Hominin landscapes and co-evolutionary ecology : accommodating logical incoherence and complexity

Understanding primate (and human) evolutionary environments is a key goal of palaeoanthropology. The most recent contribution to this debate, the ‘tectonic landscape model’ (TLM) is the first to explicitly invoke either the spatial structure of environments generally or the physical landscape specifically as important to hominin evolution. It adds a layer of complexity to existing models and – if correct – has broader implications for the nature and analysis of evolutionary change. This thesis evaluates the TLM and its implications for palaeoanthropology. It explores the conceptual structure that surrounds the TLM to establish how this has so far impacted palaeoanthropology, then surveys the state-ofthe-art in hominin landscape research to establish existing levels of knowledge. This suggests that little basic information is available about the structure of African landscapes themselves, their interactions with primates, or the possibility that complex cognition ‘removes’ humans from their influence. Three analytical designs are therefore developed which use landscape mapping techniques and a series of socioecological and anatomical case studies of Papio baboons and Homo sapiens to develop this baseline understanding. Although the landscape system is complex, it argues that it should be possible to explore the impacts of individual factors like topography and that there are interesting perspective-dependent relationships between landscapes and primate anatomy and socioecology, which persist in modern humans despite the considerable cultural ‘filter’ through which they view and interact with their surroundings. These insights are then used to extract three predictions from the TLM that are tested against existing knowledge of the fossil record and evolutionary pattern and process in the mammals. The key output is a new theory of human evolution, the ‘complex topography hypothesis’, which is shown to work at least as well as traditional explanations of the human evolutionary trajectory and the distinctive anatomies and ecologies of hominins including Homo sapiens.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The efficacy of antibiotics to prevent collibacilosis in broiler poultry: A protocol for a systematic review and network meta-analysis.

Antibiotics are used in broiler poultry production both for the prevention and treatment of infectious diseases. However, antibiotic use is a driver of antibiotic resistance. The World Health Organization has published numerous reports urging all stakeholders concerned with both food-producing animals and humans to establish recommended steps to enhance the prudent use of antimicrobials (WHO, 2015). Similarly, the World Animal Health Organization has also published recommendations and position statements regarding prudent use and risk management related to antimicrobial use in animals (OIE, 2017). Colibacillosis is an important bacterial pathogen of poultry, and a costly disease for the industry resulting in multimillion dollar losses annually through morbidity, mortality or carcass condemnation at slaughter. Colibacillosis refers to any localized or systemic infection caused entirely or partly by the organism avian pathogenic Escherichia coli (APEC). These bacteria may be isolated as the sole pathogen or contribute to a disease complex with mixed viral and bacterial infections (Guabirara and Schouler, 2015). Two main disease processes important in the broiler industry are early mortality and cellulitis. Early mortality is defined by chicks under a week of age experiencing a higher than normal percentage of deaths in a flock. Early mortality can be caused by many things, for example chilling, overheating, or dehydration, however E.coli infection, or colibacillosis, is one of the main culprits. Colibacillosis can present with omphalitis, yolk sacculitis, enteritis, pasty vents, pericarditis, perihepatitis, polyserositis, congested lungs, splenomegaly and darkened proventriculus or any these combinations (Guabiraba and Schouler, 2015; Geetha and Palanivel, 2018). Many chicks succumb to an early and severe infection or are culled due to excessive morbidity. Antibiotics are typically used to reduce early mortality (Chauvin et al., 2005; Dziva and Stevens, 2008). Those with severe infection are unlikely to survive, however appropriate treatment reduces transmission between birds and improves the suitability of those with a mild infection. Not every labelled drug for E.coli is efficacious, resistance is common (Kabir, 2010) and effectiveness can vary from flock to flock, even within a flock, with more than one strain and more than one treatment. Understanding the efficacy of antibiotics used to prevent colibacillosis in broiler chickens is essential to optimizing their use; ineffective antibiotics should not be used for prevention or, if there are multiple efficacious antibiotics, their importance to human medicine should be considered when making decisions on antibiotic use. Systematic reviews of randomized controlled trials, and network meta-analysis to provide input on relative antibiotic efficacy, will yield the highest level of evidence for efficacy of treatments under field conditions (Sargeant and O’Connor, 2014)

Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function-AAM

High levels of the anti-apoptotic BCL-2 family member MCL-1 are frequently found in breast cancer and, appropriately, BH3-mimetic drugs that specifically target MCL-1’s function in apoptosis are in development as anti-cancer therapy. MCL-1 also has reported non-canonical roles that may be relevant in its tumour-promoting effect. Here we investigate the role of MCL-1 in clinically relevant breast cancer models and address whether the canonical role of MCL-1 in apoptosis, which can be targeted using BH3-mimetic drugs, is the major function for MCL-1 in breast cancer. We show that MCL-1 is essential in established tumours with genetic deletion inducing tumour regression and inhibition with the MCL-1-specific BH3-mimetic drug S63845 significantly impeding tumour growth. Importantly, we found that the anti-tumour functions achieved by MCL-1 deletion or inhibition were completely dependent on pro-apoptotic BAX/BAK. Interestingly, we find that MCL-1 is also critical for stem cell activity in human breast cancer cells and high MCL1 expression correlates with stemness markers in tumours. This strongly supports the idea that the key function of MCL-1 in breast cancer is through its anti-apoptotic function. This has important implications for the future use of MCL-1-specific BH3-mimetic drugs in breast cancer treatment

Quantitative LC-MS study of compounds found predictive of COVID-19 severity and outcome

INTRODUCTION Since the beginning of the SARS-CoV-2 pandemic in December 2019 multiple metabolomics studies have proposed predictive biomarkers of infection severity and outcome. Whilst some trends have emerged, the findings remain intangible and uninformative when it comes to new patients. OBJECTIVES In this study, we accurately quantitate a subset of compounds in patient serum that were found predictive of severity and outcome. METHODS A targeted LC-MS method was used in 46 control and 95 acute COVID-19 patient samples to quantitate the selected metabolites. These compounds included tryptophan and its degradation products kynurenine and kynurenic acid (reflective of immune response), butyrylcarnitine and its isomer (reflective of energy metabolism) and finally 3’,4’-didehydro-3’-deoxycytidine, a deoxycytidine analogue, (reflective of host viral defence response). We subsequently examine changes in those markers by disease severity and outcome relative to those of control patients’ levels. RESULTS & CONCLUSION Finally, we demonstrate the added value of the kynurenic acid / tryptophan ratio for severity and outcome prediction and highlight the viral detection potential of ddhC