Science, technology and innovation @ Rodrigo Nunes Cal

This is a blog with a lot of very updated, interesting and important human health news. This blog has a very big amount of relevant links, texts, images, photos and videos. I started to elaborate it in 2018. Many people of different countries have visited it and liked it, including excellent researchers, professors and scientists in the world. I did it with so much dedication in a little time. It was a very hard work. It´s a very easy, practical and fast way to know excellent information about science, technology and innovation worldwide! So, this blog sharing is very important to the human health. I hope with this blog to contribute significantly to the technical-scientific and socio-economic development of the countries. The human expectancy of life worldwide needs to increase so much faster by more efficient researches, brilliant ideas and excellent projects, for example. The advances of technologies have to improve the human life, of course. Os avanços das tecnologias tem que melhorar a vida humana, com certeza. A difusão dos conhecimentos é muito importante para a sociedade mundial. The diffusion of knowledge is very important to the world society. ´´NÃO VÁ PARA ONDE O CAMINHO PODE TE LEVAR. VÁ ONDE NÃO HÁ CAMINHO E DEIXE UMA TRILHA. ´´ &@´´DON'T GO WHERE THE PATH CAN TAKE YOU. GO WHERE THERE IS NO PATH AND LEAVE A TRAIL. ´´ @ CONHECENDO O DESCONHECIDO.. @ KNOWING THE UNKNOWN.. @ I was invited by Twitter to participate in Science Advisory Board – an online community of scientific and medical professionals from all around the world. I have been invited to be a Speaker/Delegate in numerous International Conferences and Congresses by E-mail, Twitter, Facebook and LinkedIn. Images and videos about this subject are in this blog. É óbvio que o virtual não é igual ao real porque há algumas ou muitas diferenças e particularidades próprias de cada situação. It is obvious that the virtual is not the same as the real because there are some or many differences and peculiarities of each situation. @ Esse é um blog muito diferente dos demais blogs e sites. This is a very different blog from other blogs and websites. The blog capacity is already exhausted due to the large amount of information on this blog! The world we live is very interdependent, for sure. O mundo em que vivemos é muito interdependente, com certeza. We will make a chain of dissemination of this blog!! Do your part!! Vamos fazer uma corrente de divulgação deste blog!! Faça a sua parte!! Thank you in advance !! Obrigado desde já!!

Sem categoria

I have been invited to be a Speaker/Delegate in numerous International Conferences and Congresses in a little time by E-mail, Twitter, Facebook and LinkedIn. Images and videos about this subject are in this blog @ Link and some information about my dissertation and monograph & Human Monoclonal Antibody Neutralizes SARS-CoV-2 in Cell Culture – May 04, 2020 | Original story from Utrecht University & Article: A human monoclonal antibody blocking SARS-CoV-2 infection – Nature Communications volume 11, Article number: 2251 (2020) @ CRISPR: The Revolutionary Gene-editing Tech – Alice Larter April 18, 2020 @ ´´Research is “creative and systematic work undertaken to increase the stock of knowledge, including knowledge of humans, culture and society, and the use of this stock of knowledge to devise new applications.”[1] It involves the collection, organization, and analysis of information to increase our understanding of a topic or issue. At a general level, research has three steps: 1. Pose a question. 2. Collect data to answer the question. 3. Present an answer to the question.´´ https://en.wikipedia.org/wiki/Research @ Animal models in biological and biomedical research – experimental and ethical concerns – An. Acad. Bras. Ciênc. vol.91 supl.1 Rio de Janeiro 2019 Epub Sep 04, 2017 & Bioinformatics: Unravelling the genes – The emerging field of bioinformatics merges computer science and biology in an attempt to make sense of the torrential data of human genomes and proteomes. @ Precision NanoSystems Signs License Agreement with Fujifilm for Nanomedicine Development 2020-05-08 (5) @ Search Magazine January 03, 2017 WHAT IS A MOUSE MODEL? By Dayana Krawchuk, Ph.D. – The Jackson Laboratory @ Mouse models of human disease – An evolutionary perspective – Evol Med Public Health. 2016; 2016(1): 170–176. Published online 2016 May 21. @ Mouse Model – Mouse models are an important instrument in studies of cardiac physiology, and the murine heart is in many aspects a suitable parallel model of human physiology. From: Models of Seizures and Epilepsy (Second Edition), 2017 @ DISEASE MODELS & MECHANISMS – Generating mouse models for biomedical research: technological advances – Channabasavaiah B. Gurumurthy, Kevin C. Kent Lloyd Disease Models & Mechanisms 2019 – Published 8 January 2019 @ ANIMAL MODELS – Charles River @ Definition of mouse model – NCI – National Cancer Institute: The use of special strains of mice to study a human disease or condition, and how to prevent and treat it. @ Introduction to Mouse Models – History of mice as a model for human disease – Koch Institute for Integrative Cancer Research – Massachusetts Institute of Technology 500 Main Street, Building 76 Cambridge MA, 02139-4307 617-253-6403 &@ AN OVERVIEW OF MOUSE MODELS FOR COVID-19 – Megan M. MacBride, PhD Monday, March 30, 2020 & BACKGROUND ON MOUSE AS A MODEL ORGANISM – NATIONAL HUMAN GENOME RESEARCH INSTITUTE #&@ Mouse Models for Disease Research @ About animal disease model @ Precision mouse models with expanded tropism for human pathogens – Nature Biotechnology volume 37, pages1163–1173(2019) – Article Published: 26 August 2019 @ Mouse Models of Cancer – Annual Review of Pathology: Mechanisms of Disease Vol. 6:95-119 @ Mouse Models for Atherosclerosis Research—Which Is My Line? #@ Why use a fully customized mouse model? © genOway @ Customized Rat Models – © genOway &@ Genetically Engineered Cell Lines – © genOway @ Animal Models of Human Pathology – SPECIAL ISSUE – ->-> ANIMAL MODELS OF CARDIOVASCULAR DISEASES @ A Handbook of Mouse Models of Cardiovascular Disease @ VERY IMPORTANT LINKS AND IMAGES, INCLUDING SOME RELATED TO SLIDES ABOUT ANIMAL MODELS OF DISEASES LIKE CARDIOVASCULAR DISEASES @ GENERAL COMMENTARY ARTICLE Front. Immunol., 21 April 2020 | https://doi.org/10.3389/fimmu.2020.00811 Commentary: Origin and evolution of pathogenic coronaviruses – Shun Adachi1, Takaaki Koma2, Naoya Doi2, Masako Nomaguchi2 and Akio Adachi1* https://www.frontiersin.org/articles/10.3389/fimmu.2020.00811/full?utm_source=S-TWT&utm_medium=SNET&utm_campaign=ECO_FIMMU_XXXXXXXX_auto-dlvrit

Review Article

Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis

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 2019 Aug;16(8):457-475. doi: 10.1038/s41569-019-0179-0.

Animal models of arrhythmia: classic electrophysiology to genetically modified large animals.

Abstract

Arrhythmias are common and contribute substantially to cardiovascular morbidity and mortality. The underlying pathophysiology of arrhythmias is complex and remains incompletely understood, which explains why mostly only symptomatic therapy is available. The evaluation of the complex interplay between various cell types in the heart, including cardiomyocytes from the conduction system and the working myocardium, fibroblasts and cardiac immune cells, remains a major challenge in arrhythmia research because it can be investigated only in vivo. Various animal species have been used, and several disease models have been developed to study arrhythmias. Although every species is useful and might be ideal to study a specific hypothesis, we suggest a practical trio of animal models for future use: mice for genetic investigations, mechanistic evaluations or early studies to identify potential drug targets; rabbits for studies on ion channel function, repolarization or re-entrant arrhythmias; and pigs for preclinical translational studies to validate previous findings. In this Review, we provide a comprehensive overview of different models and currently used species for arrhythmia research, discuss their advantages and disadvantages and provide guidance for researchers who are considering performing in vivo studies.


Animal models of human cardiovascular disease, heart failure and hypertrophy 

Cardiovascular Research, Volume 39, Issue 1, July 1998, Pages 60–76, https://doi.org/10.1016/S0008-6363(98)00110-2
Published:
01 July 1998

Article history

Oxford University Press
Issue Cover
Volume 39
Issue 1
July 1998

Animal models for arrhythmias https://academic.oup.com/cardiovascres/article/67/3/426/506197

Cardiovascular Research, Volume 67, Issue 3, August 2005, Pages 426–437, https://doi.org/10.1016/j.cardiores.2005.06.012
Published:
15 August 2005

Article history

Animal Models of Cardiovascular Disease
Modelos animales de enfermedad cardiovascular
Francisco J Chorroa, Luis Such-Belenguera, Vicente López-Merinoa
a Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Departamentos de Medicina y Fisiología, Universidad de Valencia, Valencia, Spain

Motriz: Revista de Educação Física

On-line version ISSN 1980-6574

Motriz: rev. educ. fis. vol.23 no.spe Rio Claro  2017  Epub May 02, 2017

https://doi.org/10.1590/s1980-6574201700si0005

MINI REVIEW

Exercise training on cardiovascular diseases: Role of animal models in the elucidation of the mechanisms

Bruno Rodrigues1

Daniele Jardim Feriani1

Bruno Bavaresco Gambassi1

Maria Claudia Irigoyen2

Kátia De Angelis3

Coelho Hélio José Júnior4

1 Universidade Estadual de Campias, Campinas, SP, Brazil

2 Instituto do Coração, São Paulo, SP, Brazil

3 Universidade Nove de Julho, São Paulo, SP, Brazil

4 Universidade Estadual de Campias, Campinas, SP, Brazil

 

https://www.scielo.br/scielo.php?script=sci_arttext&pid=S1980-65742017000500206

EXPERIMENTAL MODEL

A resource for selecting animal models of heart disease

https://www.nature.com/articles/s41684-019-0425-4

Federspiel, J.D. et al. PLoS Biol17, e3000437 (2019)

https://www.nature.com/articles/s41684-019-0425-4

Animal Models of Heart Failure

A Scientific Statement From the American Heart Association
and on behalf of the American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology
Originally publishedhttps://doi.org/10.1161/RES.0b013e3182582523Circulation Research. 2012;111:131–150

https://academic.oup.com/cardiovascres/article/39/1/60/273021

Animal models of human cardiovascular disease, heart failure and hypertrophy 

Cardiovascular Research, Volume 39, Issue 1, July 1998, Pages 60–76, https://doi.org/10.1016/S0008-6363(98)00110-2
Published:
01 July 199

Article history

. 2017 Jan; 31(1): 3–10.
Published online 2016 Sep 29. doi: 10.7555/JBR.30.20150051
PMCID: PMC5274506
PMID: 26585560

Animal models of coronary heart disease

Rodent Models ->  https://www.creative-biolabs.com/drug-discovery/therapeutics/rodent-models.htm?gclid=CjwKCAjwqdn1BRBREiwAEbZcR4tfSCcNBTexgB1qQVKPnyTjZAbGBpbwyZ7tNECibmTG1COINypN-xoCFZ8QAvD_BwE

Animal Models of Human Pathology

View this Special Issue


Review Article | Open Access

Volume 2011 |Article ID 497841 | 13 pages https://doi.org/10.1155/2011/497841

Animal Models of Cardiovascular Diseases

Academic Editor: Oreste Gualillo
Received11 Oct 2010
Revised04 Jan 2011
Accepted17 Jan 2011
Published16 Feb 2011

Abstract

Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology, making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available, models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against human cardiovascular diseases.

https://www.hindawi.com/journals/bmri/2011/497841/

https://www.genoway.com/contact-us/contact-genoway.htm

https://www.genoway.com/services/customized-cell/overview.htm

https://www.genoway.com/services/customized-rat/overview.htm

https://www.genoway.com/services/customized-mouse/overview.htm

https://www.frontiersin.org/articles/10.3389/fcvm.2019.00046/full

https://www.annualreviews.org/doi/abs/10.1146/annurev.pathol.3.121806.154244#

https://en.wikipedia.org/wiki/Animal_disease_model

https://www.the-scientist.com/techedge/mouse-models-for-disease-research-65931

https://www.genome.gov/10005834/background-on-mouse-as-a-model-organism

https://www.taconic.com/taconic-insights/infectious-disease/covid-19-mouse-model-guide.html

https://ki.mit.edu/sbc/escell/models

https://www.cancer.gov/publications/dictionaries/cancer-terms/def/mouse-model

https://www.criver.com/products-services/find-model

https://dmm.biologists.org/content/12/1/dmm029462

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/mouse-model

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875775/

https://www.jax.org/news-and-insights/2017/january/what-is-a-mouse-model

Precision NanoSystems Signs License Agreement with Fujifilm for Nanomedicine Development

https://statnano.com/news/67623/Precision-NanoSystems-Signs-License-Agreement-with-Fujifilm-for-Nanomedicine-Development?fbclid=IwAR2oaQ3AdxF4hQi0dj3EHCuPvLI0bBTX2qRf86YriZ422XxUOo8LICR1Nys

 

https://teletype.in/@divya/aIqbjaAeU?fbclid=IwAR0NvSzC1Iw-pz_QSoXmkwCAFayfuyWbM2pPt-hZqA1HTDg8RFRj_jM3d0A

 

Animal Models of Human Pathology

View this Special Issue


Review Article | Open Access

Volume 2011 |Article ID 497841 | 13 pages https://doi.org/10.1155/2011/497841

Animal Models of Cardiovascular Diseases

Academic Editor: Oreste Gualillo
Received11 Oct 2010
Revised04 Jan 2011
Accepted17 Jan 2011
Published16 Feb 2011

Abstract

Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology, making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available, models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against human cardiovascular diseases.

ACADEMIA BRASILEIRA DE CIÊNCIAS – > http://www.abc.org.br/

http://www.abc.org.br/fale-conosco/

https://www.instagram.com/abciencias/

https://www.youtube.com/user/academiabrasciencias

https://www.facebook.com/abciencias

Abstract

The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Nonetheless, mice and humans have evolved in and become adapted to different environments and so, despite their phylogenetic relatedness, they have become very different organisms. Mice often respond to experimental interventions in ways that differ strikingly from humans. Mice are invaluable for studying biological processes that have been conserved during the evolution of the rodent and primate lineages and for investigating the developmental mechanisms by which the conserved mammalian genome gives rise to a variety of different species. Mice are less reliable as models of human disease, however, because the networks linking genes to disease are likely to differ between the two species. The use of mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans.

Keywords: allometry, cancer, gene networks, life history, model organisms

CONTATOS GERAIS DA ABC

+55 21 3907-8100
Rua Anfilófio de Carvalho, 29 – 3º Andar Centro – Rio de Janeiro, RJ – Brasil CEP:20030-060

Rua Anfilófio de Carvalho, 29, 3º andar
20030-060 Rio de Janeiro RJ Brasil
Tel: +55 21 2533-6274
+55 21 2532-0562

http://www.abc.org.br/membros/?busca_membro_categoria=titular

https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652019000200701

CRISPR: The Revolutionary Gene-editing Tech

https://teletype.in/@alice.larter/GHzEeUwEa?fbclid=IwAR0AdQbLKITOIF4A7N4GVMdcyIaTwCCp87Tu8JGj0GJwOdV_CQETJtAzTQg

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Bioinformatics: Unravelling the genes

The emerging field of bioinformatics merges computer science and biology in an attempt to make sense of the torrential data of human genomes and proteomes.Sequencing the human genome has been one of the crowning achievements of modern biology, not only because of its sheer scale but also because of its potential impact on our understanding of human evolution, physiology, and disease. And yet, unraveling the sequence of bases was the “easy” part. Now comes the hard part of figuring out the meaning of this sequence of 3 billion A’s, G’s, C’s, and T’s.The prospect of analysing such a vast torrent of data has led to the identification of a new discipline, called bioinformatics, which merges computer science and biology in an attempt to make sense of it all. For example, computer programmes that analyse DNA for stretches that could code for amino acid sequences are used to estimate the number of protein-coding genes.Download PDF Brochure of Study, Click Here!

Bioinformatics Platforms

Such analyses suggest the presence of about 30,000 protein-coding genes in the human genome, half of which were not known to exist. The fascinating thing about this estimate is that it means humans may have only about twice the number of genes as do worms or files! Computer analysis has also revealed that only about one to two per cent of the human genome actually codes for proteins.

While the remaining DNA contains some important regulatory elements as well as some genes that code for RNA products instead of proteins, most of it appears to consist of “junk” DNA with no apparent function.

Because the function of most genes is to produce proteins which are responsible for most cellular functions, scientists are now looking beyond it to study proteome — the structure and properties of every protein produced by a genome. The complexity of an organism’s proteome is considerably greater than that of its genome. For example, the roughly 30,000 genes found in human cells are thought to produce somewhere between 200,000 and a million or more proteins. This is why cells can produce so many proteins from a smaller number of genes.

In essence, it reflects the fact that an individual gene can be “read” in multiple ways to produce multiple versions of its protein product. The resulting proteins are subject to biochemical modifications that can significantly alter their structural and functional properties.

Identifying the vast number of proteins produced by a genome has been facilitated by mass spectrometry, a high speed, extremely sensitive technique that utilises magnetic and electric fields to separate proteins or protein fragments based on differences in mass and charge. One application of mass spectrometry has been to identify the peptides derived from proteins separated by gel electrophoresis and then digested with specific proteases, such as trypsin.

By comparing the resulting data to the predicted masses of peptides that would be produced by DNA sequences present in genomic databases, the proteins produced by newly discovered genes can be identified. Other techniques make it feasible to study the interactions and functional properties of the vast number of proteins found in a proteome.

For example, it is possible to immobilise thousands of different proteins (or other molecules that bind to specific proteins) as tiny spots on a piece of glass smaller than a microscope slide. The resulting protein microarrays can then be used to study a variety of protein properties, such as the ability of each individual spot to bind to other molecules added to the surrounding solution.

Want to Know more about Bioinformatics, Bioinformatics Platforms, Bioinformatics services? Just go through the Link and get PDF

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Precision NanoSystems Signs License Agreement with Fujifilm for Nanomedicine Development

2020-05-08

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Precision NanoSystems Signs License Agreement with Fujifilm for Nanomedicine Development

Precision Nanosystems announced partnership with Fujifilm Corporation for the development and GMP manufacturing of nanoparticle based therapeutics.

Precision Nanosystems, Inc. (PNI), a global leader in enabling transformative nanomedicines announced that the company entered into a license agreement with FUJIFILM Corporation to adopt PNI’s NanoAssemblr™ technology and complete suite of instruments for Fujifilm’s state-of-the-art manufacturing facility, compatible with GMP regulations of US, Europe and Japan.As part of this agreement, Fujifilm has the rights to offer contract manufacturing services using PNI’s proprietary technology and also use PNI technology to develop and commercialize its internal therapeutic drug products. PNI and Fujifilm will work together to combine and democratize the scalable manufacturing of gene therapy and small-molecule based nanomedicines using Fujifilm’s and PNI’s proprietary technologies.PNI’s NanoAssemblr technology is powered by the disruptive NxGen microfluidics mixing technology designed exclusively for scalable nanomedicine development while maintaining precise control and reproducibility. The NanoAssemblr platform is comprised of the Spark, Ignite, Blaze and GMP Systems that together offer a flexible solution for accelerated, cost-effective development and scalable manufacture of high-quality gene therapy, small molecule and protein-based nanomedicine products.

James Taylor, Co-Founder and CEO of PNI said, “We are thrilled to work with Fujifilm to enable our technology in support of clinical clients as they progress their therapeutic programs from the laboratory to the clinic and commercial. Fujifilm’s R&D teams will combine the PNI platform and their proprietary Drug Delivery Systems technologies and we look forward to the seamless scaling up and manufacturing of innovative medicines to impact human well-being.”

Nanomedicines is one of the focus areas of Fujifilm, tapping into its advanced technologies such as nano-technology, process engineering technology and analysis technology. “We are excited to work with PNI to bring on board the NanoAssemblr suite of products and cutting-edge nanomedicines manufacturing technology,” said Junji Okada, Senior Vice President, General Manager of Pharmaceutical products division, FUJIFILM Corporation.

“Tapping into Fujifilm’s state of the art technology, expertise and the facility for the provision of pre-clinical and GMP manufacturing services, we are committed to creating innovative and high-value pharmaceutical products not only through internal development but also by providing high quality liposomal formulations to our partner companies.”

 

Read the original article on Precision Nanosystems‎.

 

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Gratidão: Convites p/ eu participar de eventos científicos muito importantes do mundo em pouco tempo

Video – Gratitude: I am very grateful because I was invited by Internet through direct messages to participate in 55 very important science events in the world in 25 cities in less than 1 year. I participated of very important researches in Brazil. Information about it are in this blog.

Vídeo – Gratidão: Estou muito grato porque fui convidado através de mensagem direta por meio da Internet para participar de 55 eventos muito importantes do mundo em 25 cidades em menos de 1 ano porque participei de ótimas pesquisas no Brasil. Informações sobre este assunto estão no ´´meu´´ blog.

Acknowledgment for the recognition of the researches I participated in Brazil

Video – Acknowledgment for the recognition of the scientific works (dissertation and monograph) I participated at the Medical School of Sao Jose do Rio Preto (FAMERP) and Federal University of the Triangulo Mineiro (UFTM). Informations about it are in my blog.

Agradecimento pelo reconhecimento das pesquisas que participei no Brasil

Acknowledgment for the recognition of the scientific works (dissertation and monograph) I participated at the Medical School of Sao Jose do Rio Preto (FAMERP) and Federal University of the Triangulo Mineiro (UFTM). Informations about it are in my blog.

I was invited to participate in 35 very important science events in the world in 16 cities – Time

I was invited by Internet through direct messages to participate in 72 very important science events in 31 cities in less than 2 years (Auckland, Melbourne, Toronto, Edinburgh, Madrid, Suzhou, Stanbul, Miami, Singapore, Kuala Lumpur, Abu Dhabi, San Diego, Bangkok, Dublin, Sao Paulo, Dubai, Boston, Berlin, Stockholm, Prague, Valencia, Osaka, Amsterdam, Helsinki, Paris, Tokyo, Vienna, Rome, Zurich, London and Frankfurt) because I participated of very important researches. Fui convidado pela Internet por meio de mensagem direta para participar de 72 eventos científicos de grande importância mundial em 31 cidades em menos de 2 anos.


https://science1984.wordpress.com/contato/

I´m graduated in Biomedicine at Federal University of Triangulo Mineiro (Uberaba – 2003-2007), I have a Master´s degree in lung cancer research in mice at Faculty of Medicine of Sao Jose do Rio Preto (2008-2012). Nowadays I work as inspector of students since 2012 in Sao Jose do Rio Preto. Maybe I can do a doctorate and PhD to work as professor, scientist and researcher abroad or in Brazil.

There´re in this blog a very big amount of very important, interesting and updated information about science, technology and innovation like human health news!! I did it in a very little time. It was a very hard work. I hope in some way with my blog to help significantly in the socio-economic and technical-scientific development of the countries.
There are very relevant links, videos, images, texts, photos, 914 posts, 11,0 thousand comments and 122 followers. I started to did it in 2018. I don´t earn money from it. Many people of the world have visited and liked it such as brilliant professors, researchers and scientists in the world! The blog goals are ony help in anyway people, increasing human expectancy of life by more efficient researches, projects and ideas, for example! So, it´s very important you visit and share this blog! The diffusion of knowledgement is fundamental for a country progress always, of course. The scientific community needs to have valuable information to improve the world.

I was invited by Twitter to participate in Science Advisory Board – an online community of scientific and medical professionals from all around the world.

In less than 2 years I was invited by Internet through direct messages to participate in 77 very important scientific events in 32 cities in different countries because I participated of very innovative and important researches in Brazil like my dissertation [lung cancer research in mice – The influence of physical activity in the progression of experimental lung cancer in mice. Pathol Res Pract.  2012 Jul 15;208(7):377-81] and my monograph (Chagas disease research in laboratory at Federal University of Triangulo Mineiro – Uberaba city).

* Link about my monograph: Induction of benzonidazole resistance in human isolates of Trypanosoma cruzi: https://science1984.wordpress.com/2018/07/15/my-monography-chagas-disease-research-in-laboratory-2/

– Link related with my dissertation: https://science1984.wordpress.com/2018/07/15/i-did-very-important-detailed-and-innovative-graphics-about-variations-of-all-mice-weigths-during-all-exerimental-time-my-dissertation-they-can-be-an-excelent-reference-for-future-researches-like-2/

Science events and researches are essential for the world progress in all aspects. The human life expectancy needs to increase urgently in a short time through more efficient scientific researches of high quality and precision for example. The world is interdependent. 

Unfortunately there are fatal diseases without cure or total prevention methods like vacination. Therefore, new scientific discoveries are very necessary for human life.

It´s very important professors, scientists, students, researchers and other people worldwide know about my dissertation made at Faculty of Medicine of Sao Jose do Rio Preto because it was a very innovative and important research as well as my monograph.

The data like graphics I made about variations of weights in all mice of different ages (Control Group -> treated with urethane and without physical activity and Study Group – Aerobic Group -> treated with urethane and subjected to aerobic swimming free exercise – Anaerobic Group –> treated with urethane and subjected to anaerobic swimming exercise with gradual loading 5-20% of body weight) during all experimental time [My dissertation -> Lung cancer research in mice – Article: The influence of physical activity in the progression of experimental lung cancer in mice – Pathol Res Pract. 2012 Jul 15;208(7):377-81] are essential for the world scintific community.

 

These graphics I did related to my dissertation aren´t in the article nor in my dissertation as well as details about time of exercise and rest of the animals. They can be an excellent reference for many types of researches like in the field of genetic engineering! The discussion of certain facts in science envolving stastistics is very important to the scientific community, of course, for example, graphics with no statistical difference between them. 

 

The age of the human, of the animal like mouse with the genetics influence in certain ways in the pathophysiology and in other aspects in the humans and mice. This subject is not easy to understand, o course. So, mice researches are essential for the world society as well as human researches. More informations about it are in this link: https://science1984.wordpress.com/2018/07/15/i-did-very-important-detailed-and-innovative-graphics-about-variations-of-all-mice-weigths-during-all-exerimental-time-my-dissertation-they-can-be-an-excelent-reference-for-future-researches-like-2/

Very important observations:

  1. Cancer is very related to the weight loss of the patient. Weight loss of the patient is very associated with cancer – The syndrome of Anorexia-Cachexia (SAC) is a frequent complication in patients with advanced malignant neoplasia.
  2. Age, weight and genetics of the person are very important factors that influence cancer in a determined ways.
  3. The genetics of the mouse is very similar to that of the human.
  4. Maintaining proper body weight is one of the main ways to prevent cancer of a person.
  5. Animal testing has a very high importance to world society.
  6. The mouse is the main animal model used as the basis for research on diseases that affect humans.
  7. Weight lifting (bodybuilder) is a very good example of anaerobic physical activity in humans.

 

In my dissertation the progression of lung cancer was lower in the group of mice that practiced anaerobic physical activity. Weight lifting is an anaerobic physical activity in humans. It would be very important, innovative and interesting to do research in mice and humans testing a substance or substances and analyzing biochemical, pathological, pharmacological and physiological factors like weights in all experimental time (weight loss of the patient is very associated with cancer) and the influence of age and genetics within the group itself and in the other groups in the inhibition and progression of cancer testing a substance, for example. In this context, it is very important to seek new methodologies for the treatment, prevention and early detection of cancer and other diseases, such as vaccines and other very modern and efficient technologies.

Note about ´´my´´ dissertartion: during anaerobic exercise it was necessary to briefly hold the tail of the mice for better physical performance and better adaptation to the submitted environment. In this same type of exercise, there were times when the mice could not exercise and sank, causing manual manipulation again. The physical wear of the animals was intense.

It´s very important to consider the significance of variants of weight, age and genetics em relation to cancer. It is not easy understand it. Therefore, more researches about it are very necessary in the world. This subject is very important for human health.

I hope that researchers, teachers, students, scientists and other people linked to scientific researches worldwide use the graphics I made about the variations of all mice weights during all experimental time of my dissertation as an example, model or reference for conducting scientific researches as well as other data from my monograph and dissertation, leading to a very beneficial innovation in the methodology bringing very important and relevant results to the world society, significantly increasing the human life time more and more.

Many laboratories have been researching mice for a long time, even resulting in prizes for researchers such as the Nobel Prize. For example, the Jackson Laboratory in the United States of America – USA. The world needs to have more very good and eficiente ideas and scientific discoveries for human live longer faster more and more. This subject is very relevant to the world, of course.

YouTube Channel: https://www.youtube.com/channel/UC9gsWVbGYWO04iYO2TMrP8Q

Curriculum Lattes: http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4240145A2

LinkedIn Profile: https://www.linkedin.com/in/rodrigo-nunes-cal-81433b168/

E-mails Acoounts: rodrigonunescal@yahoo.com rodrigoncal1984@gmail.com

Twitter: @CalZole

Instagram accounts: @calrodrigonunes @rodrigoncal84

https://www.researchgate.net/scientific-contributions/76406552_Rodrigo_Nunes_Cal?_sg=ZIpVjGGv7eVzEc9yJ9aPkTMGB6pMQsrWx29bFgaQAZqbcOeBtkDU9nJbgRH4EGlpmSGNWbF7nSuHpA  

Visit, watch and share it if possible!! These subjects have high importance for world society, of course!

I hope collaborate significantly with these information in the world scientific progress always.


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Anais da Academia Brasileira de Ciências

Print version ISSN 0001-3765On-line version ISSN 1678-2690

An. Acad. Bras. Ciênc. vol.91  supl.1 Rio de Janeiro  2019  Epub Sep 04, 2017

https://doi.org/10.1590/0001-3765201720170238

BIOMEDICAL SCIENCES

Animal models in biological and biomedical research – experimental and ethical concerns

MONICA L. ANDERSEN 1  

LUCILE M.F. WINTER 2  

1Departamento de Psicobiologia, Universidade Federal de São Paulo/UNIFESP, Rua Napoleão de Barros, 925, 04024-002 São Paulo, SP, Brazil

2Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo/USP, Rua do Matão, Travessa 14, 05508-090 São Paulo, SP, Brazil


ABSTRACT

Animal models have been used in experimental research to increase human knowledge and contribute to finding solutions to biological and biomedical questions. However, increased concern for the welfare of the animals used, and a growing awareness of the concept of animal rights, has brought a greater focus on the related ethical issues. In this review, we intend to give examples on how animals are used in the health research related to some major health problems in Brazil, as well as to stimulate discussion about the application of ethics in the use of animals in research and education, highlighting the role of National Council for the Control of Animal Experimentation (Conselho Nacional de Controle de Experimentação Animal – CONCEA) in these areas. In 2008, Brazil emerged into a new era of animal research regulation, with the promulgation of Law 11794, previously known as the Arouca Law, resulting in an increased focus, and rapid learning experience, on questions related to all aspects of animal experimentation. The law reinforces the idea that animal experiments must be based on ethical considerations and integrity-based assumptions, and provides a regulatory framework to achieve this. This review describes the health research involving animals and the current Brazilian framework for regulating laboratory animal science, and hopes to help to improve the awareness of the scientific community of these ethical and legal rules.

Key words: animal use; biology; ethics; research

INTRODUCTION

Animals have been used in studies and research for millennia in human history. Evidence shows that even in ancient Greece, Aristotle used animals in his studies, mainly to advance the understanding of living animals. But it was only during the 18th and 19th centuries that the development of animal models expanded, with many scientists, such as Jean Baptiste Van Helmont, Francesco Redi, John Needham, Lazzaro Spallanzani, Lavoisier and Pasteur, conducting animal experiments to study the origin of life (Oparin 1957).

In addition to being used to investigate the basic principles of life, animals were also used to develop a better understanding of animal and human anatomy, physiology, pathology and pharmacology. The possibility of experimenting under controlled situations and mimicking biological conditions of human and animal diseases reinforced the development of scientific methods and the creation of the concept of animal biological models.

Animal models have been responsible for the most important knowledge advances in many biological fields (Institute of Medicine and National Research Council 1988, 1991, Lieschke and Currie 2007). From Claude Bernard’s classic study describing the role of the pancreas in digestion and the development of the oral live Polio virus vaccine by Albert Sabin, to the use of animals for the understanding of the pathogenicity of the Zika virus in the present day, animals have greatly contributed to scientific knowledge and improvements in quality of life. Animals have contributed to the development of new drugs and vaccines, as well as new surgical techniques and anesthesia protocols. Although there is some concern about extrapolating clinical relevance from animal data (Greek and Menache 2013), the progress made through the use of animal models is unquestionable, and nearly 90% of Nobel Prize research in Physiology and Medicine, used animal experiments in their discoveries.

To be used as a model, animal species must meet specific criteria in line with the final goal of the research. Many species are used in biomedical research, such as insects (Drosophila), nematodes (Caenorhabditis elegans), fish (Danio rerio, or zebrafish), frogs (Xenopus) and many mammals, such as mice, rats, dogs, cats, pigs and monkeys, due to their phylogenetic proximity to humans (Institute of Medicine and National Research Council 1991). Sometimes the model must be modified to meet specific characteristics: An interesting example is the development by Vivien Thomas and Alfred Blalock of a model that simulated the congenital heart defect tetralogy of Fallot (also known as the blue baby syndrome) in a dog. This model allowed the development of the surgical method that currently saves more than half a million children per year (Timmermans 2003). Nowadays, with the progress of genetic and genomic tools, genetic engineering techniques can easily be applied in order to develop knockout or transgenic animals that are used in research. Some of these constructs achieve the so-called “humanization” status through the graft of human cells that perform their primary functions in the recipient animal, allowing researchers to study responses to pathogens as if it were happening in a human environment (Ernst 2016). It is also important to emphasize that to obtain reliable results, the health quality of the animal used as a model is fundamental, and thus, it is in the interest of the researcher to have healthy and well treated animals.

THE IMPORTANCE AND CHALLENGES OF ANIMAL BIOMEDICAL RESEARCH

There is a dichotomy in the use of animals in translational research, especially research encompassing behavioral aspects: some studies produce promising results that could be applied to humans, while others fail to demonstrate any similarity between the animal model and the human condition.

We will first describe a situation in which animal models have been shown to be extremely useful in unravelling the mechanisms of human physiology, and have given scientific support to new therapeutic approaches: the use of non-human primates as models in biomedical research. Non-human primates have been used in animal research due to their close phylogenetic relationship to humans, involving proven similarities in terms of genetics, behavioral and biochemical activities. The demand for the use of non-human primates as models in scientific research continues to grow, and some species continue to be considered important for several fields of research, such as the study of human diseases (AIDS, Parkinson’s disease and hepatitis, among others), psychological and psychiatric disorders, toxicology, transplants, nutrition (including infant nutrition), dentistry, drug abuse and vaccine development. Animal research benefits not only humans, but also the animals themselves. For instance, animals, such as dogs and cats are living longer and healthier lives thanks to vaccines for rabies, parvo virus, tetanus and feline leukemia, among other breakthroughs made in Veterinary Medicine thanks to animal research.

Although the importance of the use of non-human primates in research continues to be critical to increasing our knowledge in many fields, a large bioethical discussion about the use of non-human primates in these studies has been taking place, especially regarding animals that are genetically closer to humans in the evolutionary scale, such as chimpanzees. After 2007, only the United States and Gabon continued using chimpanzees for research. In 2015, the United States passed a law classifying chimpanzees in captivity, including laboratory animals, as an endangered species. As a result, the National Institutes of Health (NIH), the main institution supporting research in the United States, has declared that it would no longer finance any research involving chimpanzees. The impact of this decision in the United States had major worldwide repercussions, leading to increased widespread discussion about the use of non-human primates for research. Activist groups in the United States welcomed this decision, and are now putting even more pressure on the United States government to end the use of non-human primates for scientific studies. However, the need for translational research is even stronger, and this process invariably requires experimental tests in non-human primates. With increasing pressure from lobby groups and some parts of the regulatory and funding systems, researchers have attempted to be more open about their animal studies and keen to promote dialog on the subject. The main objective has been to clarify the importance of non-human primate research and to make it evident that all procedures performed on experimental animals are conducted following rigorous scrutiny that guarantees that the studies are conducted to high ethical standards (Foundation for Biomedical Research 2016).

In Brazil, very little research with non-human primates is carried out compared to other countries, such as the United Kingdom and the United States. Even so, the National Council for the Control of Animal Experimentation (Conselho Nacional de Controle de Experimentação Animal – CONCEA) has been continuously updating policies related to the ethical demands for the use of primates in research. The public was invited to examine and comment on the standards proposed by CONCEA (Resolução Normativa 28 – CONCEA 13/11/2015) for the maintenance and use of non-human primates in Brazilian research. The process resulted in the publication, in November 2015, of the chapter: “The use of non-human primates in research and/or education” (Primatas não humanos mantidos em instalações de instituições de ensino ou pesquisa científica) in the CONCEA Guide for use of Animals in Research or Education (Guia Brasileiro de Produção, Manutenção ou Utilização de Animais em Atividades de Ensino ou Pesquisa Científica) (http://www.mct.gov.br/upd_blob/0240/240230.pdf pgs 207-267). In all its other official documents, CONCEA continues to clearly state that the use of primates in research is restricted to situations in which there are no other available alternative methods of study.

Despite all the benefits that can arise from animal biomedical research, several studies show negative or inconsistent results. Animal models occasionally fail to reproduce the complexity of human behavioral disturbances, and have a limited ability to detect some effects (for review, see Kalueff et al. 2007). In addition, some of the results obtained from basic (animal) research are not found during clinical trials. This provides evidence against the principles of basic biomedical research: to generate knowledge that is useful and translationally relevant to the clinical arena. To the general public, this lack of clinical applicability in some studies can outweigh the increasing amount of research results that have life-saving implications, and leads to skepticism and the questioning of the value of animal research. In this regard, basic research meta-analysis can be an important tool in providing the full picture of the results of animal use, as it allows the translational validity of animal models to be properly assessed, and provides guidance for future studies which prevents experimental animals being used in ineffective models (Pires et al. 2016).

ANIMAL MODELS FOR INFECTIOUS DISEASES STUDIES – PATHOGENICITY, DRUG TARGETING AND VACCINE APPROACHES

It is important to understand the extent of pathogeneses and the mechanisms by which the infection is established for the development of vaccines. It is historically known that the first human vaccine, developed by the young British physician Edward Jenner, was a result of his observation of dairymaids who used to handle cows in the milking process. Jenner observed that because these women had had cowpox, they were never infected with smallpox. This inspired Jenner to inoculate the cowpox virus as a protective practice against smallpox (Riedel 2005). The Jenner vaccine was very important to mankind, and resulted in the eradication of smallpox. Therefore, the first vaccine was only possible due to the use of a living model. The work of Louis Pasteur in developing the rabies vaccine, for both dogs and humans, is another example of the efficiency of vaccination in protecting against virus-caused diseases.

In addition to viruses, bacteria can also be the etiological agent of many human or animal diseases. Antibiotic therapy has helped to control many of them, and, just like for viruses, protection and prevention from some bacteria-caused diseases can be obtained through vaccination. This practice is so efficient that the World Health Organization has produced a complete vaccination schedule for infants and adults against many biological agents: (http://www.who.int/immunization/policy/immunization_tables/en/).

In the following section, we will give some examples on how animal models shed light onto the etiology of infections, leading to treatment, prevention and control protocols.

HIV/AIDS

Although vaccination is the best choice for controlling viruses, the development of a vaccine is not always easy or possible. In the end of the last century, one of the most remarkable and dramatic events in terms of public health was the advent of the acquired immunodeficiency syndrome (AIDS) epidemic that killed millions of people, especially in at-risk populations. With the lack of an efficient vaccine, the search for chemotherapy treatment for patients infected with human immunodeficiency virus (HIV) became urgent.

The major problem with HIV is its elevated human tissue tropism, making it difficult to model the condition in animals. The virus is not able to infect mice, rats, rabbits, or macaques, although it can replicate in chimpanzees (Victor Garcia 2016). Thus, initial efforts focused on the use of non-human primate models infected with a SIV (simian immunodeficiency virus), an HIV-like virus that infects Rhesus monkeys, producing clinical signals similar to human AIDS. Another non-human primate model used in efforts to refine and develop new treatments for AIDS and HIV infection, the sooty mangabey, is naturally infected with a strain of SIV and is the source of HIV-2, a less-virulent strain of HIV. This dual-model (virus/host) has been used to develop a better understanding of the pathogenesis of the virus in order to develop drugs and preventive strategies, such as the development of vaccines (Micci and Paiardini 2016).

Antiretroviral treatments are now very effective in suppressing HIV replication. However, treatment interruption leads to a resurgence of AIDS. Thanks to non-human primate research on AIDS and HIV, a leading HIV/AIDS preventive vaccine is now licensed and in phase 2a human clinical trials. In addition to primate research, other animal models have been used to address the most relevant aspects of HIV infection, mostly virus persistence. First, humanized mice were obtained by transplantation of human cells or tissues in partially irradiated immune-deficient animals (Shultz et al. 2012). From this initial effort, different humanized mice models have been developed and are now being used to advance the HIV/AIDS field (Victor Garcia 2016).

ZIKA VIRUS

The Zika virus (ZIKV) is an RNA containing virus belonging to the Flaviviridae family, related to yellow fever, dengue and West Nile viruses. ZIKV originated from the Zika forest – Uganda, and was initially isolated from a yellow fever sentinel Rhesus monkey (Macaca mulatta) in 1947 (Dick et al. 1952). It was only isolated from a human in 1968 (Moore et al. 1975Fagbami 1977), who clinically only presented fever. Artificially feeding Aedes aegypti mosquitoes on infected mice and monkeys confirmed that the transmission is made by the bite of mosquitoes from the Aedes genus (Boorman and Porterfield 1956).

Although the ZIKV was widely spread in Africa and Asia, the clinical aspects of the infection were considered mild, with a low incidence of human infection. However, in 2007 an outbreak of the infection occurred in Micronesia and patients presented fever, headache, anorexia, maculopapular rash, conjunctivitis, and arthralgia, but in all cases the clinical condition was, again, considered mild, self-limiting, and non-lethal (Lanciotti et al. 2008). In 2013, an Asiatic strain of ZIKV made its way to Brazil and became established in a large population of Aedes aegypti, a highly competent and anthropophilic vector species. This association produced an ongoing ZIKV epidemic in Brazil, with dramatic clinical consequences that correlated ZIKV infections and microcephaly cases (de Fatima Vasco Aragao et al. 2016).

To incontestably prove the correlation between ZIKV infection and microcephaly, Brazilian researchers chose the SJL mouse model, a strain defective in its ability to suppress T- cells (Hutchings et al. 1986) and notorious for its susceptibility to virus infections (Dahlberg et al. 2006). By infecting pregnant SJL females with a Brazilian ZIKV isolate, Cugola et al. (2016) demonstrated that the offspring presented clear signs of underdevelopment as well as a higher viral load in the brain when compared to mock-infected pups. Further investigation of ZIKV-infected mice brains showed cortex malformation with reduced cell number and cortical layer thickness. Those observations are consistent with human microcephaly (Cugola et al. 2016). Cugola et al. (2016) also used alternative cell cultures to correlate ZIKV-infection and microcephaly phenotype. ZIKV-infected human pluripotent stem cells derived from neural progenitor cells showed apoptotic cell death. Another alternative approach was the use of two-dimensional neural cell culture, neurospheres and cerebral organoids, that, when infected with ZIKV revealed cell death and a significantly smaller size compared to control cells. Furthermore, the use of tri-dimensional cerebral organoids derived from stem cells, simulating the first trimester of neurodevelopment in humans, also confirmed the reduction of cortical cells and the apoptotic phenotype. Infections of these tissues with the African strain of ZIKV did not show those signals, indicating that the Brazilian strain suffered a mutation/adaptation that led to the microcephaly condition (Cugola et al. 2016). In addition to the above described immunocompromised mice models, recently a study used the classical C57BL6 mice to show how an immunocompetent mammal activated the innate response and induced an antiviral T cell response in ZIKV infection. The study also showed a new epitope in the ZIKV envelope that is recognized by CD8+ T cell, an important finding for vaccines development (Pardy et al. 2017). Another study also using the immunocompetent C57BL6 showed windows, that could be correlated to human embryogenesis when infection caused the congenital abnormalities that result the microcephaly picture (Xavier-Neto et al. 2017).

Beyond the understanding of the pathophysiology of ZIKV infection, animal models are also being used for the development of therapeutic targets and vaccines for the control and prevention of ZIKV infections. Larocca et al. (2016) achieved immunity protection against the Brazilian ZIKV in mice models using different vaccination protocols (ZIKV DNA-based vaccine and purified formalin inactivated virus vaccine). The authors also showed that the protection could be achieved against the Puerto Rico ZIKV isolate as well. The same research group also observed promising results with the two immunization protocols in Rhesus monkeys (Abbink et al. 2016). The efforts in achieving an effective vaccination protocol has led the Butantan Institute in São Paulo (BR) to concentrate their efforts on the production of the DNA vaccine, with a promise of getting to a first round of human tests in 2017.

CHIKUNGUNYA VIRUS

Another important virus that is currently a subject of public health concern in Brazil is the Chikungunya virus (CHIKV). It is a Togaviridae RNA virus also transmitted by Aedes bites. The symptoms of acute infection in humans (i.e. fever, headache, myalgia, fatigue and polyarthalgia), although painful, resolve in a few days. The most prominent problem is the recurrent appearance of arthralgia that might compromise the quality of life of the affected individual (Couturier et al. 2012Schilte et al. 2013). The chronic symptoms are due to the ability of the virus to replicate in joint tissues and muscle cells. Despite the global spread of the virus, affecting millions of patients, its pathogenesis is still unknown. This emphasizes the fact that animal models related to viral replication are still warranted in order to promote the understanding of the immunological responses that can lead to the development of drugs and vaccines (Ozden et al. 2007).

Mice present many advantages as models for CHIKV infection. In addition to the low cost and ease of maintenance, the existence of a large panel of commercial antibodies, established lineages that provide colonies with the same genetic background, and the possibility of choosing genetically modified animals has led researchers to study the CHIKV in mouse models. These studies have investigated acute infections, lethal neonatal challenges, immune-commitment, as well as the main clinical signs of infection, such as arthritis, myositis and chronic development of peripheral joint lesion and muscle pain (Haese et al. 2016).

In addition to mice models, CHIKV is also being investigated using the old world monkey group belonging to the genus Macaca, such as the Rhesus (M. mulatta), Bonet (M. radiate) and Cynomolgus (M. fascicularis) monkeys (Haese et al. 2016). The macaque model is especially relevant to the study of CHIKV pathogenesis and the efficacy of drugs and vaccines.

EUKARYOTIC PATHOGENS

The list of viruses or bacteria involved in human diseases is long: here we give a few examples on how animal models have been used to understand virus/host interactions and provide solutions, such as treatments and prevention strategies.

The study and development of preventive tools for eukaryotic organisms is particularly problematic. The higher level of complexity in these organisms besides the many mechanisms they employ for evading host responses have made it impossible to develop effective vaccines for eukaryotic organisms. This highlights the relevance of animal models that can lead to a better understanding of the host/pathogen relationship, and ultimately ways to control these infectious agents.

In the early 1900’s, Carlos Chagas, a bright young Brazilian physician and researcher, described the etiological agent as well as the mode of transmission of Chagas’ disease using an animal model. Chagas was in a small town in the countryside of Minas Gerais (later named Lassance, after the engineer Ernesto Lassance Cunha) working on a campaign against malaria during the construction of an extension of the Central do Brazil Railroad. Chagas had an interest in research, and used to collect and examine the local fauna. Examining a blood sample of a marmoset (Callithrix penicillata), he noticed the presence of a protozoan of the Trypanosomatidae family. At that time, similar organisms had been implicated in the cattle disease Nagana as well as in human sleeping sickness in Africa. Thus, Chagas took a careful look at that organism and described a new species, named Trypanosoma minasense. At the same time, Chagas was alerted by another engineer, Cornélio Cantarino Mota, to the presence in the region of a hematophagous bug known as “barbeiro” (barber bug or kissing bug) from the Triatominae family. Chagas collected and dissected some of these insects and, in the digestive tract of the bugs, found protozoan forms that he initially thought to be T. minasense in another stage of the life cycle. Chagas sent some live bugs to the Instituto Manguinhos (now, Instituto Oswaldo Cruz/RJ) and asked Oswaldo Cruz to feed marmosets kept under clean conditions with the insects. Subsequently, flagellates were detected in the controlled marmoset blood. Back in Manguinhos, Chagas then examined the flagellate samples and realized that it was not T. minasense, but another new species he called T. cruzi after his mentor Oswaldo Cruz. Suspecting that the parasite could also infect humans, Chagas went back to Lassance and started to examine the blood of patients, finally connecting the presence of T.cruzi with the symptomatology of Chagas’ disease. It is remarkable to note that this classic demonstration of the etiological agent of a disease, as well as of the transmission cycle and identification of possible vectors and reservoirs, took place in early 1900’s.

Although enormous progress has been made in the understanding of the relationship between T. cruzi and the host, few drugs have been developed for the treatment of Chagas’ disease to date and no vaccines. All treatments available for the disease are a result of studies that essentially used animal models.

Leishmania is another protozoan responsible for a re-emergent disease in Brazil and in other regions of the world. Leishmaniasis consists of a complex framework of clinical signs. The World Health Organization estimates a worldwide prevalence of 12 million cases of leishmaniasis, with an annual mortality of 60,000 people and an at-risk population of approximately 350 million people in 88 countries around the world (http://www.who.int/leishmaniasis/burden/en/).

Leishmania is also transmitted by an insect bite in this case the vectors are sandflies belonging to the Psychodidae family. Many mammal species can harbor the parasite. Sylvatic mammals constitute reservoirs for the disease, complicating the epidemiological control. Domestic animals, like horses, cats and mainly dogs are infected and contribute to the transmission to humans.

In the mammal host, Leishmania is an obligate intra-cellular parasite found mainly in macrophages which, together with monocytes, constitute the body’s phagocyte system. To survive and replicate in this defense cell, the parasite evades the humoral immune response against Leishmania produced by the host, by residing within the phagocytosomes of the macrophages. One of the strategies used to fight against invaders is the activation of oxidative burst, induced with the phagocytosis of these organisms (Cunningham 2002). Nitric oxide synthase 2 (NOS2) is also a very important enzyme in macrophage response, and when activated produces citrulline and nitric oxide (NO) from the oxidation of L-arginine: NO is a highly reactive, effector molecule which can combat invasive microorganisms (Qadoumi et al. 2002). Thus, a good animal model to be used in Leishmania studies must fulfill all these features.

The chosen model uses inbred mice, specifically, the resistant C57BL/6 that produces a T helper (Th) 1 immune response and the BALB/c susceptible mice that produces a Th2 response (Sacks and Noben-Trauth 2002). The Th1 response promotes NOS2 activation and NO production (Bogdan 2001) and the Th2 response is associated with the production of IL-4 and IL-13 (Sacks and Noben-Trauth 2002). In respect to NO production, the amino acid arginine was shown to be a key molecule in the success or failure of the parasite in establishing the infection. In addition to being a substrate of NOS2, arginine can also be used by arginase I to produce urea and ornithine, the last being precursor of the polyamines involved in the replication of the parasite. It is interesting to note that in a Th2 response, arginase I is also activated. Leishmania itself presents arginase activity, and in a construction of a parasite with the arginase knocked out, it was possible to show that Leishmania arginase is related to parasite replication and survival (da Silva et al. 2012, da Silva and Floeter-Winter 2014).

In relation to NO/ornithine physiological duality, it is interesting to note that the healing of human cutaneous leishmaniasis is associated with a Th1 response (Alexander and Bryson 2005), corroborating the observation of the mice model. However, in humans, the participation of NO in killing the parasite is still an open question, which has been addressed with the use of “humanized” mice such as the NSG strain that does not have B and T cells from mice, and also presents a higher rate of engraftment with human hematopoietic cells (Wege et al. 2012).

As already mentioned in this review, it is important that the appropriate model is used to provide the required conditions to answer a specific scientific question. This was the case in a study to understand the physiological role of the “darkness hormone” melatonin in Leishmania infection. The best animal model for melatonin studies is the rat model, but rats are refractory to Leishmania infection. The best model for Leishmania study is the mice model, but mice are too small for sample collection to analyze melatonin effects. Hence, Laranjeira-Silva et al (2015) validated a hamster model in the case of melatonin/Leishmania. The results of this research showed that melatonin impairs Leishmania infection, pointing to potential new treatments, as well as indicating a possible explanation of why sylvatic mammals do not develop disease signs, because, being nocturnal animals, they are infected during the night when they present high levels of melatonin in the bloodstream.

ETHICAL CONCERNS ON THE USE OF ANIMALS IN BIOLOGICAL RESEARCH

Based on the above examples, one can understand how difficult it is to conduct animal research. It is important to note that beyond adequate technical knowledge, animal experimentation requires that ethical concerns speak louder than scientific interests. Each researcher must have a complete understanding of the animal model being used, and of the biology and behavior of that species. Researchers must also be aware of the importance of the work being conducted, and consider all the premises that justify each specific project based on a solid scientific background (see Andersen and Tufik 2010, Andersen and Helfenstein 2015).

Animal experimentation has incited a great deal of debate, with a lot of the discussion focusing on ethical considerations. The British parliament was pioneer in enacting laws regarding the use of animals in research (http://web.archive.org/web/20061214034848/http://homepage.tinet.ie/~pnowlan/Chapter-77.htm). In 1876 it introduced the Cruelty to Animals Act, which amended the previous 1849 Act, and included regulation of animal experimentation. The act highlighted three main points: 1. animal experiments should only be carried out when there is absolute need of knowledge that will be useful for saving or prolonging life or alleviate suffering; 2. the animals must be anesthetized; and 3. the animals must be killed immediately after the experimental procedure if they would be injured or in pain as a result of the experiment.

The Principle of the 3R’s also emerged from the United Kingdom. A young zoologist, William Russell, who also worked as a psychologist, and Rex Burch, a microbiologist that introduced ethical aspects in laboratory techniques, produced a report that was later published as a book with the first description of the 3R’s Principle (Russel and Burch 1959). Each R stands for a principle for the ethical use of animals in experiments: Reduction is the application of methods that allow a reduced number of animals to be used in a protocol. This can be achieved by detailed planning of the experiments, guaranteeing that results will have statistical significance. The use of animals presenting the same or a similar genetic background also ensures a low fluctuation of the data, thereby reducing the number of animals which need to be used in a study. Many websites are available to access statistical methods that allow an accurate calculation of the number of animals to be used in an experiment (for example see https://www.nc3rs.org.uk/experimental-designstatistics). Nowadays, access to several available data-bases (meta-analysis) sometimes allows the number of animals used to be reduced or in some cases allows their use to be avoided completely. Refinement consists in the application of methods that avoid animal suffering, such as: the use of anesthesia during a procedure and analgesic regimens for pain relief during recovery; the use of non-invasive techniques; housing conditions that provide a comfortable and safe environment and training the animal to cooperate with procedures. Replacement is the major goal for the use of animals in science. It consists of the substitution of animals with other models, such as microorganisms or other invertebrates, cell cultures, organs or even cellular fractions. The ideal replacement would be a protocol conducted with no use of animals.

The 3R’s Principles are now universal, and guide animal research in many countries. There is a growing commitment of the scientific community to the implementation of the Principles of Russell-Burch (Russel and Burch 1959) of “reduction, replacement and refinement” in the use of experimental animals.

In 2010, as initiative of the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines were published and are currently endorsed by scientific journals and by funding agencies, and others. The ARRIVE guidelines that has been translated in several languages have a checklist of 20 items relating information, such as the number and specific characteristics of animals used (e.g. species, sex, strain, genetic background); housing and husbandry; and the experimental, statistical, and analytical methods. The goals are to improve the design, analysis and reporting of research using animals maximizing information published and minimizing unnecessary studies, as pointed out by Kilkenny et al. (2010). Collectively, 3Rs, ARRIVE guidelines and additional initiatives are marked efforts to accomplish ethical background in biomedical research.

BRAZILIAN LEGISLATION ON THE USE OF ANIMALS IN BIOLOGICAL RESEARCH

Due to the efforts of the physician and researcher Sergio Arouca, in 2008, after lengthy discussion in the Brazilian National Congress, Brazil emerged into a new era of animal research regulation with the promulgation of Law no.11794/2008, previously known as the Arouca Law. This law established the Conselho Nacional de Controle de Experimentação Animal (CONCEA) and regulates Ethical Committees on Animal Use (CEUAs), which are responsible for regulating animal use in education and scientific research purposes. CEUAs have the role of encouraging ethical thinking and appreciation for the concept of animal welfare, as well as to promote the development of alternative measures to the use of animals in research or practical classes.

According to the law, all projects involving laboratory animals must be submitted and reviewed by an institutional CEUA, which has the authority to halt any teaching or research practice that does not comply with the legislation. The CEUAs are formally responsible for the care and use of research and teaching-purpose animals within the institution, and must ensure that facility standards and the care of animals are in accordance with CONCEA resolutions.

After the creation of the Law no. 11794/2008 and corresponding Decree, no. 6899/2009, Brazil embarked on a long ethical and learning journey in relation to animal experimentation. We are certainly in need of programs and training courses to better prepare our students, technicians and researchers to work with laboratory animals. The teaching of Laboratory Animal Science is recent in our academic scenario, but there is a range of pedagogic materials available in different spheres, being provided by the government or available in the international literature. Brazil has reached a position of importance in the scientific community through scientific publications, and it is important that Brazil works to international norms in terms of animal experimentation so that it can continue to make major contributions to the global scientific community. Thus, we expect that not only will universities and research centers throughout the country work to the standards outlined in the current legislation, but also that further initiatives will be introduced in future, including the consolidation of research from different centers across the country. We have now established an ethical standard and specific rules for animal protection and the promotion of animal well-being in Brazil.

APPROACH TO ALTERNATIVE METHODS

Alternative methods can improve and strengthen the production of scientific knowledge while fulfilling one of the Principles of the 3R’s (Replacement). The specific advantages of the use of alternative non-animal methods are: 1. Models may be used more than once, by several people, independently of time and place of study; 2. The use of alternative models allows students to self-evaluate until they reach the aimed learning objectives; 3. Alternative methods which use modern video and computer techniques, such as 3D technology, can allow the demonstration of physiological phenomena that are impossible to visualize in animal models (e.g. animations of cells and organ function); 4. The cost of implementation of alternative methods may initially be high, but in a near future may reduce costs in terms of the acquisition, transport and maintenance of animals (Van der Valk et al. 1999).

From the teaching point of view, there is a marked emphasis from CONCEA on the replacement of animals by alternative methods in classes. The “Symposium of Alternative Methods to the Use of Animals in Teaching”, sponsored by CONCEA/MCTIC in 2016, had as its main goal the presentation of alternative methods that are were being used in Brazil, and to increase the pedagogical development of similar activities in teaching classes. The symposium resulted in wider knowledge dissemination and a marked increase in the discussion of pedagogical methods for practical teaching in the areas of biology, biomedicine, health and veterinary, among others.

In February 2016, CONCEA published in the Union Official Diary the Brazilian Directive for the Care and Use of Animals in Teaching or Scientific Research Activities (Diretriz Brasileira para o Cuidado e a Utilização de Animais em Atividades de Ensino ou de Pesquisa Científica – DBCA). This directive addresses institutional responsibility in promoting the use of alternative methods for students and the so-called “Conscious Objection”, which now holds legal and ethical power. CONCEA has established that institutions involved in animal experimentation have a legal responsibility to provide alternative methods for “Conscious Objectors” (i.e., students that oppose to the use of animals for teaching purposes), and to provide support for those students. That was a fundamental step towards more modern pedagogical practices, aiming the students’ interests without compromising the learning process.

Alternative methods have also become an exceptional ally in the reduction of the unnecessary use of animals in practical classes. In addition to being introduced to a major control and research quality based on ethical legislations, students frequently return motivated from international experiences during which they experienced appropriate learning in accordance with educational and pedagogical propositions without the use of animals. Thus, students who study abroad will become familiar with non-animal methods before they come back to Brazil and that might encourage Brazilian institutions to start looking for alternative methods.

From the research point of view, in addition to the improvements being made in the development of better animal models, a great deal of effort is being dedicated to finding alternative approaches to the use of animals: Plants, such as Arabdopis taliana, can be used as models organisms in biological research. In addition, cell cultures, in vitro approaches, the use of stem cells for differentiation and regeneration, as well as advances in the use of tools such as intravital microscopy, magnetic resonance imaging (MRI) or positron emission tomography (PET) (Lieschke and Currie 2007) scans and progress in informatics such as increased use of meta-analysis (Greek and Menache 2013) have all resulted in a substantial reduction of the number of animals used in research.

Three bodies have been established in Brazil to oversee the processes of validation of alternative methods. They are:

BRACVAM: The Brazilian Center for Validation of Alternative Methods – identifies the need to validate a method, organizes the peer-review process and provides evidence of the scientific validity of a method to CONCEA;

RENAMA: National Network of Alternative Methods – A network of laboratories which execute the validation;

CONCEA: Created by Law no.11794/2008, is the official council for alternative scientific methods in Brazil. Since 2014, it has already recognized 24 scientifically validated and internationally accepted test methods (e.g. skin corrosion/irritation, etc.).

Altogether, these bodies aim to produce reliable information on the applicability of alternative methods and the benefits that may arise from the use of these methods by researchers and students/professors.

Several regulations published by CONCEA, deal with the regulation of alternative methods. It must be pointed out that, in addition to CONCEA, ANVISA (Agência Nacional de Vigilância Sanitária) has also produced regulations in this area: RDC 35/2015. The participation of members of Animal Protection Societies in CONCEA reinforces the debate on the use of animals for research, the consideration of alternative methods and the demands of our modern society.

CONCLUSIONS

This article aims to describe and contextualize animal models and the evolution of Laboratory Animal Science. The relevance of animals for the development of Veterinary and human health is undeniable. According to rules and laws imposed by the government, research projects must be within the parameters previously established for teaching or research purposes. The use of animals in experiments must be primarily anchored in ethical and integrity-based assumptions, and most certainly must justify the use of animal.

Most citizens, regardless of their background, are concerned with the well-being of animals, while wishing to see the continued development of drugs for the treatment of disease and the maintenance of quality of life. This text provides a useful tool to demonstrate to the academic community and the wider public the progress which has been made nationally in the search for excellence in the use of animals in research and teaching activities, and the benefits that animal research provides to human beings.

Those who pursue academic goals using animal research must do so based on ethical principles and with dedication under the parameters that regulate laboratory practices. Each researcher must make every effort to employ animals in academic activities in the most ethical and responsible way, while contributing to knowledge dissemination and not forgetting the principles of the legislation.

As authors and scientists, we invite Society to be part of a wider forum, promoting reflection on, and integrity in the use of animals in science. We call on the academic community to follow the ethical and legal rules approved by the entire nation: Together, we can make scientific advances that will improve the quality of life of all citizens, while at the same time reducing the number of animals used in research and providing better treatment and conditions for the laboratory animals that continue to be used.

ACKNOWLEDGMENTS

The authors receive fellowships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq): 305177/2013-3 (MLA) and 307587/2014-2 (LMFW). The authors also thank Associação Fundo de Incentivo a Pesquisa (AFIP).

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Received: March 28, 2017; Accepted: April 06, 2017

Correspondence to: Monica Levy Andersen E-mail: ml.andersen12@gmail.com

*

Contribution to the centenary of the Brazilian Academy of Sciences.

Creative Commons License This is an open-access article distributed under the terms of the Creative Commons Attribution License

ARTICLE-PDF COVID-19

A human monoclonal antibody blocking SARS-CoV-2 infection

https://www.technologynetworks.com/proteomics/news/human-monoclonal-antibody-neutralizes-sars-cov-2-in-cell-culture-334328

https://www.nature.com/articles/s41467-020-16256-y#Abs1

Abstract

The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.

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