Craig T. Basson, MD, PhD

• Gladys and Roland Harriman Professor of Medicine
• Director, Cardiovascular Research, Cardiology Division
• Weill Medical College of Cornell University
• New York, New York

The bacterium Mycoplasma genitalium belongs to a large group of bacteria allergy forecast granbury tx prednisone 20 mg lowest price, called mycoplasmas allergy forecast edmonton alberta buy prednisone 20 mg with mastercard, that lack a cell wall allergy symptoms asthma order prednisone 10 mg on-line. Mycoplasmas are free-living organisms that are parasites on a wide range of plant and animal hosts allergy forecast today nyc buy cheap prednisone 20 mg online, including human beings allergy free dog food order prednisone cheap online. The entire sequence of the genome has been determined allergy symptoms pet dander 10 mg prednisone with mastercard, which enables us to see what constitutes a minimal functional gene set for a cell. The cellular processes in which these gene products participate are summarized in Table 10. A substantial fraction of the genome is devoted to macromolecular syntheses Table 10. However, genes that encode proteins for salvaging and/or for transporting small molecules make up a substantial fraction of the total, which underscores the fact that the bacterium is parasitic. The remaining genes are largely devoted to formation of the cellular envelope and evasion of the immune system of the host. However, in a different region (for example, in a different gene) strand A might be copied rather than strand B. Each pattern is defined by a consensus sequence of bases determined from the actual sequences by majority rule: Each Page 420 Connection One Gene, One Enzyme George W. Tatum 1941 Stanford University, Stanford, California Genetic Control of Biochemical Reactions in Neurospora How do genes control metabolic processes? The suggestion that genes control enzymes was made very early in the history of genetics, most notably by the British physician Archibald Garrod in his 1908 book Inborn Errors of Metabolism. Perhaps each enzyme is controlled by more than one gene, or perhaps each gene contributes to the control of several enzymes. The classic experiments of Beadle and Tatum showed that the relationship is usually remarkably simple: One gene codes for one enzyme. The pioneering experiments united genetics and biochemistry, and for the "one gene—one enzyme" concept, Beadle and Tatum were awarded a Nobel Prize in 1958 (Joshua Lederberg shared the prize for his contributions to microbial genetics). Because we now know that some enzymes contain polypeptide chains encoded by two (or occasionally more) different genes, a more accurate statement of the principle is "one gene, one polypeptide. Neurospora had been introduced as a genetic organism only a few years earlier, and Beadle and Tatum realized that they could take advantage of the ability of this organism to grow on a simple medium composed of known substances. From the standpoint of physiological genetics the development and functioning of an organism consist essentially of an integrated system of chemical reactions controlled in some manner by genes. In investigating the roles of genes, the physiological geneticist usually attempts to determine the physiological and biochemical bases of already known hereditary traits. Perhaps the most serious of these is that these preliminary results appear to us to indicate that the approach may offer considerable promise as a method of learning more about how genes regulate development and function. Such characters are likely to involve more or less non-essential socalled "terminal" reactions. A second difficulty is that the standard approach to the problem implies the use of characters with visible manifestations. Many such characters involve morphological variations, and these are likely to be based on systems of biochemical reactions so complex as to make analysis exceedingly difficult. Considerations such as those just outlined have led us to investigate the general problem of the genetic control of development and metabolic reactions by reversing the ordinary procedure and, instead of attempting to work out the chemical bases of known genetic characters, to set out to determine if and how genes control known biochemical reactions. The ascomycete Neurospora offers many advantages for such an approach and is well suited to genetic studies. The procedure is based on the assumption that x-ray treatment will induce mutations in genes concerned with the control of known specific chemical reactions. If the organism must be able to carry out a certain chemical reaction to survive on a give medium, a mutant unable to do this will obviously be lethal on this medium. Such a mutant can be maintained and studied, however, if it will grow on a medium to which has been added the essential product of the genetically blocked reaction. Among approximately 2000 strains [derived from single cells after x-ray treatment], three mutants have been found that grow essentially normally on the complete medium and scarcely at all on the minimal medium. These preliminary results appear to us to indicate that the approach may offer considerable promise as a method of learning more about how genes regulate development and function. For example, it should be possible, by finding a number of mutants unable to carry out a particular step in a given synthesis, to determine whether only one gene is ordinarily concerned with the immediate regulation of a given specific chemical reaction. Any particular sequence may resemble the consensus sequence very well or very poorly. Most of the differences in promoter strength result from variations in the -35 and -10 promoter elements and in the spacing between them. In general, the more closely the promoter elements resemble the consensus sequence, the stronger the promoter. Mutations that change the base sequence in a promoter can alter the strength of the promoter; changes that result in less resemblance to the consensus sequence lower the strength, whereas those with greater resemblance to the consensus increase the strength. Furthermore, there are promoters that differ greatly from the consensus sequence in the -35 region. The consensus sequences located 10 and 35 nucleotides upstream from the transcription start site (+1) are indicated. Much of the variation in promoter strength results from differences between the promoter elements and the consensus sequences at -10 and -35. Transcription of the lacZ gene enables the cell to synthesize the enzyme β-galactosidase. Mutations have also been instrumental in defining the transcription-termination region. Mutations have been isolated that create a new termination sequence upstream from the normal one. This enzyme consists of five protein subunits and can be easily seen by electron microscopy (Figure 10. Termination sites are usually located such that transcribed regions do not overlap. In eukaryotes, a typical lifetime is several hours, although some last only minutes, and others persist for days. In both kinds of organisms, the degradation enables cells to dispose of molecules that are no longer needed. A second important feature peculiar to the primary transcript in eukaryotes, also shown in Figure 10. The symbols are N, any nucleotide; R, any purine (A or G); Y, any pyrimidine (C or U); and S, either A or C. MeG denotes 7-methylguanosine (a modified form of guanosine), and the two asterisks indicate two nucleotides whose riboses are methylated. The attack results in cleavage at the donor splice site and formation of a branched molecule (Figure 10. The ends of the exons are brought together by U5, which forms base pairs with nucleotides in the exons at both the donor splice site and the acceptor splice site. Because the loop includes most of the intron, the loop of the lariat is usually very much longer than the tail. The arrow shows the first step, in which the adenosine of the branch site, held in place by U2, attacks the phosphodiester bond at the splice donor site, resulting in cleavage at the splice donor site and formation of a lariat structure. Introns are also present in some genes in organelles, but the mechanisms of their excision differ from those of introns in nuclear genes because organelles do not contain spliceosomes. In one class of organelle introns, the intron contains a sequence coding for a protein that participates in removing the intron that codes for it. Genes in lower eukaryotes, such as yeast, nematodes, and fruit flies, generally have fewer introns than genes in mammals, and the introns tend to be much smaller. In those cases in which an intron seems to be required for function, it is usually not because the interruption of the gene is necessary, but because the intron happens to include certain nucleotide sequences that regulate the timing or tissue specificity of transcription. The implication is that many mutations in introns, including small deletions and insertions, should have essentially no effect on gene function, and this is the case. Moreover, the nucleotide sequence of a particular intron is found to undergo changes (including small deletions and insertions) extremely rapidly in the course of evolution, and this lack of sequence conservation is another indication that most of the nucleotide sequences present within introns are not important. Mutations that affect any of the critical splicing signals do have important consequences, because they interfere with the splicing reaction. The 16 introns, which are excised from the primary transcript, are shown in light green. The exons range in size from 29–331 bp (average 138 bp); the introns range in size from 124–1313 bp (average 512 bp). Most introns are long enough that, by chance, they contain a stop sequence that terminates protein synthesis, and once a stop is encountered, the protein grows no further. The cryptic splice site is usually a poorer match with the consensus sequence and is ignored when the normal splice site is available. Although introns are not usually essential in regulating gene expression, they may play a role in gene evolution. In some cases, the exons in a gene code for segments of the completed protein that are relatively independent in their folding characteristics. For example, the central exon of the β-globin gene codes for the segment of the protein that folds around an iron-containing molecule of heme. Relatively autonomous folding units in proteins are known as folding domains, and the correlation between exons and domains found in some genes suggests that the genes were originally assembled from smaller pieces. For example, the human gene for the low-density lipoprotein receptor that participates in cholesterol regulation shares exons with certain blood-clotting factors and epidermal growth factor. The model of protein evolution through the combination of different exons is called the exon-shuffle model. Although some genes support the model, in other genes the boundaries of the folding domains do not coincide with exons. Furthermore, the finding that some genes have introns in the same places in both plants and animals suggests that the introns may have been in place before plants and animals became separate lineages. If introns are ancient, then exon shuffling might have been important early in evolution by creating new genes with novel combinations of exons. On the other hand, it has also been argued that introns arose relatively late in evolution and became inserted into already existing genes, particularly in vertebrate genomes. The 70S ribosome consists of one small subunit of size 30S and one large subunit of size 50S. In prokaryotes, all of the components for translation are present throughout the cell; in eukaryotes, they are located in the cytoplasm, as well as in mitochondria and chloroplasts. Peptide bonds are made between successively aligned amino acids, each time joining the amino group of the incoming amino acid to the carboxyl group of the amino acid at the growing end. They are called the E (exit) site, the P (peptidyl) site, and the A (aminoacyl) site. In the assembly of the completed ribosome, the initiation factors dissociate from the complex. The configuration of the subunits in the top panel is called the pretranslocation state. In the next step of polypeptide synthesis, shown in the bottom panel in Figure 10. With each successive translocation of the 30S subunit, one more amino acid is added to the growing polypeptide chain. A peptide bond is formed between the polypeptide and the amino acid held in the A site, in this case Val. Simultaneously, the 50S subunit is shifted relative to the 30S subunit, forming the pretranslocation state. In effect, the ribosome shuttles between the pretranslocation and posttranslocation states. Polypeptide elongation may therefore be considered as a cycle of events repeated again and again. The steps B C B C (or, equivalently, C D C D) are carried out repeatedly until a termination codon is encountered. At the same time, the ribosome is converted to the pretranslocation state in preparation for translocation. Termination the elongation steps of protein synthesis are carried out repeatedly until a stop codon for termination is reached. After the synthesis of one polypeptide is finished, the next along the way is translated (Figure 10. Translated sequences are shown in purple, yellow, and orange; stop codons in red; the ribosome binding sites in green; and the spacer sequences in light green. The polypeptide is synthesized from the amino end toward the carboxyl end by the addition of amino acids. Polynucleotides are generally written so that both synthesis and translation proceed from left to right, and polypeptides are written so that synthesis proceeds from left to right. This convention is used in all of the following sections concerning the genetic code. The genetic code is the list of all codons and the amino acid that each one encodes. Before the genetic code was determined experimentally, it was reasoned that if all codons were assumed to Page 439 Connection Messenger Light Sydney Brenner,1 Francois Jacob,2 and Matthew Meselson3 1961 1Cavendish Laboratory, Cambridge, England. An Unstable Intermediate Carrying Information from Genes to Ribosomes for Protein Synthesis Brenner and Jacob were guest investigators at the California Institute of Technology in 1961. At that time there was great interest in the mechanisms by which genes code for proteins. The key to the experiment is density gradient centrifugation, which can separate macromolecules made "heavy" or "light" according to their content of 15Nor 14N, respectively. Jacob and Monod have put forward the hypothesis that ribosomes are non-specialized structures which receive genetic information from the gene in the form of an unstable intermediate of "messenger. Phage-infected bacteria therefore provide a situation in which the synthesis of a protein is suddenly switched from bacterial to phage control. We may summarize our findings as follows: (1) After phage infection no new ribosomes can be detected. If this turns out to be universally true, interesting implications for the coding mechanisms will be raised.

Most of these are of limited usefulness allergy wristbands buy generic prednisone 20 mg on line, but quite a few are invaluable to the student and to the practicing geneticist allergy symptoms burning skin best prednisone 20mg. One reason for developing these exercises is that genetics is a dynamic science allergy testing winston salem nc purchase 5mg prednisone free shipping, and most of the key Internet resources are kept up to date allergy testing shellfish buy prednisone 20mg without a prescription. Continually updated allergy shots pregnancy buy generic prednisone pills, the Internet exercises introduce the newest discoveries as soon as they appear allergy symptoms blurred vision discount prednisone 10mg overnight delivery, and this keeps the textbook up to date as well. Instead, the sites are accessed through the use of key words that are highlighted in each exercise. The use of key words also allows an innovation: one exercise in each chapter makes use of a mutable site that changes frequently in both the site accessed and the exercise. The instructor may wish to make short assignments from some of them, or use them for extra credit or as short term papers. We have included a suggested assignment for each of the exercises, but many instructors may wish to develop their own. We would be pleased to receive suggestions for new web exercises at the Jones and Bartlett home page: Page xviii Problems Each chapter provides numerous problems for solution, graded in difficulty, for the students to test their understanding. Analysis and Applications problems are more traditional types of genetic problems in which several concepts must be applied in logical order and often require some numerical calculation. The level of mathematics is that of arithmetic and elementary probability as it pertains to genetics. Challenge Problems are similar to those in Analysis and Applications, but they are a degree more challenging, often because they require a more extensive analysis of data before the question can be answered. Supplementary Problems, in a special section at the end of the book, consist of over 300 additional problems. These include representatives of all three types of problems found at the ends of the chapters, and they are graded in difficulty. The Supplementary Problems may be used for additional assignments, more practice, or even as examination questions. Lozovskaya of Harvard University, and they were selected and edited by the authors. Unlike the other problems, the solutions to the Supplementary Problems are not included in the answer section at the end of the book. Guide to Problem Solving Each chapter contains a Guide to Problem Solving that demonstrates problems worked in full. The concepts needed to solve the problem, and the reasoning behind the answer, are explained in detail. The Guide to Problem Solving serves as another level of review of the important concepts used in working problems. It also highlights some of the most common mistakes made by beginning students and gives pointers on how the student can avoid falling into these conceptual traps. Solutions All Analysis and Applications Problems and all Challenge Problems are answered in full, with complete methods and explanations, in the answer section at the end of the book. The rationale for giving all the answers is that problems are valuable opportunities to learn. Problems that the student cannot solve are usually more important than the ones that can be solved, because the sticklers usually identify trouble spots, areas of confusion, or gaps in understanding. As often as not, the conceptual difficulties are resolved when the problem is worked in full and the correct approach explained, and the student seldom stumbles over the same type of problem again. Further Reading Each chapter also includes recommendations for Further Reading for the student who either wants more information or who needs an alternative explanation for the material presented in the book. Complete author lists are also given for a few Connections that had too many authors to cite individually in the text. Illustrations the art program is spectacular, thanks to the creative efforts of J/B Woolsey Associates, with special thanks to John Woolsey and Patrick Lane. Every chapter is richly illustrated with beautiful graphics in which color is used functionally to enhance the value of each illustration as a learning aid. The illustrations are also heavily annotated with "process labels" explaining step-by-step what is happening at each level of the illustration. They also allow the illustrations to stand relatively independently of the text, enabling the student to review material without rereading the whole chapter. Page xix Flexibility There is no necessary reason to start at the beginning and proceed straight to the end. This feature gives the book the flexibility to be used in a variety of course formats. Throughout the book, we have integrated classical and molecular principles, so you can begin a course with almost any of the chapters. Most teachers will prefer starting with the overview in Chapter 1, possibly as suggested reading, because it brings every student to the same basic level of understanding. Some teachers are partial to a chromosomes-early format, which would suggest continuing with Chapter 3, followed by Chapters 2 and 4. A novel approach would be a genomes first format, which could be implemented by continuing with Chapter 9. Some teachers like to discuss mechanisms of mutation early in the course, and Chapter 13 can easily be assigned early. The writing and illustration program was designed to accommodate a variety of formats, and we encourage teachers to take advantage of this flexibility in order to meet their own special needs. Supplements An unprecedented offering of traditional and interactive multimedia supplements is available to assist instructors and aid students in mastering genetics. Additional information and review copies of any of the following items are available through your Jones and Bartlett Sales Consultant. The Test Bank, authored by Michael Draper of Tufts University with contributions from Patrick McDermot of Tufts University, contains 850 test items, with 50 questions per chapter. A typical chapter file contains 20 multiple-choice objective questions, 15 fillins, and 15 quantitative problems. A Solutions Manual containing worked solutions of all the supplemental problems in the main text is bound together with the Test Bank. This easy-to-use multimedia tool contains an Image Bank of over 450 figures from the text specially enhanced for classroom presentation. This lecture aid readily interfaces with other presentation tools, including a complete set of PowerPoint lecture outlines. It also contains key simulated web sites that allow you to bring the Internet into the classroom without the need for a live Internet connection. Dean of the University of Western Ontario and Harry Roy of Rensselaer Polytechnic Institute, is already in use at over 200 institutions worldwide. You can also bring the lab into the classroom, as the program allows you to perform on-screen tasks such as the selection of mutant colonies, using a pipette to make a dilution series, inoculating mutants to petri dishes to test for response to growth factors, and then to analyze and interpret the data. Through the testing feature and presentation capabilities, you can offer a complete lab environment. Genetics-related topics include: Origin and Evolution of Life, Human Gene Therapy, Biotechnology, the Human Genome Project, Oncogenes, and Science and Ethics. Weller of the University of California, Irvine, this study aid uses illustrations, tables, and text outlines to review all of the fundamentals of genetics. It includes extensive practice problems and review questions with solutions for self-check. The Gist helps students formulate appropriate questions and generate hypotheses that can be tested with classical principles and modern genetic techniques. Jones and Bartlett Publishers ensures that links for the site are regularly maintained. Ganetzky of the University of Wisconsin, Madison, reviews Page xx important genetics concepts covered in class using state-of-the-art interactive multimedia. It consists of hundreds of animations, diagrams, and videos that dynamically explain difficult concepts to students. In addition, it contains over 400 interactive multiple-choice, "drag and drop," true/false, and fill-in problems. These resources will prove invaluable to students in a self-study environment and to instructors as a lecture-enhancement tool. The lab allows students to perform tasks on screen—such as selecting mutant colonies, making a dilution series, inoculating mutants into petri dishes to test for response to growth factors—and then guides them in analyzing and interpreting the data. Acknowledgments We are indebted to the many colleagues whose advice and thoughts were immensely helpful throughout the preparation of this book. These colleagues range from specialists in various aspects of genetics who checked for accuracy or suggested improvement to instructors who evaluated the material for suitability in teaching or sent us comments on the text as they used it in their courses. Berlyn, Yale University Pierre Carol, Université Joseph Fourier, Grenoble, France John W. Brooks Low, Yale University Gustavo Maroni, University of North Carolina Jeffrey Mitton, University of Colorado, Boulder Gisela Mosig, Vanderbilt University Robert K. Phillips, University of Minnesota Robert Pruitt, Harvard University Pamela Reinagel, California Institute of Technology, Pasadena Kenneth E. Weber, University of Southern Maine We would also like to thank the reviewers, listed below, who reviewed one or more chapters and who, in several cases, reviewed the complete fourth edition manuscript. Their comments and recommendations helped improve the content, organization, and presentation of the material. We offer special thanks to Dick Morel, who carefully reviewed and commented on all of the illustrations as well as the text. Savage, Oregon State University David Shepard, University of Delaware Charles Staben, University of Kentucky David T. Thomas, University of Washington We also wish to acknowledge the superb art, production, and editorial staff who helped make this book possible: Mary Hill, Patrick Lane, Andrea Fincke, Judy Hauck, Bonnie Van Slyke, Sally Steele, John Woolsey, Brian McKean, Kathryn Twombly, Rich Pirozzi, Mike Campbell, and Tom Walker. Much of the credit for the attractiveness and readability of the book should go to them. Thanks also to Jones and Bartlett, the publishers, for the high quality of the book production. We are also grateful to the many people, acknowledged in the legends of the illustrations, who contributed photographs, drawings, and micrographs from their own research and publications, especially those who provided color photographs for this edition. Every effort has been made to obtain permission to use copyrighted material and to make full disclosure of its source. We are grateful to the authors, journal editors, and publishers for their cooperation. Any errors or omissions are wholly inadvertant and will be corrected at the first opportunity. Page xxi Introduction: For the Student In signing up for a genetics course, our students often wonder how much work is going to be required, how much time it will take to do the reading and written assignments, how hard the examinations will be, and what is their likelihood of getting a good grade. These are perfectly legitimate issues, and you should not feel guilty if they are foremost in your mind. You may also be wondering what you are going to learn by taking a course in genetics. Is there any reason to study genetics other than to satisfy an academic requirement? This introduction is designed to reassure you that the answer to each question is yes. The study of genetics is relevant not only to biologists but to all members of our modern, complex, technological society. Understanding the principles of genetics will help you to make informed decisions about numerous matters of political, scientific, and personal concern. At least 4000 years ago in the Caucasus, the Middle East, Egypt, South America, and other parts of the world, farmers recognized that they could improve their crops and their animals by selective breeding. Their knowledge was based on experience and was very incomplete, but they did recognize that many features of plants and animals were passed from generation to generation. They discovered that desirable traits—such as size, speed, and weight of animals—could sometimes be combined by controlled mating and that, in plants, crop yield and resistance to arid conditions could be combined by cross-pollination. The ancient breeding programs were not based on much solid information because nothing was known about genes or any of the principles of heredity. In a few instances, the pattern of hereditary transmission of a human trait came to be recognized. One example is hemophilia, or failure of the blood to clot, which results in life-threatening bleeding from small cuts and bruises. By the second century of the present era, rules governing exemptions from circumcision had been incorporated into the Talmud, indicating that several key features of the mode of inheritance of hemophilia were understood. However, the paternal half brothers of a boy who had died from excessive bleeding were not exempt. In Chapter 2, you will learn the rules followed by genes and chromosomes as they pass from generation to generation, and you will be able to calculate in many instances the probabilities by which organisms with particular traits will be produced. Some people have called it formal genetics, because the subject can be understood and the rules clearly seen without any reference to the biochemical nature of genes or gene products. Beginning about 1900, geneticists began to wonder about a subject we now call molecular genetics. At that time, there was no logical starting point for such an investigation, no experimental 'handle. Within a decade, there came an understanding of the chemical nature of genes and how genetic information is stored, released to a cell, and transmitted from one generation to the next. These were exciting times, and you will be presented with a distillation of these findings in the chapters of this book that deal with molecular genetics. This technology is a collection of methods that enable genes to be transferred, at the will of the molecular geneticist, from one organism to another. Genetic engineering has had an enormous impact in genetic research, particularly in our ability to understand Connection Balancing Act Thomas Hunt Morgan 1913 Columbia University, New York, New York Genetics and cell biology have both advanced with surprising rapidity in recent years. Hardly a wee goes by without a new discovery of notable importance being reported in the pages of Science or Na or some other major research journal. Nontechnical accounts of new discoveries are regularly repor the popular press and on television. We are in the midst of a knowledge explosion—doubtless you remember being told this before.

What sobriety looks like will vary from person to person allergy symptoms from wine buy prednisone discount, but in all cases it has the individual allergy symptoms ginger cheap prednisone express, rather than the addictive compulsion allergy shots vs oral drops buy 10mg prednisone, in the lead allergy testing jersey order prednisone with american express. For many people allergy symptoms productive cough buy cheap prednisone on line, whether with substance addictions like alcoholism or behaviour addictions like gambling or sexual acting out allergy symptoms nausea buy prednisone 10mg lowest price, Twelve-Step programs are a crucial part of that healing environment. Take, for example, the technique of an addict having a sponsor to contact whenever the addictive urge threatens to gain the upper hand—the desire to have a drink or to play cards at the casino. When the addict makes that call he recognizes his powerlessness over the compulsion, in other words, the relative weakness of the impulse-regulating parts of his cerebral cortex. Until those circuits develop some muscle of their own, the sponsor acts the regulator by talking the addict through his compulsion. Although not for everyone—nothing is for everyone—Twelve-Step programs provide the best available healing environment for many people. They’re not without flaws and they may even take on an addictive quality themselves. Being human institutions, they may have, here and there, become forums for gossips or for people on the make. But they have saved more lives—emotionally and probably even physically—than the medical treatments of addiction. They have been well described many times from many angles—historical, psychological, practical, personal, religious and spiritual. I’ve read illuminating Twelve-Step books written from Christian, Buddhist and Taoist perspectives. I have no reasons to give—it just didn’t quite feel like a fit, despite my positive experience at the one meeting I did attend. And, I admit, I have difficulty committing to attending long-term programs of any kind. For all that, I have found the Twelve-Step principles and my discussions with Twelve-Step members most helpful. I encourage anyone dealing with any addiction to investigate Twelve-Step approaches, even if they have no interest in participating in group work. Not long ago I was confronted by an example of just how thoroughly addictive attitudes have pervaded my life and how sharply they affect other people. One Friday afternoon in mid-September of 2006 I was sitting in my car on Cortes Island, waiting for the ferry. Cortes is the home of Hollyhock, a spectacular oceanside gathering place and healing centre where many people come for programs and seminars or for rest and rejuvenation. As I watched the ferry arrive, I was basking in the warm gratitude expressed by the participants, who, many of them said, had experienced transformational insights and an awakening of vitality. The first was from Susan Craigie, the Portland health coordinator: a missive exploding with long-suppressed anger and frustration. For the week I’d been away, another doctor had filled in for me and she was actually on time every day. You excuse yourself by saying that you’re too busy working on your addictions book, but you’ve been doing this for years, long before that book was a glint in your eye. My initial reaction was anger—the addicted mind’s way of resisting shame—but only for a moment. I soon allowed the feelings of shame to wash over me without either resisting them or letting them knock me down, and I felt grateful. Roman emperors, as they proceeded in triumphant procession with the war booty and captives driven before them amongst the cheering throngs, had a slave behind them on the chariot whose duty it was to whisper in their ear at regular intervals: “Sire, you are mortal. Susan had done me the favour of reminding me what my reality was in the absence of sobriety and integrity. It became crystal clear that the addiction process—and the worldview that accompanies it—had polluted my life on levels I had not ever considered. Addiction is primarily about the self, about the unconscious, insecure self that at every moment considers only its own immediate desires—and believes that it must behave that way. In all cases the process arises from the unmet needs of the helpless young child for whom this constant self-obsession appears, to begin with, as a matter of survival. No such environment even exists—or so he has come to believe in his bones and in his heart, which were parched by early loss. The mind of the addict is beset by constant worry, soothed only by the addictive substance or activity. The hunger and the urgent drive to satisfy it are ever present, regardless of circumstances. My family has remarked that when I eat, unless I take particular care, my habit is to bend low over the plate and shovel the food into my mouth as if it’s about to disappear. And yet only one time in my life have I starved or experienced deprivation: during my first year in the Jewish ghetto of Nazi-occupied Budapest. That was enough to program my brain with the image of an uncertain, unyielding and indifferent world. Once programmed, the addicted mind creates a world of emptiness where one must scratch and grab for every bit of nourishment and be ever vigilant for every opportunity to get more. The addict hasn’t grown out of the stage of infancy that has been called the narcissistic phase, the period when the fledgling human being believes that everything happens because of her, to her and for her. We move through stages of development when the needs we have in each are fully satisfied. The teaching in Susan’s letter came at a time when I was secure enough to receive it, when I would neither deny its truth nor be overwhelmed by the shame it triggered. I had just been teaching and demonstrating compassionate curiosity to the workshop participants and, lo and behold, had absorbed some of it myself. Now, as I applied it to my own behaviour, I saw the chronic lateness not as a character flaw to beat myself up about or as a “nuisance” I could just dismiss flippantly, but as another attempt by my addiction-prone mind to maintain its illusion of freedom and control. The only charge to which I don’t plead guilty is that I behave this way because these patients are junkies. A quick phone call to my former nurse, Maria, would convince you that it was no better in my private practice. Among the many ways I could make myself late for work was to stop by at Sikora’s in the morning or during lunch break. My letter to Susan continued: I’ve made so many promises in the past that it’s meaningless to make another one. I deeply regret the hassle and frustration I’ve caused you and the inconvenience to our clients. I’ve had the pleasure of facing my clients without shame clouding my eyes and of working alongside colleagues who no longer have to compensate for my tardiness and to disguise their resentment. The prewritten cheques are not a form of self-punishment, but a way of building a structure that helps keep me sober. They would not be necessary if I possessed sufficient self-regulation; I would just show up on time. They serve me as the sponsor serves the Twelve-Step novice: when in the morning an urge arises to stay writing by my computer or to keep pedalling on my exercise bike, the thought of the lost income reminds me of my responsibilities and helps to regulate my insufficiently active prefrontal impulse-control brain circuits. Creating such structures is part of establishing an external environment that supports mental awareness and responsible behaviour. Even before I completely stopped buying compact discs, for example, for months I did not lie about my purchases. Exposed to the light of day the addictive compulsion does not develop power and heft. I had much less of the urge to binge, and the occasional visit to the music store did not evoke a helpless desire to go back the same day or the next— another freedom I relished. Better you should look “bad” in the eyes of others than to sink further in your own estimation of yourself. Rae has three signed, undated cheques, each for one thousand dollars, as my guarantee. It’s now the beginning of October 2007 as I’m revising the manuscript for this book. Quite contrary to feeling frustrated about any thwarted desires, I have discovered a much more satisfying freedom in not allowing the addiction process to run my life. And I’ve found another, unlooked-for benefit: just as the addiction process permeates every area of your existence, so does sobriety. As you become less attached to your addiction, you also become calmer, less attached to other things that don’t matter nearly as much as you used to believe. Not having reason to be so harsh on yourself, you are not so inclined to find fault with others. I am not suggesting that every addict should write cheques to their spouses or fellow workers. My particular method here is not for everyone, but every behaviour addict can find his own way to build some appropriate structures into his life. It’s also obvious that many people with behaviour addictions face much greater challenges. But anyone who has successfully achieved sobriety knows that no evanescent pleasure can be compared with the peace that comes from living in integrity. Governing your life are your values and your intentions, not some mechanical compulsion arising from the past. That emancipation means much more than the illusory freedom of obeying any impulse that arises in the moment. One important warning: if you want to find liberation in your commitments, your word needs to be freely given or not given at all. If you don’t know how to say no to other people’s expectations, howsoever well meant or valid those may be, your yes has no authenticity. Besides denying my own responsibility, I’d also often denied that my words or actions could have any effect on anyone. So, even though what was revealed was painful and destructive, just admitting that I had hurt others was empowering. To pretend that our existence doesn’t affect others is to deny karma, to deny that every action has a reaction, to pretend that cause and effect aren’t constantly in play. When we see how our actions hurt others—and ourselves—we become more careful about what we are doing in the present. When we see our destructive patterns of thought, speech, and behavior, we begin to change, to unravel these habits, to act in ways that won’t require more inventory writing. I felt a sense of possibility, and sense of hope…It was the pragmatism of the approach that I liked. The idea was that through examining my conscience daily, even multiple times a day—a kind of naming the assets and the deficits—I could keep my guilt level really low. And that if one had self-acceptance and low guilt, it would be easier to stay away from painkillers—in my case, alcohol. By structuring such responsible but nonjudgmental self-examination into our routine, by owning the impact of our behaviours on others, we diminish our karmic burden. A part of creating external structures to support recovery is the avoidance of environments and environmental cues that trigger addictive thoughts and feelings. Those cues and environments vary from person to person, from addiction to addiction but for all addicts they are powerful in setting off addictive behaviour. Someone quitting smoking, for example, who associates cigarettes with a round of lager at the pub with friends needs to stay out of beer parlors. In my case, once the addictive drive to binge on compact discs comes to predominate, I find it hard to resist the shopping urge. However, I do not need to look up music reviews on the Internet—that’s a choice I find easier to make. When I take the dog for a walk I can now focus on just being in the present, mindful of my sensory experience of the moment. Establishing the healing environment also entails removing what is toxic—the stresses that enhance the addictive drive and trigger addictive cravings. Once more, we have to move beyond abstinence and view things from an ecological and sustainable perspective. Isabella, a married mother of three young children, asked for my advice about addictive sexual acting out that she could neither give up nor choose openly in her life. An energetic Guatemalan woman in her late twenties, she felt paralyzed by her inability to abstain from a preoccupation she felt ashamed of and saw as destructive to her family. There may be stresses in your life that you haven’t fully recognized and haven’t confronted. Perhaps you’re using your sexuality as a painkiller and temporary stress reliever. While still in her teens Isabella developed a relationship with a man for whom she had never felt passion and whom she finally married out of a vague sense of guilt and responsibility. She came to perceive herself as controlled financially and restricted by him in her need for artistic self expression. Having given up her own successful jewellery-design business after the birth of their second child, she felt dependent and resentful. She also suspected he might be attracted to men, although the two had never discussed his sexual preferences in a frank manner. My advice was that unless she dealt with the stresses in her life, she would continue to be tempted by her addiction. At best, she could remain sexually abstinent but pay a price in depression or some other addiction. Indeed, she was already concerned about her marijuana use, which had gone from occasional to daily in the past six months. Let’s quickly review some of what we have learned about it, so that we can apply this knowledge to the ecology of recovery: Stressors are the external triggers for the physiological stress reaction, a maelstrom of hormonal secretions and nervous discharges that involve virtually every organ and system in the body. Addiction is often a misguided attempt to relieve stress, but misguided only in the long term.

Physicians/institutions should keep records of brands and batch numbers of all biological medicines (including biosimilars) administered allergy testing rocky mount nc prednisone 5mg without prescription. Healthcare professionals should ensure that people with diabetes well managed on an existing insulin are not changed to another insulin formulation allergy testing negative results cheap prednisone online american express, including biosimilars allergy symptoms pain 20 mg prednisone with mastercard, without good clinical reason and evidence of interchangeability allergy forecast lincoln ne purchase prednisone once a day. Comprehensive data on interchangeability in practice allergy shots toddlers cheap prednisone 40 mg line, pharmacovigilance and post-marketing surveillance should be provided allergy blood test cost cheap prednisone 40 mg amex. Austria –Multiple relevant medical societies (2014) Medical dialogue consensus statement – Biosimilars: current status Available here (German only) Summary: No summary available. Meanwhile, we recommend to start with naïve patients but not to switch a patient who has a durable response on infliximab to the biosimilar-infliximab. Cyprus – Cyprus League Against Rheumatism (2014) the 10 commandments of access to biological treatments Available here (Greek only) Summary: No summary available patients. Last year they were very hesitant towards switch and did not understand decision that was taken to switch patients when a tender was won and a biosimilar infliximab was recommended. So today they are positive towards biosimilars and see the possibilities in a switch and the long-term positive outcome. At initiation, the choice is clear between the originator and biosimilar infliximab. In a patient during treatment, it is recommended to treat, to the extent possible, with the same specialty without making any changes within a biosimilar family, so not to switch between infliximab. The switch of infliximab to another is not recommended but is nevertheless possible. It is understood that this must remain at the initiative of the prescriber which would otherwise be liable if any. In addition, it is important to remember that we must not give another infliximab if a first infliximab was not tolerated and that kits of infliximab assays and antibodies to infliximab seem suitable for all infliximabs. If additional information on the safety of biosimilar infliximab was brought to our attention, these recommendations may be revised. AkdÄ recommends prescribing the more cost-effective biosimilars in treatment initiation and supports changes between biosimilars for subsequent prescriptions. The detailed information and advice provided by doctors to their patients is an essential prerequisite for the prescription and use of biosimilars. Without this, unfounded fears could lead to a reduction in adherence and compromise therapeutic success in patients. Automatic substitutions of biosimilars for reference medicinal products are therefore rejected. Germany – German Rheumatism League (2014) Deutsche Rheuma-Liga Positioning of the German Rheumatism League Bundesverband on introducing biosimilars in Germany Available here (German only) Summary: the Rheumatism League believes it is essential that patients with rheumatic diseases whose disease activity was brought under control with a biotechnologically manufactured drug will not be forced to change to another biotechnology drug due to cost-considerations. And if a change should take place per se, only on the basis of medical considerations and justified in terms of patient welfare. Because the practice shows that often neither the patient nor the clinicians are informed about this exchange. In patients who start with a therapy of a biotechnologically manufactured drug, the security must be at the forefront. There are concerns when the biosimilar was not tested for the specific indication but was admitted by extrapolation. In this case studies must have shown that the safety profile for this specific indication does not differ from the reference product and no undesirable side effects for the indication occur. Switches have to be the responsibility of the treating physician while a general substitution is rejected. This applies for example to the extent of use of biosimilars effective in the forms of inflammatory arthritis in patients with spondylo-arthritis and, especially, to those suffering from entero-artritis and paediatric patients. Validation should be conducted by comparing the results of the innovative product with those obtained with the original treatment. Although greater access to appropriate use of biological therapies for entero-artritis paediatric reumopatie is a potential, for significant savings in direct costs, the strict test of a controlled clinical trial is required to ensure that the effectiveness and safety standards are met. We believe that the assertion that biosimilar epoetin alpha should only be used to treat naive patients might be limiting. In addition, the change must be approved by the specialist prescribing the original biologic and be implemented after obtaining the patient’s written informed consent. The complexity of the molecule, dosing, and immunogenicity issues needs careful investigation on these aspects. Interchangeability cannot be automatic, unless its effectiveness and safety will be exhaustively demonstrated. Neither other paramedical characters nor Healthcare payers should be allowed to change the prescription or impose the use of biosimilars instead of their originator. The switch may be considered only in patient who respond to infliximab treatment; despite the encouraging results obtained to date, the possibility that neutralizing antibodies directed against the originator molecule would diminish the efficacy of cT-P13 cannot be ruled out and therefore switching may be considered with caution. Patients should be adequately informed about the advantages and the possible adverse effects of biotechnological therapy before starting treatment. Clinically well controlled patients should not be switched from an original drug to its biosimilar, or vice versa. Medical and immunological considerations, including high-quality evidence of bioequivalence, quality, efficacy and safety of each developed biosimilar should always take priority over any economic or financial benefit. However, since several biosimilars are being evaluated in psoriasis patients, these agents should be chosen to treat psoriasis patients instead of biosimilars studied in other conditions. Moreover, patients should be kept informed about their treatment agent, and should not be transitioned for other agent without their knowledge and informed consent. Post marketing surveillance, mainly through national registers, is crucial to permanently assess safety and increase confidence in the use of biosimilars. A biosimilar is a medicine that, using molecular biology techniques, is intended to provide an action equivalent to that of the product it attempts to copy and requires a complex process based on all the preclinical and clinical trials demanded by European Law. A licence obtained for the management of a certain disease allows an extrapolation of results to a different disorder, if the European Medicine Agency considers it based on the results of trials mentioned previously. The product label should clearly show the name of the biosimilar so that the drug a patient is taking may always be identified. The appropriate use of the biosimilar always requires an interaction of physicians and patients with the aim of favouring the right of the health of the patient by offering quality, effective and safe products. This task force favours the development of biosimilar drugs and therefore, their approval by regulatory agencies. These guidelines, where biosimilarity criteria are established, guarantee comparability between biosimilar product and reference one. Biosimilars’ authorization is carried out through a centralized procedure based on clinical, non-clinical and quality studies. These studies allow the extrapolation of indications, frequently, without carrying out additional analyses. In several European countries, switching between original and biosimilar medicine is considered safe. Biosimilars cannot be equated to generic drugs of their reference drugs, as they are not substitutable. The exchange of a biological drug with its biosimilar is an act only physicians should performed, with the consent of the patient. Available here Summary: Decisions about which drug to prescribe should not be based on economic considerations alone, but rather on scientific evidence. We therefore recommend that dermatologists, pharmacists, managers, and other stakeholders be involved in decisions about how biosimilars are introduced into our health care system. We believe that the decision to prescribe a biosimilar should be assessed on a case-by-case basis and that the patient must agree with the choice. Switching from a biologic to a biosimilar should also be decided by the physician with the patient’s consent. Biosimilar insulins could be considered for all newly diagnosed patients with type 1 diabetes who have not been exposed to the reference drug and in patients who require a review of their therapy due to poor control. When patients are established on a current insulin regimen, those achieving their target HbA1c without hypoglycaemia should not be automatically switched to a biosimilar insulin. Following the switch to a biosimilar insulin, it is recommended that provision for review and ongoing supervision by a specialist team is provided. With the advent of an increasingly complex portfolio of insulin therapy, it is imperative that all healthcare staff receive education about safe insulin prescribing which specifically includes information on biosimilar insulin. However switching from originator to biosimilar (or biosimilar to biosimilar) is acceptable and can be recommended as part of a medicines optimisation strategy. Until further data become available, these products should not be considered globally interchangeable. The patient must be kept informed at all times of the discussions taking place in regard to their medicine. Patients should feel empowered to check with both the prescribing clinician and the pharmacist that the medicine dispensed is the same as the prescribed. However, it is important that biosimilars are prescribed purely for clinical reasons and not simply as a quick cost saving alternative to biologics, just because they may be priced more cheaply. Unless adequate safeguards are introduced, it is possible that some patients could be inappropriately switched from a biologic to a biosimilar even though they may be responding well to their existing medicine. Switching a patient for non medical reasons could compromise their health and long term prognosis. For patients starting infliximab: Remicade, Remsima or Inflectra can be prescribed, taking into account the evidence showing similar clinical effectiveness. There is evidence that monitoring of patients, including measurement of drug and anti-drug antibody levels, is no different for the biosimilar drugs compared to Remicade. The choice of preparation should take into account the cost of the drug and its administration. There is sufficient evidence to recommend that patients who are in a stable clinical response or remission on Remicade therapy can be switched to Remsima or Inflectra at the same dose and dose interval. This should be done after discussion with individual patients, with explanation of the reason for switching (which is usually on the grounds of benefit to the overall service by reduction in costs of the drug and its administration). Automatic substitution, (dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber), is not appropriate. In adolescent patients, it is discard 52 mL, for 3 vials discard 78 mL, 4 vials discard 104 mL). If a physician determines that it is appropriate, a patient may self-inject or a 3. The needle cover should not be handled by persons infusion should be completely administered within eight hours of the dilution in sensitive to latex. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein binding flter (pore size 0. The infusion should be completed within 8 hours after the dilution in the infusion bag (cumulative time after preparation 2. Injection of the entire prefilled infections, reported in clinical studies included the following: syringe contents is necessary to activate the needle guard. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and been reported in such patients. Because clinical trials are conducted under widely varying conditions, adverse Appropriate diagnostic testing should be considered. Conditions with which it has been associated include preeclampsia, follow-up of 12. Ultraviolet-induced observed malignancies other than non-melanoma skin cancer during the clinical skin cancers developed earlier and more frequently in mice genetically manipulated studies were: prostate, melanoma, colorectal and breast. Clinical presentations included cough, dyspnea, and interstitial infltrates Adolescent Subjects with Plaque Psoriasis following one to three doses. Patients improved with discontinuation of therapy with moderate to severe plaque psoriasis. The safety profle in these subjects through and in certain cases administration of corticosteroids. If diagnosis is confrmed, Week 60 was similar to the safety profle from studies in adults with plaque psoriasis. These 1407 patients included 40 patients who received a prior investigational intravenous ustekinumab In patients with ulcerative colitis, serious or other clinically signifcant infections formulation but were not included in the effcacy analyses. Malignancies other than non-melanoma skin cancers oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s occurred in 0. Common adverse As with all therapeutic proteins, there is potential for immunogenicity. In psoriasis clinical studies, antibodies to ustekinumab Vomiting 3% 4% were associated with reduced or undetectable serum ustekinumab concentrations and reduced effcacy. Injection site erythema 0 5% Immune system disorders:Serious hypersensitivity reactions (including anaphylaxis Vulvovaginal candidiasis/mycotic infection 1% 5% and angioedema), other hypersensitivity reactions (including rash and urticaria) [see Warnings and Precautions (5. Bronchitis 3% 5% Infections and infestations:Lower respiratory tract infection (including opportunistic Pruritus 2% 4% fungal infections and tuberculosis) [see Warnings and Precautions (5. Urinary tract infection 2% 4% Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, Sinusitis 2% 3% eosinophilic pneumonia and cryptogenic organizing pneumonia [see Warnings and Precautions (5. In patients with Crohn’s disease, serious or other clinically signifcant infections included anal abscess, gastroenteritis, and pneumonia. In case of overdosage, it is recommended immunotherapy (decrease tolerance) which may increase the risk of an allergic that the patient be monitored for any signs or symptoms of adverse reactions or reaction to a dose of allergen immunotherapy. Therefore, caution should be effects and appropriate symptomatic treatment be instituted immediately. The manufacturing process contains steps for the Risk Summary clearance of viruses. The estimated background risk of major birth defects and miscarriage Available as 45 mg of ustekinumab in 0. The syringe is ftted with a passive needle Data guard and a needle cover that contains dry natural rubber (a derivative of latex). Each 1 mL preflled syringe delivers 90 mg ustekinumab, L-histidine and L-histidine Animal Data monohydrochloride monohydrate (1 mg), Polysorbate 80 (0. However, if ustekinumab is transferred into human milk the effects of local baseline and up to two weeks post-treatment in subjects with psoriasis. There was no apparent accumulation in serum ustekinumab between older and younger patients, the number of patients aged 65 and over is concentration over time when given subcutaneously every 12 weeks.

Detecting genetic linkage in human pedigrees requires special methods because human sibships are typically quite small allergy symptoms for babies 5 mg prednisone amex. What does it mean to say that two genes have a recombination frequency of 12 percent? Explain why the factor of one-half occurs when we compare recombination frequency to chiasma frequency allergy medicine 24 generic prednisone 5 mg on line. Draw a diagram of each kind of double crossover in a bivalent in a region between two genes allergy forecast dallas today discount prednisone line, each heterozygous allergy shots kitchener discount prednisone 10 mg on line. In a region of high interference allergy medicine makes me depressed order prednisone 5mg on line, would you observe more or fewer double crossovers? Guide to Problem Solving Problem 1: In Drosophila allergy quiz diagnosis order prednisone 40mg with amex, the genes cn (cinnabar eyes) and bw (brown eyes) are located in the same chromosome but so far apart that they appear unlinked. Compare the possible offspring produced by the cross and the cross the + symbols denote the wildtype alleles. Flies with the genotype cn cn have cinnabar Page 165 (text box continued from previous page) genetic marker in a pedigree in which a trait, for example, a genetic disease, is present, the likelihood of linkage is assessed by a "lod score. Use the keyword to learn more about this approach and examine the sample lod score calculation for a simple pedigree. If assigned to do so, write a 250-word summary of the method and the logic on which it is based. Select the Mutable Site for Chapter 4, and you will be linked to the current exercise that relates to the material presented in the chapter. Answer: the key to this problem is to remember that crossing-over does not take place in Drosophila males. When the male is cn bw/++, his gametes are 1/2 cn bw and 1/2 + +, so the progeny are cn bw/cn bw (white eyes) and + +/cn bw (wildtype eyes) in equal proportions. Crossing-over does happen in female Drosophila, but cn and bw are so far apart that they undergo independent assortment. When the female is cn bw/+ +, her gametes are 1/4 cn bw, 1/4 cn +, 1/4 + bw, and 1/4 + +, so the progeny are cn bw/cn bw (white eyes), cn +/cn bw (bright red), + bw/cn bw (brown), and + +/cn bw (wildtype) in equal proportions. Problem 2: One of the earliest reported cases of linkage was in peas in the year 1905 between the gene for purple versus red flowers and the gene for elongate versus round pollen. Plants of genotype B have purple flowers, and plants of the genotype bb have red flowers. Plants of genotype E have elongate pollen, and those of genotype ee have round pollen. Determine what genotypes and phenotypes among the progeny would be expected from crosses of F1 hybrids × red, round when the F1 hybrids are obtained as follows (a) purple, elongate × red, round purple, elongate F1 (b) purple, round × red, elongate purple, elongate F1 Answer: the red, round parents have genotype b e/b. Although both F1 hybrids have the dominant purple, elongate phenotype, they are different kinds of double heterozygotes. To calculate the types of progeny expected, use the fact that 1 map unit corresponds to 1 percent recombination: Because the genes are 12 map units apart, 12 percent of the gametes will be recombinant (6 percent of each of the reciprocal classes) and 88 percent will be nonrecombinant (44 percent of each of the reciprocal classes). Problem 3: In Drosophila, the genes ct (cut wing margin), y (yellow body), and v (vermilion eye color) are X linked. Females heterozygous for all three markers were mated with wildtype males, and the following male progeny were obtained. As is conventional in Drosophila genetics, the wildtype allele of each gene is designated by a + sign in the appropriate column. The way to solve it is to start by deducing the genotype of the triply heterozygous parent. This is done by noting that the most common classes of offspring are the nonrecombinants, in this case ct+ + and +y v. This is done by noting that the least common classes of offspring are the double recombinants, in this case ct y v and + + +. Moreover, each class of double recombinants will be identical with one of the nonrecombinants except for the marker that is in the middle. In this case, comparing ct y v with + y v and + + + with ct + + shows that ct is in the middle. In fact, the double recombinants are recombinant in both regions and so must be counted twice—once in calculating the recombination frequency in region 1 and again in calculating the recombination frequency in region 2. To calculate the interference, note that the expected number of double recombinants is 0. Diploids are made by mating a B × A b, in which the uppercase symbols denote the wildtype alleles, and asci are examined. In this problem, the specific questions illustrate the principle that any marker tightly linked to its centromere in a fungus with unordered tetrads serves to identify first-division and second-division segregation of every other gene in the organism. This principle makes possible the mapping of other genes with respect to their centromeres. Reasoning through problems of tetrad analysis is best approached by considering the possible chromosome configurations during the meiotic divisions. The various possibilities are illustrated in the adjoining figure, in which parts A through C correspond to questions (a) through (c). Page 167 (a) Part A shows the genes closely linked to each other (and therefore to the same centromere). If a single crossing-over occurs between the genes in every cell undergoing meiosis, and no multiple crossing-overs occur between the genes, what is the recombination frequency between the genes? The two genes are in the same chromosome and recombine with a frequency of 16 percent. From the cross A b/a B × A B/a b, what is the expected frequency of dwarfed plants among the progeny? The recessive gene bz for bronze body color (the dominant phenotype is black) is linked to the sex-determining gene and recombines with it at a frequency of 6 percent. In the cross of a heterozygous bz+ M/bz m male with a bronze female, what genotypes and phenotypes of progeny are expected? When a plant heterozygous for each of these alleles was crossed with a homozygous recessive plant, the progeny consisted of the following genotypes with the numbers of each indicated: Gl ra/gl ra 88 gl Ra/gl ra 103 Gl Ra/gl ra 6 gl ra/gl ra 3 Calculate the frequency of recombination between these genes. If the genes are 8 map units apart, what are the expected genotypes and phenotypes and their relative frequencies among the progeny of the cross + +/b cn × + +/b cn? What was the genotype of the triple heterozygote parent, and what is the order of the genes? When females heterozygous for each of these X-linked genes were testcrossed with yellow, vermilion, singed males, the following classes and numbers of progeny were obtained: yellow, vermilion, singed 53 yellow, vermilion 108 yellow, singed 331 yellow 5 vermilion, singed 3 vermilion 342 singed 95 wildtype 63 (a) What is the order of the three genes? Construct a linkage map with the genes in their correct order, and indicate the map distances between the genes. When plants grown from seeds heterozygous for each of these pairs of alleles were testcrossed with plants from colorless, waxy, shrunken seeds, the progeny seeds were as follows: Colorless, nonwaxy, shrunken 84 colorless, nonwaxy, plump 974 colorless, waxy, shrunken 20 colorless, waxy, plump 2349 colored, waxy, shrunken 951 colored, waxy, plump 99 colored, nonwaxy, shrunken 2216 colored, nonwaxy, plump 15 Total 6708 Determine the order of the three genes, and construct a linkage map showing the genetic distances between adjacent genes. The following progeny were obtained from a testcross of females heterozygous for all three genes. If the heterozygote dpy-21 +/+ unc-34 undergoes self-fertilization (the normal mode of reproduction in this organism), what fraction of the progeny is expected to be both dumpy and uncoordinated? Animals homozygous for either or both of the recessive alleles have light-colored eyes. In one experiment, homozygous dark-eyed rats were crossed with doubly recessive light-eyed rats, and the resulting F1 animals were testcrossed with rats of the homozygous light-eyed strain. The progeny from the test-cross consisted of 628 dark-eyed and 889 light-eyed rats. In another experiment, R p R p animals were crossed with r P r P animals, and the F1 progeny were crossed with animals from an r p r p strain. Determine whether the genes are linked, and if they are, estimate the frequency of recombination between the genes from each of the experiments. The mutations are tested in pairs in complementation tests, with the results shown in the accompanying table. A + indicates complementation (that is, flies carrying both mutations survive), and a indicates noncomplementation (flies carrying both mutations die). How many genes (complementation groups) are represented by the mutations, and which mutations belong to each complementation group? From a plant of genotype Sh wx Gl/sh Wx gl, what is the expected frequency of sh wx gl gametes: (a) in the absence of interference? Six possible arrangements of spore colors are possible in crosses segregating for one of these allelic pairs, as shown in the accompanying diagram. For each cross, indicate how the different arrangements arise and what you can deduce about the location of the segregating gene. The following tetrad types were found, with the observed number of each shown below. Analyze these data as fully as you can with respect to the linkage of each gene with respect to every other gene and with respect to its centromere. For convenience, rad6, trp5, leu1, and met14 are abbreviated as r, t, l, and m, respectively. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. The 'Genesis of the White-Eyed Mutant" in Drosophila melanogaster: A reappraisal. The Chromosome Theory of Inheritance: Classical Papers in Development and Heredity. Note the many abnormal chromosomes, containing two or more colors,that have been formed by breakage of other chromosomes and Reunion of their broken parts in abnormal combinations. Note also that this cell has 63 chromosomes (instead of the normal 46) and that one of the X chromosomes is missing. Understanding these basic features of heredity requires identification of the chemical nature of the genetic material and the processes through which it is replicated. Watson-Crick base pairing between A and T and between G and C in the complementary strands holds the strands together. The complementarity also holds the key to replication, because each strand can serve as a template for the synthesis of a new complementary strand. Note that two of the bases have a double-ring structure; these are called purines. When a phosphate group is also attached to the sugar, the nucleoside becomes a nucleotide (Figure 5. Nucleotides may contain one phosphate unit (monophosphate), two such units (diphosphate) or three (triphosphate). Most of these terms are not needed in this book; they are included because they are likely to be encountered in further reading. The chemical bonds by which the sugar components of adjacent nucleotides are linked through the phosphate groups are called phosphodiester bonds. As we describe his technique, we will let the molar concentration of any base be represented by the symbol for the base in square brackets; for example, [A] denotes the molar concentration of adenine. Chargaff also observed certain regular relationships among the molar concentrations of the different bases. In the next section, we examine the molecular basis of base pairing in more detail. The helix is right-handed, which means that as you look down the barrel, each chain follows a clockwise path as it progresses. Each base is paired to a complementary base in the other strand by hydrogen bonds, which provide the main force holding the strands together. The stick figures are the sugar-phosphate chains winding around outside the stacked base pairs, forming a major groove and a minor groove. The color coding for the base pairs is A, red or pink; T, dark green or light green; G, dark brown or beige; C, dark blue or light blue. The bases depicted in dark colors are those attached to the blue sugar-phosphate backbone; bases depicted in light colors are attached to the beige backbone. The two grooves spiraling along outside of the double helix are not symmetrical; one groove, called the major groove, is larger than the other, which is called the minor groove. The hydrogen bonds that form in the adenine-thymine base pair and in the guanine-cytosine pair are illustrated in Figure 5. On the left, the hydrogen bonds (dotted lines) and the joined atoms are shown in red. In the space-filling models (B and D), the colors are C, gray; N, blue; O, red; and H (shown in the bases only), white. Each hydrogen bond is depicted as a white disk squeezed between the atoms sharing the hydrogen. The stick figures on the outside represent the backbones winding around the stacked base pairs. Crick 1953 Cavendish Laboratory Cambridge, England A Structure for Deoxyribose Nucleic Acid this is one of the watershed papers of twentieth-century biology. The importance of the paper was recognized immediately, in no small part because of its lucid and concise description of the structure. Watson and Crick benefited tremendously in knowing that their structure was consistent with the unpublished structural studies of Maurice Wilkins and Rosalind Franklin. The same issue of Nature that included the Watson and Crick paper also included, back to back, a paper from the Wilkins group and one from the Franklin group detailing their data and the consistency of their data with the proposed structure. It has been said that Franklin was poised a mere two half-steps from making the discovery herself, alone. Both chains follow right-handed helices, but the two chains run in opposite directions. The If only specific pairs of bases can be formed, it follows that if the sequences of bases on one chain is given, then the sequence on the other chain is automatically determined. They are joined together in pairs, a single base from one chain being hydrogen-bonded to a single base from the other chain, so that the two lie side by side.

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