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STUDENT DIGITAL NEWSLETTER ALAGAPPA INSTITUTIONS |
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Charlene Gamaldo, M.D.
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Genetic tests typically screen for only the most common mutations; uncommon and rare mutations are not detected virus 1 cheap 250 mg terramycin mastercard. Therefore antibiotic treatment for strep throat trusted 250mg terramycin, a negative result does not mean that a genetic defect is absent; it indicates only that the person does not have a common mutation antimicrobial foods terramycin 250mg discount. However infection 1 game cheap 250mg terramycin mastercard, this is not the case for many genetic diseases in which penetrance is incomplete and environmental factors play a role. The risk associated with a particular mutation is a statistical estimate, Pedigree Analysis, Applications, and Genetic Testing 153 based on the average effect of the mutation on many people. In this case, the calculated risk may provide little useful information to a specific person. Direct-To-Consumer Genetic Testing An increasing number of genetic tests are now being offered to anyone interested in investigating his or her own hereditary conditions, without requiring a health-care provider. These direct-to-consumer genetic tests are available for testing a large and growing array of genetic conditions in adults and children, everything from single-gene disorders such as cystic fibrosis to multifactorial conditions such as obesity, cardiovascular disease, athletic performance, and predisposition to nicotine addiction. Direct-to-consumer tests are also available for paternity testing and for determining ancestry. Many direct-to-consumer genetic tests are advertised and ordered through the Internet. The person collects the sample and sends it back to the company, which performs the test and sends the results to the person. Geneticists, public health officials, and consumer advocates have raised a number of concerns about directto-consumer genetic testing, including concerns that some tests are offered without appropriate information and genetic counseling and that consumers are often not equipped to interpret the results. Other concerns focus on the accuracy of some tests, the confidentiality of the results, and whether indications of risk provided by the test are even useful. Advocates of direct-to-consumer genetic tests contend that the tests provide greater access to testing and enhanced confidentiality. Many states do not regulate direct-to-consumer testing and, currently, there is little federal oversight. This law prohibits health insurers from using genetic information to make decisions about health-insurance coverage and rates. It also prevents employers from using genetic information in employment decisions and prohibits health insurers and employers from asking or requiring a person to take a genetic test. Results of genetic testing receive some degree of protection by other federal regulations that cover the uses and disclosure of individual health information. Chimpanzees are our closest living relatives, yet we differ from chimps anatomically and in a huge number of behavioral, social, and intellectual skills. The perceived large degree of difference between chimpanzees and humans is manifested by the placement of these two species in entirely different primate families (humans in Hominidae and chimpanzees in Pongidae). Recent sequencing of human and chimpanzee genomes has provided more-precise estimates of the genetic differences that separate these species: about 1% of the two genomes differ in base sequences and about 3% differ in regard to deletions and insertions. Geneticists are now identifying genes that contribute to human uniqueness and potentially played an important role in the evolution of modern humans. In some cases, Genetic Discrimination and Privacy With the development of many new genetic tests, concerns have been raised about privacy regarding genetic information and the potential for genetic discrimination. Research shows that many people at risk for genetic diseases avoid genetic testing because they fear that the results would make it difficult for them to obtain health insurance or that the information might adversely affect their employability. Some of those who do seek genetic testing pay for it themselves and use aliases to prevent the results from becoming part of their health records. In the 1970s, some African Americans were forced to undergo genetic testing for sickle- 154 Chapter 6 these genes have been identified through the study of mutations that cause abnormalities in our human traits, such as brain size or language ability. One set of genes that potentially contribute to human uniqueness regulates brain size. The observation that mutations in microcephalin drastically affect brain size has led to the suggestion that, in the course of human evolution, selection for alleles encoding large brains at one or more of these genes might have led to enlarged brain size in humans. Geneticists have studied variation in the microcephalin genes of different primates and have come to the conclusion that there was strong selection in the recent past for the sequences of the microcephalin genes that are currently found in humans. Other genes that may contribute to human uniqueness have been identified on the basis of their rapid evolution in the human lineage. This gene is expressed in brain cells and some evidence suggests that it may be important in the development of the cerebral cortex, an area of the brain that is greatly enlarged in humans. When both parents are heterozygous for a particular autosomal recessive trait, approximately one-fourth of their offspring will have the trait. Recessive traits are more likely to appear in families with consanguinity (mating between closely related persons). When one parent is affected and heterozygous for an autosomal dominant trait, approximately half of the offspring will have the trait. Unaffected people do not normally transmit an autosomal dominant trait to their offspring. When a woman is a heterozygous carrier for an Xlinked recessive trait and a man is unaffected, approximately half of their sons will have the trait and half of their daughters will be unaffected carriers. Affected men pass an X-linked dominant trait to all of their daughters but none of their sons. Heterozygous women pass the trait to half of their sons and half of their daughters. The Genetic Information Nondiscrimination Act prohibits the use of genetic information in deciding health insurability and employment. It might skip generations when a new mutation arises or the trait has reduced penetrance. If the trait were Y linked, an affected male would pass it on to all his sons, whereas, if the trait were autosomal and sexlimited, affected heterozygous males would pass it on to only half of their sons on average. Preimplantation genetic diagnosis determines the presence of disease-causing genes in an embryo at an early stage, before it is implanted in the uterus and initiates pregnancy. Prenatal genetic diagnosis determines the presence of disease-causing genes or chromosomes in a developing fetus. Joanna marries Tom, who has normal fingers; they adopt a son named Bill who has normal fingers. After adopting Bill, Joanna and Tom produce two children: an older daughter with short fingers and a younger son with normal fingers. If Joanna and Tom have another biological child, what is the probability (based on your answer to part b) that this child will have short fingers Tom in brackets; connect him to his biological parents by drawing a diagonal line and to his adopted parents by a dashed line. In the pedigree for the family, identify persons with the trait (short fingers) by filled circles (females) and filled squares (males). The most likely mode of inheritance for short fingers in this family is autosomal dominant. We can eliminate Y-linked inheritance because the trait is found in females as well as males. The trait is unlikely to be autosomal recessive, because it does not skip generations and approximately half the children of affected parents have the trait. If having short fingers is autosomal dominant, Tom must be homozygous (bb) because he has normal fingers. Joanna must be heterozygous (Bb) because she and Tom have produced both short- and normal-fingered offspring. Concordance values for a series of traits were measured in monozygotic twins and dizygotic twins; the results are shown in the following table. For each trait, indicate whether the rates of concordance suggest genetic influences, environmental influences, or both. This high concordance in monozygotic twins does not, by itself, indicate a genetic basis for the trait. An important indicator of a genetic influence on the trait is lower concordance in dizygotic twins. The concordance for diabetes is substantially higher in monozygotic twins than in dizygotic twins; therefore, we can conclude that genetic factors play some role in susceptibility to diabetes.
Chemotherapy antibiotic knee spacer terramycin 250mg, which involves the use of anticancer drugs to kill the cancer cells tween 80 bacteria effective 250 mg terramycin, is usually administered after the surgery to destroy any remaining cancer infection related to discount terramycin 250mg online. New drugs to treat ovarian cancer are in the clinical trial stage antibiotics yellow teeth generic terramycin 250mg mastercard, including monoclonal antibody treatment for advanced ovarian cancer. In most procedures, the ovaries, uterus, and fallopian tubes are completely removed. In rare cases, if the cancer is not very aggressive and the woman is young and has not had children, a more conservative approach may be adopted. Only one ovary may be removed, and, if possible, the fallopian tubes and the uterus may be left intact. Occasionally, in addition to the female reproductive organs, the appendix may also be removed. The liver and the intestine will be examined for signs of cancer and may be biopsied. Ovarian cancer spreads contiguously, which means that it moves to the organs that are next to it. In some cases, extensive surgery may be needed to remove as much of the cancer as possible. The most common drug used is paclitaxel (Taxol), combined with either cisplatin or carboplatin. Cancers that do not respond to these combinations may be treated with topotecan (Hycamtin) or with a a combination of paclitaxel and epirubicin (Ellence). Expected results Most often ovarian cancer is not diagnosed until it is in an advanced stage, making it the most deadly of the female reproductive cancers. More than 50% of the women who are diagnosed with the disease die within five years. If ovarian cancer is diagnosed while it is still localized to the ovary, more than 90% of the patients will survive five years or more. Alternative medicine rarely claims to be able to cure cancer on a regular basis, but many treatments have been shown to help improve symptoms, control the pain and side effects of conventional treatments, speed healing, and increase the quality of life for cancer patients. Some alternative therapies may be strongest as preventative measures, before major prob1517 Ovarian cancer lems like cancer occur in the body, and as supportive measures, used with allopathic medicine. People should become educated on and practice dietary principles that reduce the risk of cancer. These principles include eating plenty of raw and fresh fruits, vegetables, beans, and whole grains. People should consume organically grown foods when possible, minimize overeating, reduced the intake of meat and dairy products, increase fiber, avoid processed and artificial foods. They should also avoid canned foods including soft drinks, avoid sugar and refined starch products such as white flour, reduce the intake of fat, avoid hydrogenated vegetable oils such as margarine and shortening, and drink filtered or spring water. Currently, genetic tests are available that can help to determine whether a woman who has a family history of breast, endometrial, or ovarian cancer has inherited the mutated gene that predisposes her to these cancers. Allopathic medicine often recommends removing the ovaries as prevention even when a clear genetic component is not found, and this procedure is called a prophylactic oophorectomy. The American Cancer Society recommends annual pelvic examinations for all women after age 40, in order to increase the chances of early detection of ovarian cancer. Alternative medicine stresses preventative measures that avoid removing the ovaries, unless a clear genetic risk has been established. Some studies have shown that removal of the ovaries does not necessarily reduce the risk of cancer, and does not necessarily increase longevity rates in women. Having sound physical and mental health can significantly reduce the chances of getting cancer of any type. The following guidelines are generally recommended by doctors, nutritionists, and alternative practitioners for cancer prevention and recovery. Those women in all groups who performed regular exercise had less risk for uterine, breast, cervical, ovarian, and vaginal cancers. This includes avoiding unnecessary x rays, not residing near sources of natural or man-made radiation, and avoiding occupational exposure to radiation. Ectopic pregnancies often cause severe pain in the lower abdomen and are potentially life-threatening because of the massive blood loss that may occur as the developing embryo/fetus ruptures and damages the tissues in which it has implanted. Endometriosis-A condition in which the tissue that normally lines the uterus (endometrium) grows in other areas of the body, causing pain, irregular bleeding, and frequently, infertility. These signals are used to construct detailed images of internal body structures and organs, including the brain. Monoclonal antibody-A protein substance that is produced in the laboratory from a single clone of a B-cell, the type of cell of the immune system that makes antibodies. Paclitaxel-A drug derived from the common yew tree (Taxus baccata) that is the mainstay of chemotherapy for ovarian cancer. Prostasin-A blood protein that appears to be a reliable early indicator of ovarian cancer. Transvaginal ultrasound-A technique for imaging the ovaries using sound waves generated by a probe inserted into the vagina. This diagnostic imaging procedure serves as the baseline for a hysterosonographic examination. Frey, PhD Ovarian cysts Definition Ovarian cysts are fluid-filled sacs that form inside or on the surface of the ovaries, which are the female reproductive organs that lie in the lower abdomen. Ovarian cysts appear and disappear regularly as part of the normal menstrual cycle. The cysts can, however, become a medical problem if they remain in the ovaries, enlarge, and cause pain or other symptoms. Description Ovarian cysts develop as a normal part of a healthy menstrual cycle; mature ovaries very often have cysts in them. The cysts that appear during the regular activity of the ovaries are called functional cysts. Sometimes a cyst can bleed; it is then known as a corpus hemorrhagicum, meaning a body that bleeds. When bleeding lasts for longer than several days and a large cyst remains, surgical intervention is sometimes called for. Surgery on the ovaries is usually performed through an instrument called a laparoscope. Neoplastic (new growth) cysts may appear, which are benign (noncancerous) growths. These cysts occur when cells of the ovaries not related to ovulation begin to grow abnormally. Dermoid tumors are a type of benign growth that may occur on the ovaries and resemble cysts. Abnormal cysts may contain fluid or blood, and may be inside the ovary or next to it under the surface. Hormonal imbalances play a major role in this condition, including high levels of the hormone androgen and low levels of progesterone, the female hormone necessary for egg release. In adolescent girls, ovarian cysts may be associated with a genetic disorder known as McCune-Albright syndrome, which is characterized by abnormal bone growth, discoloration of the skin, and early onset of puberty. In the ovaries, immature eggs are stored in the follicles, which are tiny tube-like membranes. When menstruation begins in the early teens, women have nearly 400,000 follicles that store and produce eggs in the ovaries. During each menstrual cycle, an egg matures inside one of the follicles, and the follicle sac fills up with a liquid (liquor folliculi) that nourishes the growing egg. When the egg is released into the fallopian tube during ovulation, the follicle opens or ruptures and the fluid drains away. Sometimes there is pain associated with ovulation, known as Mittelschmerz, which is a German word that means middle pain. A small amount of bleeding may also accompany the normal release of an egg from the follicle. After ovulation, another functional cyst forms on the ovary where the egg was released. The luteal cyst has the function of secreting progesterone, an important female hormone that regulates the reproductive cycle. If no pregnancy occurs, the luteal cyst should disappear with the continuation of the menstrual cycle. Abnormalities in the menstrual cycle may cause cysts to remain and grow irregularly. Sometimes the follicles stay filled with liquid after the egg is released, or the egg does not get released in the proper way and the follicle continues to grow.
Stacks of the triple-sheet crystalline units are held together by van der Waals forces26 (Figure27 I) antibiotic kidney failure terramycin 250mg low cost. Accord ingly bacteria water test discount terramycin 250 mg online, by utilizing proper mining methodologies virus 81 purchase terramycin 250mg fast delivery, asbestos contamination is avoided antibiotics for uti cats cheap terramycin 250mg free shipping. Moreover, the absence of asbestos in talc is routinely confirmed in ore samples through a battery of analytical techniques. A dilute talc/slurry water is conditioned for flotation by the addition of a frothing agent (often a low-molecular-weight alcohol), and the slurry is then processed through a series of cells through which air is pumped. This processing causes bubbles to form, and as the bubbles rise to the surface, the talc particles attach to the bub bles due to their organophilic nature; the nontalc impurities are hydrophilic and do not tend to attach to the bubbles. The talc particles can be further processed by magnetic separation or acid washing to remove iron-bearing minerals, soluble salts, and metals. In 2012, the Council completed a survey to assess the frequency and the use concentration of talc in spray products and the highest reported concentration used in spray products was 35% in a makeup base (aerosol). Products containing talc may be applied to baby skin, used in products that could be incidentally ingested, or used near the eye area or mucous membranes. Additionally, talc is used in cosmetic sprays and powders; for example, talc is reported to be used in face powders at I 00%, baby powders at 99%,47 aerosol makeup bases at up to 35%, and in aerosol deodorants at up to 30%. Fine talc, with a larger than average particle size (200 mesh), is often preferred for use in blushes, eye shadows, and finishing pow ders. Loose-talc-based formulations, such as loose finishing makeup powders, baby powders, body powders, and foot pow ders, do not include a binder system. The majority of cosmetic talcs in loose-matrix powders contain talc particles that are of a larger diameter than those used in other cosmetic applications; for loose powders, a 200 mesh is normally used, and in these loose powders, substantial agglomeration occurs due to elec trostatic and crystalline charges on the talc powders. While some researchers state that the inclusion of a fra grance oil may act as a minimal binder system causing further agglomeration,26 another researcher found that there was no evidence that the presence of perfume in adult or baby dusting powders containing Italian 00000 grade talc or Chinese talc influenced the level of respirable talc dust. According to the World Health Organization, the acceptable daily intake for talc (as magnesium silicate) is "not specified. The particle size of talc raw material varies widely by prod uct type and by manufacturer but has "no practical significance ~ Table 3. Talc is also used as a pigment in paints, varnishes, and rubber; as a filler for paper, rubber, and soap; in fireproof and cold-water paints for wood, metal, and stone; for lubricating molds and machinery; as glove and shoe powder; and as an electric and heat insulator. Talc is used in the leather industry, in the roofing and ceramic tile industry, as a carrier for insecticides and herbicides,55 and it is used in plastics. As noted, no transloca tion from the respiratory tract to other tissues was found in this study, and the clearance of talc from the lungs was complete within 4 months after exposure. The neutron-activated talc was exposed to an integrated neutron flux of 7 x 1016 n/cm2 30 days prior to dosing. The y-ray counts of the tissue and excreta of the dosed animals were equivalent to a total of 2. The absorption, distribution, and excretion of orally admi 64 nistered talc were determined in mice, rats, and guinea pigs. In the mice killed 6 hours after dosing, 95% and 96% of the radioactivity was recovered in the large intes tines and feces, 9% and 7% was recovered in the small intestines and stomach, and 0. In the 2 mice killed at 24 hours after dosing, 99% and l O l % of the radioactivity wasrecovered in the large intestines and feces, 4% and 6% was recovered in the small intestines and stomach, and 1. Three male Wistaralbino rats were given a single oral dose and 3 rats were given 6 daily oral doses by gavage of 50 mg/kg bw [3H]talc. After the last dose, urine and feces were collected every 24 hours for 4 days and on day 10 and then the rats were killed. Within 24 hours after administration of the single dose, approx imately 75% of the radioactivity was recovered in the feces and only I% was recovered in the urine. No radioactivity was recovered in the liver or kidneys l O days after a single dose oftalc. To determine the deposition, distribution, and clearance of talc, 44 female Syrian golden hamsters received a single 2-hour nose-only exposure to a neutron-activated talc aerosol and subgroups of 4 animals were then ki lied at 11 different intervals from 15 minutes to 132 days after expo sure. Nine unexposed control animals were used, of which 4 were killed on the day the test animals were exposed and 5 were killed on the final day of the study. In the presentation of the results, the y-ray counts from the con trols were expressed as ~1g talc equivalent, and they-ray counts of the exposed animals were not corrected for control values. The mean pulmonary talc content in the lungs of test animals at various time intervals was 33. At the time of termination of the final group, that is, 132 days, there was no statistically significant difference in the talc burden of the lungs of test (3. The amount of talc [n the liver, kidneys, and lungs was also determined; the only statistically significant differences compared to controls in any of these organs were found in the liver; there was a decrease at 4 hours compared to day O controls, an increase at day 36 compared to both days O and 132 controls, and an increase on day 68 compared to day 132 controls. Analysis of the data using the Kruskal-Wallis test showed that there were no sig nificant differences among the mean talc burden values for the liver, kidneys, and ovaries, including the control values, and that there was no significant trend, indicating there was I I I Fiume et al 75S gavage with 5000 mg/kg bw talc suspended in 0. Groups of 5 rats were then intubated with 50, I 00, 500, I 000, 2000, or 3000 mg/kg bw talc in saline. All 5 animals dosed with 3000 mg/kg bw, 4 dosed with 2000 mg/kg bw, 3 with I 000 mg/kg bw, and I with 500 mg/kg bw talc died. Eight mice were placed in a box with baby powder that was circulated with compressed air. Two mice were removed from the box at 30-minute intervals, that is, after 30, 60, 90, or 120 minutes. The mice removed after 30 and 60 minutes recovered completely; symptoms that were observed were not specified. The mice removed after 90 minutes died in 5 to 6 hours; the mice removed at 120 minutes died immedi ately upon removal. The mice that died were necropsicd, and the mucous membrane of the airway was found covered with baby powder. Microscopically, hemorrhage, edema, and des quamation of bronchial epithelium admixed with baby powder were observed. Gross examination was made for all animals, and microscopic examination was per formed 12 months after dosing. One or both ovaries of rats dosed with talc were cystic in appearance at all time periods; no gross changes were seen in the ovaries of the control ani mals; the cystic structures were not derived from the ovaries but were due to distention of the bursa! Focal areas of papillary change were seen in the surface epithelium of 4 injected ovaries but not in any of the controls. No evidence of cellular lesions or of mitotic activity was seen in the nonpapil lary areas of the surface epithelium of injected ovaries, and neoplasia was not observed. Three female Dunkin Hartley guinea pigs were administered a single oral dose of25 mg/kg bw [3H]talc, and urine and feces were collected as described previously; all animals were killed on day 10. Within 24 hours after dosing, 31 % of the radio activity was recovered in the feces, and 0. At 24 to 48 and 48 to 72 hours after dosing, 39% and 19% of the radioactivity, respectively, was recovered in the feces, with <0;0 I% of the dose being recovered in the urine at each of these time periods. Wistar rats were used to determine the systemic distribution of talc following intrapleural administration. The lungs, chest wall, liver, kidneys, spleen, heart, and brain of each animal were removed for examination. Microscopic examination revealed that the chest wall had the most common lesions, and these lesions were represented by an early pneumoconiosis char acterized by stellate interstitial collections of dust-laden macro phages containing pale yellow particles associated with inflammatory infiltrate of lymphocytes with mild fibroblastic proliferation. Pneumoconiosis reactions were not observed in the other organs; however, talc crystals were present inside the microvessels of these organs. The researchers suggested talc was absorbed rapidly through the pleura, reaching the systemic cir culation with deposition in other organs within 24 hours after administration, and that the distribution was not dose related. The induction of fibrosis following an ip injec tion of 50 mg/kg bw nonfibrous talc in physiological saline was evaluated in 6 male and 6 female Wistar rats. The control group was administered postulated that the talc originated from surgical gloves used saline only. Application of talc on wounds can give rise to scab formation, Talc particles could be seen in the adhesions. The parietal possible infection, and foreign body granulomas in the der peritoneal rnesothelium was examined microscopically using mis. In another case study, hundreds cells were observed scattered on the surface of the peritoneum. Powder deposits adherent to the viscera or omentum without adhesions were reported in 3 animals dosed with 0.
This unwinding allows helicase and other single-strand-binding proteins to attach to the polynucleotide strand (Figure 12 antibiotic growth promoters generic terramycin 250 mg otc. Unwinding and replication (c) Linear eukaryotic replication 1 At each fork antimicrobial waiting room chairs buy terramycin 250mg on line, the leading strand is synthesized continuously in the same direction as that of unwinding virus 68 ny order terramycin 250mg with mastercard. Helicase binds to the lagging-strand template at each replication fork and moves in the 53 direction along this strand antimicrobial 2012 generic terramycin 250mg online, thus also moving the replication fork (Figure 12. Single-strand-binding proteins form tetramers (groups of four); each tetramer covers from 35 to 65 nucleotides. On the lagging strand, where replication is discontinuous, a new primer must be generated at the beginning of each Okazaki fragment (Figure 12. Primase forms a complex with helicase at the replication fork and moves along the template of the lagging strand. Its 35 exonuclease activity allows it to remove nucleotides in the 35 direction, enabling it to correct errors. To view the entire process of replication in action, take a look at Animations 12. Most of the errors that do arise in nucleotide selection are corrected in a second process called proofreading. Components of the replication machinery at the replication fork are shown at the top. To better understand the coordination of leading- and lagging-strand synthesis, see Animation 12. Together, proofreading and nucleotide selection result in an error rate of only one in 10 million nucleotides. A third process, called mismatch repair (discussed further in Chapter 18), corrects errors after replication is complete. It can therefore be distinguished from the newly synthesized strand, and mismatch repair takes place preferentially on the unmethylated nucleotide strand. No single process could produce this level of accuracy; a series of processes are required, each process catching errors missed by the preceding ones. New nucleotide strands are complementary and antiparallel to their template strands. Replication takes place at very high rates and is astonishingly accurate, thanks to precise nucleotide selection, proofreading, and repair mechanisms. First, the much greater size of eukaryotic genomes requires that replication be initiated at multiple origins. Second, eukaryotic chromosomes are linear, whereas prokaryotic chromosomes are circular. This accuracy is due to the processes of nucleotide selection, proofreading, and mismatch repair. They were subsequently shown to be the origins of replication in yeast chromosomes. These components are important, but we must not become so immersed in the details of the process that we lose sight of the general principles of replication. The use of multiple origins, however, creates a special problem in the timing of replication: the entire genome must be precisely replicated once and only once in each cell cycle so that no genes are left unreplicated and no genes are replicated more than once. How does a cell ensure that replication is initiated at thousands of origins only once per cell cycle In the first step, the origins are licensed, meaning that they are approved for replication. This step is early in the cell cycle when a replication licensing factor attaches to an origin. In the second step, the replication machinery initiates replication at each licensed origin. As the replication forks move away from the origin, the licensing factor is removed, leaving the origin in an unlicensed state, where replication cannot be initiated again until the license is renewed. To ensure that replication takes place only once per cell cycle, the licensing factor is active only after the cell has completed mitosis and before the replication is initiated. Thus, these specialized enzymes can bypass such errors but, because their active sites are more open and accommodating, they tend to make more errors. In replication, high-speed, high-fidelity enzymes are generally used until they encounter a replication block. Then, the translesion polymerases detach from the replication fork and high-fidelity enzymes resume replication with high speed and accuracy. Cells were cultivated for several generations in a medium containing amino acids labeled with a heavy isotope. The cells were then transferred to a culture medium that contained amino acids labeled with a light isotope. Histones assembled after the transfer possessed the new, light amino acids and were less dense. After replication, the histone octamers were isolated and centrifuged in a density gradient. Results showed that, after replication, the octamers were in a continuous band between high density (representing old octamers) and low density (representing new octamers). This finding indicates that newly assembled octamers consist of a mixture of old and new histones. Current evidence suggests that the original nucleosome is broken down into two H2A-H2B dimers (each dimer consisting of one H2A and one H2B) and a single H3-H4 tetramer (each tetramer consisting of two H3 histones and two H4 histones). The details of how epigenetic marks are maintained during replication are poorly understood. Passage through the cell cycle, including the onset of replication, is controlled by cell-cycle checkpoints. Methods 1 Grow cells for several generations in medium that contains amino acids labeled with a heavy isotope. Change medium Replication Isolate octamers Spin 3 Isolate histone octamers before and after replication. Nucleosomes break down in the course of replication and reassemble from a mixture of old and new histones. The reassembly of nucleosomes during replication is facilitated by histone chaperones and chromatin-assembly factors. Epigenetic changes in chromatin structure are often maintained during replication. Replication at the Ends of Chromosomes A fundamental difference between eukaryotic and bacterial replication arises because eukaryotic chromosomes are linear and thus have ends. Chromosome shortening would mean that, when an organism reproduced, it would pass on shorter chromosomes than it had inherited. Chromosomes would become shorter with each new generation and would eventually destabilize. Chromosome shortening does in fact take place in many somatic cells but, in single-celled organisms, germ cells, and early embryonic cells, chromosmes do not shorten and self-destruct. Telomeres and telomerase the ends of chromosomes- the telomeres-possess several unique features, one of which is the presence of many copies of a short repeated sequence. The removal of this primer once again leaves a gap at the 5 end of the chromosome, but this gap does not matter, because the end of the chromosome is extended at each replication by telomerase; so, the chromosome does not become shorter overall. Telomerase is present in single-celled organisms, germ cells, early embryonic cells, and certain proliferative somatic cells (such as bone-marrow cells and cells lining the intestine), all of which must undergo continuous cell division. Most somatic cells have little or no telomerase activity, and chromosomes in these cells progressively shorten with each cell division. These cells are capable of only a limited number of divisions; when the telomeres have shortened beyond a critical point, a chromosome becomes unstable, has a tendency to undergo rearrangements, and is degraded. The telomeres of genetically engineered mice that lack a functional telomerase gene (and therefore do not express telomerase in somatic or germ cells) undergo progressive shortening in successive generations.
Chromosome defects are present in at least 50% of spontaneously aborted human fetuses virus or bacterial infection effective 250 mg terramycin, with aneuploidy accounting for most of them antibiotic eye drops for cats terramycin 250mg online. This rate of chromosome abnormality in humans is higher than in other organisms that have been studied; in mice antibiotic 500 mg order terramycin 250 mg visa, for example kinds of antibiotics for acne order terramycin 250 mg with amex, aneuploidy is found in no more than 2% of fertilized eggs. Aneuploidy in humans usually produces such serious developmental problems that spontaneous abortion results. Echinus Cocklebur Microcarpic Reduced Spinach Poinsettia Globe Ilex Sex-chromosome aneuploids the most common aneuploidy seen in living humans has to do with the sex chromosomes. As is true of all mammals, aneuploidy of the human sex chromosomes is better tolerated than aneuploidy of autosomal chromosomes. Autosomal aneuploids Autosomal aneuploids resulting in live births are less common than sex-chromosome aneuploids in humans, probably because there is no mechanism of dosage compensation for autosomal chromosomes. Most autosomal aneuploids are spontaneously aborted, with the exception of aneuploids of some of the small autosomes such as chromosome 21. Because these chromosomes are small and carry fewer genes, the presence of extra copies is less detrimental than it is for larger chromosomes. Down syndrome the most common autosomal aneuploidy in humans is trisomy 21, also called Down syndrome (discussed in the introduction to the chapter). The incidence of Down syndrome in the United States is similar to that of the world, about 1 in 700 human births, although the incidence increases among children born to older mothers. Approximately 92% of those who have Down syndrome have three full copies of chromosome 21 (and therefore a total of 47 chromosomes), a condition termed primary Down syndrome (Figure 9. Primary Down syndrome usually arises from spontaneous nondisjunction in egg formation: about 75% of the nondisjunction events that cause Down syndrome are maternal in origin, most arising in meiosis I. Most children with Down syndrome are born to normal parents, and the failure of the chromosomes to divide has little hereditary tendency. A couple who has conceived one child with primary Down syndrome has only a slightly higher risk of conceiving a second child with Down syndrome (compared with other couples of similar age who have not had any Down-syndrome children). About 4% of people with Down syndrome are not trisomic for a complete chromosome 21. Instead, they have 46 chromosomes, but an extra copy of part of chromosome 21 is attached to another chromosome through a translocation. A major exception to the relation between gene number and protein dosage pertains to genes on the mammalian X chromosome. In mammals, X-chromosome inactivation ensures that males (who have a single X chromosome) and females (who have two X chromosomes) receive the same functional dosage for X-linked genes (see pp. Extra X chromosomes in mammals are inactivated; so we might expect that aneuploidy of the sex chromosomes would be less detrimental in these animals. Indeed, it is the case for mice and humans, for whom aneuploids of the sex chromosomes are the most common form of aneuploidy seen in living organisms. Y-chromosome aneuploids are probably common because there is so little information in the Y-chromosome. Aneuploidy in Humans For unknown reasons, an incredibly high percentage of all human embryos that are conceived possess chromosome abnormalities. Willatt, East Anglian Regional Genetics Service/Science Photo Library/Photo Researchers. This karyotype is from a translocation carrier, who is phenotypically normal but is at increased risk for producing children with Down syndrome. The phenotypic characteristics of familial Down syndrome are the same as those of primary Down syndrome. Familial Down syndrome arises in offspring whose parents are carriers of chromosomes that have undergone a Robertsonian translocation, most commonly between chromosome 21 and chromosome 14: the long arm of 21 and the short arm of 14 exchange places (Figure 9. This exchange produces a chromosome that includes the long arms of chromosomes 14 and 21, and a very small chromosome that consists of the short arms of chromosomes 21 and 14. Although exchange between chromosomes 21 and 14 is the most common cause of familial Down syndrome, the condition can also be caused by translocations between 21 and other chromosomes such as 15. Persons with the translocation, called translocation carriers, do not have Down syndrome. Although they possess only 45 chromosomes, their phenotypes are normal because they have two copies of the long arms of chromosomes 14 and 21, and apparently the short arms of these chromosomes (which are lost) carry no essential genetic information. Although translocation carriers are completely healthy, they have an increased chance of producing children with Down syndrome. When a translocation carrier produces gametes, the translocation chromosome may segregate in three different ways. First, it may separate from the normal chromosomes 14 and 21 in anaphase I of meiosis (Figure 9. In this type of segregation, half of the gametes will have the trans- location chromosome and no other copies of chromosomes 21 and 14; the fusion of such a gamete with a normal gamete will give rise to a translocation carrier. The other half of the gametes produced by this first type of segregation will be normal, each with a single copy of chromosomes 21 and 14, and will result in normal offspring. Alternatively, the translocation chromosome may separate from chromosome 14 and pass into the same cell with the normal chromosome 21 (Figure 9. This type of segregation produces abnormal gametes only; half will have two functional copies of chromosome 21 (one normal and one attached to chromosome 14) and the other half will lack chromosome 21. If a gamete with the two functional copies of chromosome 21 fuses with a normal gamete carrying a single copy of chromosome 21, the resulting zygote will have familial Down syndrome. If a gamete lacking chromosome 21 fuses with a normal gamete, the resulting zygote will have monosomy 21 and will be spontaneously aborted. In the third type of segregation, the translocation chromosome and the normal copy of chromosome 14 segregate together (Figure 9. This pattern is presumably rare, because the two centromeres are both derived from chromosome 14 and usually separate from each other. All the gametes produced by this process are abnormal: half result in monosomy 14 and the other half result in trisomy 14. Thus, only three of the six types of gametes that can be produced by a translocation carrier will result in the birth of a baby and, theoretically, these gametes should arise with equal frequency. In reality, however, fewer than one-third of the children born to translocation carriers have Down syndrome, which suggests that some of the embryos with Down syndrome are spontaneously aborted. Trisomy 18, also known as Edward syndrome, arises with a frequency of approximately 1 in 8000 live births. Babies with Edward syndrome are severely retarded and have low-set ears, a short neck, deformed feet, clenched fingers, heart problems, and other disabilities. Trisomy 13 has a frequency of about 1 in 15,000 live births and produces features that are collectively known as Patau syndrome. Characteristics of this condition include severe mental retardation, a small head, sloping forehead, small eyes, cleft lip and palate, extra fingers and toes, and numerous other problems. About half of children with trisomy 13 die within the first month of life, and 95% die by the age of 3. Rarer still is trisomy 8, which arises with a frequency ranging from about 1 in 25,000 to 1 in 50,000 live births. This aneuploid is characterized by mental retardation, contracted fingers and toes, low-set malformed ears, and a prominent forehead. Aneuploidy and maternal age Most cases of Down syndrome and other types of aneuploidy in humans arise from maternal nondisjunction, and the frequency of aneuploidy increases with maternal age (Figure 9. Female mammals are born with primary oocytes suspended in the diplotene substage of prophase I of meiosis. Just before ovulation, meiosis resumes and the first division is completed, producing a secondary oocyte. At this point, meiosis is suspended again and remains so until the secondary oocyte is penetrated by a sperm. The second meiotic division takes place immediately before the nuclei of egg and sperm unite to form a zygote.
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