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Activators Recruit Additional Factors Needed for Efficient Initiation or Elongation at Some Promoters the elaborate transcriptional machinery of a eukaryotic cell contains numerous proteins required for initiation high blood pressure quiz buy nifedipine online pills. At some genes pulse pressure of 78 generic nifedipine 30 mg with amex, sequences downstream from the promoter cause pausing or stalling of the polymerase soon after initiation blood pressure 10060 buy nifedipine discount. At those genes heart attack romance order nifedipine visa, the presence or absence of certain elongation factors greatly influences the level at which the gene is expressed. This gene, activated by heat shock, is controlled by two activators working together. Childhood leukemias are rather common, seen in one in 2000 children under the age of 15. These complexes activate promoter regions by methylating lysine 4 of histone H3 (H3K4 trimethylation, or H3K4m3). In Drosophila, the Trithorax H3K4 methylation complex counteracts Polycomb repression complexes, which are responsible for trimethylation of H3K27. They impart a "positive" chromatin mark (H3K4me3) in the promoter regions of genes slated for activation. It has been suggested that the functional merging of these two complexes results in "runaway" gene expression in white blood cells. This results in the release of polymerase, the transcription of the viral genome, and infection of the host cell, typically a T-lymphocyte. It is now believed that paused polymerase is more commonly seen, particularly during development. Action at a Distance: Loops and Insulators Many eukaryotic activators-particularly in higher eukaryotes-work from a distance. Thus, in a mammalian cell, for example, enhancers can be found several tens or even hundreds of kilobases upstream (or downstream) of the genes they control. Once the sites to which they bind are separated by more than a few kilobases, this advantage is largely lost. Various models have been proposed to explain how proteins binding between enhancers and promoters might help activation in the cells of higher eukaryotes. Cohesin, a protein complex engaged in the pairing of homologous chromosomes during cell division (described in Chapter 8; see. In addition, chromatin may in some places form special structures that actively bring enhancers and promoters closer together. If an enhancer activates a specific gene 400 kb away, what stops it from activating other genes whose promoters are within that range When placed between an enhancer and a promoter, an insulator inhibits activation of the gene by that enhancer. As shown in Figure 19-14, the insulator does not inhibit activation of that same gene by a different enhancer, one placed downstream from the promoter; nor does the insulator inhibit the original activator from working on a different gene. Thus, the activator can activate another promoter nearby (c), and the original promoter can be activated by another enhancer placed downstream (d). As we have seen, the modification state of local chromatin influences gene expression. We shall see later that propagation of certain repressing histone modifications over stretches of chromatin lies at the heart of a phenomenon called transcriptional silencing. Silencing is a specialized form of repression that can spread along chromatin, switching off multiple genes without the need for each to bear binding sites for specific repressors. Insulator elements can block this spreading, and thus insulators protect genes from both indiscriminate activation and repression. A gene inserted at random into the mammalian genome is often "silenced" because it becomes incorporated into a particularly dense form of chromatin called heterochromatin. But if insulators are placed upstream and downstream from that gene, they protect it from silencing. Appropriate Regulation of Some Groups of Genes Requires Locus Control Regions the human globin genes are expressed in red blood cells of adults and in various cells in the lineage that forms red blood cells during development. Although clustered, these genes are not all expressed at the same time; rather, the different genes are expressed at different stages of development starting with 1 (in the fetus) then the g genes, followed by d and culminating with the expression of b-globin after birth. Each gene has its own collection of regulatory sites needed to switch that gene on at the right time during development and in the proper tissues. Not shown is the a-globin gene, which is expressed throughout development; its product combines with each of the globins shown here, in turn, to produce different forms of hemoglobins at different stages of development. Only in adult bone marrow are the correct regulators all active and present in appropriate concentrations to bind these enhancers. But more than this is required to switch on the various globin genes in the correct order. These genes are involved in patterning the developing limbs and are expressed in a precise manner in the embryo (Chapter 21). Some of these have the properties of enhancers: that is, if these sequences are attached experimentally upstream of a reporter gene, they can activate that gene. These individual promoters would then produce high-level expression of each gene as required. In all cases, the results show that regulatory proteins bound to the upstream regulatory sequences are found in close proximity to the promoter as that promoter is activated. It might also alter the chromatin between the two in a manner that helps loop formation. Recall, for example, that the lac genes of Escherichia coli are efficiently expressed only when both lactose is present and glucose is absent.

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Another example comes from the construction of "sender" and "responder" strains that create banded patterns of gene expression on agar plates heart attack flac torrent cheap nifedipine 20 mg mastercard. The sender strain is in the center of the plate and produces a signaling molecule that diffuses out from the center to create a gradient blood pressure medication options generic nifedipine 30 mg with mastercard. Each of two responder strains heart attack movie online purchase 30 mg nifedipine overnight delivery, which are present throughout the plate diastolic blood pressure 0 best buy for nifedipine, responds differentially to high and low concentrations of the signaling molecule by producing distinguishable, chromogenic reporter proteins. As a result, one responder strain produces coloring in a halo pattern that is close to the sender cells, and the other produces a halo that is further away from the sender cells. When applied to regulatory circuits, systems biology attempts to reveal principles of gene control that cannot be understood from the study of individual components in isolation. The complementary field of synthetic biology also seeks to elucidate design principles, but it attempts to do so by the creation of artificial regulatory networks that mimic features of natural circuits. Transcription networks consist of nodes, which represent genes, and edges, which represent the regulation of one gene by another. In a simple, two-node regulatory motif, one gene controls the expression of another, and this regulation can be either negative or positive. Another simple motif is autoregulation, in which a gene regulates its own expression. Negative autoregulation, in which a gene represses its own expression, has the property of dampening noise, which is the variation in gene expression under seemingly uniform conditions. Positive autoregulation has the property of allowing steady-state expression to be reached slowly. A feed-forward loop is a three-node motif in which a regulatory gene (gene A) governs both the expression of a target gene and the expression of a second regulatory gene (gene B). Thus, in a feed-forward loop, gene A controls the expression of the target gene both directly and indirectly via gene B. Some regulatory circuits in nature generate oscillating cycles of gene expression as observed in the cell cycle, development, and circadian rhythms. The design of these circuits is such that the appearance of one regulatory protein leads to its own disappearance and the appearance of a second regulatory protein. A synthetic network consisting of three repressors linked in tandem in a circular circuit mimics natural oscillators in that it generates a cyclic pattern of gene expression but not with the robustness of natural oscillators. Systems Biology 791 the methods used in systems biology permit the systematic identification of every component engaged in a complex cellular process. The ability to obtain such information is prompting a paradigmatic shift in the way biologists analyze data. Instead of asking how a process works, it is now possible to ask why it is organized in a particular fashion. Looking ahead, the insights gained from systems biology in combina- tion with the increasing sophistication of synthetic biology may some day make it possible to create artificial cells with the minimal circuitry for self-propagation. If so, then the future holds the prospect of artificial cells with tailor-made features, such as the capacity to efficiently metabolize pollutants, recycle waste materials, convert sunlight into fuel, or combat human disease. Setting the pace: Mechanisms tying Caulobacter cell-cycle progression to macroscopic cellular events. A genetic oscillator and the regulation of cell cycle progression in Caulobacter crescentus. Describe the plot for negative autoregulation (level of gene expression [%] over time) shown in Figure 22-3. Consider the experiment in which the expression of two copies of the same gene are measured using the green fluorescent protein reporter for the first copy of the gene and red fluorescent protein reporter for the second copy of the gene in E. Explain why a regulatory circuit under negative autoregulation is described as robust. In Figure 22-3, what portion of the positive autoregulation curve represents when the output reaches steady state Explain how steady state is reached when the gene expression is subject to positive autoregulation. What property of ComK binding to the promoter for comK allows this regulatory circuit to be a bistable switch What type of regulatory circuit controls Bacillus subtilis cells switching between the swimming and chaining states Using edges and nodes, name and draw a regulatory circuit that represents the expression of a regulatory protein if turned on quickly and maintained at a constant level. Using edges and nodes, draw a regulatory circuit that represents the synthetic repressilator. Name the genes at the nodes and describe the pattern of expression from the repressilator. As depicted below, researchers constructed a circuit consisting of a series of artificial promoters (each containing an AraC binding site and a lac operator). Remember that the presence of arabinose and AraC promotes transcription of downstream genes, lacI encodes the LacI repressor, and binding of LacI to the lac operator turns off transcription (even in the presence of arabinose and AraC). The Nobel Prize in Physiology or Medicine in 2002 was awarded for work on the worm, and it was shared by Horvitz (for his work defining genes that controlled programmed cell death) with Brenner himself, who had established the system, and another of his postdocs, John Sulston. In this photo, Horvitz is shown with two members of his lab at the time, Elizabeth Sawin (now a co-director of Climate Interactive) and Asa Abeliovich (a neurobiologist at Columbia). Mary Lyon and Rudolf Jaenisch, 1985 Symposium on Molecular Biology of Development.

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Successful replacement joints are now available for the shoulder blood pressure quiz questions order 30mg nifedipine with visa, elbow arrhythmias generic nifedipine 20mg overnight delivery, hip and knee blood pressure ranges by age discount nifedipine 30 mg online. Replacements for the wrist and ankle have proved less 112 management of musculoskeletal problems successful arrhythmias order cheap nifedipine on-line. General complications include deep vein thrombosis, pulmonary embolus, myocardial infarction and stroke, although these usually occur in more elderly patients. The risk of this complication varies with the implant used, the indication for surgery and the age of the patient at the time of surgery. However, less satisfactory results can be expected in younger, more active patients, in whom loosening rates may be higher. Orthopaedic surgeons, therefore, prefer to avoid joint replacement in patients under the age of 60 years. However, there is no specific age limit and some patients with severe symptomatic arthritis may require joint replacement at a much younger age if there is no other surgical alternative. This is commonly used following trauma in which one side of the joint is damaged but the other surface is involved. All of these injuries can be treated with a hemiarthroplasty that replaces the articular surface involved by the fracture, but the other side of the joint is not replaced and articulates with the artificial component. The complications of hemiarthroplasty are the same as those associated with a total joint replacement. In modern orthopaedic practice it is usually employed only as a last resort or as an interim treatment. This may entail excision of the infected artificial joint, leaving the patient with an excision arthroplasty until clinical and haematological markers of infection return to normal, at which stage a revision joint replacement is undertaken. Fusion of joints for arthritis is most often used for small joints in the hand or foot. It is generally avoided for major upper and lower limb joints, as there is considerable disability associated with fusion of these. Patellar tendon versus hamstring tendon autograft for anterior cruciate ligament rupture in adults. Surgical versus functional treatment for acute ruptures of the lateral ligament complex of the ankle in young men: a randomized controlled trial. Primary arthroscopic stabilization for a first-time anterior dislocation of the shoulder. Fusion of the hip or knee is better tolerated by men than by women and tends to transfer excessive forces to the joint above and below the fusion. Mok Chapter 12 Regionalinjuries John Keating, Geoffrey Hooper and James Robb Chapter 13 Sportandexerciseassociatedproblemsinadults 169 Julia L. The term fractureencompassesallbonyinjuries,fromsimple undisplaced cracks in bone to major complex long-bonefractureswithextensivesoft-tissueinjuries. Rotationisbestjudgedonclinicalexaminationand refers to the degree of rotational malalignment at the fracture site. Reduction is usually desirable in displaced or angulatedfractures,butisnotalwaysrequired. Once the fracture is reduced, the surgeon then has to choose some method of treatment to maintain the reduction until union occurs. Each method has advantages and disadvantages, and several options can be considered in most situations. The decision is influencedbylocationandmorphologyofthefracture, the presence of associated injuries and the experienceofthesurgeon. Fracture union is dependent mainly on the blood supply of the bone at the site of the injury. Ingeneral,cancellousbonehasabetter blood supply than cortical bone and heals more rapidlyandreliably. Higher-energy injuries do more damage to the blood supply and are, therefore,associatedwithmoreprolongedhealingtimes. Disadvantages are problems with pin-track infection,poorpatientacceptanceandahigherrate of mal-union. These devices are particularly suitable for use in situations where application of internalfixationwouldbedifficultorrisky. Examples include distal metaphyseal fractures, bone wheretherehasbeenpreviousosteomyelitis,multiplefractures,orextensiveskindamageandswellingfollowinghigh-energytrauma. Externalfixation may be used temporarily in these situations until internalfixationisdeemedsafe. Intramedullary nails are widely used in the treatment of lower-limb long-bone fractures in adults. They can be inserted with minimally invasive surgery and are excellent for restoring normal length, alignment and rotation. They are biomechanicallyverystrongandareidealforlower-limb diaphyseal fractures, where union times may be prolonged. They are associated with a reliably high rate of union and very low rates of mal-union.

Tests are convenient and easily scored but are by nature artificial pre hypertension emedicine order discount nifedipine on line, and their relevance to everyday behavior is not always clear heart arrhythmia 4 year old order genuine nifedipine line. These are the kinds of questions that psychologists must address whenever they wish to use test results to draw conclusions about behaviors outside of the testing situation blood pressure goal diabetes buy 20mg nifedipine with mastercard. Research Designs Research Settings Data-Collection Methods In an experiment (such as the experiment on treatments for depression) arteria mesenterica superior buy nifedipine uk, the researcher can test hypotheses about causation by manipulating the independent variable(s) and looking for corresponding differences in the dependent variable(s) while keeping all other variables constant. In a correlational study, a researcher measures two or more variables to see if there are systematic relationships among them. Descriptive studies are designed only to characterize and record what is observed, not to test hypotheses about relationships among variables. Laboratory settings allow researchers the greatest control over variables, but they may interfere with the behavior being studied by virtue of being unfamiliar or artificial. Field studies, done in "real-life" settings, have the opposite advantages and disadvantages, offering less control but perhaps more natural behavior. Self-report methods require the people being studied to rate or describe themselves, usually in questionnaires or interviews. Statistical Methods in Psychology To make sense of the data collected in a research study, we must have some way of summarizing the data and some way to determine the likelihood that observed patterns in the data are (or are not) simply the results of chance. The statistical procedures used for these purposes can be divided into two categories: (1) descriptive statistics, which are used to summarize sets of data, and (2) inferential statistics, which help researchers decide how confident they can be in judging that the results observed are not due to chance. We look briefly here at some commonly used descriptive statistics and then at the rationale behind inferential statistics. A more detailed discussion of some of these procedures, with examples, can be found in the Statistical Appendix at the back of this book. Descriptive Statistics Descriptive statistics include all numerical methods for summarizing a set of data. There are a number of relatively simple statistics that are commonly used to describe a set of data. Describing a Set of Scores If our data were a set of numerical measurements (such as ratings from 1 to 10 on how generous people were in their charitable giving), we might summarize these measurements by calculating either the mean or the median. The mean is simply the arithmetic average, determined by adding the scores and dividing the sum by the number of scores. The median is the center score, determined by ranking the scores from highest to lowest and finding the score that has the same number of scores above it as below it, that is, the score representing the 50th percentile. Variability refers to the degree to which the numbers in the set differ from one another and from their mean. In set A, the scores cluster close to the mean (low variability); in set B, they differ widely from the mean (high variability). A common measure of variability is the standard deviation, which is calculated by a formula described in the Statistical Appendix. Correlational studies, as discussed earlier in this chapter, examine two or more variables to determine whether or not a nonrandom relationship exists between them. When both variables are measured numerically, the strength and direction of the relationship can be assessed by a statistic called the correlation coefficient. Correlation coefficients are calculated by a formula (described in the Statistical Appendix) that produces a result ranging from 1. The sign (or) indicates the direction of the correlation (positive or negative). In a positive correlation, an increase in one variable coincides with a tendency for the other variable to increase; in a negative correlation, an increase in one variable coincides with a tendency for the other variable to decrease. The absolute value of the correlation coefficient (the value with sign removed) indicates the strength of the correlation. A correlation close to zero (0) means that the two variables are statistically unrelated-knowing the value of one variable does not help you predict the value of the other. Suppose the data collected in the study are those depicted in the table on the next page in Figure 2. Each row in the table shows the data for a different student, and the students are rank ordered in accordance with their scores on the test. The scatter plots relating test score to each of the other variables are shown in Figure 2. Notice that each point represents both the test score and the hours of study for a single student. Thus, the point indicated by the red arrow denotes a student whose score is 85 and who spent 9 hours studying. By looking at the whole constellation of points, you can see that, in general, higher test scores correspond with more hours spent studying. Test Hrs of Test Height score study Score Depression (cm) 100 97 85 80 78 78 62 54 38 22 9 11 9 14 8 5 3 6 10 3 85 88 70 79 62 65 44 30 20 30 8 4 3 1 10 11 6 12 14 7 177 160 171 158 184 152 176 165 159 176 100 80 Test score 60 40 20 3 6 9 12 Depression score Plot C 15 Test score 100 80 60 40 20 150 157 164 171 178 185 Height in centimeters Plot D. At the bottom of each of the four right-hand columns is the correlation coefficient relating the data of that column to the test score. By comparing the plots, you can see the difference between weaker and stronger correlations and between positive and negative correlations. The closer the points are to forming a straight line, the stronger is the correlation between the two variables. In this study, score on the previous test is an excellent predictor of the score on the new test. In the experiment comparing treatments for depression summarized back in Figure 2.

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