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Is tigecycline a substrate for the efflux pump mechanism of resistance to tetracyclines Give an example of an oxazolidinone antibiotic: What is the mechanism of action of linezolid Amphotericin B is synergistic with what other antifungal drug in the treatment of candidal and cryptococcal infections How can the "shake and bake" adverse reaction caused by amphotericin B be prevented Pretreatment with meperidine prior to amphotericin B infusion is used to prevent what specific adverse reaction Load with normal saline solution; use of amphotericin B in combination with another medication so that the dose of amphotericin B can be decreased; use of liposomal amphotericin B formulations Fluconazole; itraconazole; ketoconazole; voriconazole; miconazole; clotrimazole; posaconazole; ravuconazole Prevents the synthesis of ergosterol from lanosterol by inhibiting cytochrome P-450-dependent 14-demethylation Mucocutaneous candidiasis; coccidioidomycosis; prevention and treatment of cryptococcal meningitis Sporotrichoses; blastomycoses Ketoconazole Give examples of the azole antifungal drug class: What is the mechanism of action of the azole antifungals What antifungal can be formulated into a topical shampoo gel to treat tinea capitis Is absorption of ketoconazole increased or decreased by alkalinization of gastric pH Some physicians may tell patients to drink what in order to enhance the oral absorption of ketoconazole Gynecomastia (via inhibition of androgen synthesis) Invasive aspergillosis; invasive candidiasis; candidemia It is decreased; do not use antacids in combination with ketoconazole Coca-Cola gastritis diet foods eat buy rabeprazole 20 mg amex, Pepsi-Cola, etc. Is -(1-3)-d-Glucan an integral part of the fungal cell membrane or the fungal cell wall Which antifungal, active only against dermatophytes, acts by depositing in newly formed keratin and disrupting microtubule structure Oral terbinafine is used to treat what specific types of dermatophytic infections Monophosphorylated acyclovir is converted to the triphosphate form by viral enzymes. What is the name of the prodrug that is converted to acyclovir and l-valine by first-pass metabolism What is the bioavailability of penciclovir after oral administration of famciclovir Is famciclovir effective in viral strains resistant to acyclovir secondary to lack of thymidine kinase Blocks the uncoating of influenza A virus, thereby preventing penetration of the virus into host cells Parkinson disease; drug-induced extrapyramidal symptoms; it also increases dopamine levels in the synaptic cleft by either inhibiting reuptake into presynaptic neurons or by increasing release from presynaptic neurons; it may have anticholinergic effects Seizures; insomnia; nervousness; livedo reticularis; orthostatic hypotension; peripheral edema; dry nose; xerostomia; nausea; anorexia A purplish discoloration of the skin caused by dilation of capillaries and venules secondary to stasis or changes in underlying blood vessels Oseltamivir; zanamivir What are the adverse effects of amantadine Name two drugs that inhibit neuraminidase of both influenza A and B, thereby decreasing the likelihood of viral penetration into host cells: Which neuraminidase inhibitor has an oral inhalational route of administration Lamivudine Abacavir (symptoms include fever, rash, nausea, vomiting, malaise, fatigue, and respiratory dysfunction) Didanosine 1. Patients with sulfonamide allergy should use caution when taking which two protease inhibitors Give examples of medications that can cause a disulfiram-like reaction: What is the antimicrobial spectrum of metronidazole What are the three stages of the malarial parasite life cycle primarily targeted by antimalarial drugs Gametocytic stage Antimicrobial Agents 39 What is the oldest antimalarial drug still in use Give examples of antimalarial drugs that are effective against the erythrocytic forms of malaria: What drug is effective against relapsing forms of P. What is the drug of choice for acute attacks of malaria caused by chloroquine-sensitive strains of P. Name two newer antimalarials that are chemically related to quinine: What can be used to acidify the urine The antimalarial effects of pyrimethamine can be potentiated by combining it with which drugs How is folate-deficient megaloblastic anemia reversed in patients taking pyrimethamine Antimicrobial Agents 41 What is the antimalarial mechanism of action of artemisinin Antimicrobial Agents 43 What types of cutaneous adverse effects are caused by thiabendazole What is the drug of choice for treating Onchocerca volvulus (onchocerciasis or river blindness) Moreover, she is very conscious as to maintain fitness in keeping with her required scuba licensing; thus, she regularly takes calcium tablets with her meals. She is diagnosed with a Mycobacterium marinum infection and begins treatment with minocycline. However, 6 weeks after treatment her condition has not resolved and she has developed new granulomas. Her unique occupation gives the patient exposure to microorganisms that are uncommon causes of infection. In terms of her medications, even supplements have significant side effects and drug interactions, and must be asked about as part of your history. Calcium salts such as those used to increase calcium intake in menopausal women will chelate tetracyclines like minocycline, decreasing their oral bioavailability. Therefore, this patient should have been instructed not to take her calcium supplement tablets 2 hours before or after a dose of her antibiotic. Respiratory effort was diminished and the patient was intubated and placed on a ventilator. The intern on call placed the patient on a tobramycin nebulizer to suppress ventilator-associated pneumonia. The next morning, the attending physician sees this and immediately terminates this treatment. Aminoglycosides, such as tobramycin, are nephrotoxic and will cause further damage to the kidneys. Since this patient is unresponsive, we are unaware of his baseline hearing status. A small amount of damage in an individual who is already hard of hearing could have dramatic consequences. A 24-year-old female medical student participates in an exchange program in rural South Korea. Despite chemoprophylaxis (mefloquine), she develops cyclic shaking chills and fever and is diagnosed with malaria. Resistance to chloroquine is suspected, and the treatment is switched to quinidine plus a tetracycline with complete resolution of her symptoms. Two months after her return to the United States, she has a reoccurrence of the malarial symptoms. Reactivation of these hypnozoites can lead to recurrence of infection months to years later. Note: Licensing exams will not expect you to determine whether a specific geographic area is endemic with chloroquine-resistant strains of malaria. You should know treatment alternatives for drug-resistant strains, as well as when addition of primaquine is necessary to eradicate hepatic repositories of the malaria parasite. During the second week of a trip to Belize, a traveler experienced some diarrhea, which was sufficient to remind him of previous admonitions about consuming food dispensed by street vendors. About a month after his return, the traveler developed severe pain in the right upper quadrant of his abdomen. It is absorbed rapidly from oral doses with a half-life in serum of about 8 hours. The drug is well tolerated and adverse effects are not common, but nausea, headaches, and dry mouth can occur. During a colonoscopy on an 80-year-old Filipino woman, a live worm is encountered. Why is the physician interested in this information in relation to this discovery If the patient has been in the United States for a while, where infection with the helminth is less likely, treatment is likely to be effective immediately.

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Because the codons are read in multiples of three gastritis tylenol buy rabeprazole online from canada, this type of mutation shifts the reading frame. It can involve a base substitution in the sequence within a gene or a removal or addition of one or more base pairs. This figure shows only a portion of the polypeptide sequence, which is 146 amino acids long. In globin, the first methionine at the amino terminus is removed after the polypeptide is made. As seen here, a missense mutation changes the sixth amino acid from a glutamic acid to a valine. Genes Traits A missense mutation alters the structure of globin, which is a subunit of hemoglobin, the oxygen-carrying protein in the red blood cells. When an individual is homozygous for the sickle cell allele, this missense mutation causes the red blood cells to sickle under conditions of low oxygen concentration. At the organism level, the sickled cells can clog the capillaries, causing painful episodes that can result in organ damage. For example, when nonsense mutations produce polypeptides that are substantially shorter, the shorter polypeptides are unlikely to function properly. Likewise, frameshift mutations dramatically alter the amino acid sequence of polypeptides and are thereby likely to disrupt function. Missense mutations are less likely to alter function because they involve a change of a single amino acid within polypeptides that typically contain hundreds of amino acids. When a missense mutation has no detectable effect on protein function, it is referred to as a neutral mutation. A missense mutation that substitutes an amino acid with a chemistry similar to that of the original amino acid is likely to be neutral or nearly neutral. For example, a missense mutation that substitutes a glutamic acid for an aspartic acid is likely to be neutral because both amino acids are negatively charged and have similar side chain structures. Mutations can occasionally produce a polypeptide with an enhanced ability to function. Although these favorable mutations are relatively rare, they may result in an organism with a greater likelihood of surviving and reproducing. If this is the case, natural selection may cause such a favorable mutation to increase in frequency within a population. A down promoter mutation causes the promoter to become less like the consensus sequence, decreasing its affinity for transcription factors and decreasing the transcription rate. This causes the lac operon to be constitutively expressed even in the absence of lactose. Gene Mutations Can Occur Outside of a Coding Sequence and Influence Gene Expression Thus far, we have focused our attention on mutations in the coding regions of genes and their effects on polypeptide structure and protein function. In previous chapters, we learned how various sequences outside of coding sequences play important roles during the process of gene expression. A mutation can occur within a noncoding sequence, thereby affecting gene expression (Table 19. For example, a mutation may alter the sequence within the core promoter of a gene. Mutations that make a sequence more like the consensus sequence are likely to be up promoter mutations. Gene Mutations Are Also Given Names That Describe How They Affect the Wild-Type Genotype and Phenotype Thus far, several genetic terms have been introduced that describe the molecular effects of mutations. Genetic terms are also used to describe the effects of mutations relative to a wild-type genotype or phenotype. In a natural population, a wild type is a relatively prevalent genotype or phenotype. Many or most genes exist as multiple alleles, so a population may have two or more wild-type alleles. When such a mutation is rare in a population, the result is generally referred to as a mutant allele. A reverse mutation, more commonly called a reversion, changes a mutant allele back to a wild-type allele. Another way to describe a mutation is based on its influence on the wild-type phenotype. A neutral mutation does not alter protein function, so it does not affect survival or reproductive success. A deleterious mutation, however, decreases the chances of survival and reproduction. The extreme example of a deleterious mutation is a lethal mutation, which results in the death of a cell or organism. On the other hand, a beneficial mutation enhances the survival or reproductive success of an organism. In some cases, an allele may be either deleterious or beneficial, depending on the genotype and/or the environmental conditions. However, an individual who is heterozygous for the sickle cell and wild-type alleles has an increased chance of survival due to malarial resistance. Geneticists often study conditional mutants in microorganisms; a common example is a temperature-sensitive (ts) mutant. A bacterium that has a ts mutation grows normally in one temperature range-the permissive temperature range-but exhibits defective growth at a different temperature range-the nonpermissive range. Suppressor Mutations Reverse the Phenotypic Effects of Another Mutation A second mutation sometimes affects the phenotypic expression of a first mutation. Geneticists call these second-site mutations suppressors, or suppressor mutations. This name is meant to indicate that this type of mutation acts to suppress the phenotypic effects of another mutation. Suppressor mutations are classified according to their relative locations with regard to the mutation they suppress (Table 19. Intragenic Suppressors When the second mutation site is within the same gene as the first, the mutation is termed an intragenic suppressor. This type of suppressor often produces a change in protein structure that compensates for an abnormality in protein structure caused by the first mutation. Researchers may isolate suppressor mutations to obtain information about protein structure and function. For example, Robert Brooker and colleagues have isolated many intragenic suppressors in the lacY gene of E. This protein must undergo conformational changes to transport lactose across the cell membrane. These researchers began with single mutations that altered amino acids on transmembrane regions, which inhibited this conformational change, thereby preventing growth on media containing lactose. Suppressor mutations were then isolated that restored transport function and allowed growth on lactose. By analyzing the locations of these suppressor mutations, the researchers were able to determine that certain transmembrane regions in the protein are critical for conformational changes required for lactose transport. Intergenic Suppressors Alternatively, a suppressor mutation can occur in a different gene from the first mutation-an intergenic suppressor. These suppressor mutations usually involve a change in the expression of one gene that compensates for a loss-of-function mutation affecting another gene (see Table 19. For example, a first mutation may cause one protein to be partially or completely defective. An intergenic suppressor in a different protein-encoding gene might overcome this defect by altering the structure of a second protein so that it can take over the functional role the first protein cannot perform. Alternatively, intergenic suppressors may affect proteins that participate in a common cellular pathway. When a first mutation affects the activity of a protein, a suppressor mutation could alter the function of a second protein involved in this pathway, thereby overcoming the defect in the first. In some cases, intergenic suppressors have effects on multimeric proteins, in which each subunit is encoded by a different gene. A mutation in one subunit that inhibits function may be compensated by a mutation in another subunit. Another type of intergenic suppressor involves mutations in genetic regulatory proteins such as transcription factors.

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By transplanting cortical progenitors between fetal and neonatal ferrets gastritis water purchase online rabeprazole, McConnell and colleagues investigated whether neurons destined for particular layers are intrinsically different from each other before they migrate. Weeks later, cells born at postnatal day 1 (P1) are fated for Layers 2 and 3, and must migrate through Layers 6, 5, and 4, which have already formed. When P1 precursors were transplanted into E29 brain, they all differentiated into Layer 2 and 3 cells. This loss of competence is a sequential process, as illustrated by the transplantation of progenitors at the middle stages of cortical development. These results suggest that environmental cues can influence precursors to produce neurons of different cell types, but that the competence of these precursors to respond to different environments becomes increasingly restricted over time. As development proceeds, the telencephalic regions that give rise to the cortex become further patterned and turn on more local transcription factors that control specific aspects of their fate, such as their projection patterns (Molyneaux et al. Cux-1 and Cux-2 are expressed exclusively in upper layer neurons, while other transcription factors such as Ctip2 and Fezf2 are expressed in lower layer neurons (Arlotta et al. In mice lacking Fezf2, all Layer 5 neurons are still produced, but the neurons now make projections through the corpus callosum like the neurons of Layers 2 and 3 (Chen et al. Moreover, misexpression of Fezf2 in Layers 2 and 3 neurons causes them to project corticofugal axons like those of Layer 5. Tbr1 represses the activity of Fezf2 and thus allows these cells to project to the thalamus in the diencephalon rather than to Layer 5 targets in the midbrain and spinal cord (Han et al. For example, in the visual cortex the Layer 5 corticofugal neurons, in addition to Fezf2, also express Otx1. The key differences are that in the visual cortex Otx1 (blue) is expressed, and the layer 5 neurons project to the superior colliculus in the midbrain, while in the somatomotor cortex the layer 5 neurons project to the spinal cord. If it is knocked out these neurons project to subcortical targets of layer 5 neurons, whereas if it is misexpressed in layer 5 neurons, they project to the thalamus. In common with all corticofugal projection neurons, Betz cells also express the transcription factor Fezf2, but they lack Otx1. In mice mutant for Otx1, Layer 5 cells of the visual cortex project into the spinal cord instead of the midbrain (Weimann et al. The lineages of cortical projection neurons arising from the pallium are organized in radial columns and composed of both neurons and glia. This columnar organization is largely due to the fact that cortical neurons migrate along the radially oriented basal processes of progenitor cells that stretch all the way to the top of the cortical plate (see Chapter 3). In many cortical areas, neurons in a column share key physiological properties (see Chapter 8), leading to the speculation 114 Development of the Nervous System that clonally related cells form functional units. By isolating cortical progenitors from this region and growing them in vitro under constant observation so that lineage trees could be reconstructed, Shen et al. Moreover, as predicted from the heterochronic transplants described above, once upper layer neurons start to be generated, progenitors in these clones lose their competence to produce deep layer neurons even if cocultured with an excess of younger cells. These studies suggest that cortical progenitors are intrinsically programmed to go through a progression of competence states as their lineage unfolds. In vivo studies in the mouse using a clonal labeling technique that allows sister cells to be distinguished from each other (Gao et al. This has obvious parallels to the neuroblasts of the embryonic Drosophila nerve cord (see above). The first postmitotic daughters are destined for deep layers and the last for upper layers. At the end of this process, after having produced a column of neurons in all the layers, a progenitor cell may make glial cells. Less is known about the lineages of inhibitory neurons that migrate into the cortex from the ganglionic eminences, but recent studies show that the clonal progeny of individual progenitors disperse themselves widely in tangential layers when they reach the cortex, unlike the columnar arrangement of the excitatory clones. Although much more needs to be discovered, it is evident that all the mechanisms that we discussed earlier in this chapter are integrated to construct the diversity of cell types in the mammalian cerebral cortex. There is immense variation in the role of lineage vs environment in neuronal determination. In fact, it seems that each determination pathway brings its own mix of lineage-dependent and lineage-independent mechanisms. The multitude of transcription factors that haunt this chapter often work in interactive circuits, such as those that reinforce decisions by mutual cross-activation, or those that sharpen boundaries by cross-repression, or those that specify fate through combinatorial coding, or those that drive forward progression by a mixture of activation of the next step and repression of the previous one, the progressive refinement of cell fates and gradual loss of pluripotency and competence. The last phases of determination involve interactions with synaptic targets, which may provide the final differentiative signals for maturing neurons. At the end of this process, the neuron becomes an individual cell with its own biochemical and morphological properties and its unique set of synaptic inputs and outputs. At a particular stage, the cells become neurogenic, they divide asymmetrically to produce a sequential set of daughters that are either neurons themselves or intermediate progenitors that divide only one more time to produce two neurons. The first neurons to be generated are deep layer neurons while the last are upper layer neurons. Spectrum of fates: a new approach to the study of the developing zebrafish retina. Cell lineage determination and the control of neuronal identity in the neural crest. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Segment polarity genes in neuroblast formation and identity specification during Drosophila neurogenesis. The independent probabilistic firing of transcription factors: a paradigm for clonal variability in the zebrafish retina. The transcription factor Sox10 is a key regulator of peripheral glial development. Importance of intrinsic mechanisms in cell fate decisions in the developing rat retina. The orientation of cell division influences cell-fate choice in the developing mammalian retina. Genetic control of differentiation of the Caenorhabditis elegans touch receptor neurons. Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Prospero acts as a binary switch between self-renewal and differentiation in Drosophila neural stem cells. Vnd/nkx, ind/gsh, and msh/msx: conserved regulators of dorsoventral neural patterning Directional Delta and Notch trafficking in Sara endosomes during asymmetric cell division. Progressive restriction in fate potential by neural progenitors during cerebral cortical development. Caenorhabditis elegans mutants defective in the functioning of the motor neurons responsible for egg laying. Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system. Deterministic progenitor behavior and unitary production of neurons in the neocortex. Reconstruction of rat retinal progenitor cell lineages in vitro reveals a surprising degree of stochasticity in cell fate decisions. Role of environmental signals and transcriptional regulators in neural crest development. Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Genetic dissection of signal transduction mediated by the sevenless receptor tyrosine kinase in Drosophila. Genetic dissection of the photoreceptor system in the compound eye of Drosophila melanogaster. Early neurogenesis in Xenopus: the spatio-temporal pattern of proliferation and cell lineages in the embryonic spinal cord. Development of left/right asymmetry in the Caenorhabditis elegans nervous system: from zygote to postmitotic neuron.

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He chose salamanders because gastritis nausea cure cheap rabeprazole online mastercard, like all amphibian embryos, they grow from shellless eggs in water and are accessible for observation from the earliest stages of development, and because extensive developmental neuroanatomical information was just then becoming available in this system (Herrick, 1928). By putting the developmental anatomy together with the behavior, Coghill matched the maturation of specific anatomical circuits with the development of specific behaviors. As development proceeds, muscles react more quickly and those further caudal in the body become involved, so that the "bend," which starts as a slow movement at the neck region, becomes a more rapid C-shaped coiling of the entire body. Indeed, careful examination of coiling reveals that a coil starts at the neck region and then proceeds down the body. Coghill recognized that this rostral to caudal progress in behavior is correlated with the progression of neuronal maturation, from hindbrain to more caudal regions of the spinal cord. However, at the time that bending away from a light touch emerges, a set of interneurons appear, forming the first commissural pathways from sensory neurons on one side to motor neurons on the other. Longitudinal ipsilateral tracts extend down the motor columns and up the sensory columns, but these commissural interneurons appear first in the hindbrain. Thus a neural signal from a touch anywhere on the skin travels ipsilaterally up the sensory path, crosses over in the neck region, and stimulates motor neurons in that region of the other side, causing a bending of the neck away. The signal then proceeds down the motor pathway on that side of the spinal cord involving successively more posterior segments as they mature. After the animal is capable of coiling, the next component of its behavioral repertoire is the "S" phase. This arises as the coiling movements become faster and alternate from side-to-side. If a right-hand coiling movement proceeds only halfway down the body before a left-hand coiling movement starts in the neck region, the result is an "S"-shaped wave proceeding caudally, and this propels the animal forward. This was as much as Coghill was able to surmise at the time, because he could not be certain about the pattern of neural activity. Nevertheless, his behavioral observations were correct, and he was able to make a compelling case that the progression of locomotor behavior depends on the stepwise integration of circuitry. In the modern era, zebrafish embryos have become a favored species in which to study the emergence of motility, not only because they are transparent, but also because genetic knowledge and techniques have made it possible to visualize, record from, and interfere with the activity of specific neurons (Higashijima et al. As Coghill described for the salamander, zebrafish display a sequence of stereotypic behaviors with increasing complexity as their spinal circuitry matures (Kimmel et al. The cross section of the body wall is represented at the top and bottom of the diagram as though the segment has been cut longitudinally along the ventral midline and spread out. The only known inhibitory synaptic connections in the circuit (represented by black circles at the end of the lines connecting the neurons) are made between motor neurons: inhibitory motor neurons synapse onto muscles in the periphery, but they also make inhibitory chemical synaptic connections onto excitatory motor neurons that project to the same muscle. Excitation of a particular site of the skin excites one or two particular p cells. Brain lesions placed rostral to spinal cord do not affect them, indicating that the necessary neural circuit is contained within the spinal cord. These early spontaneous behaviors are correlated with spontaneous inward currents in the motor neurons themselves. Even when chemical synaptic activity is abolished, these motor neurons still go through periodic bouts of coordinated firing. Moreover, the same rhythmic activity can be recorded in 322 Development of the Nervous System many of the early interneurons in the cord. Indeed physiological recordings show that groups of neurons are simultaneously coactive on one side of the cord during a coiling movement, suggesting that these neurons are electrically coupled and fire together (Saint-Amant and Drapeau, 2001). In Xenopus embryos, pairwise recordings from all of these neurons in the embryonic spinal cord reveal that synapses can be found between all types of neurons. Furthermore, the probability of such synaptic connections is predicted simply by the anatomical overlap of their axons and dendrites (Li et al. After 19 hpf in zebrafish, the spontaneous coiling behaviors diminish and are replaced by stimulus-driven movements. The large Mauthner neurons of the hindbrain have been implicated in this escape response. Much as Coghill thought, Mauthner neurons receive sensory input from the ipsilateral ear and lateral line, and then send their axons across the midline where they project caudally onto contralateral motor neurons. In the embryonic zebrafish, as early as 40 hpf, the Mauthner neurons, and homologous neurons in other hindbrain segments, can initiate a directional escape response away from a stimulus. The transition from coiling to brief swims is also reflected in the emergence of chemical circuitry. A stimulus anywhere on one side of the body is transmitted to the contralateral spinal motor pathway by commissural cells in the anterior cord or hindbrain where the neural signal descends, stimulating primary motor neurons of the cord. Motor excitation travels down one side of the cord, but by this stage in development, some reciprocally exciting commissural neurons that cross the floorplate in the hindbrain have developed so that excitation on one side at the neck region can cross over after a delay to excite the contralateral motor pathway, leading to coiling on one side being quickly followed by coiling on the other side. This correlates with the neonatal bending of the back muscles in moving waves, reminiscent of swimming behavior in tadpoles and fish (Falgairolle and Cazalets, 2007). Moreover, in neonatal mouse limbs, there is a proximal to distal activation of flexor motor pools, indicating that waves of activity also propagate outward (Machado et al. These studies suggest that the coordination of mammalian terrestrial locomotion may adopt the primitive swim circuitry found in ancestral vertebrates to coordinate left and right sides. Images emphasize key stages of zebrafish embryo development before and after hatching (52 h). CiAs are so named due to their primary ascending axon, however, they also have a secondary descending one. Successive images at different time points (hours postfertilization noted in respective images) illustrate the growth of the descending axon (at thin and thick white arrows), as well as the elaboration of the dendrites. Even in humans, the precursors to mature locomotion can be seen long before infants take their first steps. When infants are placed on a gentle downhill slope, one can elicit left-right motor coordinated movements even at precrawling stages. The spinal circuits that control repetitive leftright movements in walking or swimming are conserved in vertebrates, largely because the mechanisms that generate spinal neuron cell types and their connectivity are also conserved. Subsequently, the movements of many species become quite complex, such as the different gaits of a horse or the fine finger movements of a piano player. Descending pathways from the cortex bring movements under voluntary control and coordinate the effects of motor learning. Thus it is not until the corticospinal tract develops fully that macaque monkeys are able to make fine finger movements and exhibit mature manual dexterity (Armand et al. Genetic strategies that make use of the transcription factors that define each domain allow studies of the physiological contributions of each cell type. Optogenetic stimulation of these cells reveals that they modulate the excitability of the swimming networks (Wyart et al. Lhx3-expressing interneurons sit in the V2 domain, immediately above the motor neurons. In mice, these neurons are involved in left-right alternation during running (Crone et al. Engrailed1-expressing interneurons of the V1 domain are the next most dorsal neurons and are required for generating "fast" bursting. When these neurons are genetically ablated, the affected mice are constrained to walking very slowly. Some of these neurons are the Renshaw cells that provide feedback inhibition onto motor neurons. When activated, they shorten burst intervals and secure reciprocal flexor-extensor activity (Gosgnach et al. More dorsal still, in the V0 domain, are commissural inhibitory and excitatory interneurons that express Dbx1. Mutant dbx1 mice often make synchronous rather than alternating left-right bursts of motor activity, leading to mice that hop rather than walk (Lanuza et al. In the next most dorsal region (dl6) are the commissural interneurons that express the transcription factor Dmrt3. The role of these neurons is partially revealed by the strange fact that Icelandic horses, which have five natural gaits rather than the three or four of most other breeds, have a truncated Dmrt3 protein (Andersson et al. Indeed, electrophysiological studies from spinal cords of dmrt3 mutant mice show disorganized motor stepping movements. While many other types of interneurons are known, their roles in locomotion are yet to be studied in detail. From a developmental point of view, it will be particularly interesting to explore how these transcription factors control the connectivity and network properties of these neurons.

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You respond that the active ingredient is dextromethorphan chronic gastritis yahoo answers order 20mg rabeprazole with mastercard, an opioid medication that is effective for cough suppression. The mother becomes quite agitated that you would suggest an addictive substance for her young child. It has the advantage over codeine of having less addictive potential and causing less constipation. It is also true that while physiologic dependence does not occur in this agent to the level of other narcotic drugs, cough medications containing dextromethorphan are nevertheless used as a drug of abuse, especially in adolescent populations. List the names of the H2-receptor antagonists: Which H2-receptor antagonist inhibits hepatic cytochrome P-450 metabolizing enzymes Acid rebound Cimetidine; famotidine; ranitidine; nizatidine Cimetidine Gastrointestinal Agents 147 Name at least five drugs showing potential drug interactions with cimetidine: 1. Sulfasalazine is cleaved by gut bacteria in the colon to produce what two compounds What type of vitamin supplementation should patients receive while on sulfasalazine What is intractable emesis leading to dehydration and hypotension during pregnancy called Diclegis, metoclopramide Gastrointestinal Agents 151 What antihistamine is often used to treat motion sickness What medication is often used in combination regimens to enhance antiemetic activity Antisecretory agents A substance offering a suitable active surface, upon which other substances may adhere to 152 Zoom Review: Pharmacology Give examples of specific drugs in each of the following drug classes used in the treatment of diarrhea: Adsorbents Antimotility agents Antisecretory agents Give the antidiarrheal mechanism of action for each of the following drug classes: Adsorbents Antimotility agents Adsorbs (adheres to) drugs, nutrients, toxins, and digestive juices Decrease peristalsis by activating presynaptic opioid receptors in the enteric nervous system Decrease fluid secretion in the bowel Polycarbophil Kaolin; pectin; polycarbophil; attapulgite Diphenoxylate; loperamide; morphine Bismuth subsalicylate Antisecretory agents What adsorbent can absorb 60 times its weight in water and treat both diarrhea and constipation Salicylism (tinnitus, nausea, vomiting); darkening of tongue; darkening of stools; induce gout attacks in susceptible patients Bismuth subsalicylate Diphenoxylate; the anti-muscarinic activity of atropine decreases bowel activity Antimotility agents Octreotide What antidiarrheal can decrease tetracycline absorption if given concomitantly Synthetic analog of somatostatin which blocks release of serotonin and other vasoactive peptides; direct inhibitory effects on intestinal secretion; direct stimulatory effects on intestinal absorption Gastrointestinal Agents 153 What are the non-antidiarrheal uses of octreotide What medication can be used in conjunction with antibiotics to bulk stools and absorb C. What other prophylactic medication, commonly employed in a critical care setting, may be responsible for her drop in platelet count However, this patient was most likely started on omeprazole for prevention of stress-induced gastric ulcers. Esomeprazole, the S-enantiomer of omeprazole, while controversial as to whether or not it is more effective to inhibit stomach acid secretion, does not carry the same risk of lowering platelets. Colonoscopy is negative, but a gastric ulceration is discovered upon upper endoscopy. However, this therapy can lead to gastric ulceration and chronic gastrointestinal bleeding that can lead to iron deficiency anemia. This anemia is often overlooked in patients with chronic autoimmune disorders as anemia of chronic disease. In patients such as this, addition of misoprostol, a prostaglandin analog, may be appropriate. Gastrointestinal Agents 155 An 86-year-old woman with a history of chronic constipation is treated with lactulose with good relief of her constipation. However, she complains of painful abdominal cramps and embarrassing flatus and wishes to try another medication. What laxative has a similar mechanism of action to lactulose and will not cause large electrolyte imbalances, making it safe to use in this elderly patient Unlike lactulose and sorbitol, it is not metabolized by colonic bacteria, decreasing colonic gas formation. A patient with a history of motion sickness is administered a scopolamine patch preoperatively to help avoid postoperative nausea and vomiting. The patient is advised to not touch their eye after removing the patch approximately 24 hours after the operation. If one eye receives the medication, anisocoria can develop with resultant unfounded alarm for neurologically devastating conditions such as stroke. Loss of pancreatic b-cells (insulin deficiency) Usually early onset Usually adult onset Decreased response to insulin Ketoacidosis prone Absolute dependence on exogenous insulin May be controlled by diet and oral hypoglycemics alone Usually thin Usually obese Islet cell antibodies Near 100% concordance in monozygotic twins What types of drugs can elevate blood glucose concentrations Type 1 Type 1 Type 2 Type 2 Type 1 Type 1 Type 2 Type 1 Type 2 Type 1 Type 2 Alcohol; b-adrenergic blockers; calcium channel blockers; combination oral contraceptives; diazoxide; diuretics; corticosteroids; lithium; niacin; phenytoin; sympathomimetics Anion gap metabolic acidosis; Kussmaul respirations (deep, labored hyperventilation); fruity breath; abdominal pain; nausea; vomiting; polyuria; polydipsia; dehydration; fatigue; hyperkalemia but whole body potassium depletion 157 1. Oral hypoglycemic agents What are the signs and symptoms of diabetic ketoacidosis What is the term used to describe a rise in blood glucose usually between 4 and 11 am due to the release of growth hormone, cortisol, glucagons, and epinephrine What is the term used to describe a rebound rise in morning blood glucose secondary to a low overnight blood glucose Hypoglycemia Confusion; diaphoresis; tremors; tachycardia; seizures; coma; lethargy Diaphoresis, as this is a cholinergicmediated response Endocrine Agents 159 What is the name of the incretin mimetic that increases insulin secretion, slows gastric emptying, and decreases food intake What is the name of the human amylin analog that is cosecreted with insulin and reduces postprandial glucose by prolonging gastric emptying time, reduces postprandial glucagon secretion, and suppresses appetite What hypoglycemic agent is not contraindicated in a pregnant woman with diabetes mellitus Other than blood glucose reduction, regular insulin can also be used for what condition Exenatide Pramlintide Insulin Hyperkalemia; insulin causes an intracellular shift of potassium; insulin is given in combination with glucose to prevent hypoglycemia in this situation For each of the following oral hypoglycemic agents, state which drug class it belongs to What drug with positive inotropic and chronotropic activity can be used to stimulate the heart during a b-blocker overdose No, biguanides do not cause hypoglycemia Hypoglycemia; upper respiratory tract infection Abdominal cramping; diarrhea; flatulence Glucagon 15 to 30 minutes before each meal 162 Zoom Review: Pharmacology Would oral sucrose be effective in a hypoglycemic patient who is currently taking an -glucosidase inhibitor Would oral glucose be effective in a hypoglycemic patient who is currently taking an -glucosidase inhibitor Which type of diabetes insipidus is characterized by insensitivity to vasopressin in the collecting ducts Which type of diabetes insipidus is characterized by inadequate secretion of vasopressin from the posterior pituitary gland Nephrogenic Nephrogenic diabetes insipidus Neurogenic diabetes insipidus Lithium; demeclocycline; vincristine; amphotericin B; alcohol Demeclocycline Thiazide diuretics in combination with amiloride; chlorpropamide; clofibrate 1. Heat intolerance; nervousness; fatigue; weight loss with increased appetite; increased bowel movements; palpitations; irregular menses; proximal muscle weakness; moist skin; fine hair; hyperactive deep tendon reflexes; tachycardia; widened pulse pressure; tremor Growth retardation in children; slowing of physical and mental activity; weight gain; cold intolerance; constipation; weakness; depression; dry skin; cold skin; coarse skin; coarse hair; bradycardia; muscle cramps; delayed relaxation of deep tendon reflexes; hyponatremia High fever; dehydration; delirium; tachycardia; tachypnea; nausea; vomiting; diarrhea; coma A severe, life-threatening hypothyroid state precipitated by an acute insult; symptoms: altered mental status, hypercapnia from hypoventilation, bradycardia, hypotension, hyponatremia, hypoglycemia Propranolol What are the signs and symptoms of hypothyroidism Triiodothyronine (T3) T3 (up to five times more active) 164 Zoom Review: Pharmacology What is the half-life of T4 When a hypothyroid patient is started on levothyroxine therapy, how long will the drug take to reach a steady state What antiarrhythmic agent can potentially cause either hypothyroidism or hyperthyroidism (more commonly hypothyroidism) Radioactive iodine (I) Hypothyroidism almost inevitably results; other possible complications include hypocalcemia due to removal of the parathyroid glands along with the thyroid Thionamides (propylthiouracil and methimazole) Iodide; lithium Propylthiouracil; methimazole 131 What are the drugs of choice to treat hyperthyroidism What drugs block the conversion of T4 to T3 in the periphery by inhibiting 5-deiodinase Zona reticularis (inner) 166 Zoom Review: Pharmacology Name the steroid hormones produced by each of the following layers of the adrenal cortex: Zona glomerulosa Zona fasciculata Zona reticularis What is the major precursor of all steroid hormones What is the primary mechanism by which corticosteroids increase the neutrophil count List the adverse effects of glucocorticoids: What drug inhibits glucocorticoid synthesis by inhibiting 11-hydroxylase activity What antifungal can be used to lower cortisol levels in Cushing disease and may cause gynecomastia as an adverse effect What diuretic blocks mineralocorticoid receptors and also inhibits the synthesis of aldosterone and androgens. No, as it is inactivated by first-pass metabolism 5-reductase Skin; epididymis; prostate; seminal vesicles Finasteride; dutasteride 1. What are the uses of testosterone and its derivatives (danazol; stanozolol; nandrolone; oxandrolone) What antifungal drug inhibits the synthesis of androgens and is also used as an antifungal

Syndromes

• Metals (chromium/chromates, platinum salts, nickel compounds, copper, lead, cis-platinum)
• Sharp, shooting, or burning pains in the ball of your foot (and sometimes toes)
• Care for wounds in you have any open sores or infections. Your health care provider can show you how.
• Breathing support
• Coughing up blood
• Blood pressure rapidly drops
• Missed menstrual periods
• Breathing problems
• A ridge in the forehead caused by premature closure of the bones (metopic ridge)
• Muscles becoming smaller (atrophy)

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Slit is expressed anterior of and posterior to the chiasm gastritis diet ������������ rabeprazole 10mg with amex, but not in the chiasm itself (Erskine et al. At the chiasm itself, there is a high concentration of another repulsive guidance molecule called EphrinB. These ventrotemporal axons are repelled by the EphrinB at the chiasm and do not cross. The dorsonasal axons, however, do not express EphB and remain insensitive to EphrinB, and so are not repelled from the midline (Nakagawa et al. The transcription factor Zic2 is expressed only in the ventrotemporal part and acts as a direct activator of EphB (Lee et al. We know that there is a link between the enzyme Tyrosine Hydroxylase that is involved in the synthesis of pigment and the expression of Zic2, but the link between these is mysterious (Bhansali et al. In Xenopus embryos, where this has been studied most, these axons travel first dorsally up through the diencephalon and then in the middle of the optic tract, they take a dogleg caudally toward their final target, the tectum in the dorsal midbrain. There, the repellent cues Slit and Sema3A confine the axons in the ventral optic tact from growing into the telencephalon or extending too far dorsally (Piper et al. In the target area they encounter orthogonal gradients of various Ephs, Ephrins, and Wnts that signify tectal coordinates. At this point, the process of adaptation and resensitization allows axons to crawl to the appropriate position in these gradients (see Chapter 6). It is fair to say that for even the best-studied neurons, such as retinal ganglion cells, we understand only parts of their navigation and not their entire route. Many more factors than mentioned here are known to be involved, and many others remain to be discovered. Dynamic expression of axon guidance cues required for optic tract development is controlled by fibroblast growth factor signaling. Axon fasciculation and differences in midline kinetics between pioneer and follower axons within commissural fascicles. Intraretinal projection of retinal ganglion cell axons as a model system for studying axon navigation. Disoriented pathfinding by pioneer neurone growth cones deprived of filopodia by cytochalasin treatment. Delayed neurogenesis leads to altered specification of ventrotemporal retinal ganglion cells in albino mice. Neurite outgrowth on muscle cell surfaces involves extracellular matrix receptors as -dependent and -independent cell adhesion moleculeswell as Ca2. Growth cone morphology varies with position in the developing mouse visual pathway from retina to first targets. We mentioned the need for a motor and we have seen that the growth cone by virtue of its dynamic cytoskeleton is able to locomote forward, turn, stop, and even retract. We mentioned the need for guidance cues and a map of the route, and we have seen a variety of cues attached to the extracellular matrix and cell surfaces, and other guidance molecules that appear to act through diffusive gradients. Some of these guidance factors promote growth and adhesion, while others inhibit growth and adhesion. These various signals are sensed by receptors on the plasma membrane of the growth cone and integrated through signaling cascades and communicated to the dynamic cytoskeleton of the growth cone in context-specific ways, as the same cues can have opposite meanings to different axons or even the same axons at different positions along the route. Our understanding of how these cues regulate growth and guidance either alone or in combination is still rudimentary but it is possible that Wiring Up the Brain: Axon Navigation Chapter 5 153 Bradley, P. Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Newly assembled microtubules are concentrated in the proximal and distal regions of growing axons. Morphological differentiation of embryonic rat sympathetic neurons in tissue culture. Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Semaphorin 3A elicits stage-dependent collapse, turning, and branching in xenopus retinal growth cones. Pioneer growth cone steering along a series of neuronal and non-neuronal cues of different affinities. The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion. Navigational errors made by growth cones without filopodia in the embryonic xenopus brain. A specific brain tract guides follower growth cones in two regions of the zebrafish brain. Differential effects of laminin and merosin on neurite outgrowth by developing retinal ganglion cells. Development and fine structure of murine Purkinje cells in dissociated cerebellar cultures: dendritic differentiation, synaptic maturation, and formation of cellclass specific features. Modulation of cell adhesion during induction, histogenesis, and perinatal development of the nervous system. Genetic analysis of a Drosophila neural cell adhesion molecule: interaction of fasciclin I and Abelson tyrosine kinase mutations. Using Xenopus laevis retinal and spinal neurons to study mechanisms of axon guidance in vivo and in vitro. Retinal ganglion cell axon guidance in the mouse optic chiasm: expression and function of robos and slits. Local presentation of substrate molecules directs axon specification by cultured hippocampal neurons. Atomic force microscopy and its contribution to understanding the development of the nervous system. Recruitment of the Arp2/3 complex and mena for the stimulation of actin polymerization in growth cones by nerve growth factor. Different levels of the homeodomain protein cut regulate distinct dendrite branching patterns of Drosophila multidendritic neurons. Neuronal chemotaxis: chick dorsalroot axons turn toward high concentrations of nerve growth factor. Osteogenic protein-1 and related bone morphogenetic proteins regulate dendritic growth and the expression of microtubule-associated protein-2 in rat sympathetic neurons. Coordination between extrinsic extracellular matrix cues and intrin- sic responses to orient the centrosome in polarizing cerebellar granule neurons. Local positional cues in the neuroepithelium guide retinal axons in embryonic xenopus brain. Retinal axons with and without their somata, growing to and arborizing in the tectum of xenopus embryos: a time-lapse video study of single fibres in vivo. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. Orientation and directed growth of Mauthners cell axons form duplicated vestibular nerve roots. Rapidly transported organelles containing membrane and cytoskeletal components: their relation to axonal growth. A single-cell analysis of early retinal ganglion cell differentiation in Xenopus: from soma to axon tip. A unique membrane protein is expressed on early developing limbic system axons and cortical targets. Irx4-mediated regulation of Slit1 expression contributes to the definition of early axonal paths inside the retina. The selective inhibition of growth cone extension by specific neurites in culture. Interactions between growth cones and neurites growing from different neural tissues in culture. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. From Abl to actin: Abl tyrosine kinase and associated proteins in growth cone motility.

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The distance between two molecular markers that are linked along the same chromosome can be determined by analyzing the outcomes of crosses gastritis migraine buy generic rabeprazole canada. However, the accuracy of linkage mapping with human pedigrees is fairly limited because the number of people in most families is relatively small. Map distance is computed as the number of recombinants divided by the total number of sperm analyzed, times 100. From your understanding of the topic, you may remember that linkage mapping involves the identification of recombinants, which are produced by crossovers. Make a One strategy to begin to solve this problem is to compare and contrast the lanes on the gel. When markers are linked, the nonrecombinant pattern of bands will be more common than the recombinant Conceptual Questions C1. A person with a rare genetic disease has a sample of her chromosomes subjected to fluorescence in situ hybridization using a probe that is known to recognize band p11 on chromosome 7. For each of the following, decide if it could be appropriately described as a genome: A. We can follow the transmission of a molecular marker by analyzing the phenotype. We can follow the transmission of molecular markers using molecular techniques such as gel electrophoresis. Why is it necessary to fix the cells (and the chromosomes inside of them) to the slides How many spots would you see if the probe was used on a sample from an individual with 46 chromosomes versus an individual with Down syndrome In the Human Genome Project, researchers collected linkage data from many crosses in which the male was heterozygous for molecular markers and many crosses where the female was heterozygous for the same markers. The distance between these two markers, computed in map units, is different between males and females. Do you think the sizes of chromosomes (excluding the Y chromosome) in human males and females are different A sample of sperm was collected from this man, and individual sperm were placed into 30 separate tubes. Discuss why it is generally easier to locate and map molecular markers rather than functional genes. Discuss the types of ethical problems that might arise as a result of identifying all of our genes. Lung cancer remains the top cause of deaths from cancer in the United States, and 87% of deaths due to lung cancer are linked to smoking. Currently, several hundred genetic tests are in clinical use, with many more under development. Most of these tests detect mutations associated with rare genetic disorders that follow Mendelian inheritance patterns. These include Duchenne muscular dystrophy, cystic fibrosis, sickle cell disease, and Huntington disease. In addition, there are now genetic tests to detect the predisposition to develop certain forms of cancer. Most of the genetic disorders discussed in the first part of this chapter are the direct result of a mutation in one gene. However, many diseases have a complex pattern of inheritance involving several genes. These include common medical disorders such as diabetes, asthma, and certain forms of mental illness. In these cases, a single mutant gene does not determine whether a person has a disease. The availability of the human genome sequence, discussed in Chapter 21, will be of great help. In this article, we will focus our attention on ways that mutant genes contribute to human disease. In the first part of the chapter, we will explore the molecular basis of several genetic disorders and their patterns of inheritance. We will also examine how genetic testing can determine if an individual carries a defective allele. We will then consider cancer, a disease that involves the uncontrolled growth of somatic cells. We will examine the underlying genetic basis for cancer and discuss the roles that many different genes may play in the development of this disease. Analyze human pedigrees, and be able to distinguish autosomal recessive, autosomal dominant, X-linked recessive, and X-linked dominant patterns. Almost everyone who looks at a newborn is tempted to speculate whether the baby resembles the mother, the father, or perhaps a more distant relative. In this section, we will focus primarily on the inheritance of human genetic diseases rather than common traits found in the general population. Even so, the study of human genetic diseases often provides insights regarding such common traits. By analyzing people with this disorder, researchers have identified genes that participate in the process of blood clotting. The study of hemophilia has helped to identify a clotting pathway involving several different proteins. Therefore, as with the study of mutants in model organisms such as Drosophila, mice, and yeast, when we study the inheritance of genetic diseases, we often learn a great deal about the genetic basis for normal physiological processes as well. Because thousands of human diseases have an underlying genetic basis, human genetic analysis is of great medical importance. In this section, we will examine the causes and inheritance patterns of human genetic diseases that result from defects in single genes. As you will learn, mutant genes that cause diseases often follow simple Mendelian inheritance patterns. List seven observations that suggest a disease may have a in the following list, several observations are consistent with the idea that a disease is caused, at least in part, by the inheritance of mutant genes. When the occurrence of a disease correlates with several of these observations, a geneticist becomes increasingly confident that the disease has a genetic basis. For example, someone with cystic fibrosis is more likely to have relatives with this disease than would a randomly chosen member of the general population. When a disorder has a genetic component, a pair of identical twins is more likely to exhibit the disorder than is a pair of fraternal twins. Theoretically, for diseases caused by a single gene, concordance among identical twins should be 100%. For fraternal twins, concordance for dominant disorders is expected to be 50%, assuming only one parent is heterozygous for the disease. For recessive diseases, concordance among fraternal twins is expected to be 25% if we assume both parents are heterozygous carriers. However, the actual concordance values observed for most single-gene disorders are usually less than such theoretical values for a variety of reasons. For example, some disorders are not completely penetrant, meaning that the symptoms associated with the disorder are not always produced. Also, one twin may have a disorder due to a new mutation that occurred after fertilization; it would be very unlikely for the other twin to have the same mutation. The disease does not spread to individuals sharing similar environmental situations. Because mutations are rare events, they may arise in one population but not another. Also, each population is exposed to its own unique set of environmental conditions that may influence the prevalence of a given allele. Therefore, the frequencies of genetic diseases due to mutant alleles usually vary among different populations of humans. Many genetic disorders exhibit a characteristic age of onset at A Genetic Basis for a Human Disease May Be Suggested by a Variety of Observations When we view the characteristics of people, we usually think that some traits are inherited, whereas others are caused by environmental factors. For example, when the facial features of two related individuals look strikingly similar, we think that this similarity has a genetic basis.

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If you were a potato breeder and you wanted to develop potatoes with a heavier weight chronic gastritis yahoo answers order rabeprazole 20mg otc, would you choose the variety with a low or high variance When a correlation coefficient is statistically significant, what do you conclude about the two variables If the allele frequencies in the population are equal for both types of alleles. Would you conclude that the environment is unimportant in the outcome of this trait It is common for plant breeders to take two different, highly inbred strains, which are the product of many generations of selective breeding, and cross them to make hybrids. Many beautiful varieties of roses have been produced, particularly in the last few decades. These newer varieties often have very striking and showy flowers, making them desirable as horticultural specimens. However, breeders and novices alike have noticed that some of these newer varieties do not have very fragrant flowers compared with the older, more traditional varieties. Why is a heritability value valid only for a particular population of individuals raised in a particular environment What is the difference between broad-sense heritability and narrow-sense heritability Why is narrow-sense heritability such a useful concept in the field of agricultural genetics Nearly all of the phenotypic variation for this trait in this group of chickens is due to genetic variation. Based on the observation of the heritability in the Maine chickens, it is reasonable to conclude that the heritability for egg weight in a group of chickens on a farm in Montana is also very high. In a fairly large population of people living in a commune in the southern United States, everyone cares about good nutrition. All of the members of this population eat very nutritious foods, and their diets are very similar to each other. How do you think the heights of individuals in this commune population would compare with those of the general population in the following categories When artificial selection is practiced over many generations, eventually a plateau is reached in which further selection has little effect on the outcome of the trait. Discuss whether a natural population of wolves or a domesticated population of German shepherds is more likely to have a higher heritability for the trait of size. Height (cm) 159 162 161 175 174 198 172 180 161 173 Weight (kg) 48 50 52 60 64 81 58 74 50 54 following sizes: 0. You mate them and then determine the thorax lengths of 30 offspring (half male and half female): 0. In a strain of mice, the average 6-week body weight is 25 g and the narrow-sense heritability for this trait is 0. What would be the average weight of the offspring if parents with a mean weight of 27 g were chosen What parental mean weight would you have to choose to obtain offspring with an average weight of 26. A danger in computing heritability values from studies involving genetically related individuals is the possibility that these individuals share more similar environments than do unrelated individuals. A large, genetically heterogeneous group of tomato plants was used as the original breeding stock by two different breeders, named Mary and Hector. Each breeder was given 50 seeds and began a selective breeding strategy, much like that described in figure 24. The seeds were planted, and the breeders selected the 10 plants with the highest mean tomato weights as the breeding stock for the next generation. The abdomen length (in millimeters) was measured in 15 male Drosophila, and the following data were obtained: 1. Calculate the mean, standard deviation, and variance for this population of male fruit flies. Both strains of cabbage are from the same species, although they may have been subjected to different degrees of inbreeding. The pigs are crossed to each other, and the members of the f1 generation are also crossed among themselves to produce an f2 generation. Outline the steps you would follow to determine the number of genes that influence the yield of rice. Describe the results you might get if rice yield is governed by variation in six different genes. In a wild strain of tomato plants, the phenotypic variance for tomato weight is 3. In another strain of highly inbred tomatoes raised under the same environmental conditions, the phenotypic variance is 2. Using the heritability value that you calculated in part A, what mean weight would you have to choose for the parents to get offspring that weigh 275 pounds on average (at 3 years of age) The trait of blood pressure in humans has a frequency distribution that is similar to a normal distribution. The following graph shows the ranges of blood pressures for a selected population of people. The red line depicts the frequency distribution of the systolic pressures for the entire population. Several individuals with high blood pressure were identified, and the blood pressures of their relatives were determined. An animal breeder had a herd of sheep with a mean weight of 254 pounds at 3 years of age. He chose animals with a mean weight of 281 pounds as parents for the next generation. What statistical approach could you use to determine the heritability for this trait Students with a strong background in math and statistics may want to explain how a normal distribution is generated, and what it means. Minimal growth medium contains the bare essentials for cell growth: salts, a carbon source, an energy source, essential vitamins, amino acids, and trace elements. In their experiments, geneticists often compare strains that can grow in minimal media and mutant strains that cannot grow unless the medium is supplemented with additional components. Researchers also add other substances to the culture medium for experimental reasons. For example, radioactive isotopes can be added to the culture medium to radiolabel cellular macromolecules. In all of these cases, cell culturing is advantageous because the experimenter can control and vary the composition of the growth medium. The first step in creating a cell culture is the isolation of a cell population that the researchers wish to study. For bacteria, such as Escherichia coli, and eukaryotic microorganisms, such as yeast and Neurospora, researchers simply obtain a sample of cells from a colleague or a stock center. When cells are contained within a complex tissue, they must first be dispersed by treating the tissue with agents that separate it into individual cells to create a cell suspension. Once a desired population of cells has been obtained, researchers can grow them in a laboratory. Both methods have been commonly used in the experiments considered throughout this text. As discussed in Chapter 20, a solid medium is used in the isolation of individual clones that contain a desired gene. A key aspect in microscopy is resolution, which is the minimum distance between two objects that enables them to be seen as separate from each other. The ability to resolve two points as being separate depends on several factors, including the wavelength of the illumination source (light or electron beam), the medium in which the sample is immersed, and the structural features of the microscope (which are beyond the scope of this text). The light microscope is used to resolve cellular structures to a resolution limit of approximately 0. Karyotyping is accomplished via light microscopy after the chromosomes have been treated with stains. A variation of light microscopy known as fluorescence microscopy is often used to highlight a particular feature of a chromosome or cellular structure. These kinds of light microscopes are useful in monitoring cell division in living (unstained) cells or in transparent worms. The coarse topology of these macromolecules can be determined by electron microscopy.

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However gastritis diet �� 20mg rabeprazole with visa, as development proceeds, the percentage of cells in the Q fraction increases and the overall growth rate of the cortex declines. On the other hand, the converse experiment of overexpressing p27kip leads to a greater percentage of cells in the Q fraction, and a markedly thinner cortex. Therefore the level of the Cdki p27kip modulates the probability that a cell will enter the Q fraction. Since different cortical layers are generated at different times during development (see below), the level of p27kip expression also affects the relative numbers of cortical cells in the various layers. The studies of Cyclins and their regulators have indeed revealed part of the answer to the question that began this section; however, we have really just pushed the question back a step and you may be wondering: "what regulates the Cyclins In many tissues in the body, secreted signaling factors have been identified that stimulate or inhibit the progress of mitotically active cells through the cell cycle. During this expansion phase of histogenesis, the progenitor population expands rapidly. In the middle phase of histogenesis, the progenitor cells divide asymmetrically to produce another progenitor and a postmitotic neuron (sometimes call the Q or quit fraction because they do not reenter the mitotic cycle). At the end of histogenesis, the progenitors produce two postmitotic progeny (either neurons or glia) and the progenitor pool is depleted. The total number of neurons produced in the cerebral cortex is a function of the number of cell divisions of the progenitors that produce more progenitors (P) and the divisions that produce neurons (the "quit" or Q fraction). By contrast, if the Q fraction is experimentally raised in mice, the cortex is markedly thinner. These growth factors most commonly act to control the progression from G1- to S-phase of the cell cycle, in part by controlling the level of expression of cell cycle regulator Genesis and Migration Chapter 3 61 proteins like CyclinD1. One potential explanation for the gradual lengthening of the G1-phase of the cell cycle in the progenitor cells at later stages of development (above) is an increasing dependence on these mitogenic growth factors for progression through the cell cycle as development proceeds. However, there are many other types of signaling molecules that act on progenitor cells in the nervous system and also play a role in their proliferation. Sonic hedgehog and members of the Wnt protein family are examples of molecules that are involved in patterning the nervous system (reviewed in Chapter 2), but are also critical for the regulation of progenitor proliferation at later stages of brain development. Progenitor cells express receptors for the various mitogenic factors, and depending on their location and stage of development, they are more responsive to one mitogen or another. These work through surface receptors to upregulate expression of cell cycle inhibitors, like p27kip. The progenitors must integrate these signals to determine whether they progress to the next S-phase and in this way the extracellular signals are connected with the intrinsic cell cycle regulation machinery to allow for the correct cell numbers in each region of the brain. In this section we have seen that the regulation of the numbers of neurons and glia in the developing brain is influenced by factors that cause the gradual lengthening of the cell cycle during development and factors that control the shift from symmetric "expansion phase" cell divisions of the progenitors to their neurogenic, asymmetric divisions In fact, there is some evidence that the two questions might be intimately connected; Caviness et al. In the next section, we will discuss the mechanisms that control the developmental decision of the progenitor to produce neurons, glia, or both. In addition, these studies also showed that the ratio of the different types of cells produced by a progenitor is quite variable. One multipotent progenitor might produce only a few neurons, but many astrocytes, while another might generate mostly neurons. Early in development, most of the progenitors are multipotent, but in some regions of the brain, there are committed progenitors that produce only neurons or only glia. What controls the relative number of these different types of cells made from the multipotent progenitors Tracking the potency of single progenitor cells in vitro has shed some light on these questions. It can also be seen from the figure that at the beginning of the observation period, two of the four progenitors that were followed over time produced neurons, astrocytes, and oligodendrocytes, while one generated only oligodendrocytes and one produced neurons and oligodendrocytes. Looking more closely, sometimes two different cell types were produced by the last cell division, but more commonly, the multipotent progenitor cells eventually produce bipotent and then unipotent progenitor cells. For example, cell number 2 is tripotent at the start, but after one generation, produces two bipotent progenitor cells, one of which makes neurons and oligodendrocytes and the other makes neurons and astrocytes. These data suggest that the potential of progenitor cells becomes progressively restricted over time and that unipotent progenitor cells are derived from multipotent progenitors. Cell culture studies indicate that both extracellular signaling factors, like those that control cell proliferation of the progenitor and intrinsic processes within the cells, both play important roles in regulating the potential of the progenitor cells to either a neuronal or glial lineage. In cell cultures, one can add defined factors and assay the effects on the production of either neurons or glia from the progenitor cells. Labeling the culture with antibodies against cell-specific proteins (far right) shows that several of the new cells have developed into neurons (red), while others express antigenic markers of either oligodendrocytes (blue) or astrocytes (green). This provides a direct transcriptional connection between the signaling molecule and a glial-specific gene. A similar block in access is present in the promoters of other glial genes, and hence, early progenitors are blocked from producing astrocytes. This interplay between signaling factors in the local environment of the progenitors, along with intrinsic properties of the cells, allows for the developmental program to respond to the surrounding cells. Another important pathway that regulates the production of neurons and glia is the Notch pathway. As we saw in the previous chapters, the Notch signaling pathway and the proneural transcription factors are important in the early stages of nervous system formation. These genes also play critical roles in the process of neurogenesis (Bertrand et al. The components of the Notch pathway and the proneural transcription factors are expressed in the progenitors and the differentiating neurons. The progenitor cells express several proneural transcription factors, including Ascl11, Neurogenin, and Olig1/2. These proneural transcription factors are important for maintaining the progenitors by activating the expression of the Notch ligands, Dll1/3 (Kageyama et al. The Notch ligands in turn activate the Notch receptors on the progenitor cells, and activate the expression of the Hes genes, Hes1/5, and related factors. The Hes genes, and the Notch receptor itself, are necessary for the maintenance of the progenitor state in the cells. Neurogenesis and gliogenesis are regulated by many growth factors, and these are summarized in the figure. Overexpression of activated Notch causes the opposite: the progenitor cells fail to differentiate into neurons, and either remain progenitors or become glia (see below). If all the progenitors have approximately equal levels of Ascl1, Dll, and Hes1, the progenitor pool is maintained; however, if one of the daughter cells from a mitotic division expresses a higher level of Ascl1 than the other, it will also express more Dll; this will activate Notch in the sister progenitor cell at a higher level, and lower its level of Dll, leaving the cell with more Ascl1 free to differentiate as a neuron. Creating even a small bias in the two daughter cells in their expression of Ascl1, its repressor, Hes1, or the activity of the Notch receptor, would lead to the amplification of the difference because of this feedback between the two cells. This Hes1 oscillation within each progenitor cell causes a counter-oscillation of the Ascl1 and Dll in each cell. Now when two progenitors, each with their own Hes1/Ascl1 cycle, are brought into contact, they should cycle in opposite phase to one another. A second oscillation in the progenitor cell expression of Notch pathway activity also occurs with the mitotic cell cycle. Hes1 levels are higher when the cell is in the S-phase and lower as the cells enter the M-phase and G1 phase of the cell cycle (near the ventricular surface). This Hes1 oscillation within each progenitor cell causes a counteroscillation of the Ascl1 and Dll in each cell. Cells that maintain high levels of proneural gene expression go on to differentiate as neurons, while those that oscillate remain as progenitor cells and ultimately develop as astrocytes (Imayoshi and Kageyama, 2014), or oligodendrocytes (if they have a high level of Olig1/2). Since astrocytes are frequently produced later than neurons in most areas of the nervous system, it could be that the activation of the Notch pathway simply prevents progenitors from differentiating until other signals that induce glial differentiation are produced. However, there is other evidence that overactivating Notch plays an instructive role in gliogenesis as well as this more permissive role. Nfia is both necessary and sufficient for induction of astrocyte genes: knocking this gene out in mice leads to a reduction in astrogliogenesis, while overexpressing this gene leads to an increase in astrocyte production by the progenitors. The ability of Nfia to repress neurogenesis is mediated at least in part by Hes5, which as we saw in the previous section, is downstream of Notch signaling. This nicely ties together the findings that Notch and Hes5 can promote the glial fate. In addition to astrocytes, the other type of macroglia in the central nervous system is the oligodendrocytes.

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Imaging of dissociated living cortical neurons shows that wherever a growth cone undergoes a lengthy pause gastritis diet potatoes generic rabeprazole 10mg online, and then advances again, cytoskeletal remnants of the paused growth cone are left behind on the axon shaft (Szebenyi et al. These results suggest that branching is part of a plastic process, likely regulated by signals that trigger remodeling of the internal cytoskeleton via local translation. Sema3a, which we discussed in the last chapter, repels the growth cones of cutaneous sensory neurons. Analysis of knockout mice supports a critical role for Sema3a as an exclusion factor confining the peripheral ends of these axons to the correct target areas of the skin (Taniguchi et al. In these Sema3a knockout mice, axons that are normally restricted from innervating skin now enter these territories. Sema3a is also expressed at the posterior boundary of the olfactory bulb, where it seems to act to restrict olfactory axons to the bulb, preventing them from entering the telencephalon (Kobayashi et al. The repulsive molecule Ephrin-A5, which we will discuss in more detail below with respect to topography, reaches its highest concentration just posterior to the superior colliculus or tectum, the target of retinal axons, suggesting that this ligand may also serve as a factor that confines these axons to the target. Indeed, retinal axons extend beyond the posterior border of the superior colliculus in Ephrin-A5 knockout mice (Frisen et al. This raises the question of whether this type of mechanism is used to help segregate neural circuits that carry different kinds of information to different, but nearby, centers of the brain, thus preventing inappropriate targeting. Re-innervation and cross-innervation experiments show that, when the normal targets of axons have been surgically removed, functional synapses can indeed be made on the wrong targets. Similarly, when the brain is injured, the normal targets of some axons may die and nearby regions may become denervated. In these cases, axons that originally innervated the injured areas may sprout new growth cones to invade denervated but inappropriate targets. To test how promiscuous axons are, and whom they will synapse with if given the chance, one can test a variety of foreign targets with different axonal populations. In these experimental animals the thalamocortical connections have not been changed and are basically normal, giving rise to the weird condition that these animals process visual information in the somatosensory or auditory cortex, respectively, thus perhaps having the conscious sensation of feeling or hearing the visual world (von Melchner et al. Normally, of course, the nuclei of the thalamus have modality-specific innervation. There is some evidence to suggest that this segregation is a result of molecular barriers that normally separate these brain areas. High levels of Ephrin-A2 and Ephrin-A5 define a distinct border between the visual and auditory thalamus. If the normal input to the auditory thalamus is denervated while the visual thalamus is spared, retinal axons mostly remain in their uninjured normal targets. However, when this experiment is done in knockout mice that lack both Ephrin-A2 and Ephrin-A5, there is extensive rewiring and retinal axons invade and innervate the deafferented auditory thalamus (Lyckman et al. These findings suggest that signals that promote innervation of a target region are complemented by barriers, such as repulsive guidance molecules, that serve to contain axons within the target zone. Implicit in the above experiments that examine the capacity for cross-innervation is the notion that border patrol is not the only mechanism for appropriate targeting. In cross-innervation experiments in amphibians, in which extensor motor nerves were forced to innervate flexor muscles and flexor motor nerves were forced to innervate extensor muscles, the animals developed expected inappropriate motor behaviors after surgery. Interestingly, however, normal behavior recovered after a rather long period of time. This was first interpreted as the animals having learned to use these muscles in a new way, but detailed anatomical investigations of these animals showed that the crossed nerves, over the course of time, had managed to uncross themselves and find their original muscles again (Mark, 1969). Competition experiments between original and foreign nerves for the innervation of particular muscles showed that the original nerves always have an advantage (Dennis and Yip, 1978). Thus axons, although they will innervate inappropriate denervated targets when their own targets are unavailable, seem to have a natural preference for their own original targets, suggestive perhaps of specific cell-cell recognition molecules and partner-specific trophic support. Retinal ganglion cells in a particular position in the retina are maximally stimulated from a region of the visual world, and these cells send their axons to a particular region in the tectum. Neurons in neighboring retinal positions send their projections to neighboring regions in the tectum. Even simple animals like the nematode, with only 302 neurons, have ordered arrays of sensory receptors that make somatopically organized central projections. These help them respond appropriately to stimuli that strike the animal from different directions. There is a second type of neural map, a computational map, which can be revealed by recording from neighboring single nerve cells in vivo. What is represented in such maps is not obvious from the anatomy of the connections, yet these maps may also display orderly representations of a physical parameter. For example, in the auditory system, we find nuclei that display topography of sound source location, even though the ear contains only a one-dimensional array of spiral ganglion cells representing sound frequency. Such maps are constructed from cells that extract information and are referred to by the functional characteristic that they encode. There are also less intuitively obvious maps, such as maps of smell that we will discuss below. What is the developmental basis for establishing topographic projections in the nervous system When Langley stimulated the first or top thoracic root to the ganglion in a rat, this activated ganglion cells that caused dilation of the pupil. When he stimulated the fourth thoracic root to the ganglion, the blood vessels of the ear constricted. Each ganglion is selectively innervated by afferents from a limited number of spinal cord segments from a specific A-P domain. In one experiment, a T5 ganglion was transplanted to different locations along the sympathetic chain, exposing this target to afferents from a large range of spinal cord segments (Purves et al. The sympathetic chain ganglia were dissected out along with the ventral nerve roots through which all preganglionic fibers course from the ventral spinal cord. Stimulating electrodes were then placed on the ventral roots from each spinal cord segment, and an intracellular recording was obtained from the reinnervated T5 ganglion. The explanation he gave was the possible existence of biochemical tags across the retina and tectum. He postulated the existence of two or more cytochemical gradients "that spread across and through each other with their axes roughly perpendicular" (Sperry, 1963). These separate gradients successively superimposed on the retinal and tectal fields would stamp each cell with its appropriate latitude and longitude in a kind of chemical code with matching values between the retinal and tectal maps. The chemoaffinity hypothesis inspired many biologists and biochemists to try to find the molecules that were responsible for topographic targeting in the retinotectal system. Such studies often took an in vitro approach, and for over 20 years, not much progress was made. When retinal tissue was cultured on such striped membrane carpets, they found that temporal retinal axons, but not nasal axons, grow preferentially on anterior tectal membranes (Walter et al. This suggests that the relevant activity is a membrane-linked protein that is repulsive to temporal axons, and to which nasal axons are rather insensitive. By examining the choices that temporal axons make between membranes extracted from successive rostrocaudal sixths of the tectum, it became clear that this inhibitory activity is graded across the tectum, highest at the caudal (posterior) pole and lowest at the rostral (anterior) pole. The Ephrin-As generally activate Eph-As, while the Ephrin-Bs generally activate Eph-Bs (Flanagan and Vanderhaeghen, 1998). The retina, as expected, shows a gradient of Eph-As, the receptors for these ligands. The nasal fibers from the retinal explant grow on both A and P tectal membranes, but the temporal fibers grow only on the A membranes. When Ephrin-A2 is misexpressed by transfection across the entire tectum in chick embryos, temporal axons find it difficult even to enter the tectum. When membrane stripes are made from the transfected anterior tectal cells, temporal axons will not grow on them. These results predict that when the Ephrins are knocked out, there will be mapping errors. In mutant mice, in which Ephrin-A5 is knocked out, temporal axons make errors of frequently mapping more posteriorly (Frisen et al. In these mice, the anteroposterior order of both nasal and temporal axons is largely, though not totally, lost. Temporal axons terminate all over the tectum and freely invade the posterior poles (Feldheim et al.