3 Minute 3Rs

3 Minute 3Rs

By The NC3Rs, the North American 3Rs Collaborative, and Lab AnimalScience
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3 Minute 3Rs episodes

  • 3 Minute 3Rs August 2020

    You’re listening to the August episode of 3 Minute 3Rs.


    The papers behind the pod:

    1.      The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PloS Biology https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000410

    2.      Acute and chronic stress prevents responses to pain in zebrafish: evidence for stress-induced analgesia. Journal of Experimental Biology. https://jeb.biologists.org/content/223/14/jeb224527

    3.      3Rs-based optimization of mice behavioral testing: The habituation/dishabituation olfactory test. Journal of Neuroscience Methods. https://doi.org/10.1016/j.jneumeth.2019.108550

     

    Transcript:

    It’s the 3rd Thursday of August, and you’re listening to 3 Minute 3Rs, your monthly recap of efforts to replace, reduce, and refine the use of animals in research. This month we’ve got papers on fish pain and a refined mouse olfaction task. But let’s kick the episode off with the arrival of ARRIVE 2.0

    [NC3Rs] Improving the reproducibility of biomedical research is a major challenge. A lack of experimental detail in publications reporting in vivo experiments, such as experimental design and statistical analysis used, means researchers cannot adequately scrutinise the experimental results or repeat experiments. Consequently, data from these published experiments do not contribute to the knowledge base as researchers need to perform or to develop experimental procedures themselves. To highlight the information required the ARRIVE guidelines were developed in 2010. Although these guidelines were widely endorsed by journals and funders they have not led to improvements in reporting.

    To address this, ARRIVE 2.0 has been launched and published in PLOS Biology. The recommendations have been organised into two sets, so scientists can more easily incorporate them into their reporting. The first set, the essential 10 constitute the minimum reporting requirement for reviewers and readers to assess the reliability of the findings presented. The second set, the recommended set, provides further context to the study described. An Explanation and Elaboration document giving further information about each of the 21 items in ARRIVE 2.0 has also been published in PLOS Biology.

    To learn more about ARRIVE 2.0, explore the recommendations and find resources, visit its new home on the web at arriveguidelines.org.

                                                          

    [Lab Animal] Next up, let’s think about pain processing. In mammals, studies have shown that stress can alter pain-detection thresholds. Acute stress can have an analgesic effect, while chronic sources can enhance responses to pain, an effect known as hyperalgesia. Both can potentially confound experiments.

    Scientists at the University of Liverpool recently explored whether such stress-induced responses are also evident in zebrafish.

    The short answer? Yes. The team looked at the behavior of acutely and chronically stressed fish, as well as stress-free controls, after fin clipping. Following the potentially painful procedure, unstressed fish swam more slowly and lingered near the bottom of their tanks.

    No such change in behavior was observed in...

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    5 min
  • 3 Minute 3Rs July 2020


    You’re listening to the July episode of 3 Minute 3Rs.


    The papers behind the pod:


    1.      Reproducibility of animal research in light of biological variation. Nature review Neuroscience https://www.nature.com/articles/s41583-020-0313-3


    2.      Inactivated rabies vaccines: Standardization of an in vitro assay for residual viable virus detection. Plos Neglected Tropical Diseases https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0008142


    3.      A novel biosafety level 2 compliant tuberculosis infection model using a ΔleuDΔpanCD double auxotroph of Mycobacterium tuberculosis H37Rv and Galleria mellonella. Virulence https://doi.org/10.1080/21505594.2020.1781486


    Transcript:


    [NA3RsC] Reproducibility is a cornerstone of the scientific method. But unfortunately, it’s considered to be quite poor for all research findings, and especially animal studies. Experts in animal biology, experimental design, and statistics argue that one major cause of poor reproducibility is inappropriate standardization in the face of biological variation. In nature, individual animals and humans vary greatly as a result of the interaction between their genes and the environment. So if studies standardize this natural variation too much, then they risk producing findings that are not reproducible outside of a very specific set of conditions. 

     

    As a solution, experts recommend that researchers should deliberately diversify their study subjects such as by varying sex, genotype, age, and environmental conditions. This does not necessarily need to increase sample size or cost. And ultimately, this diversification can reduce long-term research costs, increase efficiency, and reduce overall animal suffering. To learn more, go online to read the full paper in Nature Perspectives.

     [NC3Rs] Vaccines are a vital tool in the fight against disease. This includes neglected tropical diseases such as rabies, which kills around 60,000 people each year, mainly in Africa and Asia.

    When inactivated rabies vaccines are produced, they go through many stages of quality control, including testing for any remaining live virus. This process traditionally uses a lot of animals, but a recent paper by Beatriz Lourenço Moreira and colleagues explores an alternative in vitro assay that could replace some of this animal use

    The new method combines two in vitro techniques to create an assay that’s three times more sensitive than in vivo testing and five times quicker than other in vitro assays. What’s more, it could replace the use of animals in residual live virus detection, decreasing animal use in quality control by two thirds overall.

    While further validation is needed, and regulatory challenges still exist, this study shows what the 3Rs have to offer in vaccine development. Read the paper now in PLoS Neglected Tropical Diseases.


    [LA]...

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    5 min
  • 3 Minute 3Rs June 2020

    You’re listening to the June episode of 3 Minute 3Rs.


    The papers behind the pod:


    1. A novel, high-welfare methodology for evaluating poultry red mite interventions in vivo. https://www.sciencedirect.com/science/article/pii/S030440171930041X
    2. Pluripotent state transitions coordinate morphogenesis in mouse and human embryos. https://www.nature.com/articles/nature24675


    Transcript


    It’s the Third Thursday of June and you’re listening to 3 Minute 3Rs, your monthly recap of efforts to replace, reduce, and refine the use of animals in research. Instead of the usual 3 segments this month, we’re featuring two, in recognition of the two winners of the 2019 3Rs Prize, awarded by the NC3Rs and sponsored by GlaxoSmithKline. We’ll start with a recap of Dr. Francesca Nunn’s paper on red mite interventions in poultry.

     

     

    [NA3RsC] Laying hens can be infested with poultry red mites which causes major economic and animal welfare issues. These mites can cause anemia, reduced production, and even death. Current treatments are often inadequate and research methods to find new treatments typically have poor translation to field trials.

     

    A recent paper in Veterinary Parasitology describes a novel, high-welfare method for evaluating poultry red mite interventions in vivo. This paper is the winner of 2020 NC3Rs 3Rs Prize award.

     

    Nuun and colleagues developed and optimized a sealed mesh device that attaches to a hen’s thigh. The depth and width of the mesh is precisely sized to both contain the mites and allow them to feed on the hens. This device will both reduce and refine the use of animals in research by allowing efficient pre-screening of new treatments before they enter large field trials. To learn more, read the full paper online.

     

    [NC3Rs] The second winner of the 2019 3Rs Prize award is Dr Marta Shahbazi from the MRC Laboratory of Molecular Biology for her work reducing the number of mice needed for embryonic developmental research.

     

    Historically embryos have been difficult to culture beyond the implantation stage of pregnancy. But with up to 40 per cent of pregnancies ending by implantation, it’s a critical stage to understand. So researchers typically use extensive breeding programmes to generate transgenic mice and retrieve embryos needed for experiments with invasive surgeries.

     

    Now, building upon previous research, Marta and colleagues have established advanced 3D cultures of human and mouse embryonic stem cells to mimic the embryo at implantation. Using these cultures, they’ve been able to study the cellular events triggering implantation in greater detail than ever before. Not only that, they’ve also replaced the use of 500 mice. 

     

    Groups worldwide are now adopting the cultures to answer their own biological questions about embryonic development. Why not join them, and check out Marta’s prize-winning research by following the link in the description.



    With congratulations to Dr. Nunn and Dr. Shahbazi, that’ll do it for June! 3 Minute 3Rs is brought to you by the NC3Rs, the North American 3Rs Collaborative, and Lab Animal. Come back in July for three more 3rs papers. 


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    4 min
  • 3 Minute 3Rs May 2020

    You’re listening to the May episode of 3 Minute 3Rs.

    The papers behind the pod:


     

    1        Refining rodent models of spinal cord injury: https://doi.org/10.1016/j.expneurol.2020.113273

    2        Preclinical validation of the micropipette-guided drug administration (MDA) method in the maternal immune activation model of neurodevelopmental disorders https://www.sciencedirect.com/science/article/pii/S0889159120302543

    3      Identifying obstacles preventing the uptake of tunnel handling methods for laboratory mice: An international thematic survey https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231454


    Transcript

    It’s the Third Thursday of May and you’re listening to 3 Minute 3Rs, your monthly recap of efforts to replace, reduce, and refine the use of animals in research. This episode, we’ll be talking about that last R, starting with a refined rodent model of spinal cord injury.


    [NC3Rs] Spinal cord injury research relies heavily on the use of rodent models, but these models can cause significant suffering. To address this, the UK’s RSPCA convened an expert working group whose practical experience and expertise have informed a new set of recommendations on applying the 3Rs to rodent models of spinal cord injury.

     

    The 13 recommendations include reducing the severity of cervical level injuries or applying them to just one side of the body; providing adequate pain relief as standard; and planning and publishing research in accordance with good practice guidelines. A common theme is finding a balance between refining protocols and reducing animal use – for example, the appropriate use of both male and female subjects to reduce sex bias and improve translatability.

     

    If you work on spinal cord injury, these recommendations can help guide your 3Rs initiatives and ultimately improve treatments for those affected. Read them online now in Experimental Neurology.

     

     

    [Lab Animal] Next, what if there was a better way to administer treatments to your mice? Oral gavage can cause stress and minipumps require surgery, while providing a drug in food or water for the animals to consume at their leisure can be imprecise.


    To refine oral delivery, Joseph Scarborough and colleagues at the University of Zurich present their micropipette-guided drug administration, or MDA, method.


    They trained their mice to voluntarily consume what was on offer from a micropipette by sweetening the deal, adding a touch of sweetened condensed milk mixed with water as a delivery vehicle. The mice found things palatable indeed but to validate the approach, the researchers compared pharmokinetic profiles of risperidone administered via traditional gavage and the new MDA method. Those profiles were similar, except for stress levels. Cortisone was lower in the animals who consumed the risperidone willingly.  


    To check out MDA protocol and see additional results with mouse models of maternal immune activation, see the publication in Brain, Behavior, and Immunity.



    And finally, let’s take a look at...

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    4 min
  • 3 Minute 3Rs April 2020

    You’re listening to the April episode of 3 Minute 3Rs, brought to you by the NC3Rs, North American 3Rs Collaborative, and Lab Animal.


    The papers behind the pod:

    1. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (https://www.ncbi.nlm.nih.gov/pubmed/32150618)

    2. Engineering a 3D functional human peripheral nerve in vitro using the Nerve-on-a-Chip platform. https://www.nature.com/articles/s41598-019-45407-5 

    3. Laboratory Animal Welfare Meets Human Welfare: A Cross-Sectional Study of Professional Quality of Life, Including Compassion Fatigue in Laboratory Animal Personnel https://www.frontiersin.org/articles/10.3389/fvets.2020.00114/full


    Transcript:

    Still social distancing, 3 Minute 3Rs is back with your April recap of efforts to replace, reduce, and refine the use of animals in research. Let’s get right to it, starting this month with a replacement paper related to a topic that’s probably near the top of many of our minds.


    [NC3Rs] Understandably, within recent weeks the focus of scientific research has predominantly shifted to COVID-19. While many experiments investigating treatment options or vaccines may require animals, there are opportunities where the 3Rs could be implemented in COVID-19 research.


    Researchers in Beijing have been doing just that by using in vitro and in silico methods to investigate the impacts of Chloroquine and Hydroxycholoroquine, two drugs that have recently received media attention. In their publication in Clinical Infectious Diseases, Yao et al used an established cell line to determine both drugs reduced the replication of COVID-19 in vitro. When administered prior to viral challenge, Hydroxychloroquine provided increased protection over Chloroquine. The group then used existing data from clinical trials and in vivo studies to develop an in silico physiologically based pharmacokinetic model and investigate potential effective dosing regimens in humans. The data from this publication are now being used to inform the design of a future clinical trial.


    While further experiments will be needed to confirm whether Hydroxycholoroquine is able to help patients with COVID-19, the publication demonstrates there continues to be opportunities to apply the 3Rs in scientific research. And where these opportunities exist, the 3Rs principles should always be considered. 


     [NA3RsC] Neurodegenerative diseases such as Alzheimer’s and ALS are often serious, life-threatening, and without a cure. Treatments can help, but finding drugs that work in final human clinical trials has been challenging. In part, this is due to the difference in biology between human and animal models. Microphysiological systems hold potential to increase translation but developing neural related models...

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    5 min
  • 3 Minute 3Rs March 2020
    The March 2020 episode of 3 Minute 3Rs, brought to you by the NC3Rs (www.nc3rs.org.uk), the North American 3Rs Collaborative (www.na3rsc.org), and Lab Animal (www.nature.com/laban)The papers:1. https://pubmed.ncbi.nlm.nih.gov/320766332. https://www.sciencedirect.com/science/article/pii/S02732300203005073. https://www.nature.com/articles/s41598-020-59012-4Transcript[NC3Rs] Nanomedicines have many potential advantages, including their ability to home to specific diseased tissues and exert a localised effect. Due to their relatively large size, the biodistribution of nanomedicines does not follow the same rules as small molecules and is largely dictated by the diameter of the blood vessels they pass through en route to their target tissue. This means that although current methods to assess biodistribution rely heavily on the use of animals including rodents and non-human primates, the results can vary greatly between preclinical species and man. Using an in vitro cell based model of nanoparticle uptake to build a computer simulation, Edward Price and colleagues at the University of Central Florida have developed a predictive system to replace animal use for determining nanomedicine PKPD. The model takes account of blood vessel size, tissue-specific porosity and the kinetics of distribution to cellular and paracellular compartments. By being able to better predict where nanomedicines will end up in the body, scientists can design safer and more effective drugs based on nanomaterials without using animals to assess biodistribution. For more information on their study, see the paper linked in the podcast description.[NA3RsC] Human safety is a key priority when developing new drugs. Toxicity testing often requires drugs to be used in animal models before human clinical trials. Historically, toxicology testing has involved two species: one rodent and one non-rodent. However, in some cases, only 1 animal species is used successfully. This month, an international working group of 37 diverse organizations led by Dr. Helen Prior published a paper on this topic in Regulatory Toxicology and Pharmacology. They reviewed data from 172 potential new drugs, across a wide range of small molecules and vaccines. These potential new drugs were tested in either 1 or 2 species. The working group found that often when 2 species were used they showed similar toxicity profiles in both. Therefore, it may be possible to reduce the number of species new drugs are tested in while maintaining human safety. [LA]. Social housing is generally recommended for social species, such as the mouse, whenever possible. But housing animals together can lead to incidences of aggression – an unwanted outcome for the welfare of the animals involved. Female mice tend to get along just fine, but males can sometimes be another story. In a new 14 week study measuring aggression and physical signs of well-being in male Cd-1 mice, a stock with an aggressive reputation, Paulin Jirkof and colleagues consider three variables that might influence how well those animals get along: group size, the age at which males are allocated to their groups, and handling frequency. The full results can be found in the journal Scientific Reports but overall levels of aggression were actually low. And for these mice, three was not a crowd. Trios got on better than pairs, with solo males scoring the lowest on measures of well-being.

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    4 min
  • 3 Minute 3Rs February 2020
    The February 2020 episode of 3 Minute 3Rs, brought to you by the NC3Rs (www.nc3rs.org.uk), the North American 3Rs Collaborative (www.na3rsc.org), and Lab Animal (www.nature.com/laban).1. https://www.sciencedirect.com/science/article/pii/S00928674193132362. https://www.sciencedirect.com/science/article/pii/S01650270193030973. https://www.ncbi.nlm.nih.gov/pubmed/31852563[NC3Rs] If you are bitten by a snake today, your anti venom treatment would be largely similar to if you were bitten 100 years ago.Anti venom is created by isolating antibodies from a large animal, typically a horse, after the animal has been given repeated injections of small amounts of venom. But due to issues with anti venom production, efficacy and safety standards, over 100,000 people worldwide will die from snake bites each year. Venom is a complex mix of molecules, which vary between different snake species and can only be obtained by milking snakes. This has been an obstacle in anti venom research. But now scientists from the Netherlands have generated an in vitro method for producing venom from snake venom gland cells cultured in 3d structures. In a publication Cell, Post et al. successfully cultured snake venom gland organoids from nine different snake species including the Cape Coral Cobra.The organoids growing definitely and produce functioning toxins, which could be used to further anti venom research. The organoids could also have further reaching consequences by enabling the development of new treatment options that might avoid the need for animals altogether. You can read more about snake venom gland organoids by following the link in the description.[LA] Neurons are often studied in cell cultures, but those cultures have to come from an animal originally. Nor do they last all that long – primary neuron cultures generally need to be used in a few weeks. That can put a rush on reproducing experiments, and often means extra animals need to be maintained for future use. To make cultures from a given cohort of mice last, researchers from University College London present a protocol to cryopreserve brain tissue and prepare neuronal cultures from it. Neurons retrieved from cryopreserved mouse hippocampi perform on par with freshly dissected cultures, with most physiological properties appearing unaffected by the process. Properly stored in liquid nitrogen, tissues can be frozen for at least two years. The results and step-by-step details can be found in the Journal of Neuroscience Methods. [NA3RsC] In a manuscript recently published in JAALAS, Dr. Brianna Gaskill and Dr. Joe Garner address considerations for publishing negative results and make practical recommendations for conducting sufficiently powered research. This includes challenging the traditional use of a priori power analyses and pilot studies for justifications is animal numbers and instead using more sophisticated experimental designs and calculating the least significant number of experimental units necessary to produce sufficient power. The authors suggest that researchers collaborate with experts in biostatistics, comparative medicine and other disciplines early in the research planning process in order to consider improvements in experimental design and select of appropriate statistical tests. Such collaboration will ensure the creation of high-quality experiments, helping researchers to address the 3Rs while improving reproducibility and translational value of animal studies. Finally, the authors offer recommendations for reporting to improve the interpretation of results.

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    4 min
  • 3 Minute 3rs January 2020
    The January 2020 episode of 3 Minute 3Rs, brought to you by the NC3Rs (www.nc3rs.org.uk), the North American 3Rs Collaborative (www.na3rsc.org), and Lab Animal (www.nature.com/laban).Papers:1. https://doi.org/10.15252/embr.2019497092. https://www.nature.com/articles/s41598-019-56860-73. https://doi.org/10.1177/0023677219879455[NC3Rs] Academic scientists produce many of the clever ideas which end up as medicines. However, the results in the papers reporting the work are almost always positive, and null or negative results rarely get a look in – a phenomenon known as publication bias. This is problematic as the negative or null data could be useful to other researchers. It can also lead to a culture of striving for positive results, potentially increasing poor experimental design or the inappropriate use of statistics. Overall this contributes to the so-called ‘reproducibility crisis’ and means that animals are used in studies that are not correctly designed to demonstrate an effect. In response to this, scientists at the German Centre for the Protection of Laboratory Animals have set up a global ‘Animal Studies Registry’ where a researcher can preregister their study and following completion the Registry is updated with the results. This publicly accessible database allows scrutiny of the planning and execution of animal studies. The Registry could become an important addition to the preregistration landscape - time will demonstrate the impact this can have on reproducibility and the use of animals in research. You can read more about the registry in this month’s EMBO Reports via the link in the description. [LA] Next, how do you handle your mice? There’s growing evidence that picking up the animals with cupped hands or a tunnel is less aversive than picking them up by the tail, but mice still need to be familiarized with the process. Across an entire animal facility, that time can add up. What’s practical? Kelly Gouveia and Jane Hurst from the University of Liverpool have some suggestions. They recently evaluated BALBc mice handled by the tail, cupped hands, or a tunnel in three experiments: the first looked at the impact of holding duration; the second, the frequency of handling; and the third, responses to repeated immobilization for necessities such as subcutaneous injections. Tunnels rose to the top. Mice became familiar with tunnel handling from use during routine animal husbandry – a couple seconds each cage change was sufficient, and tunnel-acclimated animals remained less stressed than their tail-handled peers, even after the repeated immobilizations,. For all the details, see the publication in the Journal Scientific Reports. And finally, let’s hit the wheel running with another refinement. [NA3RsC] Objectively measuring well-being in laboratory mice can be challenging. In a study published in the journal Laboratory Animals, voluntary wheel running behavior was evaluated as a measure of discomfort and disease severity in a mouse model of human Inflammatory Bowel Disease. While voluntary wheel running has been successfully used to assess severity levels in singly housed mice, mice are social animals. Here, voluntary wheel running was assessed in group housed mice undergoing DSS-induced colitis and in group housed mice that underwent a blood collection procedure at 3 different time points throughout the study. While a there was a significant reduction in wheel running and body weight, and a significant elevation in histological scores as disease severity increased, there were few signs of disturbed well-being based on clinical scores alone. Wheel running was also decreased in mice that underwent blood collection while other measures remained unaffected. This study suggests that voluntary wheel running may be a sensitive and suitable tool for individual severity assessment in group housed mice and offers a refinement to welfare by enabling social housing

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    5 min
  • 3 Minute 3Rs December 2019
    The December episode of 3 Minute 3Rs, brought to you by the NC3Rs (www.nc3rs.org.uk), the North American 3Rs Collaborative (www.na3rsc.org), and Lab Animal (www.nature.com/laban).Papers: 1. Cage aggression in group-housed laboratory male mice: an international data crowdsourcing project. https://www.nature.com/articles/s41598-019-51674-z2. Towards animal-free neurotoxicity screening: Applicability of hiPSC-derived neuronal models for in vitro seizure liability assessmenthttps://www.altex.org/index.php/altex/article/view/13213. Optimal solid state neurons https://www.nature.com/articles/s41467-019-13177-3[NC3Rs] Mice are social creatures. It's why we house them in groups in the lab to improve their welfare and allow the animals to make social interactions that simply aren't possible if they're individually housed. However, the social groupings mice make in the wild are complex, with hierarchies of social dominance. In the lab group has mice are kept in cages, which means dominant and subordinate males must stay in close quarters, which can lead to aggression related stress and injuries. To better understand this welfare concern, the NC3Rs have used a crowdsourcing approach, engaging with lab technicians worldwide to estimate the prevalence of male mouse aggression. Data from over 100,000 mice in over 45,000 cages was submitted for analysis, which has been published last month in Scientific Reports.The publication by Lidster et al. recommends small practical husbandry changes such as spot cleaning cages or transferring nesting material to minimize male mouse aggression. You can find out more in the link in the description. [NA3RsC] While drug approval rates are on the rise, only about 10% of drugs in phase 1 development will gain full approval. One of the causes of drug attrition is drug-induced seizures; There is a need for more translational in vitro alternatives to predict seizure liability. Here, the authors evaluated three human induced pluripotent stem cell (hiPSC)-derived neuronal models. All models demonstrated development of functional neuronal networks that exhibited parameters linked to seizure-like events in vivo. These parameters were then modulated with three compounds known to induce seizures. Differences in sensitivity were found between the models. Yet, compared to rat primary cortical neurons, the in vitro models were equally, or better able to detect seizureogenicity. While the authors recommend more compounds be tested and the available models further characterized before serving as full replacement, this data indicates the potential of these in vitro models as initial screening tools for seizure liability assessment which could lead to reduced animal use requirements. [LA] Neurons transmit electrical signals – so too do silicon chips. Moving that in vivo function in silico has long been a goal of many neuroscientists, but biological neurons are complex, and their electrical properties and nuances have been difficult to predict and mimic artificially. That hasn’t stopped researchers from trying. A team led by Alain Nogaret at the University of Bath recently made progress, presenting artificial neurons on a silicon chip that matched the patterns of rat neurons with over 90% accuracy. It took lots of mathematical modeling, derived equations, and tweaking, but the team was able to optimize the chips so that they relayed electrical signals in the non-linear fashion that’s characteristic of biological neurons, all with considerably less power required than prior attempts. The design details and rat neuron comparisons can be found in the journal Nature Communications.

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    4 min
  • 3 Minute 3Rs November 2019
    The November episode of 3 Minute 3rs, brought to you by the NC3Rs (www.nc3rs.org.uk), the North American 3Rs Collaborative (www.na3rsc.org), and Lab Animal (www.nature.com/laban).Papers:1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662399/2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371849/3. https://pubs.rsc.org/en/content/articlelanding/2019/LC/C9LC00160C [NA3RsC] Evaluation of developmental and reproductive toxicity is a key aspect of drug development. Each year, 5-7% of newborns worldwide are born with serious birth defects, a number correlated to increased use of pharmaceutical drugs for managing health conditions. Reproductive toxicology studies account for roughly 90% of all animal use in toxicological safety assessment. The FDA requires that these animal studies be performed in two species, often rodents and rabbits. The embryonic stem cell test (EST) is an alternative in vitro assay that does not require the use of pregnant animals but is not yet powerful enough to provide a complete alternative, as it only considers the direct toxicity of compounds. Consequently, in vivo animal models are still required to evaluate effects on drug metabolism.This research established an in vitro platform (metaEST) which uses 3D embryoid bodies and 3D primary human liver microtissues on a chip to evaluate alterations in metabolism. Not only does this significantly reduce the number of animals required, these results demonstrate the platform’s ability to evaluate metabolic effects that are missed using the standard EST assay and mimic physiologically relevant conditions in vitro.[NC3Rs] Botulinum neurotoxin can cause fatal paralysis following ingestion or infection of a wound and is a potential bioterrorism agent. Therefore, the ability to quickly and accurately detect the toxin in a sample is crucial. The current method used to detect the toxin is the mouse lethality bioassay, where mice are injected with neurotoxin to determine the LD50 value, or the dose that kills half the animals. This uses approximately 70,000 mice per year in the UK and more than 600,000 mice annually worldwide and causes severe suffering prior to death. Researchers at the Centers for Disease Control and Prevention in the US have developed a mass spectrometry-based method that can successfully identify botulinum neurotoxin activity for the four human-toxic serotypes. It is faster - the test can be done in just 4- 6 hours on the spectrometer rather than the 1- 4 days typically required by the mouse bioassay. The test also requires samples with volumes as low as 100 µL per toxin type, instead of the 1 mL required for the mouse bioassay, avoiding the problem of insufficient sample volumes. This mass spectrometry- based assay is a fast and accurate alternative to the mouse bioassay and further implementation of the technique has the potential to reduce the number of animals used for this purpose. [LA] Tissues do not exist in isolation from one another. As increasingly sophisticated organ-on-chip technologies continue to emerge, many researchers want to link those chips together to mimic multi-organ systems. That’s been easier said than done. Yi-Chin however has been working on making better connections. The new microfluidic platform she helped developed consists of modular tissue and fluid control units, referred to as TILE modules. With the help of magnetic connectors, these modules can be arranged and re-arranged into different perfusion circuits as needed. It’s backwards compatible too, meaning existing microfluidic devices can be used. The team involved demonstrated the platform in action with 2 and 3 tissue modules that mimic liver-mediated bio activation in response to a nutraceutical and a cancer prodrug. All using human cells, rather than animal models.

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    5 min

About 3 Minute 3Rs

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3 Minute 3Rs is your monthly recap of efforts to replace, reduce, and refine the use of animals in research, brought to you by the NC3Rs, the North American 3Rs Collaborative, and Lab Animal.

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