Anti-adrenergic effects of endothelin on human atrial action potentials are potentially anti-arrhythmic

Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca<sup>2+</sup> current (I<sub>CaL</sub>) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 μM prolonged the action potential duration at 50% repolarisation (APD<sub>50</sub>: 54 ± 10 vs. 28 ± 5 ms; <i>P</i> < 0.05, <i>N</i> = 15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD<sub>50</sub>, and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 μM) produced arrhythmic depolarisations (<i>P</i> < 0.05). Each was abolished by ET-1 at 10 nM (<i>P</i> < 0.05). ISO (0.05 μM) increased peak I<sub>CaL</sub> from –5.5 ± 0.4 to –14.6 ± 0.9 pA/pF (P < 0.05; N = 79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98 ± 10% (P < 0.05), with no effect on basal I<sub>CaL</sub>. Chronic treatment of patients with a β-blocker did not significantly alter basal APD50 or I<sub>CaL</sub>, the increase in APD50 or I<sub>CaL</sub> by 0.05 μM ISO, nor the subsequent reversal of this effect on APD50 by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I<sub>CaL</sub>, without affecting ERP and independently of β-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure

Fitting models of multiple hypotheses to partial population data: investigating the causes of cycles in red grouse

There are two postulated causes for the observed periodic fluctuations (cycles) in red grouse (Lagopus lagopus scoticus). The first involves interaction with the parasitic nematode Trichostrongylus tenuis. The second invokes delayed regulation through the effect of male aggressiveness on territoriality. Empirical evidence exists to support both hypotheses, and each hypothesis has been modeled deterministically. However, little effort has gone into looking at the combined effects of the two mechanisms or formally fitting the corresponding models to field data. Here we present a model for red grouse dynamics that includes both parasites and territoriality. To explore the single and combined hypotheses, we specify three versions of this model and fit them to data using Bayesian state‐space modeling, a method that allows statistical inference to be performed on mechanistic models such as ours. Output from the three models is then examined to determine their goodness of fit and the biological plausibility of the parameter values required by each to fit the population data. While all three models are capable of emulating the observed cyclic dynamics, only the model including both aggression and parasites does so under consistently realistic parameter values, providing theoretical support for the idea that both mechanisms shape red grouse cycles

Indirect effects of primary prey population dynamics on alternative prey

We develop a theory of generalist predation showing how alternative prey species are affected by changes in both mean abundance and variability (coefficient of variation) of their predator's primary prey. The theory is motivated by the indirect effects of cyclic rodent populations on ground-breeding birds, and developed through progressive analytic simplifications of an empirically-based model. It applies nonetheless to many other systems where primary prey have fast life-histories and can become locally superabundant, which facilitates impact on alternative prey species. In contrast to classic apparent competition theory based on symmetric interactions, our results suggest that predator effects on alternative prey should generally decrease with mean primary prey abundance, and increase with primary prey variability (low to high CV) - unless predators have strong aggregative responses, in which case these results can be reversed. Approximations of models including predator dynamics (general numerical response with possible delays) confirm these results but further suggest that negative temporal correlation between predator and primary prey is harmful to alternative prey. We find in general that predator numerical responses are crucial to predict the response of ecosystems to changes in key prey species exhibiting outbreaks, and extend the apparent competition/mutualism theory to asymmetric interactions

Experience based action planning for environmental manipulation in autonomous robotic systems

The ability for autonomous robots to plan action sequences in order to manipulate their environment to achieve a specific goal is of vital importance for agents which are deployed in a vast number of situations. From domestic care robots to autonomous swarms of search and rescue robots there is a need for agents to be able to study, reason about, and manipulate their environment without the oversight of human operators. As these robots are typically deployed in areas inhabited and organised by humans it is likely that they will encounter similar objects when going about their duties, and in many cases the objects encountered are likely to be arranged in similar ways relative to one another. Manipulation of the environment is an incredibly complex task requiring vast amounts of computation to generate a suitable state of actions for even the simplest of tasks. To this end we explore the application of memory based systems to environment manipulation planning. We propose new search techniques targeted at the problem of environmental manipulation for search and rescue, and recall techniques aimed at allowing more complex planning to take place with lower computational cost. We explore these ideas from the perspective of autonomous robotic systems deployed for search and rescue, however the techniques presented would be equally valid for robots in other areas, or for virtual agents interacting with cyber-physical systems

Calpain cleavage and subcellular characterisation of the ferlin family.

The ferlins are a family of C2-domain containing proteins. C2 domains regulate vesicle fusion in synaptotagmins, and animal models of ferlin deficiency display pathologies related to Ca2+-dependent vesicle fusion. Dysferlin mutations cause limb-girdle muscular dystrophy due to defective membrane repair. Our group has previously shown that Ca2+-dependent proteases, calpains, cleave dysferlin following membrane injury, releasing mini-dysferlinC72, that we hypothesise mediates membrane repair. Otoferlin mutations cause non-syndromic deafness, while no pathology causing mutations have been identified in other ferlins. My project establishes that dysferlin and myoferlin, type-I ferlins, are present at the plasma membrane and endo-lysosomal pathway while otoferlin and Fer1L6, type-II ferlins, are present at the plasma membrane and recycling trans-Golgi compartments. I also show that dysferlin is cleaved to mini-dysferlinC72 following injury in all cell types by the ubiquitous calpains-1 and -2 in the alternatively spliced exon 40a, indicating dysferlin cleavage is a fundamental response to membrane injury. Exon 40a-containing dysferlin recruits to sites of membrane injury in myotubes, indicating mini-dysferlinC72 may function directly at sites of injury. Finally, I have shown that calpains also cleave otoferlin and myoferlin. Cleavage of other ferlins indicates ferlin cleavage is an evolutionarily conserved event, predating the split between type-I and type-II ferlins

Restoration and management of wildflower-rich machair for the conservation of bumblebees

Over the last half century, the widespread decline of bumblebees across the agricultural landscapes of Western Europe and North America has been well documented. This decline has undoubtedly been driven to a large extent by the intensification of agriculture, which has fragmented landscapes and removed large areas of suitable foraging habitat, nesting and hibernation sites. Consequently, some of the rarest Bombus species now persist only in isolated pockets of semi-natural habitat, which have been subjected to little agricultural intensification. Of the 25 Bombus species native to the UK, three species have gone extinct in recent decades and several others are severely threatened. Remaining populations of the UK’s rarest bumblebee, Bombus distinguendus, have become strongly associated with florally-rich machair grassland habitats found only in the North and West of Scotland and Western Ireland. Machair, a unique habitat that forms on soils rich in shell sand, has been maintained by rotational agricultural practices implemented by crofters. However, recent changes in crofting practices, which include the intensive grazing of machair in some areas, or conversely the abandonment of machair management all together in others, have resulted in sections of machair that have become degraded and consequently exhibit low floral abundance and species diversity. This has significant implications for species such as B. distinguendus, which have for the most part come to rely of the florally-rich swards of machair grassland. This thesis aimed to develop a greater understanding of how machair grassland habitats are utilised by foraging bumblebees, including B. distinguendus, and in turn examined the potential for restoring degraded areas of machair via a variety of methods. The research presented here examines the influence of current crofting practices on the abundance of bumblebees and their forage plant species and combines this information with a detailed exploration of the machair seed bank and potential machair restoration treatments. The specific foraging requirements of B. distinguendus were found to be similar to those of other long-tongued bumblebee species and the provision of plants from the Fabaceae family was found to be of particular importance. Current crofting practices implemented in the North and West of Scotland were, on the whole, found support low numbers of foraging bumblebees. Similarly, existing habitat management schemes, designed to provide early cover for corncrakes and foraging resources for bumblebees, were found to be largely ineffective in attracting B. distinguendus, when compared with florally-rich machair habitat. In addition, this research suggests that the existing machair seed bank is unlikely to provide a sufficient resource for reinstating florally-rich habitat to degraded areas of machair. However, this thesis has demonstrated that it is possible to implement seed mixes on machair which can reinstate species typical of machair plant communities and which also attract high numbers of foraging bumblebees. The findings of these habitat assessments and restoration trials are examined in full in the following chapters and implications for the future management of wildflower-rich machair are discussed throughout

Liminality as a Space of Self Reflection on El Camino de Santiago del Norte

As ancient pilgrimage across Spain, El Camino de Santiago has affected the lives of the pilgrims that travel it for centuries taking on new meanings as it passes through time. Traditionally, scholars maintain that the focus of a pilgrim’s journey lies at the final destination, or pilgrimage center in Santiago de Compostela. This project demonstrates, however, that the emphasis should lie on the journey or period of liminality which through concepts of place has created a space for self-reflection and meditation. Analysis of pilgrim interviews within the context of a wide array of scholarly literature in the disciplines of anthropology, religion, and philosophy, demonstrates how walking as a mode of transportation between places creates this unique liminality in our busy world