tutorial. u Problem-Solving Videos, created by Scott Ensign of Utah State University, provide 24/7 online problem-solving help to students. Through a twopart approach, each 10-minute video covers a key textbook problem representing a topic that students traditionally struggle to master. Dr. Ensign first describes a proven problem-solving strategy and then applies the strategy to the problem at hand in clear, concise steps. Students can easily pause, rewind, and review any steps as they wish until they firmly grasp not just the solution but also the reasoning behind it. Working through the problems in this way is designed to make students better and more confident at applying key strategies as they solve other textbook and exam problems. u Student versions of the Animated Enzyme Mechanisms and Animated Biochemical Techniques help students understand key mechanisms and techniques at their own pace. xii Preface u Molecular Structure Tutorials, using the JmolWeb browser applet, allow students to explore in more depth the molecular structures included in the textbook, including: Protein Architecture Bacteriorhodopsin Lac Repressor Nucleotides MHC Molecules Trimeric G Proteins Oxygen-Binding Proteins Restriction Endonucleases Hammerhead Ribozyme Protein Architecture Molecular Structure Tutorial FMTOC.indd Page xii 19/10/12 1:36 PM user-F408 /Users/user-F408/Desktop
Preface xiii The Absolute,Ultimate Guide to Lehninger Principles Major Coneepts:a road map through the chapter of Biochemistry,SixthEdition,Study Guidend 4 What to Review:questions that recap key points lutions Man from previous chapters New Mexico School of Medicine)and Karen Ocorr 4 Discussion Questions:provided for each section (Sanford-Burnham Medical Research Institute); designed for individual review,study groups.or classroom discussion I5BN1429294760 A Self-Test:"Do you know the terms?";crossword The absobute inltimate guide combine study guide with a reliable solutions manual (providing e,fact-driv ons;and extended solutions to end-of-chapter problems)in one each class-tested,the study Acknowledgments setti of Ne man and Company who supported us at every step alone proofs.caught numerous mistakes.and made many sug the way.Susan M gestions that improved the book an w nhi o. new this edition,made many helpful suggestions,encourage in Madison.who often made valuable suggestions tha led to better and clear poiedexie and Adam on our te ters We are also deeply indebted to brian White of th how kept the oomoving through production in University of Massachusetts-Boston, who wrote the with her usual grace and skil.We thank Art Dire stry in designing both the text interest in the proje ct and the timely input.Prominen ent at the University of California.Berkeley.Charles G lasting contributions from the f Hoogstraten of Michigan State Unversity made mar ger Ted th g of califo an State University at Long Beach for his critical com Many others helped us shape this s sixth ed of them we are deeply grateful for ass mportan media compo Richard Amasino,of 0s7 creativity and good humor in co Alan Attie.University of Wisc marketing effort. A very special thanks goes to Kat Kenneth Balazovich.University of Michigan tions and co ihuted much to it ing on to other things:we will miss her insight.humor Brian bothner.Montana state University and e n Maent tas ste in re lary Bryk,Texas AdM Untversity and critic.She is the first t o see manuscript chapters Keith Dunker,Indiana Universit as in manu te College of Denver us on task with more-or-less gentle prodding.As she did Brent Feske,Armstrong Atlantic State University
The Absolute, Ultimate Guide to Lehninger Principles of Biochemistry, Sixth Edition, Study Guide and Solutions Manual, by Marcy Osgood (University of New Mexico School of Medicine) and Karen Ocorr (Sanford-Burnham Medical Research Institute); ISBN 1429294760 The Absolute, Ultimate Guide combines an innovative study guide with a reliable solutions manual (providing extended solutions to end-of-chapter problems) in one convenient volume. Thoroughly class-tested, the study guide includes for each chapter: u Major Concepts: a road map through the chapter u What to Review: questions that recap key points from previous chapters u Discussion Questions: provided for each section; designed for individual review, study groups, or classroom discussion u A Self-Test: “Do you know the terms?”; crossword puzzles; multiple-choice, fact-driven questions; and questions that ask students to apply their new knowledge in new directions—plus answers! Preface xiii Acknowledgments This book is a team effort, and producing it would be impossible without the outstanding people at W. H. Freeman and Company who supported us at every step along the way. Susan Moran (Senior Developmental Editor), Susan Winslow (Publisher), and Lauren Schultz (Senior Acquisitions Editor) helped develop the revision plan for this edition, made many helpful suggestions, encouraged us, and tried valiantly (if not always successfully) to keep us on schedule. Matthew Tontonoz (Developmental Editor) provided extremely helpful feedback on many chapters. Our outstanding Project Editor, Jane O’Neill, somehow kept the book moving through production in spite of our missed deadlines and last-minute changes, and did so with her usual grace and skill. We thank Art Director Diana Blume for her artistry in designing both the text and cover for the book. We appreciate the work of present and past copyeditors, including Karen Taschek, Liz Geller, and Linda Strange. Although Linda did not copyedit this edition, her lasting contributions from the first through the fifth editions are still clearly evident in the text. We thank Photo Research Manager Ted Szczepanski and Photo Researcher Elyse Rieder for their help in locating images and Courtney Lyons for help in orchestrating reviews and providing administrative assistance at many turns. We also thank Allison Michael, Media Editor, for assembling the ever more important media components to accompany the text. Our gratitude also goes to Debbie Clare, Associate Director of Marketing, for her creativity and good humor in coordinating the sales and marketing effort. A very special thanks goes to Kate Parker, who oversaw this project for the past three editions, and contributed much to its success, before moving on to other things; we will miss her insight, humor, and excellent taste in restaurants. In Madison, Brook Soltvedt is (and has been for all the editions we have worked on) our first-line editor and critic. She is the first to see manuscript chapters, aids in manuscript and art development, ensures internal consistency in content and nomenclature, and keeps us on task with more-or-less gentle prodding. As she did for the fourth and fifth editions, Shelley Lusetti of New Mexico State University read every word of the text in proofs, caught numerous mistakes, and made many suggestions that improved the book. The new art in this edition, including the new molecular graphics, was done by Adam Steinberg, here in Madison, who often made valuable suggestions that led to better and clearer illustrations. We feel very fortunate to have such gifted partners as Brook, Shelley, and Adam on our team. We are also deeply indebted to Brian White of the University of Massachusetts–Boston, who wrote the data analysis problems at the end of each chapter. Many colleagues played a special role through their interest in the project and their timely input. Prominent among these are Jeffrey D. Esko of the University of California, San Diego; and Jack Kirsch and his students at the University of California, Berkeley. Charles G. Hoogstraten of Michigan State University made many incisive and helpful comments on the manuscript and figures. We also thank Jeffrey A. Cohlberg of California State University at Long Beach for his critical comments. Many others helped us shape this sixth edition with their comments, suggestions, and criticisms. To all of them, we are deeply grateful: Richard Amasino, University of Wisconsin–Madison Laurens Anderson, University of Wisconsin–Madison Alan Attie, University of Wisconsin–Madison Kenneth Balazovich, University of Michigan James Blankenship, Cornell University Tracey Boncher, Ferris State College of Pharmacy Brian Bothner, Montana State University Mary Bryk, Texas A&M University Sharada Buddha, Saint Xavier University Jeff DeJong, University of Texas, Dallas Keith Dunker, Indiana University Kelly Elkins, Metropolitan State College of Denver Gerald Feigenson, Cornell University Brent Feske, Armstrong Atlantic State University FMTOC.indd Page xiii 09/10/12 1:57 PM user-F408 /Users/user-F408/Desktop
xiv Preface Greta Giles,Georgia Gwinnett College Kerry Smith.ctemson Uiversity Julian Snow,University of the Sciences James Gober,University of California,Los Angeles Burt Goldberg,New York University Amy Stockert,Ohio Northern University Eric Hegg.Michigan State University Chuan Xiao.University of Teras El Pase Michael Yaffe,Massachuseuts Istitute of Laura Zapanta,University of Pittsburgh 、20627s7 We lack the space here to acknowledge all the Douglas Julin,Uniersity f Maryland ntral Florida Nicole LaRonde-LeBlane, sity of Maryland We want especially to thank our students at the Uni- versity of Wisconsin-Madison for their numerous com stions.If it n the oh d e University of Montana groups,who helped us balance the competing dem of Wisc helped us with advice and criticism;and to the many and te 41 of Medicine Donald Ourth,University of Memphis epest appreciation to ou ont who our book Joseph Provost, writing. t foorhead Madison,Wisconsir Johannes Rudolph.University of Colorado June 2012
Marcello Forconi, College of Charleston Wilson Francisco, Arizona State University Greta Giles, Georgia Gwinnett College Glenda Gillaspy, Virginia Tech University Margaret Glasner, Texas A&M University James Gober, University of California, Los Angeles Burt Goldberg, New York University Julie Gosse, University of Maine Lesley Greene, Old Dominion University Eric Hegg, Michigan State University Justin Hines, Lafayette College Peter Hinkle, Cornell University Pui Ho, Colorado State University David Hurley, Gatton College of Pharmacy, ETSU Joseph Jez, Washington University in St. Louis Kelly Johanson, Xavier University of Louisiana Douglas Julin, University of Maryland Mark Kearley, Florida State University Dmitry Kolpashchikov, University of Central Florida Min-Hao Kuo, Michigan State University Nicole LaRonde-LeBlanc, University of Maryland Scott Lefler, Arizona State University Andy LiWang, University of California, Merced Thomas Marsh, University of St. Thomas Michele McGuirl, The University of Montana Michael Mendenhall, University of Kentucky David Merkler, University of South Florida Debra Moriarity, University of Alabama: Huntsville Hunter Moseley, University of Louisville Allen Nicholson, Temple University James Ntambi, University of Wisconsin–Madison Neil Osheroff, Vanderbilt University School of Medicine Donald Ourth, University of Memphis Terry Platt, University of Rochester Wendy Pogozelski, State University of New York, Geneseo Joseph Provost, Minnesota State University, Moorhead Gregory Raner, University of North Carolina, Greensboro Lisa Rezende, University of Arizona Douglas Root, University of North Texas Johannes Rudolph, University of Colorado Phillip Ryals, University of West Florida Kevin Siebenlist, Marquette University Kerry Smith, Clemson University Julian Snow, University of the Sciences Alejandra Stenger, University of Illinois, Urbana–Champaign Amy Stockert, Ohio Northern University Jon Stoltzfus, Michigan State University Toni Vidal-Puig, University of Cambridge Chuan Xiao, University of Texas, El Paso Michael Yaffe, Massachusetts Institute of Technology Laura Zapanta, University of Pittsburgh We lack the space here to acknowledge all the other individuals whose special efforts went into this book. We offer instead our sincere thanks—and the finished book that they helped guide to completion. We, of course, assume full responsibility for errors of fact or emphasis. We want especially to thank our students at the University of Wisconsin–Madison for their numerous comments and suggestions. If something in the book does not work, they are never shy about letting us know it. We are grateful to the students and staff of our research groups, who helped us balance the competing demands on our time; to our colleagues in the Department of Biochemistry at the University of Wisconsin–Madison, who helped us with advice and criticism; and to the many students and teachers who have written to suggest ways of improving the book. We hope our readers will continue to provide input for future editions. Finally, we express our deepest appreciation to our wives, Brook and Beth, and our families, who showed extraordinary patience with, and support for, our book writing. David L. Nelson Michael M. Cox Madison, Wisconsin June 2012 xiv Preface FMTOC.indd Page xiv 09/10/12 1:57 PM user-F408 /Users/user-F408/Desktop