For example symptoms 97 jeep 40 oxygen sensor failure discount cefuroxime 250 mg free shipping, cold snaps in temperate and tropical regions can cause a large influx of shore-cast sea turtles needing veterinary intervention treatment hepatitis c generic cefuroxime 500 mg fast delivery. However medications known to cause miscarriage buy cefuroxime 250 mg fast delivery, the bulk of the rescue work may be done by small 897 treatment plant rd buy 250mg cefuroxime, non-profit rescue organizations rather than the larger symptoms 5 weeks into pregnancy safe cefuroxime 250 mg, commercial facilities medications equivalent to asmanex inhaler purchase cefuroxime 250mg without prescription, who apparently do not prioritize space or funding for such species,115 and thus limit the number of individuals they will take in. Often the rescue efforts of the industry seem motivated by the desire to create better public relations. By saving injured manatees (Trichechus manatus) or by rehabilitating stranded dolphins, often spending many thousands of dollars in the process,116 facilities persuade the public that they are altruistic and that they care for marine mammals in the wild-a public relations benefit worth the large investment of funds. Stranded cetaceans who do not die on the beach or are not pushed back into the ocean alive may be taken into captivity for rehabilitation, where survival is uncertain. Also disturbing is the fact that public display facilities that rescue stranded animals appear to evaluate each animal in terms of display potential. Species that are highly desirable, such as orcas,119 or rarely observed in captivity, such as spotted dolphins (Stenella frontalis) or pilot whales (Globicephala spp. By rescuing these animals, a facility acquires an exotic exhibit at little cost, either financial or in terms of public relations. However, much of what can be learned from captive marine mammals has in fact already been learned. Reproductive physiology, such as length of gestation, and general physiology, such as visual acuity, have already been examined in some detail for several species. Furthermore, using reproductive information from captive marine mammals may actually be detrimental to conservation and management, due to unnatural and atypical breeding behavior in the artificial groupings of captive animals. Most of the current behavioral research using captive animals relates to husbandry concerns,125 does little to benefit free-ranging animals,126 and can provide some dubious results. The Captive studies have been known to give erroneous and misleading information, not borne out by comparative studies on free-ranging animals, and researchers using captive animals have admitted that the constraints put on marine mammals, such as small tank sizes limiting natural behaviors, lead to biases in their results. There may be some research questions that the study of captive marine mammals can answer most directly (such as questions regarding cognition or the impacts of human-caused sound on hearing), but research programs that are not part of the entertainment industry could address those questions. Indeed, due to advancements in technology, such as biopsy darts, satellite tags, drones, and underwater remotely operated vehicles, as well as improvements in capture and release techniques,124 in-depth study of the behavior and physiology of free-ranging marine mammals is now possible, adding to the redundancy of captive animals as research subjects. One of the most famous critics of using the behavior of cetaceans in captivity as a model for animals in future in behavioral research lies indisputably in the wild. In fact, captive studies have been known to give erroneous and misleading information, not borne out by comparative studies on free-ranging animals,128 and researchers using captive animals have admitted that the constraints put on cetaceans, such as small tank sizes limiting natural behaviors, lead to biases in their results. Of these few studies, more than a third were conducted through research institutions that are not open to the public. In 2007, there were only two abstracts submitted by SeaWorld, the largest holder of captive marine mammals in the world. In 2010, researchers studying captive cetaceans found similar results, reporting that only 1. It should be conducted whenever possible through research-sabbatical programs, in which animals are held only for brief periods or through non-invasive research using marine mammals maintained in seaside sanctuaries (see Chapter 12, "The Blackfish Legacy"). Sabbatical programs have been pioneered successfully by several marine mammal researchers. All cetacean capture methods are invasive, stressful, and can potentially be lethal. During a seine-net capture, dolphins are chased by small boats and then herded together and encircled by the net. Chasing and net encirclement of dolphins are extremely stressful and, when experienced repeatedly, have led to the decline or hindered the recovery of some dolphin populations. However, there have been no studies, by the industry or management agencies, on the survival rates of released animals. A capture method once commonly used on oceanic cetaceans, such as Pacific white-sided dolphins (Lagenorhynchus obliquidens), is "hoop netting. The captor lowered a pole attached to a collar from the front of the capture vessel over the head of a swimming dolphin. This collar was attached to a break-away net, and as the dolphin swam away, the animal became entangled. The most violent and cruel method of collecting cetaceans for dolphinaria is the drive fishery, currently used only in Taiji, Japan. This hunt involves a flotilla of small boats that-through producing loud noises when the crews bang on hulls or clang metal pipes together underwater-herd cetacean groups into shallow water. Some of the animals are set aside for sale to public display facilities, while the rest are killed and butchered for human and pet food and other products;142 occasionally some are released, to an unknown fate. The drives in Japan achieved international infamy as the result of the Academy Awardwinning documentary the Cove,143 which highlighted both the hunt and the trade in dolphins to aquaria. Research on bottlenose dolphins and modeling of orca societies show that certain individuals play a crucial role in holding communities together. If these individuals are removed, by natural causes, hunts, or captures, the group might lose cohesion and disperse. In addition, if a relatively small population of cetaceans is persistently targeted by capture operators, a large proportion of an entire generation (the juveniles preferred for capture, as they are more easily transported, better able to adjust to confinement, and make the transition to eating dead fish more readily) may be removed. Depletion at the time will be obvious, but at some time in the future, these animals will also not be available to the population as breeders. This means it is not just the "first wave" of removals that will hit targeted populations, but a "second wave" may strike years after captures end, manifesting as a decline in birth rate and harmful inbreeding. There are currently at least 76 operational dolphinaria and marine theme parks in China, but at least 25 more are planned for construction over the next few years. As of January 2019, approximately 954 cetaceans, of at least 12 species, were being displayed in China, with most of these originally captured from the wild and imported, primarily from Japan and Russia. Captures of non-cetacean marine mammals occur only rarely today, as these species either breed relatively well in captivity (for example, California sea lions, Zalophus californianus) or are acquired when dependent young are orphaned in hunts or through strandings (for example, polar bears). However, some pinniped species, particularly from the Southern Hemisphere for Asian facilities, are still taken from the wild. As of January 2019, there were at least 76 operational dolphinaria and marine theme parks in China, but at least 25 more are planned for construction over the next few years. Approximately 954 cetaceans, of at least 12 species, are currently displayed in China, with most of these originally captured from the wild and imported, primarily from Japan and Russia. Such an assessment, including delineation of stock boundaries, abundance, reproductive potential, mortality, and status (trend) cannot be achieved quickly or inexpensively, and the results should be reviewed by an independent group of scientists before any captures are made. Responsible operators (at both the capturing end and the receiving end) must show a willingness to invest substantial resources in assuring that proposed removals are ecologically sustainable. While once a major source for dolphinaria worldwide, public outcry forced the end of captures there. This area of the Russian Far East coast freezes in winter- the ice must constantly be broken up so the animals can surface to breathe. There have been no studies to determine whether these removals were or are sustainable or what, if any, impact they have had on these dolphin populations. Examples include another capture in Mexico, in December 2000, when eight bottlenose dolphins were captured off the Pacific coast of Baja California. In another incident, in August 2002, eight bottlenose dolphins were captured from the coastal waters of 31 these juvenile orcas, captured from a mammal-eating population and held at the same Russian Far East facility shown on page 31 (although held in separate pens), face an uncertain future. The government issued capture permits to several operators and established a capture/export quota of 100 dolphins per year, and despite a lack of science to ascertain the sustainability of these removals,193 many animals were exported internationally. Despite this ban, there was an attempt to capture and export 30 animals in 2016, although the captured dolphins were discovered and released. The ultimate disposition of these 27 animals (released, died, retained, or exported) was not reported. A wildlife trading company in Guinea-Bissau approached the government for permission to capture and export bottlenose dolphins in 2007. Given the various threats to dolphins in this region, any additional losses from live captures would likely have had a substantial impact on this population. Many members of the general public continue to believe captures of free-ranging cetaceans are a thing of the past, encouraged in this mistaken belief by the public display industry. Indeed, in the United States there have been no captures of bottlenose dolphins from the wild since 1989. For example, the director of the Dolphin Academy in Curaзao (see above) expressed outrage when the import of six Cuban dolphins was proposed. However, the imports went ahead, with one dolphin dying soon after transfer; the director was reportedly fired for speaking out against the trade. This was in addition to an estimated 25 to 50 animals who were caught every year to supply local dolphinaria and aquaria in countries bordering the Black Sea. Because exports of wild-caught animals for the lucrative international live trade are now effectively prohibited (although enforcement of the zero quota continues to be an issue), one threat to this declining population has been reduced. From 1962 until it was made illegal under state law in 1976, at least 53 orcas were taken from the "Southern Resident" population in Washington. At least 12 animals died during capture, and the survivors were shipped to aquaria and dolphinaria, of which only one animal is currently alive. These captures stopped in the late 1980s, when the controversy surrounding live orca captures increased. They also occurred historically in the waters off Japan but ended due to local depletions in the late 1980s. Orcas had not been seen off Many members of the general public continue to believe captures of free-ranging cetaceans are a thing of the past, encouraged in this mistaken belief by the public display industry. Ten animals were captured by fishermen from Taiji, of which five, all juveniles or sub-adults, were sold to dolphinaria and aquaria and the remainder released. In Russia, authorities issued quotas for live captures off Kamchatka starting in 2001-these annual quotas ranged from six to 10 animals. However, Russian government fisheries scientists reported the capture of a total of six animals in Russian waters during the period 20032010, although details have only ever been released on the three noted above; what happened to the other three animals is unknown. This animal was supposedly released, although the animal was discovered on a cargo boat, with two other young orcas, later in the year. Unfortunately, despite this promising development in bringing the unsustainable and essentially unregulated trade in live orcas (and belugas, see below) under control in Russia, permit issuances and captures began again in summer 2018, with a total allowable catch of 13 whales. In August 2018, two more orcas were reported to have been captured in the Sea of Okhotsk, with a third orca apparently being killed during the capture process. The age of the animals was another concern-none had reached sexual maturity and 15 of the belugas were almost certainly less than a year old (their teeth had not erupted), which violated Russian regulations. Subsequent to this investigation, it was announced that no captures of cetaceans for any purpose other than science would be permitted in 2019;222 this ban on captures in Russian waters for public display may (or may not) become permanent. There is a major international collaborative project being conducted to ascertain, among other things, how many orcas inhabit the Sea of Okhotsk, but at present, there is still no definitive estimate of population size. Marineland was still importing live-caught cetaceans during a time when the practice of keeping Belugas have been captured in Russia for the live dolphinarium trade for several decades. Their survival after this rough handling is poor; facilities in China in particular come back again and again to buy more as the belugas purchased earlier die. In a 2003 poll, approximately twothirds of those surveyed did not support the captivity of whales and dolphins and thought that the use of captive whales and dolphins for commercial purposes in Canada should be stopped. In addition, more than half of those interviewed said they would support laws that prohibit the import of live whales and dolphins into Canada. In its import permit application, Georgia Aquarium admitted the North American beluga breeding program had been a failure, thus "necessitating" an influx of new breeding stock from the wild. These decisions came after a series of beluga deaths at the aquarium232 and the resulting adverse publicity arising from these deaths, the permit application, and the subsequent legal proceedings. Belugas have also been imported (primarily from Russia) by China, Thailand, Egypt, Taiwan, Bahrain, and Turkey. As with Cuba and its bottlenose dolphins, Russia saw its belugas as a resource for generating hard currency-the sustainability of its capture program and the welfare of the animals were and are distant considerations at best. In the discussion that follows, physical, environmental, and behavioral factors, as well as life history parameters, are examined and compared, where possible, for marine mammals living in captivity and in the wild to illustrate systematically the fundamental welfare concerns related to holding these species in confinement. If every measure were taken to create comfortable, safe, and appropriate conditions, then the size, depth, shape, surroundings, props, colors, and textures of concrete enclosures would be different from those seen now. In 37 addition, noisy and disruptive activities and structures (such as fireworks displays, musical events, and roller coasters), all too commonly placed adjacent to or near marine mammal enclosures at marine theme parks, would be relocated to avoid disruption to marine mammals exposed to them daily and in some cases intermittently throughout the day. Their overall size, shape, and depth are determined by the need for maximum visibility from the surrounding bleachers and underwater viewing windows. Finally, efficiency of maintenance and disinfection dictates slick surfaces as opposed to naturalistic textures and substrates. The husbandry requirements for captive marine mammals, particularly cetaceans, are considered to be among the most highly specialized of all wildlife. Nevertheless, in some parts of the world, swimming pools meant for people, both concrete in-ground and plastic above-ground, have been repurposed to hold dolphins, belugas, and other marine mammals, permanently in some locations and temporarily in others. Petersburg Dolphinarium in Russia-considered a "premiere" facility-is merely a training pool from the 1980 Olympics. This swimming pool holds several dolphins, belugas, walruses, and sea lions in cages at the shallow end. This absence of retreat space has led to serious aggressive interactions between animals, in at least some cases resulting in serious injury and even death. The animals are held in natural seawater, as opposed to chemically treated, filtered, and/or artificial seawater. The surroundings are often more "natural" or complex and thus more "interesting" for the marine mammals than a typically featureless tank. However, sea pen facilities have their own unique problems and their conditions can compromise the health of, and even lead to the death of, marine mammals kept within them. Dolphinaria select sites for sea pen enclosures that maximize tourism traffic this sea pen was built here to be accessible from the aquarium on shore, not because it is a good place for captive dolphins to live. The water in this bay is typically as blue and clear as the water just around the point, but after a heavy storm the runoff turns it into brown sludge, unfit for human swimmers-or dolphins. For example, pens may be close to sources of pollution (such as runoff from roads, sewage outfalls, or water leached from land-based septic tanks). Noise from boat traffic and coastal development may echo off the seabed if it is too shallow, creating sound levels well above those in the open ocean.
Release of the amino terminal peptide is facilitated by donation of a proton to the newly formed amino group by His 57 of the charge-relay system treatment brachioradial pruritus cheap cefuroxime 500mg visa, yielding an acylSer 195 intermediate treatment 5cm ovarian cyst cheap cefuroxime 250mg with mastercard. His 57 and Asp 102 collaborate to activate a water molecule medicine versed cheap cefuroxime 500 mg with mastercard, which attacks the acyl-Ser 195 treatment tennis elbow cheap 250 mg cefuroxime overnight delivery, forming a second tetrahedral intermediate medications 1-z generic cefuroxime 250mg. The charge-relay system donates a proton to Ser 195 treatment 4 toilet infection cheap cefuroxime 250mg fast delivery, facilitating breakdown of tetrahedral intermediate to release the carboxyl terminal peptide. The portion of the original peptide with a free amino group then leaves the active site and is replaced by a water molecule. The charge-relay network now activates the water molecule by withdrawing a proton through His 57 to Asp 102. While modified during the process of catalysis, chymotrypsin emerges unchanged on completion of the reaction. Trypsin and elastase employ a similar catalytic mechanism, but the numbers of the residues in their Ser-His-Asp proton shuttles differ. Lys 356 + 6 2 Glu 327 O + + H P + Arg 352 6 Arg 307 Glu 327 2 O H+ + + Lys 356 Arg 352 P + P + Arg 307 P Fructose-2,6-Bisphosphatase Fructose-2,6-bisphosphatase, a regulatory enzyme of gluconeogenesis (Chapter 20), catalyzes the hydrolytic release of the phosphate on carbon 2 of fructose 2,6-bisphosphate. Catalysis involves a "catalytic triad" of one Glu and two His residues and a covalent phosphohistidyl intermediate. Most enzyme families arose through gene duplication events that create a second copy of the gene that encodes a particular enzyme. The proteins encoded by the two genes can then evolve independently to recognize different substrates-resulting, for example, in chymotrypsin, which cleaves peptide bonds on the carboxyl terminal side of large hydrophobic amino acids, and trypsin, which cleaves peptide bonds on the carboxyl terminal side of basic amino acids. Proteins that diverged from a common ancestor are said to be homologous to one another. The common ancestry of enzymes can be inferred from the presence of specific amino acids in the same position in each family member. Table 71 illustrates the primary structural conservation of two components of the charge-relay network for several serine proteases. Among the most highly conserved residues are those that participate directly in catalysis. However, the amplification conferred by their ability to rapidly transform thousands of molecules of a specific substrate into products imbues each enzyme with the ability to reveal its presence. Assays of the catalytic activity of enzymes are frequently used in research and clinical laboratories. Under appropriate conditions (see Chapter 8), the rate of the catalytic reaction being monitored is proportionate to the amount of enzyme present, which allows its concentration to be inferred. Like the members of other protein families, these protein catalysts or isozymes arise through gene duplication. Isozymes may exhibit subtle differences in properties such as sensitivity to particular regulatory factors (Chapter 9) or substrate affinity (eg, hexokinase and glucokinase) that adapt them to specific tissues or circumstances. Some isozymes may also enhance survival by providing a "backup" copy of an essential enzyme. Single-Molecule Enzymology the limited sensitivity of traditional enzyme assays necessitates the use of a large group, or ensemble, of enzyme molecules in order to produce measurable quantities of product. Recent advances in nanotechnology have made it possible to observe, usually by fluorescence microscopy, catalysis by individual enzyme and substrate molecules. Consequently, scientists can now measure the rate of single catalytic events and sometimes the individual steps in catalysis by a process called single-molecule enzymology (Figure 79). Drug Discovery Requires Enzyme Assays Suitable for "High-Throughput" Screening Enzymes constitute one of the primary classes of biomolecules targeted for the development of drugs and other therapeutic agents. Many antibiotics, for example, inhibit enzymes that are unique to microbial pathogens. The discovery of new drugs is greatly facilitated when a large number of potential pharmacophores can be assayed in a rapid, automated fashion- a process referred to as high-throughput screening. Highthroughput screening takes advantage of recent advances in robotics, optics, data processing, and microfluidics to conduct and analyze many thousands of simultaneous assays of the activity of a given enzyme. The most commonly used highthroughput screening devices employ 10100 L volumes in 96, 384, or 1536 well plastic plates and fully automated equipment capable of dispensing substrates, coenzymes, enzymes, and potential inhibitors in a multiplicity of combinations and concentrations. High-throughput screening is ideal for surveying the numerous products of combinatorial chemistry, the simultaneous synthesis of large libraries of chemical compounds that contain all possible combinations of a set of chemical precursors. Enzyme assays that produce a chromagenic or fluorescent product are ideal, since optical detectors are readily engineered to permit the rapid analysis of multiple samples. At present, the sophisticated equipment required for truly large numbers of assays is available only in pharmaceutical houses, government-sponsored laboratories, and research universities. Serum or other biologic samples to be tested are placed in a plastic microtiter plate, where the proteins adhere to the plastic surface and are immobilized. Any remaining absorbing areas of the well are then "blocked" by adding a nonantigenic protein such as bovine serum albumin. The presence and quantity of bound antibody is then determined by adding the substrate for the reporter enzyme. Enzyme-Linked Immunoassays the sensitivity of enzyme assays can be exploited to detect proteins that lack catalytic activity. Examples include pseudocholinesterase, lipoprotein lipase, and components of the cascade of events in blood clotting and clot dissolution. While these latter enzymes perform no physiologic function in plasma, their appearance or levels can assist in the diagnosis and prognosis of diseases and injuries affecting specific tissues. Following injury, the plasma concentration of a released enzyme may rise early or late, and may decline rapidly or slowly. Proteins from the cytoplasm tend to appear more rapidly than those from subcellular organelles. The speed with which enzymes and other proteins are removed from plasma varies with their susceptibility to proteolysis and permeability through renal glomeruli. Quantitative analysis of the activity of released enzymes or other proteins, typically in plasma or serum but also in urine or various cells, provides information concerning diagnosis, prognosis, and response to treatment. Assays of enzyme activity typically employ standard kinetic assays of initial reaction rates. For example, elevated blood levels of prostatic acid phosphatase are associated typically with prostate cancer, but also with certain other cancers and noncancerous conditions. Consequently, enzyme assay data must be considered together with other factors elicited through a comprehensive clinical examination. Factors to be considered in interpreting enzyme data include patient age, sex, prior history, possible drug use, and the sensitivity and the diagnostic specificity of the enzyme test. Spectrophotometric assays exploit the ability of a substrate or product to absorb light. In each case, the rate of change in optical density at 340 nm will be proportionate to the quantity of enzyme present. Many Enzymes Are Assayed by Coupling to a Dehydrogenase the assay of enzymes whose reactions are not accompanied by a change in absorbance or fluorescence is generally more difficult. In some instances, the product or remaining substrate can be transformed into a more readily detected compound. In other instances, the reaction product may have to be separated from unreacted substrate prior to measurement. An alternative strategy is to devise a synthetic substrate whose product absorbs light or fluoresces. For example, p-nitrophenyl phosphate is an artificial substrate for certain phosphatases and for chymotrypsin that does not absorb visible light. However, following hydrolysis, the resulting p-nitrophenylate anion absorbs light at 419 nm. Typically, a dehydrogenase whose substrate is the product of the enzyme of interest is added in catalytic excess. Enzymes Assist Diagnosis of Myocardial Infarction An enzyme useful for diagnostic enzymology should be relatively specific for the tissue or organ under study, should appear in the plasma or other fluid at a time useful for diagnosis (the "diagnostic window"), and should be amenable to automated assay. Enzymes that only appear in the plasma 12 h or more following injury are thus of limited utility. Tissue-specific expression of the H and M genes determines the relative proportions of each subunit in different tissues. Pattern A is serum from a patient with a myocardial infarct; B is normal serum; and C is serum from a patient with liver disease. Immunological measurement of plasma levels of cardiac troponins I and T provide sensitive and specific indicators of damage to heart muscle. The search for additional markers for heart disease, such as ischemia modified albumin, and the simultaneous assessment of a spectrum of diagnostic markers via proteomics, continues to be an active area of clinical research. Enzymes also can be employed in the clinical laboratory as tools for determining the concentration of critical metabolites. For example, glucose oxidase is frequently utilized to measure plasma glucose concentration. Enzymes are employed with increasing frequency as tools for the treatment of injury and disease. The isolation of an individual enzyme, particularly one present in low concentration, from among the thousands of proteins present in a cell can be extremely difficult. If the gene for the enzyme of interest has been cloned, it generally is possible to produce large quantities of its encoded protein in Escherichia coli or yeast. However, not all animal proteins can be expressed in active form in microbial cells, nor do microbes perform certain posttranslational processing tasks. For these reasons, a gene may be expressed in cultured animal cell systems employing the baculovirus expression vector to transform cultured insect cells. The gene of interest is linked to an oligonucleotide sequence that encodes a carboxyl or amino terminal extension to the encoded protein. The resulting modified protein, termed a fusion protein, contains a domain tailored to interact with a specific affinity support. One popular approach is to attach an oligonucleotide that encodes six consecutive histidine residues. The expressed "His tag" protein binds to chromatographic supports that contain an immobilized divalent metal ion such as Ni2+. Fusion proteins also often encode a cleavage site for a highly specific protease such as thrombin in the region that links the two portions of the protein. Specific proteases can then remove affinity "tags" and generate the native enzyme. Site-Directed Mutagenesis Provides Mechanistic Insights Once the ability to express a protein from its cloned gene has been established, it is possible to employ site-directed mutagenesis to change specific aminoacyl residues by altering their codons. Used in combination with kinetic analyses and x-ray crystallography, this approach facilitates identification of the specific roles of given aminoacyl residues in substrate binding and catalysis. For example, the inference that a particular aminoacyl residue functions as a general acid can be tested by replacing it with an aminoacyl residue incapable of donating a proton. Sundaresan V, Abrol R: Towards a general model for proteinsubstrate stereoselectivity. Urich T et al: X-ray structure of a self-compartmentalizing sulfur cycle metalloenzyme. Organic and inorganic prosthetic groups, cofactors, and coenzymes play important roles in catalysis. Aminoacyl residues that participate in catalysis are highly conserved among all classes of a given enzyme. Substrates and enzymes induce mutual conformational changes in one another that facilitate substrate recognition and catalysis. The catalytic activity of enzymes reveals their presence, facilitates their detection, and provides the basis for enzymelinked immunoassays. Combinatorial chemistry generates extensive libraries of potential enzyme activators and inhibitors that can be tested by high-throughput screening. Assay of plasma enzymes aids diagnosis and prognosis, for example, of myocardial infarction. Restriction endonucleases facilitate diagnosis of genetic diseases by revealing restriction fragment length polymorphisms. A complete, balanced set of enzyme activities is of fundamental importance for maintaining homeostasis. An understanding of enzyme kinetics, thus, is important to understanding how physiologic stresses such as anoxia, metabolic acidosis or alkalosis, toxins, and pharmacologic agents affect that balance. Kinetic analysis can reveal the number and order of the individual steps by which enzymes transform substrates into products. Together with site-directed mutagenesis and other techniques that probe protein structure, kinetic analyses can reveal details of the catalytic mechanism of a given enzyme. The involvement of enzymes in virtually all physiologic processes makes them the targets of choice for drugs that cure or ameliorate human disease. Applied enzyme kinetics represents the principal tool by which scientists identify and characterize therapeutic agents that selectively inhibit the rates of specific enzyme-catalyzed processes. Enzyme kinetics thus plays a central and critical role in drug discovery and comparative pharmacodynamics, as well as in elucidating the mode of action of drugs. The term "products" is, however, often used to designate the reactants whose formation is thermodynamically favored. Reactions for which thermodynamic factors strongly favor formation of the products to which the arrow points often are represented with a single arrow as if they were "irreversible": A+B P+Q (2) Unidirectional arrows are also used to describe reactions in living cells where the products of reaction (2) are immediately consumed by a subsequent enzyme-catalyzed reaction. The rapid removal of product P or Q therefore effectively precludes occurrence of the reverse reaction, rendering equation (2) functionally irreversible under physiologic conditions. G for a chemical reaction equals the sum of the free energies of formation of the reaction products Gp minus the sum of the free energies of formation of the substrates Gs. G0 denotes the change in free energy that accompanies transition from the standard state, one-molar concentrations of substrates and products, to equilibrium. A more useful biochemical term is G0, which defines G0 at a standard state of 10-7 M protons, pH 7.
This integration symptoms stomach ulcer purchase cefuroxime 500 mg, which is a form of recombination medicine interaction checker purchase cefuroxime 250mg amex, occurs by the mechanism illustrated in Figure 3511 medications epilepsy cheap cefuroxime 250mg with visa. The site at which the bacteriophage genome integrates or recombines with the bacterial genome is chosen by one of two mechanisms symptoms webmd trusted cefuroxime 250 mg. The examples given show the locations of the crossover regions between amino acid residues symptoms congestive heart failure generic cefuroxime 500 mg fast delivery. That is medicine q10 effective cefuroxime 500mg, the 5-nontranslated region, the coding region without intron representation, and the 3 poly(A) tail are all present contiguously. The only recognized mechanism this reverse transcript could have used to integrate into the genome would have been a transposition event. In fact, these "processed genes" have short terminal repeats at each end, as do known transposed sequences in lower organisms. In the absence of their transcription and thus genetic selection for function, many of the processed genes have been randomly altered through evolution so that they now contain nonsense codons that preclude their ability to encode a functional, intact protein (see Chapter 37). Similar sequences on homologous or nonhomologous chromosomes may occasionally pair up and eliminate any mismatched sequences between them. These are detectable by Giemsa staining of the chromosomes of cells replicated for two cycles in the presence of bromodeoxyuridine. Of course, these sister chromatid exchanges (Figure 3512) have no genetic consequence as long as the exchange is the result of an equal crossover. About 30 proteins are involved in the replication of the E coli chromosome, and this process is more complex in eukaryotic organisms. This enzyme has multiple catalytic activities, a complex structure, and a requirement for the triphosphates of the four deoxyribonucleosides of adenine, guanine, cytosine, and thymine. Although this entire process is not completely understood in eukaryotic cells, replication has been quite precisely described in prokaryotic cells, and the general principles are the same in both. The major steps are listed in Table 354, illustrated in Figure 3513, and discussed, in sequence, below. A number of proteins, most with specific enzymatic action, are involved in this process (Table 355). Immunoglobulin Genes Rearrange In mammalian cells, some interesting gene rearrangements occur normally during development and differentiation. In bacteriophage, the ori is bound by the -encoded O protein to four adjacent sites. In uninfected E coli, this function is provided by a complex of dnaB helicase and the dnaC protein. In phageinfected E coli, the phage protein P binds to dnaB and the P/ dnaB complex binds to ori by interacting with the O protein. Three E coli heat shock proteins (dnaK, dnaJ, and GrpE) cooperate to remove the P protein and activate the dnaB helicase. In this way, the replication of the phage is accomplished at the expense of replication of the host E coli cell. These share three important properties: (1) chain elongation, (2) processivity, and (3) proofreading. Chain elongation accounts for the rate (in nucleotides per second; ntd/s) at which polymerization occurs. Processivity is an expression of the number of nucleotides added to the nascent chain before the polymerase disengages from the template. Of all polymerases, it catalyzes the highest rate of chain elongation and is the most processive. Several Okazaki fragments (up to a thousand) must be sequentially synthesized for each replication fork. The helicase associates with the primase to afford the latter proper access to the template. As the synthesis of an Okazaki fragment is completed and the polymerase is released, a new primer has been synthesized. When an adenine deoxyribonucleoside monophosphoryl moiety is in the template position, a thymidine triphosphate will enter and its phosphate will be attacked by the 3-hydroxyl group of the deoxyribonucleoside monophosphoryl most recently added to the polymer. The single enzyme replicates one strand ("leading strand") in a continuous manner in the 5 to 3 direction, with the same overall forward direction. The entire mammalian genome replicates in approximately 9 h, the average period required for formation of a tetraploid genome from a diploid genome in a replicating cell. If a mammalian genome (3 Ч 109 bp) replicated at the same rate as bacteria (ie, 3 Ч 105 bp/min) from but a single ori, replication would take over 150 h! Second, replication proceeds from multiple origins in each chromosome (a total of as many as 100 in humans). Thus, replication occurs in both directions along all of the chromosomes, and both strands are replicated simultaneously. However, it is clear that initiation is regulated both spatially and temporally, since clusters of adjacent sites initiate replication synchronously. These molecules stabilize the single-stranded structure as the replication fork progresses. The stabilizing proteins bind cooperatively and stoichiometrically to the single strands without interfering with the abilities of the nucleotides to serve as templates (Figure 3513). In addition to separating the two strands of the double helix, there must be an unwinding of the molecule (once every 10 nucleotide pairs) to allow strand separation. The swivel function is provided by specific enzymes that introduce "nicks" in one strand of the unwinding double helix, thereby allowing the unwinding process to proceed. The nicks are quickly resealed without requiring energy input, because of the formation of a high-energy covalent bond between the nicked phosphodiester backbone and the nicking-sealing enzyme. The bidirectional replication and the proposed positions of unwinding proteins at the replication forks are depicted. These reactions are facilitated through the actions of histone chaperone proteins working in concert with chromatin remodeling complexes. A left-handed toroidal (solenoidal) supercoil, at left, will convert to a right-handed interwound supercoil, at right, when the cylindric core is removed. Such a transition is analogous to that which occurs when nucleosomes are disrupted by the high salt extraction of histones from chromatin. This is usually temporally separated from the mitotic, or M phase, by nonsynthetic periods referred to as gap 1 (G1) and gap 2 (G2), occurring before and after the S phase, respectively (Figure 3520). All eukaryotic cells have gene products that govern the transition from one phase of the cell cycle to another. The cyclins are a family of proteins whose concentration increases and decreases throughout the cell cycle-thus their name. These two kinases are also synthesized during G1 in cells undergoing active division. The thickness of the various colored lines is indicative of the extent of activity. Many of the cancer-causing viruses (oncoviruses) and cancer-inducing genes (oncogenes) are capable of alleviating or disrupting the apparent restriction that normally controls the entry of mammalian cells from G1 into the S phase. In this context it is noteworthy that the bcl oncogene associated with B cell lymphoma appears to be the cyclin D1 gene. In some cases, if the damage cannot be repaired, such cells undergo programmed cell death (apoptosis). It seems that once chromatin has been replicated, it is marked so as to prevent its further replication until it again passes through mitosis. In general, a given pair of chromosomes will replicate simultaneously and within a fixed portion of the S phase upon every replication. If about 1016 cell divisions occur in a lifetime and 1010 mutations per base pair per cell generation escape repair, there may eventually be as many as one mutation per 106 bp in the genome. The defective region in one strand can be returned to its original form by relying on the complementary information stored in the unaffected strand. For example, a C could be inserted opposite an A, or the polymerase could slip or stutter and insert two or more extra unpaired bases. As described in Chapter 34, the major responsibility for the fidelity of replication resides in the specific pairing of nucleotide bases. Proper pairing is dependent upon the presence of the favored tautomers of the purine and pyrimidine nucleotides, but the equilibrium whereby one tautomer is more stable than another is only about 104 or 105 in favor of that with the greater stability. Although this is not favorable enough to ensure the high fidelity that is necessary, favoring of the preferred tautomers-and thus of the proper base pairing-could be ensured by monitoring the base pairing twice. Such double monitoring does appear to occur in both bacterial and mammalian systems: once at the time of insertion of the deoxyribonucleoside triphosphates, and later by a follow-up energyrequiring mechanism that removes all improper bases which may occur in the newly formed strand. The analogous mammalian enzymes (and) do not seem to possess such a nuclease proofreading function. Replication errors, even with a very efficient repair system, lead to the accumulation of mutations. This difference allows the repair enzymes to identify the strand that contains the errant nucleotide which requires replacement. This defect is then filled in by normal cellular enzymes according to base pairing rules. In E coli, three proteins (Mut S, Mut C, and Mut H) are required for recognition of the mutation and nicking of the strand. The process is somewhat more complicated in mammalian cells, as about six proteins are involved in the first steps. That is, the cancer cells had a microsatellite of a length different from that found in the normal cells of the individual. Specific enzymes recognize a depurinated site and replace the appropriate purine directly, without interruption of the phosphodiester backbone. This removal marks the site of the defect and allows an apurinic or apyrimidinic endonuclease to excise the abasic sugar. An endonuclease cuts the backbone near the defect; then, after an endonuclease removes a few bases, the defect is filled in by the action of a repair polymerase and the strand is rejoined by a ligase. This process, which involves more gene products than the two other types of repair, essentially involves the hydrolysis of two phosphodiester bonds on the strand containing the defect. A special excision nuclease (exinuclease), consisting of at least three subunits in E coli and 16 polypeptides in humans, accomplishes this task. In eukaryotic cells the enzymes cut between the third to fifth phosphodiester bond 3 from the lesion, and on the 5 side the cut is somewhere between the twenty-first and twenty-fifth bonds. The clinical syndrome includes marked sensitivity to sunlight (ultraviolet) with subsequent formation of multiple skin cancers and premature death. Cells cultured from patients with xeroderma pigmentosum exhibit low activity for the nucleotide excision-repair process. Double-Strand Break Repair the repair of double-strand (ds) breaks is part of the physiologic process of immunoglobulin gene rearrangement. Some chemotherapeutic agents destroy cells by causing ds breaks or preventing their repair. Patients with Fanconi anemia, an autosomal recessive anemia characterized also by an increased frequency of cancer and by chromosomal instability, probably have defective repair of crosslinking damage. All three of these clinical syndromes are associated with an increased frequency of cancer. The four specific steps at which this monitoring occurs have been termed checkpoint controls. If problems are detected at any of these checkpoints, progression through the cycle is interrupted and transit through the cell cycle is halted until the damage is repaired. Increased levels of p53 activate transcription of an ensemble of genes that collectively serve to delay transit through the cycle. In this case, p53 induces the activation of a collection of genes that induce apoptosis. It may come as no surprise, then, that p53 is one of the most frequently mutated genes in human cancers. Additional research into the mechanisms of checkpoint control will prove invaluable for the development of effective anticancer therapeutic options. Thus, three critical cellular processes may be linked through use of common proteins. There is also good evidence that some repair enzymes are involved in gene rearrangements that occur normally. Histones are subject to an extensive array of dynamic covalent modifications that have important regulatory consequences. Each strand of the double helix is replicated simultaneously but by somewhat different mechanisms. The lagging strand is replicated discontinuously, in short pieces of 150250 nucleotides, in the 3 to 5 direction. The entire process takes about 9 h in a typical cell and only occurs during the S phase of the cell cycle. Sullivan et al: Determining centromere identity: cyclical stories and forking paths. The general steps required to synthesize the primary transcript are initiation, elongation, and termination. It is also how differentiated cell structures and functions are established and maintained. Though not shown in Figure 361 there are instances of genes embedded within other genes. In prokaryotes, this can represent the product of several contiguous genes; in mammalian cells, it usually represents the product of a single gene. The nucleotide in the promoter adjacent to the transcription initiation site in the upstream direction is designated -1, and these negative numbers increase as the sequence proceeds upstream, away from the initiation site. This provides a conventional way of defining the location of regulatory elements in the promoter. This homology has been shown recently to extend to the level of three-dimensional structures. The enzyme polymerizes the ribonucleotides in the specific sequence dictated by the template strand and interpreted by WatsonCrick base-pairing rules. Thus, the proximal end of the transcribed gene has short transcripts attached to it, while much longer transcripts are attached to the distal end of the gene.
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A randomized trial comparing graduated compression stockings alone or graduated compression stockings plus intermittent pneumatic compression with control. Arch Intern Med 1989; 149:679681 Agu O, Hamilton G, Baker D: Graduated compression stockings in the prevention of venous thromboembolism. Chest 2012; 141(Suppl 2):7S47S Basso N, Bagarani M, Materia A, et al: Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients. Cook D, Guyatt G, Marshall J, et al: A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Lin P, Chang C, Hsu P, et al: the efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: A meta-analysis. Pongprasobchai S, Kridkratoke S, Nopmaneejumruslers C: Proton pump inhibitors for the prevention of stress-related mucosal disease in critically-ill patients: A meta-analysis. Alhazzani W, Alshahrani M, Moayyedi P, et al: Stress ulcer prophylaxis in critically ill patients: Review of the evidence. Chiarelli A, Enzi G, Casadei A, et al: Very early nutrition supplementation in burned patients. Chuntrasakul C, Siltharm S, Chinswangwatanakul V, et al: Early nutritional support in severe traumatic patients. Kompan L, Kremzar B, Gadzijev E, et al: Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Pupelis G, Selga G, Austrums E, et al: Jejunal feeding, even when instituted late, improves outcomes in patients with severe pancreatitis and peritonitis. Kompan L, Vidmar G, Spindler-Vesel A, et al: Is early enteral nutrition a risk factor for gastric intolerance and pneumonia? Gramlich L, Kichian K, Pinilla J, et al: Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? Dhaliwal R, Jurewitsch B, Harrietha D, et al: Combination enteral and parenteral nutrition in critically ill patients: Harmful or beneficial? Bertolini G, Iapichino G, Radrizzani D, et al: Early enteral immunonutrition in patients with severe sepsis: Results of an interim analysis of a randomized multicentre clinical trial. Caparrуs T, Lopez J, Grau T: Early enteral nutrition in critically ill patients with a high-protein diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet. Jiang H, Chen W, Hu W, et al: [The impact of glutamine-enhanced enteral nutrition on clinical outcome of patients with critical illness: A systematic review of randomized controlled trials]. Current evidence and ongoing trials on the use of glutamine in critically-ill patients and patients undergoing surgery. 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Kumar A, Zarychanski R, Pinto R, et al; Canadian Critical Care Trials Group H1N1 Collaborative: Critically ill patients with 2009 influenza A(H1N1) infection in Canada. Lуpez-Herce Cid J, Bustinza Arriortъa A, Alcaraz Romero A, et al: [Treatment of septic shock with continuous plasmafiltration and hemodiafiltration]. Muntean W: Fresh frozen plasma in the pediatric age group and in congenital coagulation factor deficiency. Sбnchez Miralles A, Reig Sбenz R, Marco Vera P, et al: [Abnormalities in coagulation and fibrinolysis in septic shock with purpura]. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force. Schцtt U, Bjцrsell-Ostling E: Sonoclot coagulation analysis and plasma exchange in a case of meningococcal septicaemia. Mok Q, Butt W: the outcome of children admitted to intensive care with meningococcal septicaemia. Busund R, Koukline V, Utrobin U, et al: Plasmapheresis in severe sepsis and septic shock: A prospective, randomised, controlled trial. Krishnan J, Morrison W: Airway pressure release ventilation: A pediatric case series. Ben Jaballah N, Khaldi A, Mnif K, et al: High-frequency oscillatory ventilation in pediatric patients with acute respiratory failure. Pediatr Crit Care Med 2006; 7:362367 February 2013 Volume 41 Number 2 634 Crit Care 2011; 15:R44 Vlasselaers D, Milants I, Desmet L, et al: Intensive insulin therapy for patients in paediatric intensive care: A prospective, randomised controlled study. Phillip Dellinger, (Co-Chair); Rui Moreno (Co-Chair); Leanne Aitken,1 Hussain Al Rahma,2 Derek C. Douglas, Bin Du,5 Seitaro Fujishima, Satoshi Gando,6 Herwig Gerlach, Caryl Goodyear-Bruch,7 Gordon Guyatt, Jan A. Kleinpell,1 Shin Ok Koh,13 Joji Kotani, Mitchell Levy,14 Flavia Machado,15 John Marini, John C. Randolph, Konrad Reinhart,21 Jordi Rello, Ederlon Resende,22 Andrew Rhodes,23 Emanuel P. Thompson, Paolo Biban, Alan Duncan, Cristina Mangia, Niranjan Kissoon, and Joseph A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. This, for many of you, will be the doorway into your professional life of service and leadership in a profession of your choosing. Barclay College offers you a rigorous academic setting that is focused in a Bible-centered, Christian faith community. One of the strengths of Barclay College is our rural setting that requires students to engage with other students, faculty, staff, and the larger Haviland community. The achievement of a college degree is a significant step in the lives of our students and their families. But beyond the tangible, at Barclay College the benefits of your college experience go far beyond a degree. Graduates remark that the relationships they experience here are life-long connections. It is here that students find support for both academic pursuits and their spiritual growth. It is here that the realization that each individual is uniquely and wonderfully made comes into focus. God has gifted each student with skills, gifts, and talents that lend each one to a unique contribution to the Barclay community, but more importantly, to the world. It is a call to be salt and light to a world that needs to meet the incarnational Jesus. So I welcome each of you to a special place where you will take a profound, personal journey. D President 2 First time students, transfer students, and returning students, welcome, we are glad that you are here and that you have chosen to be a part of the Barclay College family. We are excited to be a part of the transformational journey as students discover gifts, and strengths, and find their places of service in the Kingdom of God. Some may wonder how they managed to find this quaint little campus located in perhaps one of the friendliest and tiniest of college towns in the Midwest. You have probably heard the expression, "Great things often come from small beginnings. Lives have been changed, and generations have been impacted by the Word of God, and by the love of God shared and lived throughout this community. In the application process, you have affirmed that you are set on a journey of faith in Jesus Christ. Additionally, former employers, teachers, ministers, and coaches have given character references because they believe in you. We know that God has a plan for you, and we believe that God has you here for a reason.
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