NOVEL SMALL MOLECULE ANTIFUNGALS FOR INVASIVE FUNGAL INFECTIONS

Human fungal pathogens cause a range of diseases from benign skin conditions (i.e., ringworm) to thrush, mucosal membrane infections, and life-threatening systemic infections including bloodstream infections (i.e., aspergillosis and candidiasis) and Cryptococcal meningitis. These systemic infections occur most often in immunocompromised individuals and have high mortality rates. Current antifungal agents used in the clinic belong to three main classes: the polyenes (e.g., amphotericin B (AmB)), the echinocandins (e.g., caspofungin (CFG)), and the azoles (e.g., fluconazole (FLC)). In addition, the antimetabolite pyrimidine analogue flucytosine is used in combination with AmB. The three main classes class of antifungals each target different aspects of cell wall synthesis or cell membrane function and each class has different strengths and weaknesses depending on the strains of fungi that they are effective against, their route of administration, and their potential side effects. Problems associated with current antifungals include toxicity to patients, only effective against a limited spectrum of fungal strains, and the development of resistance of fungal strains to treatment. Discovering new antifungal therapies is a promising strategy to decrease mortality rates. Herein, three classes of molecules are evaluated for their potential as novel antifungals and reveal that (i) the antihistamines, terfenadine (TERF) and ebastine (EBA) improve the efficacy of azole antifungals when used in combination against a range of Candida strains, (ii) square-planar gold(I)-phosphine complexes exhibit broad-spectrum antifungal activity, and (iii) fluorinated aryl- and heteroaryl-substituted monohydrazones display broad-spectrum activity against fungi with little toxicity to mammalian cells, and (iv) other classes of molecules in recent literature that have shown antifungal activity. This work serves to identify promising scaffolds for novel classes of antifungals with the ultimate goal of bringing newer and more effective antifungals to be used clinically for systemic fungal infections

Multi-Modal Effects of the Repellent Deet Across Protostomia

DEET (N, N-diethyl-m-toluamide) is the most broadly effective and widely used personal repellent available, yet we do not understand what makes it so effective. Even in well-studied species like Drosophila melanogaster flies and Aedes aegypti mosquitoes, many mysteries remain as to how DEET can affect behavior in these species. For example, Ae. aegypti mosquitoes are attracted to human arms. When an arm is covered in DEET, wild-type mosquitoes are not attracted to the arm, while mutant mosquitoes that lack the odorant receptor co-receptor (orco), approach the arm, but rarely bite. We investigated this orco-independent DEET repellency in Ae. aegypti and found that these mosquitoes can sense DEET with their tarsi as well as their proboscis. The tarsi are required for mosquitoes to be repelled after contact with a DEET-treated arm. The proboscis is required for the rejection of DEET-laced liquid food. These results suggest that DEET acts on multiple sensory modalities to repel insects. Both this work and most prior literature has focused on studying how DEET affects Arthropods, yet one of the major open questions in the field is how DEET can be effective across so many different species. To identify genes and neurons required for DEET-sensitivity outside of Arthropoda, we turned to the nematode C. elegans. Here, we demonstrated that DEET affects chemotaxis to some odors but not others. We used this behavior as the basis for a forward genetic screen, and identified two genes as candidates required for complete DEET-sensitivity. We identified a natural isolate of C. elegans that was also resistant to DEET, and found that it contains a large deletion in one of the hits from our screen, the G protein-coupled receptor str-217. This gene is required for DEET-sensitivity in both wild-type and wild isolate strains. str-217 is expressed in a single pair of chemosensory neurons called ADL, which are required for complete DEET sensitivity, and respond to DEET as assayed by calcium imaging. Although we identified additional sensory neurons that respond to DEET, their behavioral contributions are unknown. Both ADL and str-217 are required for a specific, DEET-induced behavior during chemotaxis and exploration: an increase in average pause duration. Through optogenetic stimulation of ADL, we demonstrated that ADL activity alone is sufficient to increase average pause duration. Taken together, these experiments provide insights into the genetic and neural mechanisms underlying DEET-sensitivity in C. elegans, and allow for comparisons across Protostomes. We also establish C. elegans as a model non-Arthropod species for further investigation into the effects of DEET

Magnetic Analyses of Soils from the Wind River Range, Wyoming, Constrain Rates and Pathways of Magnetic Enhancement for Soils from Semiarid Climates

In order to constrain the rate of magnetic enhancement in soils, we investigated modern soils from five fluvial terraces in the eastern Wind River Range, Wyoming. Profiles up to 1.2 m deep were sampled in 5-cm intervals from hand-dug pits or natural riverbank exposures. Soils formed in fluvial terraces correlated to the Sacajawea Ridge (730–610 ka BP), Bull Lake (130–100 ka BP) and Pinedale-age (∼20 ka BP) glacial advances. One soil profile formed in Holocene-age sediment. Abundance, mineralogy, and grain size of magnetic minerals were estimated through magnetic measurements. Magnetic enhancement of the A-horizon as well as an increase in fine-grained magnetic minerals occurred mostly in Bull Lake profiles but was absent from the older profile. Such low rates of magnetic enhancement may limit the temporal resolution of paleosol-based paleoclimate reconstructions in semiarid regions even where high sedimentation rates result in multiple paleosols. A loss of ferrimagnetic and an increase in antiferromagnetic minerals occurred with age. Our findings suggest either the conversion of ferrimagnetic minerals to weakly magnetic hematite with progressing soil age, or the presence of ferrimagnetic minerals as an intermediate product of pedogenesis. Absolute and relative hematite abundance increase with age, making both useful proxies for soil age and the dating of regional glacial deposits. All coercivity proxies are consistent with each other, which suggests that observed changes in HIRM and S-ratio are representative of real changes in hematite abundance rather than shifts in coercivity distributions, even though the modified L-ratio varies widely

European Foreign Policy in a Decarbonising World

Contributing to the emerging literature on the geopolitical and foreign policy implications of decarbonisation and energy transition processes, this book sheds light on the future of the European Union’s external relations under decarbonisation. Under the Paris Agreement on climate change, adopted in 2015, governments committed to phasing out the emissions of carbon dioxide and other greenhouse gases over the coming decades. This book addresses the many questions around this process of decarbonisation through detailed analyses of EU external relations with six fossil-fuel exporting countries: Nigeria, Indonesia, Azerbaijan, Colombia, Qatar and Canada. The authors systematically examine the six countries’ varying dependence on fossil fuels, the broader political and security context, current relations with the EU and the potential for developing these toward decarbonisation. In doing so, they put forward a series of findings that should hold across varying circumstances and provide a steppingstone to enrich and inspire further research on foreign policy, external relations and international relations under decarbonisation. The book also makes an important contribution to understanding the external implications of the 2019 European Green Deal. This volume will be of great interest to students and scholars of European environmental and climate policy, climate diplomacy, energy policy, foreign policy and climate/energy geopolitics

‘Not in our Name’: Vexing Care in the Neoliberal University

In this paper, we draw on our collaborative work running a salon for thinking about care in STS research, which quickly became more about fostering an ethico-politics for thinking with care as a mode of academic intervention. Not dissimilar to the origins of the salon in nineteenth-century France, the salon provided a provocative and disruptive space for early career researchers (ECRs) to think together. As attention and critique increasingly point towards the unequal distribution of harms arising from marketization and the vulnerability of ECRs in the ‘neoliberal university,’ we have witnessed a surge in activities that promise a supportive space, such as pre-conference conferences, seminar series, discussion forums and self-care workshops. In this paper, we ask not only what these modes of care might make possible, but also what exclusionary practices and patterns they mask or render more palatable (Ahmed, 2004; Duclos & Criado, 2020; Martin et al., 2015; Murphy, 2015). Reflecting on our experiences of organizing and participating in the salon, with the stated purpose to explore ‘ecologies of care’ as an embodied socio-material practice (Puig de la Bellacasa, 2017), we move from care ‘out there’ in STS research to care ‘in here’. We follow threads spun by and out from the group to rethink our own academic care practices and how to do the academy otherwise

Development of statistical methods for monitoring insect abundance

During a time of habitat loss, climate change and loss of biodiversity, efficient analytical tools are vital for population monitoring. This thesis concerns the modelling of butterflies, whose populations are undergoing various changes in abundance, range, phenology and voltinism. In particular, three-quarters of UK butterfly species have shown declines in their distribution, abundance, or both over a ten-year period. As the most comprehensively monitored insect taxon, known to respond rapidly and sensitively to change, butterflies are particularly valuable, but devising methods that can be fitted to large data sets is challenging and they can be computer intensive. We use occupancy models to formulate occupancy maps and novel regional indices, which will allow for improved reporting of changes in butterfly distributions. The remainder of the thesis focuses on models for count data. We show that the popular N-mixture model can sometimes produce infinite estimates of abundance and describe the equivalence of multivariate Poisson and negative-binomial models. We then present a variety of approaches for modelling butterfly abundance, where complicating features are the seasonal nature of the counts and variation among species. A generalised abundance index is very efficient compared to generalised additive models, which are currently used for annual reporting, and new parametric descriptions of seasonal variation produce novel and meaningful parameters relating to phenology and survival. We develop dynamic models which explicitly model dependence between broods and years. These new models will improve our understanding of the complex processes and drivers underlying changes in butterfly populations

European Foreign Policy in a Decarbonising World

Contributing to the emerging literature on the geopolitical and foreign policy implications of decarbonisation and energy transition processes, this book sheds light on the future of the European Union’s external relations under decarbonisation. Under the Paris Agreement on climate change, adopted in 2015, governments committed to phasing out the emissions of carbon dioxide and other greenhouse gases over the coming decades. This book addresses the many questions around this process of decarbonisation through detailed analyses of EU external relations with six fossil-fuel exporting countries: Nigeria, Indonesia, Azerbaijan, Colombia, Qatar and Canada. The authors systematically examine the six countries’ varying dependence on fossil fuels, the broader political and security context, current relations with the EU and the potential for developing these toward decarbonisation. In doing so, they put forward a series of findings that should hold across varying circumstances and provide a steppingstone to enrich and inspire further research on foreign policy, external relations and international relations under decarbonisation. The book also makes an important contribution to understanding the external implications of the 2019 European Green Deal. This volume will be of great interest to students and scholars of European environmental and climate policy, climate diplomacy, energy policy, foreign policy and climate/energy geopolitics

A conserved acidic patch in the Myb domain is required for activation of an endogenous target gene and for chromatin binding

The c-Myb protein is a transcriptional regulator initially identified by homology to the v-Myb oncoprotein, and has since been implicated in human cancer. The most highly conserved portion of the c-Myb protein is the DNA-binding domain which consists of three imperfect repeats. Many other proteins contain one or more Myb-related domains, including a number of proteins that do not bind directly to DNA. We performed a phylogenetic analysis of diverse classes of Myb-related domains and discovered a highly conserved patch of acidic residues common to all Myb-related domains. These acidic residues are positioned in the first of three alpha-helices within each of the three repeats that comprise the c-Myb DNA-binding domain. Interestingly, these conserved acidic residues are present on a surface of the protein which is distinct from that which binds to DNA. Alanine mutagenesis revealed that the acidic patch of the third c-Myb repeat is essential for transcriptional activity, but neither for nuclear localization nor DNA-binding. Instead, these acidic residues are required for efficient chromatin binding and interaction with the histone H4 N-terminal tail