Chronic Social Defeat Stress: Cage setup

Triple Horizontal Bars

Attentional Set Shifting (IDED) Chamber

Skilled Forelimb Test

Repeated Acquisition and Performance Chamber

Novel Object Recognition

Elevated Plus Maze

Barnes Maze

The Barnes maze is a widely used apparatus for learning and memory.

Conditioned Place Preference

Overview

Rats have a significant advantage over mice. In comparison to mice, rats’ physiology is in many cases closest to the corresponding human condition. Rats are also intelligent mammals, capable of learning a range of tasks. This ability of theirs makes them an excellent model organism for cognitive research. Further, the size of rats also makes them a better option than the mice. Their larger size allows for easier handling, sampling and performing surgical procedures. Up until recently the main advantage the mice models had over the rats was the ability to perform DNA manipulation to create transgenic animals. However, recent technological developments and the availability of rat genome mapping has allowed the creation of knock-in and knock-out variety of rat strains.

Rat Behaviors and Characteristics                              

Scientific Name:Rattus
Habitat:Can survive in any habitable environment
Weight:Males 300-500g, Females 250-300g
Diet:Omnivores

 

Reproduction

Sexual Maturity

Gestation Period

Litter size

Nesting

 

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Reached at 5 weeks of age.

21 to 23 days

10 to 12 pups

Females will build a nest prior to parturition if the opportunity is provided using any material that can be foraged from the area.

Social Behavior

Herding

 

 

 

Hierarchy

 

 

 

 

Communication

 

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Rats live in colonies and form family groups of a mother and her young ones. Rats also exhibit huddling behaviors.

 

Rats are territorial animals and maintain a social hierarchy. The dominant males have higher preferences and are preferred by females. Dominant rats usually lead the pack.

 

Rats communicate using vocalization and pheromones.

Senses:Rats have poor vision; however, their sense of smell, touch, and hearing is well developed. Rat whiskers also serve as an important sensory organ.
Other behaviors & characteristics:·         In order to reduce infanticide, females may mate with more than one male.

·         Communal nesting can also be observed among rats.

History

Among the rats, the Rattus Norvegicus (Brown rat) and Rattus Rattus (Black rat) are more commonly used species in research. Both these rodents are believed to have their origins in Asia, with Rattus Norvegicus most likely originating from the plains of China and Mongolia (Musser & Carleton, 1993), while the Rattus Rattus originated from the Indo-Malayan region (Krinke, 2000). Although natives of Asia, these rats are widespread across all continents with the exception of Antarctic. The species reached the banks of Europe and America via human travel, and their commensal nature has led to the settling of these creatures along human travel routes.

In the 18th century, rats ran rampant across cities in Europe where Rat-catchers thrived on the business of exterminating and trapping them for food and rat-baiting. The popularity of rat-baiting sport led to the breeding of rats, which eventually led to mutations. These mutations ended up with the first albino rat being used in experiments of fasting in 1828 and many more experiments since then, essentially making the Norway rat (Rattus Norvegicus) the first animals to be domesticated for the purpose of scientific research (Richter, 1954).

Hugo Crampe’s experiments between 1877 and 1885 became the first breeding experiments with albino rats and wild types to confirm the validity of Mendelian inheritance law. Shortly after these experiments, Henry H. Donaldson of the University of Chicago brought in America’s first white rats of European origin which went on to become the foundation of American laboratory rats (Castle, 1947). These colonies were then transferred to the Wistar University of Philadelphia in 1906, where Helen D. King initiated the inbreeding of the albino rats in 1909 (Suckow, Weisbroth, & Franklin, 2006).

The earliest known use of rats in behavioral experiments was by Willard S. Small in the early 1900s, to study the rate of learning in a maze. Elmer McCollum in January of 1908 started the first colony for nutrition research which was used by Thomas Burr Osborne and Lafayette Mendel to study nutrition based on rat’s nutritive requirements (Osborne & Medel, 1916, 1917). Since their initial use, rat models have served an important role in psychological and biomedical science research.

Strains

Rat strains are resultant of inbreeding of the rats and are almost genetically identical.  The fixed and renewable genotypes characteristics of strains enable researchers to identify whole-genome response signatures. Outbreeding of rats also takes place; however, these rats have primary application in the creation of genetically heterogeneous stocks which are of interest in the field of genetic mapping and in selective breeding experiments.

The following are few of the commonly used laboratory rats,

Wistar Kyoto Rat

The Wistar Kyoto rat was outbred using Wistar stock from the Kyoto School of Medicine by National Institutes of Health (NIH) in 1971. The albino rat was initially created as normotensive controls for the spontaneous hypertensive line rats. These rats have distinct behavioral features that make them ideal for depression and stress-related studies. Performances of these rats in behavioral assays such as Forced Swim Test and Open-Field Test reveal behavioral alterations that have face validity as markers of depression. Further, the strain also exhibits endogenous central neurotransmitter alterations, dysregulation of the hypothalamic-pituitary-adrenal axis, and exaggerated adrenocorticotropic hormone and corticosterone levels post-exposure to acute and chronic stress. (Edwards & King, 2009)

Sprague Dawley Rat

The Sprague Dawley rat was developed at Sprague Dawley farms (Harlan Sprague Dawley) in 1925 and was received by NIH in 1945. The Sprague Dawley are albino rats known for their calmness and ease of handling. The rats are used in almost all disciplines of biomedical research including nutritional research. An interesting characteristic of these rats is the secretion from their eyes when stressed. This secretion appears like dried blood and glows fluorescently under UV light. In comparison to the Wistar rats, these rats typically have a longer tail in proportion to their body length. The rats are also known for their excellent reproductive performance.

Long-Evans Rat

Dr. Herbert McClean Evans and Dr. Joseph Abraham Long initiated the Long-Evans stock at Berkley, California around 1915. The stock was obtained as a cross between female albino from the Wistar Institute and a wild male (Rattus norvegicus) captured near Berkeley. The rats are a popular choice in neurological, toxicological and ophthalmologic studies. The rats are usually white with a black hood; however, white with brown hood are also found. In comparison to outbred albino rats, the Long-Evans have a higher resistance to respiratory problems making then ideal for surgical procedures that rely on long duration inhalant anesthetics.

Lewis Rat

The Lewis rats are albino rats that were inbred from the Wistar stock by Dr. Margaret Lewis in the early 1950s at Wistar Institute. The rats have a docile nature and low fertility. The rats are commonly used in transplantation, induced arthritis/inflammation, experimental allergic encephalitis, and STZ-induced diabetes research. The Lewis rats are known to develop several spontaneous pathologies that include high incidences of neoplasms, spontaneous transplantable lymphatic leukemia, and spontaneous glomerular sclerosis.

Training Considerations

Rats are a popular laboratory animal along with mice. Rats are also prey animals and can be sensitive in nature. The following are some considerations to take into account to ensure the animal’s welfare,

  • Allow the animals to acclimate to the research environment at least one week prior to any testing. Regular, positive interactions with the rats make them easy to handle and reduce Care must be taken to prevent any negative interactions with the animals since it will result in increased fear.
  • Rats are social animals; thus, housing should allow the opportunity for social interaction and indulgence in normal behaviors such as grooming. Housing should also include the opportunity to rest and withdraw from other rats.
  • Holding cages should be large enough or designed to sufficiently accommodate the groups of rats taking into considerations the needs of the animals especially nursing mothers and the litters. Overcrowding should be avoided.
  • Appropriate bedding and flooring should be provided in addition to nesting materials. Rats have also been observed to prefer solid floors.
  • Since rats find bright lights aversive, it is recommended that dark, enclosed space is provided within the holding cages. These spaces can also be helpful for rats during conflicts with cage mates.
  • Rats must be familiarized with each other before grouping them into cages to avoid any aggressive behaviors. This can be done either by housing littermates of same-sex together or by placing the newcomer in adjacent cages to allow interactions before introduction into the same
  • Social isolation can have a detrimental effect on the animals and hence should be avoided unless absolutely required.
  • Physical restraining of the animals during research should be only done after the animal has acclimated to the device and the handling. Further, it is advisable to keep restraining to a minimum. Restraining devices such as the sling tend to have a calming effect on the animal, and hence such devices are recommended. (Click here for restraints)
  • Chemical restraint that offers minimal stress should be used for invasive procedures to prevent negative handling experiences.

For more details on housing-related considerations click here.

Rats in Research

In comparison to the mice, rats are relatively larger thereby making intricate procedures easier to perform. Further, as opposed to larger animals such as pigs and primates, rats offer a manageable size. The development of genetic manipulations also makes rats ideal for different researches.

Transplantation Studies

Reich et al. (2016) observed that repeated dosing of allogenic cardiosphere-derived cells (CDCs) might prove to be an effective treatment for myocardial infarction without resulting in immune sensitization. The study involved intramyocardial dosing of female Wistar Kyoto rats with CDCs obtained either from immunologically distinct Wistar Kyoto or Brown Norway rats (having a complete mismatch of major histocompatibility loci, RT1) or human myocardial tissue. It was observed that repeated dosing of CDCs (2.2 x 10^6 CDCs; separated by 3 weeks) led to improved left ventricular function as observed by the significantly improved ejection fraction in allogeneic and syngeneic groups (3.4% and 6.4%, respectively, after the second dose). Further, allogeneic and syngeneic groups also demonstrated equally reduced infarct size and better-preserved infarct wall thickness in comparison to the control and xenogeneic group. While the xenogeneic group displayed robust rejection-like mixed mononuclear cell infiltrates and elevated levels of anti-CDC IgG and IgM, they were not frequent and not detected, respectively, in the allogeneic and syngeneic groups.

Attenuation of cognitive decline and peripheral metabolic dysfunction resulting from intracranial islet transplantation was observed by Bloch et al. (2018) in a sporadic Alzheimer’s disease model. Sporadic Alzheimer’s disease was induced in male Lewis rats by intracerebroventricular administration of streptozotocin, 2 months following which one group received syngeneic islet (LEW/SsNHs donor rats) in the cranial subarachnoid cavity. In comparison to the islet transplant group, the streptozotocin only treated group had significant impairment in spatial memory during the acquisition phase and increased latency to find the platform during the reversal trials of the Morris Water Maze. Further assessment using the Marble Burying Test showed no impairment in the burying behavior of the streptozotocin-islet group, though it was significantly impacted in streptozotocin only treated group. The grafts resulted in normalization of food consumption and attenuation of weight gain without affecting the brain insulin receptors and peripheral glucose homeostasis expression.

Psychological and Psychiatric Disorders

Lin et al.’s (2015) investigation into the potential therapeutic effects of Lemon balm (Melissa officinalis L.) revealed a significant amelioration of depressive-like behaviors in rodents. Male Sprague-Dawley rats were divided into two treatment groups; acute treatment and sub-acute treatment, wherein drugs (fluoxetine, water extract of Melissa officinalis L., or rosmarinic acid) were administered 3 times per day or once a day for 10 days, respectively. A significant reduction in immobility duration in the Forced Swim Test was observed in the acute treatment group for all drugs with no significant effect on swimming and struggling behaviors. A significant decrease in the immobility duration could also be observed in the sub-acute treatment for all water extract of Melissa officinalis L. An increase in duration of swimming, though not struggling, was also observed with each water extract of Melissa officinalis L. administration. Analysis of neurotransmitters levels and their metabolites in the frontal cortex, amygdala, hippocampus, and striatum suggested the involvement of the water extract of Melissa officinalis L. in serotonergic neurotransmission modulation.

Research into the contribution of childhood traumatic events in the development of Post-traumatic Stress Disorder suggested that childhood can be an effective period for preventive treatment. Ariel, Inbar, Edut, and Richter-Levin (2017) observed that fluoxetine treatment following juvenile stress in male Sprague Dawley rats (post-natal day 22) resulted in significant reduction in the proportion of subjects affected in their adulthood by the experience. The stress paradigm involved forced swim, elevated platform and restraint stress (click here for restrainers), applied in that order over 3 days. In the Elevated Plus Maze, subjects that received fluoxetine treatment since juvenility displayed lower anxiety levels, though not significant, as observed by the distance covered and durations spent in the open arms. However, subjects that received fluoxetine treatment only in adulthood showed significantly higher anxiety levels in comparison to both controls and juvenile treatment group. The observations revealed that childhood is, in fact, a vulnerable phase. However, the application of preventive treatments during this phase can have a significant impact in adulthood.

Sentir, Bell, Engleman, and Chambers (2018) investigated polydrug use and addiction vulnerability in schizophrenia. Sprague Dawley rats that underwent either a neonatal ventral hippocampal lesion or sham surgery were evaluated for their acquisition for alcohol and nicotine in a self-administration set-up (see Standard Operant Chamber Packages). Following acquisition trials, the animals were subjected to operant extinction sessions and reinstatement sessions to assess drug seeking under three conditions; withholding of nicotine, withholding of both nicotine and alcohol, and reintroduction. Both groups showed an increase in self-administration for both alcohol and nicotine as the days progressed with the lesion group showing strong progress towards the nicotine lever. During the extinction trials, despite a decline in efforts, the lesion group were persistent in lever pressing for either drug. Based on the observations of the extinction trials, it was observed that the lesion group displayed elevated addiction vulnerability to either drug independently of each other.

Cognition, Learning and Memory Research

Mutlu et al. (2015) explored the effects of 7-nitroindazole (7-NI) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), Nitric oxide synthase and guanylate cyclase inhibitors respectively, on the spatial memory of male Balb-c mice. The subjects were either treated with 7-NI (15 mg/kg), ODQ (3, 10 mg/kg), L-arginine (100 mg/kg) + 7-NI (15 mg/kg), or physiological saline and evaluated on the Elevated Plus Maze, the Morris Water Maze and the Radial Arm Maze. Treatment with the drugs prior to acquisition in the Elevated Plus Maze task did not affect performances; however, both 7-NI and ODQ resulted in increased retention latency on the second day. Both the inhibitors also significantly increased escape latency in the Morris Water Maze task. In the probe trials, it was further observed that the inhibitor drugs reduced the time spent in the target while increasing the mean distance to the escape platform. In the Radial Arm Maze task, the number of errors was significantly increased for both inhibitor drugs, while an increase in latency was only observed for 7-NI.

Knocking out of Kv4.2, a subunit of the A-type potassium channel involved in the mediation of pyramidal neurons excitability in the cortex and hippocampal dendrites has been observed to affect learning. Lugo, Brewster, Spencer, and Anderson (2012) observed that the Kv4.2 knockout mice showed a learning deficit specific to the contextual condition in the Fear Conditioning Chamber test. Further, in the Morris Water Maze task, the knockout mice swam longer paths and lacked in learning to find the platform in comparison to the controls. Smith, Gao, and Lugo (2016) further assessed spatial learning impairment resulting from Kv4.2 knockout by evaluating performances in less stressful, appetitive learning based Lashley Maze. Though the knockout mice made more error across 15 trials in the maze, performances by the end of testing were similar to the controls. Learning impairment by the knockout mice was mostly observed in the early phases of the maze task.

Yamada and Sakurai (2018) utilized the Barnes Maze to assess observation-based learning of the task by male Long Evans hooded rats. The study involved two sets of rats, one of which served as the model rats while the other severed as the observer rats that had to learn the escape route based on model rats’ performances. The model rats were first trained in the maze for 5 days before the observer rats were introduced to the set-up. The observer rats were held in wire cages while the model rats performed the task over the course of 5 days. Following training, the observer rats were allowed to perform the task on their own. It was observed that the observer rats found the escape hole significantly faster in comparison to the model rats; thus, confirming observation-based learning among rats.

Souza et al.’s (2018) investigated fear memory in male Sprague-Dawley rats exposed to fear-conditioning using their novel automated M-Maze. After shaping trials in the M-Maze rats were subjected to Single Prolonged Stress (SPS) protocol which was combined the Auditory Fear Conditioning (AFC) after 7 days for one of the treatment groups. Following the stress and fear protocols, the rats were once again retrained in the M-Maze. While SPS group were no different from controls in the M-Maze, the AFC and SPS+AFC groups displayed a significant increase in the first sound transit time, increased average transit times and higher suppression ratio in comparison to controls. Another treatment group was subjected to Protracted Aversive Conditioning (PAC) which involved eight conditioned and unconditioned stimuli pairings a day using delay, unpredictable, short and long trace conditioning. It was observed that PAC and SPS+PAC groups displayed impaired extinction, had higher transit times and suppression ratio in comparison to controls in the M-Maze. Nose poke suppression continued to be displayed 3 and 5 weeks after fear-conditioning in PAC and SPS+PAC groups, respectively.

Social Behavior Research

Henbid et al. (2017) examined the effects of Z944, a clinical stage pan-T type calcium channel blocker, on the sociability behaviors of Genetic Absence Epilepsy Rats from Strasbourg (GAERS) non-epileptic control (NEC) rats. When drug naïve males and females were assessed in the Sociability Chamber, both GAERS sexes displayed a significant decrease in total distance traveled, though sociability impairment was only observed in the female GAERS. Based on the observed deficits, only females were treated with 5 ml/kg intraperitoneal injections of Z944 at 5 mg/kg dose to assess the effect of the drug on sociability. In comparison to vehicle-treated controls, both Z944 treated NEC and GAERS covered relatively less distance overall. Treated GAERS showed a significant increase in total stranger cage exploration in comparison to their vehicle-treated counterparts. On the other, in comparison to the vehicle-treated NECs, vehicle-treated GAERS displayed significantly reduced duration discrimination ratio (DR).

Cao et al. (2017) investigated the effect of environmental enrichment on the behaviors of male Sprague-Dawley rats. Rats that received environmental enrichment showed significant submissive behaviors in the Tube Dominance Test when paired with rats maintained in standard cages. However, no difference in the total amount of food foraged by either treatment groups could be observed in the competitive food foraging test. On the other hand, rats that received environmental enrichment were more attractive to females. Female rats without any prior sexual experiences spent significantly more time in the enriched environment exposed rat’s chamber in the mate preference test (see also Social Reward Chamber). Further analysis revealed the rats exposed to environmental enrichment had reduced number of microglia in the hypothalamus, though no other cell types were affected.

Manz, Levine, Seckler, Iskander, and Reich (2018) induced Social Defeat Stress (SDS) in adolescent male Sprague Dawley and Long Evans rats using the resident-intruder paradigm (see Resident-Intruder Chamber). Since the Long Evan rats are considered to be more aggressive than the Sprague-Dawley rats, they served as the resident while the latter as an intruder. The residents were exposed to a new intruder for every trial that applied periods of sensory contact only, physical contact and sensory contact only in that order. It was observed that the Sprague-Dawley rats that served as the intruders displayed significantly more attacking behaviors than the residents. The protocol also led to induction of depressive-like behaviors as observed by the higher immobility time in comparison to other groups in the Forced Swim Test. The Long Evan residents also displayed higher freezing responses in the Fear Conditioning Chamber.

Nociception Research

Klein et al.’s (2010) evaluated the effect of the application of L-Menthol to the paws of adult male Sprague-Dawley rats on pain-related behaviors. Subjects were treated with either 0.01%, 0.1%, 1.0%, 10%, or 40% topical application of L-Menthol to one or both ventral hind-paws. In the Plantar Test Hargreave’s Apparatus, a concentration-dependent withdrawal latency increase was observed with the 40% treatment resulting in significant changes compared to all other groups. When subjected to the Cold Plate test (see Hot/Cold Plate and Hot Plate) all treatment groups displayed a nocifensive response on the -5 °C cold plate with the 40% treatment group showing the most significant response. However, on the 0 °C setting only 75% of all animals displayed nocifensive response. Evaluation for temperature preferences (see Thermal Gradient) in a 15 °C versus 30 °C set-up revealed a biphasic effect of menthol. The 10% and 40% groups displayed cold hyposensitivity in comparison to the control rats by spending significantly lower time on the 30 °C plate. While lower concentration groups spent a significant amount of time on the 30 °C plate, the number of plate crossings showed a significant decline in the 0.01% group in comparison to naïve and controls. The 40% group displayed significant allodynia in comparison to other treatment groups when assessed using Von Frey filament (see Electrical Von Frey).

A dose-related effect on the antinociceptive and anti-inflammatory response by celecoxib and antinociception by Vitamin E was observed by Shamsi Meymandi, Sepehri, Izadi, and Zamiri (2019). Wistar rats were divided into different treatment groups that received olive oil, indomethacin (20 mg/kg), vitamin E (100, 200 and 400 mg/kg), celecoxib (3, 10, 30 and 60 mg/kg), or combination of vitamin E (100 and 200 mg/kg) and celecoxib (3, 10 and 30 mg/kg). In the Tail Flick test,60 mg/kg of celecoxib increased the maximum possible effect (%MPE) and Area Under Curve (AUC). Though similar effect of the vitamin E (200 mg/kg) and celecoxib (10 and 30 mg/kg) combination was also seen, the increase in %MPE and AUC was not comparable with celecoxib or vitamin E. On the other hand, a decreased pain score in comparison to vehicle group was observed for the vitamin E (100 or 200 mg/kg) and celecoxib (3 or 10 mg/kg) combination in the Formalin test. Further, a decrease in the pain scores was also observed in the chronic phase of the Formalin test for the combination groups.

Locomotion and Motor Behavior Research

Treadmill training was observed to improve gait parameters and reduce methamphetamine-induced rotation in Sprague-Dawley rat (female) model of Parkinson’s disease. Chuang et al. (2017) modeled Parkinson’s disease by administering neurotoxin 6-hydroxydopamine (6-OHDA) to lesion the nigrostriatal dopaminergic system. Treated subjects either received treadmill training for 30 min at 15 m/min per day for 4 weeks or no exercise. Treadmill trained groups displayed significantly greater contact area, relatively short duration of contact, significant improvement in successive placements (same paw) and significantly increased swing speed of the left paw in the gait analysis apparatus (see Gait Test and FTIR Walkway). Further, the training was observed to result in recovery of mitochondrial function in addition to improving dopaminergic neuron viability and attenuating oxidative stress in the rats.

Miller, Thangthaeng, and Shukitt-Hale (2017) adapted Liu, Graber, Ferguson-Stegall, and Thompson’s (2013) frailty index for mice for use with a rat model of aging, F344 rat. Miller et al. subjected male F344 rats to the Grip Strength (see also Grid Test), Rotarod test, Open-Field test, and inclined plane test (see Geotaxis Test) that assessed strength, speed, physical activity, and endurance, respectively. The Open-Field was opted for instead of Wheel-Running to measure spontaneous physical activity since the large size of these wheels made them impractical for large scale use. The cutoff points corresponded to the clinical cutoff set by Fried et al. (2001) based on the lowest quintile of performances. Subjects were ranked based on their performances and grouped as frail (lowest 20% of performance in three or four tests), mildly frail (lowest 20% of performance in two tests) and non-frail (lowest 20% of performance on one or no tests).

Strengths and Limitations

Strengths

Rats are a popular choice for research due to the size and physiological similarity to humans. Rat physiology is well understood given the vast literature available in comparison to other animal models such as pigs. In comparison to mice, rats are easier to handle, sample and perform surgical procedures on. Their intelligence and inquisitive nature make them suitable for behavioral research concerning learning, memory and cognitive tasks which can be easily translated to human behavior and learning. Their large litter size, reproductive cycle and the opportunity to manipulate the rat genome further facilitates their use in research. 

Limitations

Despite the shared similarities with humans, rats cannot be used as a cohesive model for all human pathologies and other human-related diseases and behaviors. The gait pattern and biomechanical loading rats vary significantly to that in humans. Thus, extrapolation of data such as results from drug screening should be done with the utmost care and considerations. Like pigs, rats are also social animals; therefore, isolation or lack of environmental enrichment can potentially affect behaviors. Further, negative interactions with the handler can significantly increase the fear of humans and stress. Territorial nature of the rats must be taken into consideration when introducing unfamiliar individuals to each other.

Summary

  • The earliest use of rats as laboratory animals can be dated back to the 1800s when albino rats were used in fasting experiments.
  • In comparison to mice, rat physiology tends to be closest to the corresponding human condition.
  • The relatively larger size of rats than mice makes them suitable for surgical procedures and makes them easy to handle.
  • Popular laboratory rats include the Wistar Kyoto rat, the Lewis rat, the Sprague-Dawley, and the Long Evan rats. Additionally, transgenic lines of knock-in and knock-out rats are also popular.
  • Rats produce large litters which reduce experimental variability.
  • Physical or chemical restraining that offers minimal stress to the animals should be used when required.
  • Rats are social animals. Therefore, isolation over long periods of time can be stressful for them.
  • Appropriate measures should be taken before introducing unfamiliar rats, especially males, considering their territorial nature.

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