Protein Docking by the Underestimation of Free Energy Funnels in the Space of Encounter Complexes

Similarly to protein folding, the association of two proteins is driven by a free energy funnel, determined by favorable interactions in some neighborhood of the native state. We describe a docking method based on stochastic global minimization of funnel-shaped energy functions in the space of rigid body motions (SE(3)) while accounting for flexibility of the interface side chains. The method, called semi-definite programming-based underestimation (SDU), employs a general quadratic function to underestimate a set of local energy minima and uses the resulting underestimator to bias further sampling. While SDU effectively minimizes functions with funnel-shaped basins, its application to docking in the rotational and translational space SE(3) is not straightforward due to the geometry of that space. We introduce a strategy that uses separate independent variables for side-chain optimization, center-to-center distance of the two proteins, and five angular descriptors of the relative orientations of the molecules. The removal of the center-to-center distance turns out to vastly improve the efficiency of the search, because the five-dimensional space now exhibits a well-behaved energy surface suitable for underestimation. This algorithm explores the free energy surface spanned by encounter complexes that correspond to local free energy minima and shows similarity to the model of macromolecular association that proceeds through a series of collisions. Results for standard protein docking benchmarks establish that in this space the free energy landscape is a funnel in a reasonably broad neighborhood of the native state and that the SDU strategy can generate docking predictions with less than 5 � ligand interface Ca root-mean-square deviation while achieving an approximately 20-fold efficiency gain compared to Monte Carlo methods.

Breaking ranks: the emergence of representative associations in the Irish armed forces 1989-1992

This study contexualises the relationship between the armed forces and the civil authority in Ireland using and revising the theoretical framework advanced by Huntington. It tracks the evolution of the idea of a representive body for soldiers in the late 1980s, to the setting up of statutory associations under the Defence Amendment Act 1990. The study considers Irish soldiers political agitation and their use of peaceful democratic activities to achieve their aims. It highlights the fundamental policy arguments that were made against the idea of representation for the army and positions those arguments in the study of civil-military relations. Utilising unique access to secret Department of Defence files, it reveals in-depth ideological arguments advanced by the military authories in Ireland against independent representation. This thesis provides an academic study of the establishment of PDFORRA. It answers key questions regarding the change in the position of Irish government who were categorically opposed to the idea of representation in the army. It illustrates the involvement of other agencies such as the European Organisation of Military Associations (Euromil) reveals reciprocal support by the Irish associations to other emerging groups in Spain. Accessing as yet unpublished Department of Defence files, study analyses tension between the military authorities and the government. It highlights for the first time the role of enlisted personnel in the shaping of new state structures and successfully dismmisses Huntingtons theoretical contention that enlisted personnel are of no consequence in the study of civil-military relations. It fills a gap in our understanding, identified by Finer, as to how politicisation of soldiers takes place. This thesis brings a new dimension to the discipline of civil-military relations and creates new knowledge that will enhance our understanding of an area not covered previously.

History, revolution and the British popular novel: historical fiction in the romantic age

“History, Revolution and the British Popular Novel” takes as its focus the significant role which historical fiction played within the French Revolution debate and its aftermath. Examining the complex intersection of the genre with the political and historical dialogue generated by the French Revolution crisis, the thesis contends that contemporary fascination with the historical episode of the Revolution, and the fundamental importance of history to the disputes which raged about questions of tradition and change, and the meaning of the British national past, led to the emergence of increasingly complex forms of fictional historical narrative during the “war of ideas.” Considering the varying ways in which novelists such as Charlotte Smith, William Godwin, Mary Robinson, Helen Craik, Clara Reeve, John Moore, Edward Sayer, Mary Charlton, Ann Thomas, George Walker and Jane West engaged with the historical contexts of the Revolution debate, my discussion juxtaposes the manner in which English Jacobin novelists inserted the radical critique of the Jacobin novel into the wider arena of history with anti-Jacobin deployments of the historical to combat the revolutionary threat and internal moves for socio-political restructuring. I argue that the use of imaginative historical narrative to contribute to the ongoing dialogue surrounding the Revolution, and offer political and historical guidance to readers, represented a significant element within the literature of the Revolution crisis. The thesis also identifies the diverse body of historical fiction which materialised amidst the Revolution controversy as a key context within which to understand the emergence of Scott’s national historical novel in 1814, and the broader field of historical fiction in the era of Waterloo. Tracing the continued engagement with revolutionary and political concerns evident in the early Waverley novels, Frances Burney’s The Wanderer (1814), William Godwin’s Mandeville (1816), and Mary Shelley’s Valperga (1823), my discussion concludes by arguing that Godwin’s and Shelley’s extension of the mode of historical fiction initially envisioned by Godwin in the revolutionary decade, and their shared endeavour to retrieve the possibility enshrined within the republican past, appeared as a significant counter to the model of history and fiction developed by Walter Scott in the post-revolutionary epoch.

An Irish apostle: articulating and actualising apostolicity in the early Irish church

This thesis examines the earliest extant Latin Lives of Brigit and Patrick; Cogitosus’s Vita Brigidae and Muirchú’s Vita Patricii as evidence for a seventh-century debate on Irish apostolicity. While often dismissed as mere propaganda, this thesis shows they are highly sophisticated demonstrations of the continuing connection that Kildare and Armagh had to their patron saints and their authority. It examines the importance of this connection for concepts of ecclesiastical organisation, teaching authority and episcopal succession against the backdrop of the seventh-century Easter question in the Insular Church. This will show that apostolicity was considered to be intrinsically linked with orthodoxy and universality. A textual focus brings forth general patristic themes and ideas that Irish hagiographers evoked through specific words and phrases. The thesis contextualises hagiographical material using evidence from Hiberno-Latin and early Insular exegetical commentaries, referring to major patristic exegetes such as Origen, Jerome, Augustine, and Gregory the Great as support. The introduction discusses the importance of apostolic ideology for the seventh-century Irish Church, and outlines a methodology for examining such abstract themes. The first chapter looks at how developments in apostolic ideology led to ideas of apostolic primacy seen in the Insular material. Chapters two, three, and four examine metaphors of food and feeding, the fountain and the stream, and the head and the body, as significant articulations of apostolicity. Chapter five examines how corporeal relics were understood as the visible proof of this continuity and preserved a saint’s authority for their episcopal heirs. Chapter six looks at how Muirchú engaged with Patrick’s connection to the universal Church and his self-professed lack of disciplina to reconcile his apostolicity with seventh-century norms. Chapter seven places the issues considered thus far in a thoroughly Insular context by examining how the earliest English sources present the Irish legacy in Northumbria after the synod of Whitby. Chapter eight looks at how the text of Patrick’s Confessio in the Book of Armagh relates to a wider seventh-century campaign by Armagh to rehabilitate Patrick’s apostolicity. The conclusion briefly summarizes the thesis, and suggests further avenues for researching this topic in the Insular material

“Fiction makes a better job of the truth”: dialogism, oppositional consciousness and re-membering in the novels of Helena María Viramontes

This thesis comprises close textual analyses of Chicana author Helena María Viramontes' two published novels, Under the Feet of Jesus (1995) and Their Dogs Came With Them (2007). These analyses fall under three broad frameworks: space, time and body. Chapter One engages with the first of these frameworks, space, and explores concepts of cognitive mapping and heteroptopias. Chapter Two, which looks at time, employs theories of intertextuality and the palimpsest, while Chapter Three looks at the interrrelationship between mythology and images of the body in the texts. This study emerges five years after the publication of Viramontes' last novel, Their Dogs Came With Them, but offers fresh insight into the contribution of the author to both the Chicano literary tradition and also the U.S. canon through her critique of hegemonic power structures that suppress not only the voices of lower class ethnic citizens but also of ethnic writers. In particular, her work chastises the paucity of attention given to ethnic women writers in the U.S. This thesis reaffirms Viramontes' position as one of the most important writers living and writing in the U.S. today. It corroborates her work as a contestation against ethnic and gender suppression, and applauds the craftsmanship of her narrative style that delicately but decisively exposes the socio-political wrongs that occur in ocntemporary U.S. society.

The role of structure in the electrochemical performance of nanostructured metal oxides for lithium ion battery anodes

The Li-ion battery has for a number of years been a key factor that has enabled an ever increasing number of modern consumer devices, while in recent years has also been sought to power a range of emerging electric and hybrid electric vehicles. Due to their importance and popularity, a number of characteristics of Li-ion batteries have been subjected to intense work aimed at radical improvement. Although electrode material selection intrinsically defines characteristics like maximum capacity or voltage, engineering of the electrode structure may yield significant improvements to the lifetime performance of the battery, which would not be available if the material was used in its bulk form. The body of work presented in this thesis describes the relationship between the structure of electrochemically active materials and the course of the electrochemical processes occurring within the electrode. Chapter one describes the motivation behind the research presented herein. Chapter two serves to highlight a number of key advancements which have been made and detailed in the literature over recent years, pertaining to the use of nanostructured materials in Li-ion technology. Chapter three details methods and techniques applied in developing the body of work presented in this thesis. Chapter four details structural, molecular and electrochemical characteristics of tin oxide nanoparticle based electrodes, with particular emphasis on the relationship between the size distribution and the electrode performance. Chapter five presents findings of structural, electrochemical and optical study of indium oxide nanoparticles grown on silicon by molecular beam epitaxy. In chapter 6, tin oxide inverted opal electrodes are investigated for the conduct of the electrochemical performance of the electrodes under varying rate of change of potential. Chapter 7 presents the overall conclusions drawn from the results presented in this thesis, coupled with an indication of potential future work which may be explored further.

Depression and 'crises of meaninglessness' in the political-economic theology of the money-God

The thesis starts with a historical analysis of the development of depression as a concept. Through this inquiry, the controversies behind the apparent consensus about depression’s etiology and treatment are illuminated, suggesting that the understanding of the climbing rates of depression in contemporary Western civilization is still up for grabs. That’s what the thesis sets out to investigate. In order to accomplish this aim, the study builds upon the classical accounts of Georg Simmel, Émile Durkheim and the more contemporary ideas of Dany-Robert Dufour, in dialogue with an array of supplementary theoretical sources. Navigating through this ‘sea’ of extraordinary and different theories, a new avenue of reflections arises, contributing for the sophistication of the questions made about the phenomenon of depression’s rates. The fundamental argument emerging from this theoretical undertaking is that ‘crises of meaninglessness’ that pervade the collective body of Western contemporary societies have, as one of its consequences, the expansion of depression rates. Meaninglessness in contemporary times is the primary object of investigation of the thesis. The concept, in the context of this study, is not understood as merely an effect of the historical decline of shared social norms due to processes of individualization. Rather, it is claimed, it originates from and is reinforced by the ‘political-economic theology of neo-liberalism’ which becomes virtually generalized in the West, erecting money as a God. The study concludes that by undermining culturally established values, ideals, institutions and principles that may block the dissemination of commodities this new transcendence has been challenging the task of signifying life, potentializing – among other subjective difficulties – the diffusion of depression.

Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart.

G protein-coupled receptor kinases (GRKs) phosphorylate activated G protein-coupled receptors, including alpha(1B)-adrenergic receptors (ARs), resulting in desensitization. In vivo analysis of GRK substrate selectivity has been limited. Therefore, we generated hybrid transgenic mice with myocardium-targeted overexpression of 1 of 3 GRKs expressed in the heart (GRK2 [commonly known as the beta-AR kinase 1], GRK3, or GRK5) with concomitant cardiac expression of a constitutively activated mutant (CAM) or wild-type alpha(1B)AR. Transgenic mice with cardiac CAMalpha(1B)AR overexpression had enhanced myocardial alpha(1)AR signaling and elevated heart-to-body weight ratios with ventricular atrial natriuretic factor expression denoting myocardial hypertrophy. Transgenic mouse hearts overexpressing only GRK2, GRK3, or GRK5 had no hypertrophy. In hybrid transgenic mice, enhanced in vivo signaling through CAMalpha(1B)ARs, as measured by myocardial diacylglycerol content, was attenuated by concomitant overexpression of GRK3 but not GRK2 or GRK5. CAMalpha(1B)AR-induced hypertrophy and ventricular atrial natriuretic factor expression were significantly attenuated with either concurrent GRK3 or GRK5 overexpression. Similar GRK selectivity was seen in hybrid transgenic mice with wild-type alpha(1B)AR overexpression concurrently with a GRK. GRK2 overexpression was without effect on any in vivo CAM or wild-type alpha(1B)AR cardiac phenotype, which is in contrast to previously reported in vitro findings. Furthermore, endogenous myocardial alpha(1)AR mitogen-activated protein kinase signaling in single-GRK transgenic mice also exhibited selectivity, as GRK3 and GRK5 desensitized in vivo alpha(1)AR mitogen-activated protein kinase responses that were unaffected by GRK2 overexpression. Thus, these results demonstrate that GRKs differentially interact with alpha(1B)ARs in vivo such that GRK3 desensitizes all alpha(1B)AR signaling, whereas GRK5 has partial effects and, most interestingly, GRK2 has no effect on in vivo alpha(1B)AR signaling in the heart.

A functional polymorphism in the 5HTR2C gene associated with stress responses also predicts incident cardiovascular events.

Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (rs6318) of the 5HTR2C gene located on the X-chromosome is associated with hypothalamic-pituitary-adrenal axis response to a stress recall task, and with endophenotypes associated with cardiovascular disease (CVD). These findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository. Study population consisted of 6,126 Caucasian participants (4,036 [65.9%] males and 2,090 [34.1%] females). A total of 1,769 events occurred (1,544 deaths and 225 MIs; median follow-up time = 5.3 years, interquartile range = 3.3-8.2). Unadjusted Cox time-to-event regression models showed, compared to Cys23 G carriers, males hemizygous for Ser23 C and females homozygous for Ser23C were at increased risk for the composite endpoint of all-cause death or MI: Hazard Ratio (HR) = 1.47, 95% confidence interval (CI) = 1.17, 1.84, p = .0008. Adjusting for age, rs6318 genotype was not related to body mass index, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries, or left ventricular ejection fraction in either males or females. After adjustment for these covariates the estimate for the two Ser23 C groups was modestly attenuated, but remained statistically significant: HR = 1.38, 95% CI = 1.10, 1.73, p = .005. These findings suggest that this functional polymorphism of the 5HTR2C gene is associated with increased risk for CVD mortality and morbidity, but this association is apparently not explained by the association of rs6318 with traditional risk factors or conventional markers of atherosclerotic disease.

Molecular mapping of movement-associated areas in the avian brain: a motor theory for vocal learning origin.

Vocal learning is a critical behavioral substrate for spoken human language. It is a rare trait found in three distantly related groups of birds-songbirds, hummingbirds, and parrots. These avian groups have remarkably similar systems of cerebral vocal nuclei for the control of learned vocalizations that are not found in their more closely related vocal non-learning relatives. These findings led to the hypothesis that brain pathways for vocal learning in different groups evolved independently from a common ancestor but under pre-existing constraints. Here, we suggest one constraint, a pre-existing system for movement control. Using behavioral molecular mapping, we discovered that in songbirds, parrots, and hummingbirds, all cerebral vocal learning nuclei are adjacent to discrete brain areas active during limb and body movements. Similar to the relationships between vocal nuclei activation and singing, activation in the adjacent areas correlated with the amount of movement performed and was independent of auditory and visual input. These same movement-associated brain areas were also present in female songbirds that do not learn vocalizations and have atrophied cerebral vocal nuclei, and in ring doves that are vocal non-learners and do not have cerebral vocal nuclei. A compilation of previous neural tracing experiments in songbirds suggests that the movement-associated areas are connected in a network that is in parallel with the adjacent vocal learning system. This study is the first global mapping that we are aware for movement-associated areas of the avian cerebrum and it indicates that brain systems that control vocal learning in distantly related birds are directly adjacent to brain systems involved in movement control. Based upon these findings, we propose a motor theory for the origin of vocal learning, this being that the brain areas specialized for vocal learning in vocal learners evolved as a specialization of a pre-existing motor pathway that controls movement.

Activity in descending dopaminergic neurons represents but is not required for leg movements in the fruit fly Drosophila.

Modulatory descending neurons (DNs) that link the brain to body motor circuits, including dopaminergic DNs (DA-DNs), are thought to contribute to the flexible control of behavior. Dopamine elicits locomotor-like outputs and influences neuronal excitability in isolated body motor circuits over tens of seconds to minutes, but it remains unknown how and over what time scale DA-DN activity relates to movement in behaving animals. To address this question, we identified DA-DNs in the Drosophila brain and developed an electrophysiological preparation to record and manipulate the activity of these cells during behavior. We find that DA-DN spike rates are rapidly modulated during a subset of leg movements and scale with the total speed of ongoing leg movements, whether occurring spontaneously or in response to stimuli. However, activating DA-DNs does not elicit leg movements in intact flies, nor do acute bidirectional manipulations of DA-DN activity affect the probability or speed of leg movements over a time scale of seconds to minutes. Our findings indicate that in the context of intact descending control, changes in DA-DN activity are not sufficient to influence ongoing leg movements and open the door to studies investigating how these cells interact with other descending and local neuromodulatory inputs to influence body motor output.

Adaptive intervention design in mobile health: Intervention design and development in the Cell Phone Intervention for You trial.

BACKGROUND/AIMS: The obesity epidemic has spread to young adults, and obesity is a significant risk factor for cardiovascular disease. The prominence and increasing functionality of mobile phones may provide an opportunity to deliver longitudinal and scalable weight management interventions in young adults. The aim of this article is to describe the design and development of the intervention tested in the Cell Phone Intervention for You study and to highlight the importance of adaptive intervention design that made it possible. The Cell Phone Intervention for You study was a National Heart, Lung, and Blood Institute-sponsored, controlled, 24-month randomized clinical trial comparing two active interventions to a usual-care control group. Participants were 365 overweight or obese (body mass index≥25 kg/m2) young adults. METHODS: Both active interventions were designed based on social cognitive theory and incorporated techniques for behavioral self-management and motivational enhancement. Initial intervention development occurred during a 1-year formative phase utilizing focus groups and iterative, participatory design. During the intervention testing, adaptive intervention design, where an intervention is updated or extended throughout a trial while assuring the delivery of exactly the same intervention to each cohort, was employed. The adaptive intervention design strategy distributed technical work and allowed introduction of novel components in phases intended to help promote and sustain participant engagement. Adaptive intervention design was made possible by exploiting the mobile phone's remote data capabilities so that adoption of particular application components could be continuously monitored and components subsequently added or updated remotely. RESULTS: The cell phone intervention was delivered almost entirely via cell phone and was always-present, proactive, and interactive-providing passive and active reminders, frequent opportunities for knowledge dissemination, and multiple tools for self-tracking and receiving tailored feedback. The intervention changed over 2 years to promote and sustain engagement. The personal coaching intervention, alternatively, was primarily personal coaching with trained coaches based on a proven intervention, enhanced with a mobile application, but where all interactions with the technology were participant-initiated. CONCLUSION: The complexity and length of the technology-based randomized clinical trial created challenges in engagement and technology adaptation, which were generally discovered using novel remote monitoring technology and addressed using the adaptive intervention design. Investigators should plan to develop tools and procedures that explicitly support continuous remote monitoring of interventions to support adaptive intervention design in long-term, technology-based studies, as well as developing the interventions themselves.

The body language: The spontaneous influence of congruent bodily arousal on the awareness of emotional words

Nowadays, the idea of a reciprocal influence of physiological and psychological processes seems to be widely accepted. For instance, current theories of embodied emotion suggest that knowledge about an emotion concept involves simulations of bodily experienced emotional states relevant to the concept. In line with this framework, the present study investigated whether actual levels of physiological arousal interact with the processing of emotional words. Participants performed 2 blocks of an attentional blink task, once after a cycling session (increased arousal) and once after a relaxation session (reduced arousal). Concretely, participants were instructed to detect and report 2 target words (T1 and T2) presented among a series of nonword distractors. T1 and T2 were either neutral, high arousal, or low arousal words. Results revealed that increased physiological arousal led to improved reports of high arousal T2 words, whereas reduced physiological arousal led to improved reports of low arousal T2 words. Neutral T2 remained unaffected by the arousing conditions. These findings emphasize that actual levels of physiological arousal modulate the cognitive access to arousal (in-)congruent emotional concepts and suggest a direct grounding of emotion knowledge in our bodily systems of arousal.

Continuing Professional Development: rhetoric and practice in the NHS

This article explores the experience of Continuing Professional Development (CPD) by supervisory-level clinical staff in the National Health Service. Four main themes are highlighted in the literature, namely the nature and experience of CPD, its relationship with human resource management practices and in particular in career development and planning. These themes are examined utilising sources of (triangulated) empirical data based on a 2500 sample survey conducted across five NHS Trusts. A key finding was that responsibility for learning and development was perceived as belonging to the individual rather than the organisation. Other findings concern a lack of resource-based commitment by the organisation to CPD for clinical staff undertaking supervisory-level roles and evidence of 'credentialism' with its emphasis on seeking certificated qualifications. The findings raise concerns about the potential for clinical staff to become disillusioned and to perceive a potential breach in their psychological contract because of problems in reconciling their own interests with those of their professional body, and that of their employer in relation to CPD.

Long-Term Oceanographic and Ecological Research in the Western English Channel

Long-term research in the western English Channel, undertaken by the marine laboratories in Plymouth, is described and details of survey methods, sites, and time series given in this chapter. Major findings are summarized and their limitations outlined. Current research, with recent reestablishment and expansion of many sampling programmes, is presented, and possible future approaches are indicated. These unique long-term data sets provide an environmental baseline for predicting complex ecological responses to local, regional, and global environmental change. Between 1888 and the present, investigations have been carried out into the physical, chemical, and biological components (ranging from plankton and fish to benthic and intertidal assemblages) of the western English Channel ecosystem. The Marine Biological Association of the United Kingdom has performed the main body of these observations. More recent contributions come from the Continuous Plankton Recorder Survey, now the Sir Alister Hardy Foundation for Ocean Science, dating from 1957; the Institute for Marine Environmental Research, from 1974 to 1987; and the Plymouth Marine Laboratory, which was formed by amalgamation of the Institute for Marine Environmental Research and part of the Marine Biological Association, from 1988. Together, these contributions constitute a unique data series; one of the longest and most comprehensive samplings of environmental and marine biological variables in the world. Since the termination of many of these time series in 1987-1988 during a reorganisation of UK marine research, there has been a resurgence of interest in long-term environmental change. Many programmes have been restarted and expanded with support from several agencies. The observations span significant periods of warming (1921-1961; 1985-present) and cooling (1962-1980). During these periods of change, the abundance of key species underwent dramatic shifts. The first period of warming saw changes in zooplankton, pelagic fish, and larval fish, including the collapse of an important herring fishery. During later periods of change, shifts in species abundances have been reflected in other assemblages, such as the intertidal zone and the benthic fauna. Many of these changes appear to be related to climate, manifested as temperature changes, acting directly or indirectly. The hypothesis that climate is a forcing factor is widely supported today and has been reinforced by recent studies that show responses of marine organisms to climatic attributes such as the strength of the North Atlantic Oscillation. The long-term data also yield important insights into the effects of anthropogenic disturbances such as fisheries exploitation and pollution. Comparison of demersal fish hauls over time highlights fisheries effects not only on commercially important species but also on the entire demersal community. The effects of acute ("Torrey Canyon" oil spill) and chronic (tributyltin [TBT] antifoulants) pollution are clearly seen in the intertidal records. Significant advances in diverse scientific disciplines have been generated from research undertaken alongside the long-term data series.