aspergillus flavus: human infection

Some encode siderophores (small, high-affinity iron-chelating compounds) which are necessary for iron transport, while others have been identified as encoding genes involved in biosynthesis of known A. flavus toxins (see below). Aflatoxin is known to contaminate many types of crop seeds, but in the field it is predominantly problematic for maize, peanuts, cotton seed, and tree nuts (1). Mycotoxins vary greatly in their potency and toxic effects. Aspergillus fumigatus is a ubiquitous airborne mold found in soil, air, food, and decaying organic material. Aspergillus fumigatus, A. flavus, and A. niger, in that order, are the most common aspergilli that cause human disease. Aspergillus is a saprophytic fungus that helps remove environmental carbon and nitrogen from the earth’s atmosphere. In addition to pure forms, there are overlapping features among these entities. It is known that A. fumigatus produces several extracellular proteolytic enzymes of the serine, aspartic and metalloprotease classes. Human exposure consists of inhalation or rarely skin implantation of conidia. Affected livers are firm and pale and microscopically are characterized by steatosis and necrosis of hepatocytes, biliary hyperplasia, centrilobular to bridging fibrosis, and cellular atypia of hepatocytes, characterized by variable cell size and variable nuclear size (Fig. Aspergillus may colonize a pulmonary cavity, bronchus, or nasal sinus as a fungus ball, a fungal colony composed of hyphae that, because of exposure to air, can develop conidiophores that have a terminal vesicle and one or two rows of phialides producing columns of conidia that are diagnostically characteristic of each particular Aspergillus species. Yup, you guessed it. The 3–6 μm diameter hyphae of Aspergillus have a regular contour with parallel walls, regularly distributed septa, and 45° angle dichotomous branching. By continuing you agree to the use of cookies. The cloning of the mepB gene showed that it is highly similar to mammalian thimet oligopeptidase (Chapter 101) and it was therefore classified in the M3 family of Rawlings & Barrett [6]. Aspergillus terreus infection can lead to superficial infections in humans. Diseases with chronic limited bronchial invasion and superficially invasive lesions of the skin, external auditory canal, and paranasal sinuses occur. Acute aflatoxin intoxication is rare in horses and cattle because an inordinately large amount of contaminated feed would have to be ingested to achieve a sufficient dose. Aspergillus flavus involving the lower limb in an immunocompetent individual is a rare entity. Today in many developing countries, these toxins are leading cause of some liver cancers and serious gastrointestinal problems. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL: https://www.sciencedirect.com/science/article/pii/B9780128096338120783, URL: https://www.sciencedirect.com/science/article/pii/B9780323445856000151, URL: https://www.sciencedirect.com/science/article/pii/B9781416056805000116, URL: https://www.sciencedirect.com/science/article/pii/B9780323295444000360, URL: https://www.sciencedirect.com/science/article/pii/B9780323074476000156, URL: https://www.sciencedirect.com/science/article/pii/B9780323034326500404, URL: https://www.sciencedirect.com/science/article/pii/B9780123822192001095, URL: https://www.sciencedirect.com/science/article/pii/B9780702068966000296, URL: https://www.sciencedirect.com/science/article/pii/B978012386456701710X, Rocio Garcia-Rubio, Laura Alcazar-Fuoli, in, Infections of Joints, Synovium-Lined Structures, and Soft Tissue, Elizabeth G. Demicco, ... Andrew E. Rosenberg, in, Diagnostic Pathology of Infectious Disease (Second Edition), Collagen Vascular and Infectious Diseases, Jose Gutierrez, ... Mitchell S.V. Aspergillus flavus is a common fungal pathogen of plants, animals and humans. This protein had not previously been known to be involved in regulation of aflatoxin biosynthesis (Price et al., 2005). Aspergillus species are ubiquitous thermotolerant molds that produce numerous conidia 2–4 µm in diameter. CPA is most common in patients with underlying lung disease (e.g., asthma) and affects 3 million people worldwide. Among these, being essential biomolecules, vitamins are used as coenzymes in very significant biological reactions. Aspergillus fumigatus is an opportunistic pathogen and ubiquitous in the environment. Primary cutaneous disease is rare and is most commonly caused by Aspergillus fumigatus and Aspergillus flavus.Rare cutaneous infections have been reported with Aspergillus terreus and Aspergillus ustus.. Colonization of burn eschars by Aspergillus is common, … Aspergillus infection in an immunosuppressed host very rarely causes arthritis and is usually associated with adjacent osteomyelitis. Aspergillus fumigatus and other Aspergillus spp. However, genetically engineered mutants of A. fumigatus that are deficient for oryzin (Chapter 713) (the ALP gene product) and/or for fungalysin (Chapter 285) (the MEP gene product) behave like wild type in a mouse model of invasive aspergillosis [4]. Fungal keratitis is a fungal infection of the cornea. Aspergillus most commonly enters the human body via inhalation. [3] have suggested that an elastinolytic serine proteinase is involved in aspergillosis pathogenesis. Elkind, in Stroke (Sixth Edition), 2016, Aspergillus fumigatus is a highly angiotrophic fungus that frequently causes stroke. It can also be found on marijuana leaves. These ubiquitous spores are inhaled daily and are eliminated by innate immunity of immunocompetent persons. The frequency of A. terreus infections varies from 3%–12.5% [ 5–9 ]. Treatment requires both débridement and intravenous antifungal agents.60, D. Malcolm, ... William Hope, in Clinical Mycology (Second Edition), 2009, Aspergillus fumigatus is one of the most common inhabitants of the airborne fungal flora. In contrast, although invasive aspergillosis is uncommon, it is a serious infection and can be a major cause of mortality in immunocompromised patients. A. fumigatus antigens may be proteinases. Copyright © 2020 Elsevier B.V. or its licensors or contributors. In invasive aspergillosis, the regularly radiating pattern of branching hyphae frequently invades veins and arteries, occludes them, and causes infarction of the involved tissue. A. flavus also has a great impact on human health, in which immunosuppressed people are most susceptible to infection by this fungus (1). How Aspergillus develops antifungal resistance and causes illness. By continuing you agree to the use of cookies. There remains a vast gap in our understanding of the coordinated global regulation of toxin formation, of the signal transduction pathways underlying primary and secondary metabolisms, of the biotic and abiotic factors that affect toxin formation, and of the interactions of mycotoxigenic fungi and their host plants during infection. Most nonaflatoxigenic A. flavus isolates contain deletions in the aflatoxin gene cluster. However, invasive pulmonary aspergillosis and hematogenously disseminated lesions in the brain, heart, kidney, liver, and spleen threaten the lives of patients who are neutropenic or under treatment with cytotoxic drugs or corticosteroids. Aspergillus may also colonize the necrotic surface of a burn wound and, if not removed by debridement, invade viable tissue and disseminate hematogenously. Aspergillosis is a common term used to describe infections caused by different species of Aspergillus Footnote 1. The fungus Aspergillus flavus is the most important source of aflatoxins. The presence of galactomannan in CSF by EIA looks promising. Jugular vein thrombosis (JVT) was previously reported in MOE and other conditions such as Lemierre syndrome, invasive fungal infection, or any inflammatory process including otitis media. The causes of an Aspergillus infection are fungi . Inhalation of Aspergillus is … The technological breakthrough allows scientists to study the genome of an org a˙ nism possibly in a very short time frame compared with traditional genetic studies. We use cookies to help provide and enhance our service and tailor content and ads. People with weak immune systems are the most and easily affected group. Typically, inhalation of the fungal spores allows entry of the pathogen into the body and the organism has a predilection for the respiratory tract. Aflatoxin B1 is the most common form and is also the most potent aflatoxin and carcinogen. It produces gliotoxin and is significant medically. Aspergillus flavus is a pathogenic fungus in the phylum Ascomycota. Invasive aspergillosis (IA) is the most common filamentous fungal infection observed in immunocompromised patients [ 1–4 ]. They can cause the sinusoidal obstruction syndrome (veno-occlusive disease of the liver),184 with clinical features that include abdominal pain, ascites, hepatomegaly and spleno­megaly, anorexia, nausea, vomiting, and diarrhoea. Spread of organisms may also occur when immune responses are inappropriate, such as when T helper 2 lymphocyte responses occur. Hypersensitivity lesions include luminal exudates containing eosinophils, Charcot–Leyden crystals, fibrin, mucus, necrotic neutrophils, fungal hyphae, or the cellular infiltrates in the interstitium and alveoli or granulomatous inflammation of the bronchial wall extending into the lumen. Other fungi with hyphae similar to Aspergillus are Pseudallescheria boydii and Fusarium species. The necrotic tissue may demarcate and separate from the viable tissue forming a cavity in which the fungi continue to grow in the nonviable lung tissue, superficially resembling a colonizing fungus ball. The suggested name is oligopeptidase MepB. Scleral Buckle Infection with Aspergillus Flavus Manal Bouhaimed, PhD, FRCS (Ophth) , 1 Hassan Al-Dhibi, MD , 2 and Abdullah Al-Assiri, MD 3 1 From the Department of Surgery and Community Medicine, Faculty of Medicine, Kuwait University, and Vitreoretina Division, AlBaher Eye … They also function as nonenzymatic antioxidative agents protecting the cells from oxidative stress-induced toxicity and transformation. Aspergillosis is caused by a fungus called aspergillus. Treatment requires both débridement and intravenous antifungal agents.57. The biosynthetic pathways for these mycotoxins, the clustering of biosynthetic genes, and the functions of these genes have been elucidated in great detail (Payne and Brown 1998; Bhatnagar et al. 15-6). Individuals at risk of developing aspergillosis include those with transplants, patients on immunosuppressive drugs, or individuals with AIDS, diabetes, or blood malignancies, but it can occur in immunocompetent patients as well.202–204 The majority of patients present with headache or symptoms related to sinusitis.205,206 Strokes can occur in up to 65% of cases. The synthetic liquid medium used for growing the microorganism contained 2.0 g asparagine, 1.0 g K2PO4, 0.5 g MgSO4, 2.0 g glucose, 5.0 mg thiamine hydrochloride, 1.45 mg Fe(NO3)3.9H2O, 0,88 mg ZnSO4.7H2O and 0.31 mg MnSO4.4H2O/liter water.The pH was adjusted to 6.0. The rapid development of high throughput sequencing made it possible in genetic research to advance from single gene cloning to whole genome sequencing such as the sequencing of the yeast genome (Dujon 1996; Goffeau et al. Despite the many advances described above, mycotoxin contamination problems are far from being solved. 2002a). Aspergillus is a genus name that represents over 185 fungal species, some of which cause several types of aspergillosis (fungal allergy or infection) in humans. Deaths due to aspergillosis Allergic forms of aspergillosis such as allergic bronchopulmonary aspergillosis (ABPA) and allergic Aspergillus sinusitis are generally not life-threatening. However, lipid formulations of amphotericin B were not studied. Aflatoxins (Aspergillus flavus toxins) are one of the natural toxic molecules which are produced by a group of fungi called Aspergillus. Acute aflatoxicosis in dogs is characterized by hemorrhagic central to massive necrosis. J.H. Aspergillosis is a clinical infection caused by fungi of the genus Aspergillus which can lead to allergic, superficial, saprophytic or invasive diseases. These affect the outside layer of the body. the consumption of contaminated groundnuts has been linked with hepatic carcinoma in Africa and Asia.177, Pyrrolizidine alkaloids occur in a large number of plants, notably the genera Crotalaria (Figure 76.22), Cynoglossum, Eupatorium, Heliotropium, Petasites, Senecio (Figure 76.23), and Symphytum (Table 76.4).178 They can contaminate foodstuffs;179 examples include Senecio jacobaea in Europe and Ageratum conyzoides in Ethiopia.180 They may contaminate pollen and hence honey.181,182 They may also be found in certain plants that are used in some forms of traditional medicine.183, Certain representatives of this class and the plants in which they occur, are hepatotoxic as well as mutagenic and carcinogenic. These metabolites are of great concern to agriculture because they can accumulate in edible crop plants infected with mycotoxin-producing (mycotoxigenic) fungi. Foods and drinks contaminated with aflatoxins cause global health and environmental problems. Aspergillus flavus is very closely related to A. oryzae, a species used in the manufacture of Asian fermented foods (Chang and Ehrlich, 2010). Many nonaflatoxin-producing A. flavus isolates are found to be associated with crops; however, the relationship of these to A. oryzae, long considered to be a separate species, is uncertain. Aflatoxins are usually elaborated during storage of fungus-contaminated feed, particularly in humid conditions, and may be present in many crops, including corn, peanuts, and cottonseed. Aspergillus flavus also produces a toxin, aflatoxin, which is one of the aetiological agents for hepatocellular carcinoma. Aspergillus flavus is a common soil fungus and is predominately saprotrophic, growing on dead plant tissue in the soil. In this chapter, we review the genetics and genomics of mycotoxigenic fungi A. flavus, A. parasiticus, F. graminearum, F. sporotrichioides and F. verticillioides and the atoxigenic A. oryzae, A. sojae, A. niger, as well as a medically important human pathogen, A. fumigatus. 2002f; Yu 2003). These fungi are only occasionally associated with colonizing syndromes (e.g., aspergilloma, allergic bronchopulmonary aspergillosis, or chronic sinusitis) and rarely cause invasi… They can be incorporated into commercial food, leading to significant outbreaks of acute toxicity in dogs. The number of plants that have reportedly caused acute liver damage is legion.163 The pattern is a rise in serum activities of the so-called liver enzymes (aspartate and alanine aminotransferases), which is usually rapidly reversible; occasionally death can occur. The complete genomic sequences of A. flavus and A. oryzae have been determined. However, in patients with pre-existing medical conditions, aspergillus can start to proliferate and cause disease, primarily a lung infection. (3) ... A. flavus is a common contaminant in agriculture. PATHOGENICITY/TOXICITY: Aspergillus spp. in human infection. includes many species, about 40 of which have been implicated in human or animal infections Footnote 1. For example, 28 of 67 patients died with sinusoidal obstruction syndrome in central India after consuming a local cereal, gondii, contaminated with the seeds of Crotalaria.187 Heliotropium popovii has been implicated in outbreaks in villages in north-western Afghanistan, with high mortality.188, Jiujiang Yu, ... Thomas E. Cleveland, in Applied Mycology and Biotechnology, 2004. Twenty parts aflatoxin per billion parts of food or feed substrate (ppb) is the maximum allowable limit imposed by the U.S. Food and Drug Administration for interstate shipment of foods and feeds. Invasive aspergillosis (IA), is a systemic infection that affects immunosuppressed patients but other forms of aspergillosis includes superficial infections, allergic bronchopulmonary aspergillosis (ABPA) and aspergilloma. 250 ml of medium was sterilised in 1 1 flask by autoclaving at 121 °C and 2% of refined sunflower oil was added. This has been especially true for the economically important aflatoxins, produced by Aspergillus species, and fumonisins and trichothecenes, produced by Fusarium species. Pigs, dogs, horses, calves, and avian species (e.g., ducks and turkeys), especially younger animals, are sensitive to the toxic effects of aflatoxins, whereas sheep and adult cattle are more resistant. The numbers of genes encoding secretory hydrolytic enzymes, proteins involved in amino acid metabolism, and amino acid/sugar uptake transporters are increased in A. oryzae compared to A. flavus. For example, A. oryzae and A. niger are used in the production of enzymes, peptides and other organic compounds, and A. sojae is used in the fermentation of soy sauce, which is a billion dollar industry worldwide. Isolated aspergillus infection of the lower limb is uncommon and needs more focus in terms of understanding the pathogenicity, ecological and geographical distribution, identification of species, management and follow-up. Risk factors include the following: Asthma; Fibrosis; Tuberculosis or other lung infections; Chronic obstructive pulmonary disease A. flavus is the second most common agent of aspergillosis, the first being Aspergillus fumigatus. The primary pathological change of hepatic sinusoidal obstruction syndrome is subendothelial oedema, followed by intimal overgrowth of connective tissue, with narrowing and occlusion of the central and sublobular hepatic veins. In this review, we describe the types of diseases caused by A. fumigatus and its symptoms according to the site of infection and the host health condition. Feeding stuffs are also commonly contaminated by cyclopiazonic acid and have been reported to coexist with aflatoxins in a range of substrates. The respiratory allergic responses have several forms including allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, bronchial mucoid impaction, asthmatic bronchocentric granulomatosis, and granulomatous hypersensitivity pneumonitis. Kolattukudy et al. Aspergillus flavus is an opportunistic pathogen of animals and humans, particularly in individuals who are immunocompromised. In human beings, A. flavus spores cause aspergillosis. A. flavusis the cause of a broad spectrum of human diseases predominantly in Asia, the Middle East, and Africa possibly due to its ability to survive better in hot and arid climatic conditions compared to other Aspergillusspp. A 36-kDa alpha-amylase inhibitor from Lablab purpureus (AILP) inhibited several fungal alpha-amylases but was devoid of any effect on animal and plant α-amylases. Lokman Alpsoy, Mehmet Emir Yalvac, in Vitamins & Hormones, 2011. Secretion of hydrolytic enzymes is considered as a virulence factor in this … This species is known primarily for its ability to produce a potent toxin and carcinogen known as aflatoxin (1). AILP was similar in amino acid sequence to lectin members of a lectin–arcelin-α-amylase inhibitor family described in common bean. In certain locales and hospitals, Aspergillus flavus is more common in air than A. fumigatus, for unclear reasons. A more recent study showed that conidia of A. fumigatus were found to be abundantly present in the outdoor air at sites where large-scale composting of sewage sludge was taking place. A. flavus may invade arteries of the lung or brain and cause infarction. The fungus is often found growing on dead leaves, stored grain, compost piles, or in other decaying vegetation. The assembled A. oryzae and A. flavus genomes are each 37 Mb and are organized into eight chromosomes. Chronic intoxication is more common than acute intoxication and results in ill-thrift, increased susceptibility to infection, and occasionally signs of hepatic failure. From: Advances in Applied Microbiology, 2015, Rocio Garcia-Rubio, Laura Alcazar-Fuoli, in Reference Module in Life Sciences, 2018. Elizabeth G. Demicco, ... Andrew E. Rosenberg, in Diagnostic Pathology of Infectious Disease (Second Edition), 2018, Aspergillus fumigatus and Aspergillus flavus are the most frequently identified Aspergillus spp. The three former species are economically important because of their industrial applications. Aspergillus fumigatus, A. flavus, and A. niger, in that order, are the most common aspergilli that cause human disease. Aspergillosis produces a variety of symptoms; bronchopulmonary aspergillosis caused by A. fumigatus causes a severe allergic reaction. from a paranasal sinus infection). Sporadic, but severe, outbreaks of aflatoxin contamination also occur in corn grown in the Midwest. Currently, the whole genome sequencing and/or Expressed Sequence Tag (EST) projects for some of the filamentous fungi such as Magnaporthe grisea, A. fumigatus, A. nidulans, A. oryzae, A. niger, A. flavus, F. verticillioides, are well underway (Bennett 1997a, 1997b; Bennett and Arnold 2001). Invasive aspergillosis found in immunocompromised persons results in the fungus growing outward from the lungs, invading blood vessels, and spreading to other organs. Aspergillus flavus and A. parasiticus produce aflatoxins that are toxic to the liver and are carcinogenic;176 e.g. European regulatory agencies are more stringent and restrict aflatoxin levels to as low as 5 ppb (Sharma and Salunkhe 1991; Bhatnagar et al. CPA is estimated to have 15% mortality, often as a result of a massive pulmonary hemorrhage within the first 6 months of diagnosis.4, D.H. Walker, M.R. Genomics studies of A. flavus have allowed a better understanding of secondary metabolism and its regulation. Modem research on mycotoxins gained significant momentum after the incidence of “Turkey-X” disease in 1960 when 10,000 turkeys died from consumption of peanut-meal feed contaminated with the group of mycotoxins known as aflatoxins (Lancaster et al. On imaging, soft tissue swelling and osteomyelitis may be present. Genomics studies have revealed that proteins necessary for fungal development are also necessary for regulation of aflatoxin biosynthesis and that the two processes are linked (Bayram et al., 2008; Wiemann et al., 2010). It inhibited conidial germination and hyphal growth of A. flavus. Advanced age, respiratory viruses, graft-versus-host disease (GvHD), prolonged glucocorticosteroid use, cytomegalovirus (CMV) infection, and iron overload are also common risk factors for IA.6 Given that A. fumigatus spores are inhaled, IA most frequently manifests as an invasive pulmonary disease, but the pathogen can enter the bloodstream and infect multiple organs. Aspergillus flavus cells were prepared in our laboratory. Diagnosis requires isolation of fungus from tissue or synovial fluid. Surgical management and antifungal therapy are the mainstays of treatment. Copyright © 2020 Elsevier B.V. or its licensors or contributors. A. Chrevatidis, in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003. Then, micellia was milled to powder consistence and the water activity of the powder (aw = 0.17) was determined using a Novasina apparatus. Humans routinely inhale A. fumigatus conidia, but the microorganism is rapidly eliminated by the innate immune system in immunocompetent individuals. Plants that have been reported to cause acute liver damage include Breynia officinalis,164 Callilepis laureola (ox-eye daisy),165 Camellia sinensis (green tea),166 Chelidonium majus (celandine),167 Cimicifuga racemosa (black cohosh; Figure 76.21),168,169 Larrea tridentata (chaparral),170 Piper methysticum (kava; Figure 76.20; see below under Psychotropic drugs), Polygonum multiflorum,171 Symphytum officinale (comfrey; see below under Sinusoidal obstruction syndrome)172,173 and Teucrium spp.174,175 Of these, black cohosh, chaparral, comfrey, and kava are the most common culprits. After A. fumigatus, A. flavus is the second leading cause of invasive aspergillosis and it is the most common cause of superficial infection. Aspergillus flavus is the second most common species of Aspergillus in humans after Aspergillus fumigatus. Aspergillus flavus, A. parasiticus, F. sporotrichioides, F. graminearum and F. verticillioides are plant pathogens that infect agricultural crops (corn, cotton, peanut and tree nuts) and contaminate them with mycotoxins. Disease in Humans. The later can be attributed to multiple aspects associated to the cell structure, morphogenetic reprogramming, stress response, secretion of enzymes and secondary metabolites, nutrient acquisition and synthesis, and adaptation to the host conditions. A. oryzae, A. sojae and A. niger are close relatives of A. flavus, but do not produce aflatoxins. Occasionally, Aspergillus clavatus and Aspergillus flavus cause human illness. Aspergillus flavus is an opportunistic pathogen of animals and humans, particularly in individuals who are immunocompromised. Only 43 genes are unique to A. flavus and 129 genes are unique to A. oryzae; only 709 genes were identified as uniquely polymorphic between the two species. Extension from infected sinuses usually produces lesions in the frontal or temporal lobes, which are pathologically characterized by granulomas and cerebral infarctions following hyphal angioinvasion and vessel thrombosis. Larry E. Davis M.D., Beth S. Porter M.D., Ph.D., in Current Therapy in Neurologic Disease (Seventh Edition), 2006. P.-K. Chang, ... K. Gomi, in Encyclopedia of Food Microbiology (Second Edition), 2014. As a mycotoxin it is not well documented because the existing methods of analysis are not fully developed and therefore, this precludes a full assessment. Neutropenia predisposes to aspergillus infection. A. fumigatus neither infects plants nor is of any industrial value, instead it is a human pathogen that infects human lungs causing both invasive and noninvasive human aspergillosis, especially to those who are immunocompromised patients and can be fatal (Rankin 1953; Denning 1998). A synovial effusion is present, and there is a restricted range of motion. Atrophy or necrosis of liver cells, with consequent fibrosis, leads to gross changes similar to those seen in cardiac cirrhosis; portal hypertension results.163, In the West Indies185 sinusoidal obstruction syndrome is related to the consumption of bush tea made from plants such as Crotalaria and Senecio.186 Hepatotoxic compounds in Crotalaria, Senecio, and Heliotropium, and other composite plants can also enter the diet through contamination of cereals with weed seeds. Recent in vitro and in vivo studies indicate that A. terreus is dis… Wong, T.B. The incidence of onychomycosis as a result of A. terreus (not the common agent dermatophyte) is increasing. The wide spectrum of human disease is determined by the immune system and ranges from allergic responses through noninvasive colonization and superficial infection to severe hematogenous dissemination. We use cookies to help provide and enhance our service and tailor content and ads. MepB was the name given to this first cytosolic enzyme of A. fumigatus [5]. These three species are food grade organisms having GRAS status (Generally Regarded As Safe) according to the U.S. Food and Drug Administration and are of great economic importance because of their industrial uses. The most common causative agents are Aspergillus flavus, Aspergillus fumigatus, Fusarium spp.

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