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By Q. Hanson. Missouri State University. 2018.

The Metabolic and Molecular Bases of Inherited Disease buy dapoxetine 60 mg on-line erectile dysfunction houston. Thalassemia: Weatherall D, Clegg J, Higgs D, Wood W. The Metabolic and Molecular Bases of Inherited Disease. Antibiotics that inhibit protein synthesis: Hardman JG, Limbird LE, et al. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. In the read-out of the genetic code in prokaryotes, which one of the following processes acts before any of the others? If some of this charged tRNA is added to a protein-synthesizing extract that contains ALL the normal components required for translation, which of the following statements represents THE MOST LIKELY OUTCOME after adding an mRNA that has both cys and ala codons in the normal reading frame? The genetic code is said to be degenerate because of which of the following? Which of the following is responsible for retaining the enzyme protein disulfide isomerase in the ER? The reason there are 64 possible codons is which of the following? Normally, only a fraction of the genes The prokaryotic bacterium in a cell are expressed at any time. Gene expression is regulated differently in Escherichia coli can use a wide prokaryotes and eukaryotes. It accomplishes this partially by sion is regulated mainly by controlling the initiation of gene transcription. Sets of turning on and off expression of the genes genes encoding proteins with related functions are organized into operons, and required for synthesis of enzymes in differ- each operon is under the control of a single promoter (or regulatory region). For example, enzymes encoded by the lac operon allow ulatory proteins called repressors bind to the promoter and inhibit the binding of E. Repressors are controlled by nutrients or these genes. Thus, the nutrient itself is their metabolites, classified as inducers or corepressors. Regulation also may involved in regulating gene expression. In contrast, the cells of the adult human Eukaryotes: Regulation of gene expression at the level of DNA. In eukary- are exposed to a nearly constant and safe otes, activation of a gene requires changes in the state of chromatin (chromatin environment composed of blood and inter- remodeling) that are facilitated by acetylation of histones and methylation of stitial fluid. These changes in DNA determine which genes are available for transcrip- constant environment, in spite of changes in tion. Transcription of specific genes is regulating gene transcription. The immune system protects cells against foreign organ- regulated by proteins (called specific transcription factors or transactivators) isms, partially by controlling the expression that bind to gene regulatory sequences (called promoter-proximal elements, of genes required for the immune response. For example, iron scription factors, which may bind to DNA sequences some distance from the pro- controls expression of the genes for its stor- moter, interact with coactivators or corepressors that bind to components of the age and transport proteins at the level of basal transcription complex. These protein factors are said to work in “trans”; their mRNAs. Regulation also occurs during the processing of RNA, during RNA transport from the nucleus to the cytoplasm, and at the level of translation in the cytoplasm. Regulation can occur simultaneously at multiple levels for a specific gene, and many factors act in concert to stimulate or inhibit expression of a gene. THE WAITING ROOM Arlyn Foma, a 68-year old man, complained of fatigue, loss of appetite, and a low-grade fever. An open biopsy of a lymph node indicated the pres- ence of non-Hodgkin’s lymphoma, follicular type.

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Platelet aggregation is Fibrinogen is a protein that circulates in the blood and is also found in platelet affected order dapoxetine 60mg line erectile dysfunction for women, because of the inability of GPIb to granules. It consists of two triple helices held together with disulfide bonds. Fibrinogen, the precursor protein of fibrin, is formed from two triple helices joined together at their N-terminal ends. The , peptides are held together by disulfide bonds, and the -peptides are joined to each other by disul- fide bonds. The terminal , peptide regions, shown in blue, contain negatively charged glutamate and aspartate residues that repel each other and prevent aggregation. Thrombin, a serine protease, cleaves the terminal portions of fibrinogen containing negative charges. The fibrin monomers can then aggregate and form a “soft” clot. The soft clot is then subsequently cross-linked by another enzyme. Thrombin itself is a potent activator of platelets, through binding of aggregated platelets. The microthrombi to a specific receptor on the platelet surface. The Blood Coagulation Cascade lium, exposing collagen and releasing high- Thrombus (clot) formation is enhanced by thrombin activation, which is mediated by molecular-weight vWF, promoting more the complex interaction that constitutes the blood coagulation cascade. All of these proteins are present in the plasma as pro- Familial TTP is associated with mutations proteins (zymogens). These precursor proteins are activated by cleavage of the in the vWF-specific metalloprotease, although polypeptide chain at one or more sites. The key to successful and appropriate throm- not all individuals with defective protease bus formation is the regulation of the proteases that activate these zymogens. Sporadic cases of TTP are asso- The proenzymes (Factors VII, XI, IX, X, XII, and prothrombin) are serine pro- ciated with the development of an antibody to teases that, when activated by cleavage, cleave the next proenzyme in the cascade. Because of the sequential activation, a great acceleration and amplification of the response is achieved. That cleavage and activation have occurred is indicated by the addition of an “a” to the name of the proenzyme (e. In response to collagen and throm- The cofactor proteins (tissue factor, Factors V and VIII) serve as binding sites for bin, platelets release vasoconstric- other factors. Tissue factor is not related structurally to the other blood coagulation tors. Serotonin is released from the dense granules of the platelets, and the syn- cofactors and is an integral membrane protein that does not require cleavage for thesis of thromboxane A2 is stimulated. Factors V and VIII serve as procofactors, which, when activated by will reduce blood flow to the damaged area. Platelet-derived growth factor, which stimu- Two additional proteins that are considered part of the blood coagulation cas- lates proliferation of vascular cells, is also cade, protein S and protein C, are regulatory proteins. Only protein C is regulated released into the environment surrounding by proteolytic cleavage, and when activated, is itself a serine protease. The Process of Blood Coagulation Activation of the blood coagulation cascade is triggered by the reaction of plasma The utilization of an active site ser- proteins with the subendothelium at the same time that platelets are adhering to the ine to cleave a peptide bond is subendothelial layer. Historically, two different pathways were discovered, one common to a variety of enzymes dependent on external stimuli (such as blunt trauma, which initiates the extrinsic referred to as serine proteases. Serine pro- pathway) and one using internal stimuli (the intrinsic pathway). As our understand- teases are essential for activating the forma- ing of blood clotting has expanded, it has become obvious that these distinctions are tion of a blood clot from fibrin. Fibrin and no longer correct, because there is overlap between the pathways, but the terms have many of the other proteins involved in blood persisted in the description of the pathways. Thrombin, the serine protease that converts fibrinogen culating Factor VII binds to tissue factor, which autocatalyzes its own activation to to fibrin, has the same aspartate-histidine- Factor VIIa. Factor VIIa then activates Factor X (to Xa) in the extrinsic pathway and serine catalytic triad found in chymotrypsin Factor IX (to IXa) in the intrinsic pathway.

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Use the following case history for questions 3 and 4 purchase dapoxetine 90 mg fast delivery erectile dysfunction causes in young males. To answer this question, you do not need to know more about parathy- roid hormone or pseudophypoparathyroidism than the information given. Pseudohypoparathyroidism is a heritable disorder caused by target organ unresponsiveness to parathyroid hormone (a polypeptide hormone secreted by the parathyroid gland). One of the mutations causing this disease occurs in the gene encod- ing Gs in certain cells. The receptor for parathyroid hormone is most likely (A) an intracellular transcription factor. This mutation most likely (A) is a gain-of-function mutation. SH2 domains on proteins are specific for which of the following sites? Using this knowledge, researchers then dis- covered the mechanisms by which genetic information is inherited and Translation expressed. During the last quarter of the 20th century, our understanding of this critical area of science, known as molecular biology, grew at an increas- Protein Iingly rapid pace. We now have techniques to probe the human genome that will completely revolutionize the way medicine is practiced in the 21st century. Replication, transcription, and transla- The genome of a cell consists of all its genetic information, encoded in DNA tion. Replication: DNA serves as a template for producing DNA copies. In eukaryotes, DNA is located mainly in nuclei, but small DNA serves as a template for the synthesis of amounts are also found in mitochondria. Translation: RNA provides the informa- somes that contain DNA and protein in tightly coiled structures (Chapter 12). The molecular mechanism of inheritance involves a process known as replication, in which the strands of parental DNA serve as templates for the synthesis of DNA copies (Fig. After DNA replication, cells divide, and these DNA Many drugs used in medicine to copies are passed to daughter cells. Alterations in genetic material occur by recombi- treat bacterial infections are tar- nation (the exchange of genetic material between chromosomes) and by mutation (the geted to interfere with their ability result of chemical changes that alter DNA). DNA repair mechanisms correct much of to synthesize RNA and proteins. Thus, med- this damage, but, nevertheless, many gene alterations are passed to daughter cells. DNA is transcribed to produce ribonu- protein synthesis. Three major types of RNA are transcribed from DNA and subse- quently participate in the process of translation (The synthesis of proteins). Mes- senger RNA (mRNA) carries the genetic information from the nucleus to the Ethical dilemmas have come along with technological advances in cytoplasm, where translation occurs on ribosomes, structures containing proteins moleuclar biology. Transfer RNA (tRNA) carries individual case of a patient with a mild case of amino acids to the ribosomes, where they are joined in peptide linkage to form pro- ornithine transcarbamoylase deficiency, a teins. During translation, the sequence of nucleic acid bases in mRNA is read in sets urea cycle defect that, if untreated, leads to of three (each set of three bases constitutes a codon). The sequence of codons in the elevated ammonia levels and nervous sys- mRNA dictates the sequence of amino acids in the protein. The patient was being structure, signaling, and catalysis and, therefore, determine the appearance and effectively treated by dietary restriction of behavior of cells and the organism as a whole. However, in 1999, he was treated (Chapter 16) determines which proteins are synthesized and the amount synthesized with a common virus carrying the normal at any time, thus allowing cells to undergo development and differentiation and to gene for ornithine transcarbamoylase. This case history raises the lectively as recombinant DNA technology, biotechnology, or genetic engineering, issues of appropriate patient consent, appro- that can be used for the diagnosis and treatment of disease (Chapter 17). These priate criteria to be included in this type of techniques can detect a number of genetic diseases that previously could only be study, and the types of diseases for which diagnosed after symptoms appeared.

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The endolymph is within the membranous labyrinth cheap dapoxetine 60 mg otc impotence at 17, and the perilymph surrounds it. These fluids are important to the sensory functions of the inner ear. Hearing The organ of hearing, called the organ of Corti (KOR-te), consists of ciliated receptor cells located inside the membranous cochlea, or cochlear duct (Fig. Sound waves enter the external auditory canal and cause Stapes vibrations in the tympanic membrane. The ossicles amplify these vibrations and finally transmit them from the stapes Figure 11-13 The ossicles of the middle ear. The handle of to a membrane covering the oval window of the inner ear. The base of the stapes is in contact chambers, they set up vibrations in the cochlear duct. Philadelphia: Lip- a result, the tiny, hairlike cilia on the receptor cells begin pincott Williams & Wilkins, 2003. The vestibule, semicircular canals, and cochlea are made of a bony shell (labyrinth) with an interior membranous labyrinth. Endolymph fills the membranous labyrinth and perilymph is around it in the bony labyrinth. They are lo- that travel to the brain in the cochlear nerve, a branch of cated in the vestibule and the semicircular canals. Recep- the eighth cranial nerve (formerly called the auditory or tors for the sense of equilibrium are also ciliated cells. Sound waves ultimately leave the ear the head moves, a shift in the position of the cilia within through another membrane-covered space in the bony the thick fluid around them generates a nerve impulse. Receptors located in the two small chambers of the Hearing receptors respond to both the pitch (tone) of vestibule sense the position of the head or the position of sound and its intensity (loudness). The various pitches the body when moving in a straight line, as in a moving ve- stimulate different regions of the organ of Corti. This form of equilibrium is tors detect higher pitched sounds near the base of the termed static equilibrium. Each receptor is called a mac- cochlea and lower pitched sounds near the top. Exposure to contains small crystals of calcium carbonate, called loud noises, such as very loud music, jet plane noise, or otoliths (O-to-liths), which add drag to the fluid around industrial noises, can damage the receptors for particular the receptor cells and increase the effect of gravity’s pull pitches of sound and lead to hearing loss for those tones. Similar devices are found in lower animals, The steps in hearing are: such as fish and crustaceans, that help them in balance. The receptors, called cristae (KRIS-te), are located 3. The ossicles transmit vibrations across the middle ear at the bases of the semicircular canals (Fig. The stapes transmits the vibrations to the inner ear semicircular canals go off in different directions. Nerve fibers from the vestibule and from the semicir- 5. Vibrations move cilia on hair cells of the organ of cular canals form the vestibular (ves-TIB-u-lar) nerve, Corti in the cochlear duct. Movement against the tectorial membrane generates cochlear nerve, the eighth cranial nerve. Impulses travel to the brain in the VIIIth cranial nerve. Checkpoint 11-12 Where are the receptors for equilibrium lo- 8. Checkpoint 11-11 What is the name of the organ of hearing and where is it located?

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The primary endpoint was the time until onset of motor fluctuations generic 90mg dapoxetine with visa erectile dysfunction doctor mumbai. The definitions of motor fluctuations included that reported in patient completed diaries or observations of investigators in the clinic recorded on a standard questionnaire. The time until the onset of fluctuations was the earlier of two consecutive diary periods demonstrating their presence with either 5 10% of the waking day with dyskinesias or 5 20% in the off state. It could also be the time until onset of fluctuations based on the investigator questionnaire. This definition would indicate that they were not just testing for first onset of fluctuations but instead onset of functionally meaningful symptoms. Mean dose of LD in both groups was low (400–500 mg/day). There were no differences between the two formulations with regard to efficacy or frequency of motor fluctuations. Despite low doses there was a significant improvement of the UPDRS motor score that gradually diminished over time but was still better than the baseline score as seen in the earlier studies. However, only about 20% of patients in each group developed wearing off and dyskinesias, far lower than prior numbers. The CALM-PD study (36,37), a parallel-group, double-blind, randomized trial consisting of both clinical and imaging substudies, compared the rates of dopaminergic motor complications and dopamine neuron degeneration (primary endpoints), respectively, after initial treatment of early PD with pramipexole versus LD. The clinical 2-year data reported that 28% of patients assigned to pramipexole developed motor complications compared with 51% of patients assigned to LD (p < 0. However, the mean improvement in UPDRS score was significantly greater in the LD group compared with pramipexole (9. When extended to 4 years, slightly Copyright 2003 by Marcel Dekker, Inc. The mean improvement in UPDRS scores from baseline through 48 months was significantly greater in the LD group (3. The imaging portion of the study (38,39) included 82 patients who underwent four sequential [123]I B-CIT single photon emission computed tomography (SPECT) scans over a 46-month period to compare the rate of nigrostriatal dopaminergic degeneration between the treatment groups. It is assumed that a reduction in striatal [123]I B-CIT uptake is a marker of dopamine neuron degeneration. The authors report a 40% relative reduction in the rate of loss of uptake when comparing pramipexole to LD. Whether this suggests a protective effect of the dopamine agonist with respect to LD or that LD may accelerate the rate of loss of uptake or that this is a pharmacological effect is not clear given the limits of the study design. A similar 5-year comparison of ropinirole and LD in 268 patients was reported in 2001 (40). Approximately half of the patients withdrew by the end of 5 years. The primary endpoint was the appearance of dyskinesias as measured by item 32 on the UPDRS. They were shown to occur earlier and more frequently in patients treated with LD than ropinirole. Regardless of LD supplementation, 20% of ropinirole subjects experienced dyskinesias by the end of 5 years versus 45% of LD subjects. Prior to the addition of LD, 5% of the ropinirole group and 36% of the LD group developed dyskinesias. The change from baseline of the UPDRS activities of daily living (ADL) score was similar between the two groups, but there was a significant difference in favor of the LD group for the change from baseline of the UPDRS motor score, which improved by approximately four times compared to the ropinirole group. This difference in efficacy was reported in the 6-month interim report published earlier (41). LD treatment is associated with greater therapeutic benefit (both early in the course of disease as well as later), and at least half of the patients developed motor complications after several years regardless of initial treatment. Thirty years of experience and literature have led to several conclusions regarding LD therapy in PD. It is currently the most potent symptomatic therapy for PD. We have learned quite a bit about the nuances of treatment such that our goals have changed. We now treat with the lowest effective dose, not the highest tolerated one, we avoid frequent small doses, which only add to the unpredictable responses seen, and we have developed adjunctive therapies that complement LD.

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