Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

"He Who Relies on His Brother's Property Dies Poor": The Complex Narratives of Livestock Care in Northern Tanzania.

Background: Endemic zoonoses have important impacts for livestock-dependent households in East Africa. In these communities, people's health and livelihoods are severely affected by livestock disease losses. Understanding how livestock keepers undertake remedial actions for livestock illness has the potential for widespread benefits such as improving health interventions. Yet, studies about livestock and human health behaviours in the global south tend to focus on individual health choices. In reality, health behaviours are complex, and not solely about individualised health experiences. Rather, they are mediated by a range of "upstream" factors (such as unequal provision of services), which are beyond the control of the individual. Methods: This paper presents qualitative research conducted from 2014 to 2019 for a study focused on the Social, Economic, and Environmental Drivers of Zoonoses in Tanzania (SEEDZ). Qualitative data were collected via focus group discussions, community meetings, informal interviews, formal in-depth interviews, observations and surveys that addressed issues of health, disease, zoonotic disease risks, and routes for treatment across 21 villages. Thematic analysis was carried out on in-depth interviews and focus group discussions. Conceptual analyses and observations were made through application of social science theories of health. Findings: Livestock keepers undertake a range of health seeking strategies loosely categorised around self and formal treatment. Two key themes emerged that are central to why people make the decisions they do: access to resources and trust in health care providers. These two issues affect individual sense of agency which impacts their ability to act to improve livestock health outcomes. We suggest that individual choice and agency in veterinary health seeking decisions are only beneficial if health systems can offer adequate care and health equity is addressed. Significance: This study demonstrates the value of in-depth qualitative research which reveals the nuance and complexity of people's decisions around livestock health. Most importantly, it explains why "better" knowledge does not always translate into "better" practise. The paper suggests that acknowledging and addressing these aspects of veterinary health seeking will lead to more effective provision.

Classification and characterisation of livestock production systems in northern Tanzania.

Livestock keepers in sub-Saharan Africa face a range of pressures, including climate change, land loss, restrictive policies, and population increase. Widespread adaptation in response can lead to the emergence of new, non-traditional typologies of livestock production. We sought to characterise livestock production systems in two administrative regions in northern Tanzania, an area undergoing rapid social, economic, and environmental change. Questionnaire and spatial data were collected from 404 livestock-keeping households in 21 villages in Arusha and Manyara Regions in 2016. Multiple factor analysis and hierarchical cluster analysis were used to classify households into livestock production systems based on household-level characteristics. Adversity-based indicators of vulnerability, including reports of hunger, illness, and livestock, land and crop losses were compared between production systems. Three distinct clusters emerged through this process. The ethnic, environmental and livestock management characteristics of households in each cluster broadly mapped onto traditional definitions of 'pastoral', 'agro-pastoral' and 'smallholder' livestock production in the study area, suggesting that this quantitative classification system is complementary to more qualitative classification methods. Our approach allowed us to demonstrate a diversity in typologies of livestock production at small spatial scales, with almost half of study villages comprising more than one production system. We also found indicators of change within livestock production systems, most notably the adoption of crop agriculture in the majority of pastoral households. System-level heterogeneities in vulnerability were evident, with agro-pastoral households most likely to report hunger and pastoral households most likely to report illness in people and livestock, and livestock losses. We demonstrate that livestock production systems can provide context for assessing household vulnerability in northern Tanzania. Policy initiatives to improve household and community well-being should recognise the continuing diversity of traditional livestock production systems in northern Tanzania, including the diversity that can exist at small spatial scales.

Rethinking One Health: Emergent human, animal and environmental assemblages.

One Health perspectives are growing in influence in global health. One Health is presented as being inherently interdisciplinary and integrative, drawing together human, animal and environmental health into a single gaze. Closer inspection, however, reveals that this presentation of entanglement is dependent upon an apolitical understanding of three pre-existing separate conceptual spaces that are brought to a point of connection. Drawing on research with livestock keepers in northern Tanzania, in the context of the history of livestock policy in colonial and postcolonial East Africa, this demonstrates what an extended model of One Health - one that moves from bounded human, animal and environmental sectors to co-constitutive assemblages - can do to create a flexible space that is inclusive of the multiplicity of health.

Arts-based approaches to promoting health in sub-Saharan Africa: a scoping review.

INTRODUCTION: Arts-based approaches to health promotion have been used widely across sub-Saharan Africa (SSA), particularly in public health responses to HIV/AIDS. Such approaches draw on deep-rooted historical traditions of indigenous groups in combination with imported traditions which emerged from colonial engagement. To date, no review has sought to map the locations, health issues, art forms and methods documented by researchers using arts-based approaches in SSA. METHODS: Using scoping review methodology, 11 databases spanning biomedicine, arts and humanities and social sciences were searched. Researchers screened search results for papers using predefined criteria. Papers included in the review were read and summarised using a standardised proforma. Descriptive statistics were produced to characterise the location of the studies, art forms used or discussed, and the health issues addressed, and to determine how best to summarise the literature identified. RESULTS: Searches identified a total of 59 794 records, which reduced to 119 after screening. We identified literature representing 30 (62.5%) of the 48 countries in the SSA region. The papers covered 16 health issues. The majority (84.9%) focused on HIV/AIDS-related work, with Ebola (5.0%) and malaria (3.3%) also receiving attention. Most studies used a single art form (79.0%), but a significant number deployed multiple forms (21.0%). Theatre-based approaches were most common (43.7%), followed by music and song (22.6%), visual arts (other) (9.2%), storytelling (7.6%) and film (5.0%). CONCLUSIONS: Arts-based approaches have been widely deployed in health promotion in SSA, particularly in response to HIV/AIDS. Historically and as evidenced by this review, arts-based approaches have provided a platform to facilitate enquiry, achieved significant reach and in some instances supported demonstrable health-related change. Challenges relating to content, power relations and evaluation have been reported. Future research should focus on broadening application to other conditions, such as non-communicable diseases, and on addressing challenges raised in research to date.

One Health Research in Northern Tanzania - Challenges and Progress.

East Africa has one of the world's fastest growing human populations-many of whom are dependent on livestock-as well as some of the world's largest wildlife populations. Humans, livestock, and wildlife often interact closely, intimately linking human, animal, and environmental health. The concept of One Health captures this interconnectedness, including the social structures and beliefs driving interactions between species and their environments. East African policymakers and researchers are recognising and encouraging One Health research, with both groups increasingly playing a leading role in this subject area. One Health research requires interaction between scientists from different disciplines, such as the biological and social sciences and human and veterinary medicine. Different disciplines draw on norms, methodologies, and terminologies that have evolved within their respective institutions and that may be distinct from or in conflict with one another. These differences impact interdisciplinary research, both around theoretical and methodological approaches and during project operationalisation. We present experiential knowledge gained from numerous ongoing projects in northern Tanzania, including those dealing with bacterial zoonoses associated with febrile illness, foodborne disease, and anthrax. We use the examples to illustrate differences between and within social and biological sciences and between industrialised and traditional societies, for example, with regard to consenting procedures or the ethical treatment of animals. We describe challenges encountered in ethical approval processes, consenting procedures, and field and laboratory logistics and offer suggestions for improvement. While considerable investment of time in sensitisation, communication, and collaboration is needed to overcome interdisciplinary challenges inherent in One Health research, this can yield great rewards in paving the way for successful implementation of One Health projects. Furthermore, continued investment in African institutions and scientists will strengthen the role of East Africa as a world leader in One Health research.