Guidelines for the establishment and functioning of Animal Ethics Commitees (Institutional Animal Care and Use Committees) in Africa.

Animals are used for scientific purposes across Africa to benefit humans, animals or the environment. Nonetheless, ethical and regulatory oversight remains limited in many parts of the continent. To strengthen this governance framework, the Pan-African Network for Laboratory Animal Science and Ethics brought together experts from 12 African countries to create an Africa-centric practical guide to facilitate the establishment and appropriate functioning of Institutional Animal Ethics Committees across Africa. The Guidelines are based on universal principles for the care and use of sentient animals for scientific purposes, with consideration of the cultural, religious, political and socio-economic diversity in Africa. They focus on 11 key elements, including responsibilities of institutions and of the Institutional Official; composition of the Committee; its responsibilities, functioning and authority; ethical application and review processes; oversight and monitoring of animal care and use and of training and competence; quality assurance; and the roles of other responsible parties. The intent is for African institutions to adopt and adapt the guidelines, aligning with existing national legislation and standards where relevant, thus ensuring incorporation into practice. More broadly, the Guidelines form an essential component of the growing discourse in Africa regarding moral considerations of, and appropriate standards for, the care and use of animals for scientific purposes. The increased establishment of appropriately functioning animal ethics committees and robust ethical review procedures across Africa will enhance research quality and culture, strengthen societal awareness of animals as sentient beings, improve animal well-being, bolster standards of animal care and use, and contribute to sustainable socio-economic development.

A review of challenges and prospects of 3D cell-based culture models used for studying drug induced liver injury during early phases of drug development.

Drug-induced liver injury (DILI) is the leading cause of compound attrition during drug development. Over the years, a battery of in-vitro cell culture toxicity tests is being conducted to evaluate the toxicity of compounds prior to testing in laboratory animals. Two-dimensional (2D) in-vitro cell culture models are commonly used and have provided a great deal of knowledge; however, these models often fall short in mimicking natural structures of tissues in-vivo. Testing in humans is the most logical method, but unfortunately there are ethical limitations associated with human tests. To overcome these limitations better human-relevant, predictive models are required. The past decade has witnessed significant efforts towards the development of three-dimensional (3D) in-vitro cell culture models better mimicking in-vivo physiology. 3D cell culture has advantages in being representative of the interactions of cells in-vivo and when validated can act as an interphase between 2D cell culture models and in-vivo animal models. The current review seeks to provide an overview of the challenges that make biomarkers used for detection of DILI not to be sensitive enough during drug development and explore how 3D cell culture models can be used to address the gap with the current models.

Sustainable education and training in laboratory animal science and ethics in low- and middle-income countries in Africa - challenges, successes, and the way forward.

Despite the recognised need for education and training in laboratory animal science (LAS) and ethics in Africa, access to such opportunities has historically been limited. To address this, the Pan-African Network for Laboratory Animal Science and Ethics (PAN-LASE) was established to pioneer a support network for the development of education and training in LAS and ethics across the African continent.In the 4.5 years since the establishment of PAN-LASE, 3635 individuals from 28 African countries have participated in our educational activities. Returning to their home institutions, they have both established and strengthened institutional and regional hubs of knowledge and competence across the continent. Additionally, PAN-LASE supported the development of guidelines for establishment of institutional Animal Ethics Committees, a critical step in the implementation of ethical review processes across the continent, and in enhancing animal welfare and scientific research standards.Key challenges and opportunities for PAN-LASE going forward include the formalisation of the network; the sustainability of education and training programmes; implementation of effective hub-and-spoke models of educational provision; strengthening governance frameworks at institutional, national and regional levels; and the availability of Africa-centric open access educational resources.Our activities are enhancing animal welfare and the quality of animal research undertaken across Africa, enabling African researchers to undertake world-leading research to offer solutions to the challenges facing the continent. The challenges, successes and the lessons learnt from PAN-LASE's journey are applicable to other low- and middle-income countries across the world seeking to enhance animal welfare, research ethics and ethical review in their own country or region.

A One Medicine Mission for an Effective Rabies Therapy.

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients.

COVID-19 disaster management plans for two laboratory animal facilities in South Africa.

Policies and guidelines are available for acute disasters such as earthquakes, fire and floods, however, little is available on how laboratory animal facilities should mitigate subacute disasters like the COVID-19 pandemic that imposed major restrictions on the free movement of people. As such, laboratory animal facilities had to find plausible mitigating measures to safeguard the welfare of animals in their care, to prevent animal suffering if staff could not reach the animals, albeit with limited time. The simplest approach was to stop active experiments and halt animal breeding, or to euthanize all animals. Challenges with such methods included the ethical debate regarding euthanasia of animals at the start of a pandemic and the need to perform a harm-benefit analysis while drafting the disaster plans, termination of studies at advanced stages with information loss or killing of genetically modified strains that would be difficult to replace.Two research animal facilities in South Africa addressed these challenges by implementing several changes such as allowing only essential studies to continue, maintaining small breeding colonies for essential strains, and providing staff with private transport for travelling to and from work to avoid public transport and risk of exposure to SARS-CoV-2. Engineering changes included redesigning working areas to cater for social distancing.The mitigating measures put in place by the two laboratory animal facilities were successful in ensuring the continued welfare of animals during the COVID-19 lockdown restrictions. These measures can be adopted in future pandemics that lead to restricted movement of staff.Plans de gestion en cas de catastrophes telles que le COVID-19 pour deux installations d'animaux de laboratoire en Afrique du Sud.

Characterisation of the global transcriptional response to heat shock and the impact of individual genetic variation.

BACKGROUND: The heat shock transcriptional response is essential to effective cellular function under stress. This is a highly heritable trait but the nature and extent of inter-individual variation in heat shock response remains unresolved. METHODS: We determined global transcription profiles of the heat shock response for a panel of lymphoblastoid cell lines established from 60 founder individuals in the Yoruba HapMap population. We explore the observed differentially expressed gene sets following heat shock, establishing functional annotations, underlying networks and nodal genes involving heat shock factor 1 recruitment. We define a multivariate phenotype for the global transcriptional response to heat shock using partial least squares regression and map this quantitative trait to associated genetic variation in search of the major genomic modulators. RESULTS: A comprehensive dataset of differentially expressed genes following heat shock in humans is presented. We identify nodal genes downstream of heat shock factor 1 in this gene set, notably involving ubiquitin C and small ubiquitin-like modifiers together with transcription factors. We dissect a multivariate phenotype for the global heat shock response which reveals distinct clustering of individuals in terms of variance of the heat shock response and involves differential expression of genes involved in DNA replication and cell division in some individuals. We find evidence of genetic associations for this multivariate response phenotype that involves trans effects modulating expression of genes following heat shock, including HSF1 and UBQLN1. CONCLUSION: This study defines gene expression following heat shock for a cohort of individuals, establishing insights into the biology of the heat shock response and hypotheses for how variation in this may be modulated by underlying genetic diversity.

The Governance of Animal Care and Use for Scientific Purposes in Africa and the Middle East.

Animals are commonly used for scientific purposes in Africa and the Middle East. However, this field is often inadequately regulated, with many countries lacking national legislation, policies, or guidelines for the care and use of animals used for research, testing, or education. This results in an essentially uncontrolled system where scientific quality and animal wellbeing cannot robustly be guaranteed, which may hinder acceptance (i.e., publication) of results by the scientific community and limit public confidence. Though accepted international guidelines and best practice recommendations exist that could be adopted or adapted to meet local needs, the responsible conduct of research and animal welfare may not be prioritized in regions that are affected by instability, poverty, disease, or malnutrition. Some notable exceptions do, however, exist in individual countries or institutions where ethical review processes, oversight of animal health and welfare, the competence of personnel, and other scientific standards are appropriately regulated and implemented. These countries and institutions represent nodes of expertise that could act as platforms of support for surrounding regions in terms of the provision of education, training, and sharing of experience and resources. To make such regional capacity-strengthening efforts sustainable will require regional cooperation, the establishment of regional networks, harmonization of policies, pooled resources, and long-term investment in education, training, and infrastructure. An overarching system is needed to oversee the efficient promotion of scientific and ethical standards and the dissemination of information on laboratory animal science in Africa and the Middle East, while each country should remain able to maintain a system of oversight that reflects its own cultures, traditions, religions, laws, and regulations. This article provides an overview of the governance of the care and use of animals for scientific purposes in different regions of Africa and the Middle East as a foundation for coordinated future advancement.

Validating discovered Cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations.

BACKGROUND: Localising regulatory variants that control gene expression is a challenge for genome research. Several studies have recently identified non-coding polymorphisms associated with inter-individual differences in gene expression. These approaches rely on the identification of signals of association against a background of variation due to other genetic and environmental factors. A complementary approach is to use an Allele-Specific Expression (ASE) assay, which is more robust to the effects of environmental variation and trans-acting genetic factors. METHODOLOGY/PRINCIPAL FINDINGS: Here we apply an ASE method which utilises heterozygosity within an individual to compare expression of the two alleles of a gene in a single cell. We used individuals from three HapMap population groups and analysed the allelic expression of genes with cis-regulatory regions previously identified using total gene expression studies. We were able to replicate the results in five of the six genes tested, and refined the cis- associated regions to a small number of variants. We also showed that by using multi-populations it is possible to refine the associated cis-effect DNA regions. CONCLUSIONS/SIGNIFICANCE: We discuss the efficacy and drawbacks of both total gene expression and ASE approaches in the discovery of cis-acting variants. We show that the ASE approach has significant advantages as it is a cleaner representation of cis-acting effects. We also discuss the implication of using different populations to map cis-acting regions and the importance of finding regulatory variants which contribute to human phenotypic variation.