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Metabolic Requirements (metabolic + requirement)
Selected AbstractsQuantitative modeling of triacylglycerol homeostasis in yeast , metabolic requirement for lipolysis to promote membrane lipid synthesis and cellular growthFEBS JOURNAL, Issue 22 2008Jürgen Zanghellini Triacylglycerol metabolism in Saccharomyces cerevisiae was analyzed quantitatively using a systems biological approach. Cellular growth, glucose uptake and ethanol secretion were measured as a function of time and used as input for a dynamic flux-balance model. By combining dynamic mass balances for key metabolites with a detailed steady-state analysis, we trained a model network and simulated the time-dependent degradation of cellular triacylglycerol and its interaction with fatty acid and membrane lipid synthesis. This approach described precisely, both qualitatively and quantitatively, the time evolution of various key metabolites in a consistent and self-contained manner, and the predictions were found to be in excellent agreement with experimental data. We showed that, during pre-logarithmic growth, lipolysis of triacylglycerol allows for the rapid synthesis of membrane lipids, whereas de novo fatty acid synthesis plays only a minor role during this growth phase. Progress in triacylglycerol hydrolysis directly correlates with an increase in cell size, demonstrating the importance of lipolysis for supporting efficient growth initiation. [source] Adaptive significance of food income in European snakes: body size is related to prey energeticsBIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 2 2010MARCO A. L. ZUFFI Feeding strategies and diet patterns have been extensively investigated in vertebrates and, more specifically, in snakes. Although it has been hypothesized that prey species may differ in terms of energy content, almost no theoretical or practical study has been carried out to determine actual nutritional values of the common prey types of wild snakes. Our model taxa were a selection of widely distributed and well known European snake species, which have all been studied in depth: approximately 76% of their diet is composed of mammals, reptiles, and insects. We therefore selected a single model species for each of these categories and proceeded with the analyses. Nutritional values were determined using a standard procedure: lizards and mice were richer in proteins than insects (crickets); insects and mice were richer in lipids than lizards, and mice and crickets have a higher energy content than lizards; lizards were rich in ashes. We then applied our experimental results to a selected sample of European terrestrial snakes (11 populations, ten species, seven genera, two families) characterized by different body size (50,160 cm total length) and reproductive strategies (oviparous versus viviparous), aiming to correlate these parameters with patterns of energy income. A direct relationship was found between body mass/body length ratio (BCI, body condition index) and meal energetics: the higher the BCI, the higher was the metabolic requirement, whereas BCI was independent of species or of reproductive system effect. Large-sized snakes thus need a highly diversified and more energy-rich diet than smaller snakes, supporting previous hypotheses. The simple applicability of this method could be of valuable support in further comparative research work, reducing experimental costs and stimulating further ecological, behavioural, and, possibly, phylogenetic comparisons. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 100, 307,317. [source] Forelimb postischaemic reactive hyperaemia is impaired by hypotensive low body negative pressure in healthy subjectsCLINICAL PHYSIOLOGY AND FUNCTIONAL IMAGING, Issue 2 2006Marc Charles Summary Local metabolic conditions adapt blood supply to metabolic requirement by a direct effect on vascular smooth muscles and indirectly by modulating sympathetic vasoconstrictor effectiveness. During exercise, sympathetic nervous activity could in turn interfere on local metabolic control of vascular tone and restrain blood flow to active muscles. In order to investigate that interaction non-invasively, we measured postischaemic reactive hyperaemia (RH) in the forelimb of eight healthy young men (22·7 ± 2·1 years) at rest and during two levels of sympathetic stimulation using low body negative pressure (LBNP ,15 and ,30 mmHg). During every stages, RH was measured after 40, 60, 90 and 180 s of arterial occlusion, respectively. In control conditions, RH rose with duration of ischaemia (18·9, 24·2, 30·4, 33·1 ml min,1 per 100 ml,1 for 40, 60, 90 and 180 s of ischaemia, respectively). During non-hypotensive LBNP (,15 mmHg) sympathetic activation was associated with decreased forelimb blood flow (6·4 ± 0·9 versus 3·9 ± 0·6 ml min,1 per 100 ml,1, P<0·01), but RH were not significantly different from control conditions. During hypotensive tachycardia LBNP (,30 mmHg), RH were significantly lower than under the previous LBNP stage. This fall in RH was greater after the shortest gap of ischaemia and tapered off as arterial occlusion gap increased (,22·3, ,13·1, ,10·5 and ,8·7% for 40, 60, 90 and 180 s of ischaemia, respectively). These results suggested that vascular tone adaptation to local metabolic conditions was modified by sympathetic nervous activation. This was particularly marked when an hypotensive-mediated sympathetic stimulation was opposed to short gaps of ischaemia. [source] Myocardial Perfusion As Assessed by Positron Emission Tomography During Long-Term Mechanical Circulatory SupportCONGESTIVE HEART FAILURE, Issue 2 2006George V. Letsou MD Although mechanical circulatory support (MCS) can improve myocardial function in patients with advanced heart failure, its effects on relative myocardial perfusion are unclear. Using positron emission tomographic imaging techniques, the authors assessed relative myocardial perfusion in patients with ischemic or idiopathic cardiomyopathy who were receiving chronic MCS with a left ventricular assist device (pulsatile HeartMate [n=2] [Thoratec Corporation, Pleasanton, CA] or nonpulsatile Jarvik 2000 [n=4] [Jarvik Heart, Inc., New York, NY]). Relative myocardial perfusion was compared at lower and higher levels of MCS (50 vs. 100,110 ejections/min for the HeartMate and 8000 vs. 12,000 rpm for the Jarvik 2000). The size and severity of perfusion defects at rest and after dipyridamole stress were measured objectively and subjectively by computer algorithms and visual inspection, respectively. Relative myocardial perfusion increased >5% from baseline in only one of six patients when MCS was increased. No change in relative myocardial perfusion of >5% was seen in any of the other five patients, even after subsequent dipyridamole stress positron emission tomographic imaging. These pilot study findings suggest that the decreased metabolic requirements induced by ventricular unloading correspondingly decreased blood flow requirements to physiologically inactive myocardium. [source] A pragmatic approach to estimating the distributions and spatial requirements of the medium- to large-sized mammals in the Cape Floristic Region, South AfricaDIVERSITY AND DISTRIBUTIONS, Issue 1-2 2001A. F. Boshoff Conservation planning in the Cape Floristic Region, a recognized world plant diversity hotspot, required systematic information on the estimated distributions and spatial requirements of the medium- to large-sized mammals within each of 102 Broad Habitat Units delineated according to key biophysical parameters. As a consequence of a general lack of data, we derived a pragmatic approach for obtaining estimates of these two parameters. Distribution estimates were based on a combination of a literature survey (with emphasis on early texts) and the ecological requirements of the species. Spatial requirement estimates were derived from a simple spreadsheet model that is based on forage availability estimates and the metabolic requirements of the mammals in question. Our analysis incorporated adaptations of the agriculture-based Large Stock Unit or Animal Unit approach. The predictions of the model were tested by comparing them with actual density data. The outcomes provided realistic estimates of the two parameters. However, they should be considered as testable hypotheses and the concept of adaptive management , or management by hypothesis , must apply. Examples of the outcomes are provided in the form of maps and tables. [source] Biological significance of metals partitioned to subcellular fractions within earthworms (Aporrectodea caliginosa),ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2006Martina G. Vijver Abstract Metal ions in excess of metabolic requirements are potentially toxic and must be removed from the vicinity of important biological molecules to protect organisms from adverse effects. Correspondingly, metals are sequestrated in various forms, defining the accumulation pattern and the magnitude of steady-state levels reached. To investigate the subcellular fractions over which Ca, Mg, Fe, Cu, Zn, Cd, Pb, Ni, and As are distributed, earthworms (Aporrectodea caliginosa) collected from the field were analyzed by isolating metal-rich granules and tissue fragments from intracellular microsomal and cytosolic fractions (i.e., heat-stable proteins and heat-denatured proteins). The fractions showed metal-specific binding capacity. Cadmium was mainly retrieved from the protein fractions. Copper was equally distributed over the protein fraction and the fraction comprising tissue fragments, cell membranes, and intact cells. Zinc, Ca, Mg, and As were mainly found in this fraction as well. Lead, Fe, and Ni were mainly isolated from the granular fraction. To study accumulation kinetics in the different fractions, three experiments were conducted in which earthworms were exposed to metal-spiked soil and a soil contaminated by anthropogenic inputs and, indigenous earthworms were exposed to field soils. Although kinetics showed variation, linear uptake and steady-state types of accumulation patterns could be understood according to subcellular compartmentalization. For risk assessment purposes, subcellular distribution of metals might allow for a more precise estimate of effects than total body burden. Identification of subcellular partitioning appears useful in determining the biological significance of steady-state levels reached in animals. [source] Gene and Cell Therapy for Heart DiseaseIUBMB LIFE, Issue 2 2002Regina M. Graham Abstract Heart disease is the most common cause of morbidity and mortality in Western society and the incidence is projected to increase significantly over the next few decades as our population ages. Heart failure occurs when the heart is unable to pump blood at a rate to commensurate with tissue metabolic requirements and represents the end stage of a variety of pathological conditions. Causes of heart failure include ischemia, hypertension, coronary artery disease, and idiopathic dilated cardiomyopathy. Hypertension and ischemia both cause infarction with loss of function and a consequent contractile deficit that promotes ventricular remodeling. Remodeling results in dramatic alterations in the size, shape, and composition of the walls and chambers of the heart and can have both positive and negative effects on function. In 30-40% of patients with heart failure, left ventricular systolic function is relatively unaffected while diastolic dysfunction predominates. Recent progress in our understanding of the molecular and cellular bases of heart disease has provided new therapeutic targets and led to novel approaches including the delivery of proteins, genes, and cells to replace defective or deficient components and restore function to the diseased heart. This review focuses on three such strategies that are currently under development: (a) gene transfer to modulate contractility, (b) therapeutic angiogenesis for the treatment of ischemia, and (c) embryonic and adult stem cell transfer to replace damaged myocardium. [source] Functional morphology of the gills of the shortfin mako, Isurus oxyrinchus, a lamnid sharkJOURNAL OF MORPHOLOGY, Issue 8 2010Nicholas C. Wegner Abstract This study examines the functional gill morphology of the shortfin mako, Isurus oxyrinchus, to determine the extent to which its gill structure is convergent with that of tunas for specializations required to increase gas exchange and withstand the forceful branchial flow induced by ram ventilation. Mako gill structure is also compared to that of the blue shark, Prionace glauca, an epipelagic species with lower metabolic requirements and a reduced dependence on fast, continuous swimming to ventilate the gills. The gill surface area of the mako is about one-half that of a comparably sized tuna, but more than twice that of the blue shark and other nonlamnid shark species. Mako gills are also distinguished from those of other sharks by shorter diffusion distances and a more fully developed diagonal blood-flow pattern through the gill lamellae, which is similar to that found in tunas. Although the mako lacks the filament and lamellar fusions of tunas and other ram-ventilating teleosts, its gill filaments are stiffened by the elasmobranch interbranchial septum, and the lamellae appear to be stabilized by one to two vascular sacs that protrude from the lamellar surface and abut sacs of adjacent lamellae. Vasoactive agents and changes in vascular pressure potentially influence sac size, consequently effecting lamellar rigidity and both the volume and speed of water through the interlamellar channels. However, vascular sacs also occur in the blue shark, and no other structural elements of the mako gill appear specialized for ram ventilation. Rather, the basic elasmobranch gill design and pattern of branchial circulation are both conserved. Despite specializations that increase mako gill area and efficacy relative to other sharks, the basic features of the elasmobranch gill design appear to have limited selection for a larger gill surface area, and this may ultimately constrain mako aerobic performance in comparison to tunas. J. Morphol. 271:937,948, 2010. © 2010 Wiley-Liss, Inc. [source] Gill morphometrics in relation to gas transfer and ram ventilation in high-energy demand teleosts: Scombrids and billfishesJOURNAL OF MORPHOLOGY, Issue 1 2010Nicholas C. Wegner Abstract This comparative study of the gill morphometrics in scombrids (tunas, bonitos, and mackerels) and billfishes (marlins, swordfish) examines features of gill design related to high rates of gas transfer and the high-pressure branchial flow associated with fast, continuous swimming. Tunas have the largest relative gill surface areas of any fish group, and although the gill areas of non-tuna scombrids and billfishes are smaller than those of tunas, they are also disproportionally larger than those of most other teleosts. The morphometric features contributing to the large gill surface areas of these high-energy demand teleosts include: 1) a relative increase in the number and length of gill filaments that have, 2) a high lamellar frequency (i.e., the number of lamellae per length of filament), and 3) lamellae that are long and low in profile (height), which allows a greater number of filaments to be tightly packed into the branchial cavity. Augmentation of gill area through these morphometric changes represents a departure from the general mechanism of area enhancement utilized by most teleosts, which lengthen filaments and increase the size of the lamellae. The gill design of scombrids and billfishes reflects the combined requirements for ram ventilation and elevated energetic demands. The high lamellar frequencies and long lamellae increase branchial resistance to water flow which slows and streamlines the ram ventilatory stream. In general, scombrid and billfish gill surface areas correlate with metabolic requirements and this character may serve to predict the energetic demands of fish species for which direct measurement is not possible. The branching of the gill filaments documented for the swordfish in this study appears to increase its gill surface area above that of other billfishes and may allow it to penetrate oxygen-poor waters at depth. J. Morphol. 2010. © 2009 Wiley-Liss, Inc. [source] Chemical composition and in vitro starch digestibility of pigmented corn tortillaJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 13 2007Juan Pablo Hernández-Uribe Abstract BACKGROUND: Tortillas were prepared from two (blue and regular white) maize varieties and compared with regard to chemical composition and in vitro starch digestibility, i.e., available starch (AS), total (RS) and retrograde (RRS) resistant starch contents, amylolysis rate and predicted glycemic index (pGI). The impact of cold storage (4 °C) on digestibility was also investigated. RESULTS: Despite its higher protein and lipid contents, pigmented tortilla exhibited lower AS content than the white product. AS in both types of tortilla decreased during the first 2 days of storage, and remained stable thereafter. Blue tortilla had lower RS content (21 g kg,1 dry matter basis) than the white tortilla (30 g kg,1 dry matter basis). RS values were slightly higher in 2 day-stored tortillas than in their fresh counterparts. Although the RRS content in recently made white tortillas was greater than in the colored preparation, stored blue tortillas exhibited double RRS values compared with freshly baked samples. ,-Amylolysis of blue tortilla was slower than in the white sample. Consequently, blue tortilla exhibited a lower pGI value. pGI for the white tortilla decreased upon cold storage, a change that was not be observed for the colored preparation. CONCLUSION: Starch digestibility characteristics of blue tortilla make it suitable for people with special nutritional or metabolic requirements. Copyright © 2007 Society of Chemical Industry [source] The Effect of Diet on the Energy Budget of the Brown Sea Cucumber, Stichopus mollis (Hutton)JOURNAL OF THE WORLD AQUACULTURE SOCIETY, Issue 2 2009Kimberley H. Maxwell This study investigated the ability of the brown sea cucumber, Stichopus (Australostichopus) mollis, to grow on diets made from aquaculture waste. Weight-standardized rates (ingestion, assimilation, respiration, ammonia excretion, and fecal excretion) of small (juvenile), medium (mature), and large (mature) sea cucumbers were measured and energy budgets constructed to quantify their growth rates when offered three different diets at 14, 16, and 18 C. Three types of diet were offered: uneaten abalone food (diet A) and two types of abalone feces, one where abalone were fed 50% Macrocystis pyrifera and 50% Undaria pinnatifida macroalgae (diet B) and the other where abalone were fed 25% M. pyrifera, 25% U. pinnatifida, and 50% Adam & Amos Abalone Food, where the latter is an industry standard diet (diet C). The organic contents of the diets were much higher than natural sediments and varied such that diet A (76.40%) > diet B (54.50%) > diet C (37.00%). Diet had a significant effect on S. mollis ingestion rates, assimilation efficiencies, and consequently energy budgets and growth rates. Greater quantities of organic matter (OM) from diet A and diet B were ingested and assimilated by the sea cucumbers compared with the OM in diet C. The energy budgets indicated that after taking routine metabolism into account, all sizes of sea cucumbers had energy to allocate to growth when offered diet A and diet B, but only juveniles had energy to allocate to growth when offered diet C. Fecal excretion rates when offered diet A and diet C at 14 C were greater than those at 18 C, but neither was significantly different from that at 16 C. Ammonia excretion rates increased nonlinearly with temperature for small and medium sea cucumbers but not for large sea cucumbers. Weight-standardized respiration rates increased with temperature and unexpectedly with animal size, which may have been because of the narrow weight range of test animals biasing the results. These results suggest that industry standard type abalone waste lacks sufficient energy to meet the metabolic requirements of mature sea cucumbers but that growing juveniles on these wastes appears to be feasible and warrants further investigation. [source] Hypercapnia: what is the limit in paediatric patients?PEDIATRIC ANESTHESIA, Issue 7 2004A case of near-fatal asthma successfully treated by multipharmacological approach Summary We describe a case of prolonged severe hypercapnia with respiratory acidosis occurring during an episode of near-fatal asthma in an 8-year-old boy, followed by complete recovery. After admission to the intensive care unit, despite treatment with maximal conventional bronchodilatative therapy, the clinical picture deteriorated with evident signs of respiratory muscle fatigue. The child was sedated, intubated and mechanically ventilated. Magnesium sulphate, ketamine and sevoflurane were gradually introduced together with deep sedation, curarization and continuous bronchodilatative therapy. Ten hours after admission, arterial pCO2 reached 39 kPa (293 mmHg), pH was 6.77 and pO2 8.6 kPa (65 mmHg). Chest radiograph showed severe neck subcutaneous emphysema, with signs of mediastinal emphysema. No episode of haemodynamic instability was seen despite severe prolonged hypercapnia lasting more than 14 h. Oxygenation was maintained and successful recovery followed without neurological or cardiovascular sequelae. This case shows the cardiovascular and neurological tolerance of a prolonged period of supercarbia in a paediatric patient. The most important lesson to be learned is the extreme importance of maintaining adequate tissue perfusion and oxygenation during an asthma attack. The second lesson is that when conventional bronchodilators fail, the intensivist may resort to the use of drugs such as ketamine, magnesium sulphate and inhalation anaesthesia. In this context deep sedation and curarization are important not only to improve oxygenation, but also to reduce cerebral metabolic requirements. [source] Early reproductive maturity among Pumé foragers: Implications of a pooled energy model to fast life historiesAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 4 2009Karen L. Kramer Life history theory places central importance on relationships between ontogeny, reproduction, and mortality. Fast human life histories have been theoretically and empirically associated with high mortality regimes. This relationship, however, poses an unanswered question about energy allocation. In epidemiologically stressful environments, a greater proportion of energy is allocated to immune function. If growth and maintenance are competing energetic expenditures, less energy should be available for growth, and the mechanism to sustain rapid maturation remains unclear. The human pattern of extended juvenile provisioning and resource sharing may provide an important source of variation in energy availability not predicted by tradeoff models that assume independence at weaning. We consider a group of South American foragers to evaluate the effects that pooled energy budgets may have on early reproduction. Despite growing up in an environment with distinct seasonal under-nutrition, harsh epidemiological conditions, and no health care, Pumé girls mature quickly and initiate childbearing in their midteens. Pooled energy budgets compensate for the low productivity of girls not only through direct food transfers but importantly by reducing energy they would otherwise expend in foraging activities to meet metabolic requirements. We suggest that pooled energy budgets affect energy availability at both extrinsic and intrinsic levels. Because energy budgets are pooled, Pumé girls and young women are buffered from environmental downturns and can maximize energy allocated to growth completion and initiate reproduction earlier than a traditional bound-energy model would predict. Am. J. Hum. Biol., 2009. © 2009 Wiley-Liss, Inc. [source] Heterotrophy in Tropical Scleractinian CoralsBIOLOGICAL REVIEWS, Issue 1 2009Fanny Houlbrèque Abstract The dual character of corals, that they are both auto- and heterotrophs, was recognized early in the twentieth Century. It is generally accepted that the symbiotic association between corals and their endosymbiotic algae (called zooxanthellae) is fundamental to the development of coral reefs in oligotrophic tropical oceans because zooxanthellae transfer the major part of their photosynthates to the coral host (autotrophic nutrition). However, numerous studies have confirmed that many species of corals are also active heterotrophs, ingesting organisms ranging from bacteria to mesozooplankton. Heterotrophy accounts for between 0 and 66% of the fixed carbon incorporated into coral skeletons and can meet from 15 to 35% of daily metabolic requirements in healthy corals and up to 100% in bleached corals. Apart from this carbon input, feeding is likely to be important to most scleractinian corals, since nitrogen, phosphorus, and other nutrients that cannot be supplied from photosynthesis by the coral's symbiotic algae must come from zooplankton capture, particulate matter or dissolved compounds. A recent study showed that during bleaching events some coral species, by increasing their feeding rates, are able to maintain and restore energy reserves. This review assesses the importance and effects of heterotrophy in tropical scleractinian corals. We first provide background information on the different food sources (from dissolved organic matter to meso- and macrozooplankton). We then consider the nutritional inputs of feeding. Finally, we review feeding effects on the different physiological parameters of corals (tissue composition, photosynthesis and skeletal growth). [source] Metabolic flux analysis for recombinant protein production by Pichia pastoris using dual carbon sources: Effects of methanol feeding rateBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2010Eda Çelik Abstract The intracellular metabolic fluxes through the central carbon pathways in the bioprocess for recombinant human erythropoietin (rHuEPO) production by Pichia pastoris (Mut+) were calculated to investigate the metabolic effects of dual carbon sources (methanol/sorbitol) and the methanol feed rate, and to obtain a deeper understanding of the regulatory circuitry of P. pastoris, using the established stoichiometry-based model containing 102 metabolites and 141 reaction fluxes. Four fed-batch operations with (MS-) and without (M-) sorbitol were performed at three different constant specific growth rates (h,1), and denoted as M-0.03, MS-0.02, MS-0.03, and MS-0.04. Considering the methanol consumption pathway, the M-0.03 and MS-0.02 conditions produced similar effects and had >85% of formaldehyde flux towards the assimilatory pathway. In contrast, the use of the dual carbon source condition generated a shift in metabolism towards the dissimilatory pathway that corresponded to the shift in dilution rate from MS-0.03 to MS-0.04, indicating that the methanol feed exceeded the metabolic requirements at the higher µ0. Comparing M-0.03 and MS-0.03 conditions, which had the same methanol feeding rates, sorbitol addition increased the rHuEPO synthetic flux 4.4-fold. The glycolysis, gluconeogenesis, and PPP pathways worked uninterruptedly only at MS-0.02 condition. PPP and TCA cycles worked with the highest disturbances at MS-0.04 condition, which shows the stress of increased feeding rates of methanol on cell metabolism. Biotechnol. Bioeng. 2010; 105: 317,329. © 2009 Wiley Periodicals, Inc. [source] Improved Fermentation Processes for NS0 Cell Lines Expressing Human Antibodies and Glutamine SynthetaseBIOTECHNOLOGY PROGRESS, Issue 1 2003Jonathan Dempsey To meet the increasing requirement for therapeutic antibodies to conduct clinical trials, an enhanced culture medium and fed-batch process was developed for GS-NS0 cell lines. This process was shown to produce high concentrations of monoclonal antibodies for several cell lines expressing different antibodies. Cells were adapted to growth in a glutamine- and serum-free medium containing bovine serum albumin (BSA), cholesterol, and transferrin. A number of amino acids were found to be depleted during cell culture. The concentrations of these amino acids were increased, and further cell culture analyses were performed. This process of cell growth and analysis was repeated over multiple cycles until no depletion was detected. This resulted in an amino acid supplement that was shown to be generic and enhanced antibody productivity up to 5-fold for the three cell lines tested. Transferrin was replaced using tropolone, a lipophilic iron chelator and ferric ammonium citrate. Cell growth was equivalent to that in transferrin-containing medium over the wide ranges tested. A concentrated feed solution, based on the amino acid supplement and the components of the serum-and protein-free supplements, was formulated. Addition of this feed in response to metabolic requirements resulted in a harvest titer a further 2-fold higher than the enhanced culture medium. Harvest antibody titers of up to 600 mg/L were achieved for three cell lines expressing different antibodies, representing an increase of 10-fold over the starting concentrations. [source] | ||||||||||||||||||||||||||||