8,757 research outputs found
Consent and the Construction of the Volunteer: Institutional Settings of Experimental Research on Human Beings in Britain during the Cold War
This study challenges the primacy of consent in the history of human experimentation and argues that privileging the cultural frameworks adds nuance to our understanding of the construction of the volunteer in the period 1945 to 1970. Historians and bio-ethicists have argued that medical ethics codes have marked out the parameters of using people as subjects in medical scientific research and that the consent of the subjects was fundamental to their status as volunteers. However, the temporality of the creation of medical ethics codes means that they need to be understood within their historical context. That medical ethics codes arose from a specific historical context rather than a concerted and conscious determination to safeguard the well-being of subjects needs to be acknowledged. The British context of human experimentation is under-researched and there has been even less focus on the cultural frameworks within which experiments took place. This study demonstrates, through a close analysis of the Medical Research Council's Common Cold Research Unit (CCRU) and the government's military research facility, the Chemical Defence Experimental Establishment, Porton Down (Porton), that the `volunteer' in human experiments was a subjective entity whose identity was specific to the institution which recruited and made use of the subject. By examining representations of volunteers in the British press, the rhetoric of the government's collectivist agenda becomes evident and this fed into the institutional construction of the volunteer at the CCRU. In contrast, discussions between Porton scientists, staff members, and government officials demonstrate that the use of military personnel in secret chemical warfare experiments was far more complex. Conflicting interests of the military, the government and the scientific imperative affected how the military volunteer was perceived
Examining the Impact of Personal Social Media Use at Work on Workplace Outcomes
A noticable shift is underway in today’s multi-generational workforce. As younger employees propel digital workforce transformation and embrace technology adoption in the workplace, organisations need to show they are forward-thinking in their digital transformation strategies, and the emergent integration of social media in organisations is reshaping internal communication strategies, in a bid to improve corporate reputations and foster employee engagement. However, the impact of personal social media use on psychological and behavioural workplace outcomes is still debatebale with contrasting results in the literature identifying both positive and negative effects on workplace outcomes among organisational employees.
This study seeks to examine this debate through the lens of social capital theory and study personal social media use at work using distinct variables of social use, cognitive use, and hedonic use. A quantitative analysis of data from 419 organisational employees in Jordan using SEM-PLS reveals that personal social media use at work is a double-edged sword as its impact differs by usage types. First, the social use of personal social media at work reduces job burnout, turnover intention, presenteeism, and absenteeism; it also increases job involvement and organisational citizen behaviour. Second, the cognitive use of personal social media at work increases job involvement, organisational citizen behaviour, employee adaptability, and decreases presenteeism and absenteeism; it also increases job burnout and turnover intention. Finally, the hedonic use of personal social media at work carries only negative effects by increasing job burnout and turnover intention.
This study contributes to managerial understanding by showing the impact of different types of personal social media usage and recommends that organisations not limit employee access to personal social media within work time, but rather focus on raising awareness of the negative effects of excessive usage on employee well-being and encourage low to moderate use of personal social media at work and other personal and work-related online interaction associated with positive workplace outcomes. It also clarifies the need for further research in regions such as the Middle East with distinct cultural and socio-economic contexts
Unraveling the effect of sex on human genetic architecture
Sex is arguably the most important differentiating characteristic in most mammalian
species, separating populations into different groups, with varying behaviors, morphologies,
and physiologies based on their complement of sex chromosomes, amongst other factors. In
humans, despite males and females sharing nearly identical genomes, there are differences
between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides
the genome with a distinct hormonal milieu, differential gene expression, and environmental
pressures arising from gender societal roles. This thus poses the possibility of observing
gene by sex (GxS) interactions between the sexes that may contribute to some of the
phenotypic differences observed. In recent years, there has been growing evidence of GxS,
with common genetic variation presenting different effects on males and females. These
studies have however been limited in regards to the number of traits studied and/or
statistical power. Understanding sex differences in genetic architecture is of great
importance as this could lead to improved understanding of potential differences in
underlying biological pathways and disease etiology between the sexes and in turn help
inform personalised treatments and precision medicine.
In this thesis we provide insights into both the scope and mechanism of GxS across the
genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK
Biobank. We found small yet widespread differences in genetic architecture across traits
through the calculation of sex-specific heritability, genetic correlations, and sex-stratified
genome-wide association studies (GWAS). We further investigated whether sex-agnostic
(non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we
studied the potential functional role of sex differences in genetic architecture through sex
biased expression quantitative trait loci (eQTL) and gene-level analyses.
Overall, this study marks a broad examination of the genetics of sex differences. Our findings
parallel previous reports, suggesting the presence of sexual genetic heterogeneity across
complex traits of generally modest magnitude. Furthermore, our results suggest the need to
consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms
'There's lots of suffering in here, but some people are suffering more': Age, Gender and the Pains of Imprisonment
Older offenders are the fastest growing group in the prison population in England and Wales. While most age groups of prisoners have been falling the number of prisoners over the age of 50 has continued to increase. Older prisoners have different needs to the general prison population; however, at the time of writing, the government has yet to implement a policy outlining standards of care for this group of prisoners.
This thesis is the result of and nine-month long ethnography that took place in two prisons, a man's, and a woman's, in England from June 2017 to February 2018. It explores the challenges faced by older people in prison, and how this lack of policy impacted on the older prisoner population. It also examines if those difficulties were experienced equally by the older men and women or if, in a system designed for young men, there were gendered differences in the challenges they faced.
The findings highlight how the older men and women suffered from three additional pains of imprisonment as a result of their incarceration: the Pains of Isolation, the Pains of Loss and the Pains of Ageing and Deteriorating Health. These additional pains, experienced by the older people, were exacerbated by a prison system that did not make any accommodation for their additional needs. However, these ageing pains of imprisonment were not felt equally by the older prisoner population. There was a gendered aspect to many of them and the older women experienced additional gendered ageing pains of imprisonment. Where possible, the older people attempted to mitigate their ageing pains of imprisonment; by forming social networks, by working, or by finding a benefit to their incarceration. However, their ability to use their limited agency was impacted by the policies of the prison regime.
This thesis considered if institutional thoughtlessness assisted in understanding why older people were experiencing additional ageing pains of imprisonment; but concluded that, as a concept, institutional thoughtlessness could not sufficiently explain why these prisoners' needs were overlooked. Moving beyond institutional thoughtlessness, the thesis explores the concept of institutional ageism and how it manifests itself at a macro, meso and micro level; concluding that the ageist policies of the prison service were making the time of older people in prison more difficult and increasing their additional ageing pains of imprisonment. Moreover, when these ageist policies intersected with gender, the ageing pains of imprisonment were experienced more keenly by the older women
New Techniques for High Orders in Scattering Amplitudes
This thesis uses four-dimensional unitarity and augmented recursion to calculate a selection of Yang-Mills amplitudes. This selection consists of the full-colour, two-loop, all-plus helicity amplitudes for five- and six-points; a conjecture for an n-point sub-subleading in colour two-loop amplitude; calculation of the cut-constructible piece of the full-colour, two-loop, all-plus helicity n-point amplitude. A new technique for calculating the cut constructible part of the leading in colour two-loop, five-point, single-minus helicity amplitude is presented. The correct infrared divergent piece of this single-minus amplitude was calculated, as well as the correct transcendental two pieces at finite order. Logarithms containing Mandelstam variables including only positive helicity legs were unable to be correctly calculated, but the calculation of this final amplitude uncovered many new relations involving generalised hypergeometric functions such as the Appell functions
Investigating PAX6 and SOX2 dynamic interactions at the single molecule level in live cells
The abundance of transcription factor (TF) molecules in the nuclei of
eukaryotic cells are in the range of thousands. However, the functional binding
sites of most TFs lie in the range of hundreds. This suggests that there is a
surplus of the number of molecules for many TFs, relative to their binding sites
at any given time. Nevertheless, precise TF levels are instrumental for normal
development and maintenance, with haploinsufficiency (namely lowering the
dosage of a TF by half) being a hallmark of many TF-related human
developmental disorders. Qualitative methods assessing TF binding such as
chromatin immunoprecipitation, provide static information, from fixed cell
populations and so fail to provide insight into TF dynamic behaviour. Live-cell
imaging methodologies such as Fluorescence Correlation Spectroscopy
(FCS) offer the ability to measure kinetics of binding to chromatin, protein-protein interactions, absolute concentrations of molecules and the underlying
cell-to-cell variability.
SOX2 and PAX6 TFs exhibit haploinsufficiency in humans. Heterozygous point
mutations, deletions or insertions in these genes can lead to a plethora of
abnormal ocular developmental disorders (e.g. coloboma, aniridia,
microphthalmia, anopthalmia). SOX2 encodes a high-mobility group (HMG)
domain-containing TF, essential for maintaining self-renewal of embryonic
stem cells and is expressed in proliferating central nervous system (CNS)
progenitors. PAX6 contains two DNA binding domains; a PAIRED domain (PD)
and a homeodomain (HD). Both DNA binding domains present in PAX6 (PD
and HD) can function either jointly, or separately, to regulate a plethora of
genes implicated in the development and maintenance of the CNS, the eye
and the pancreas. Despite existing genetic and phenotypic evidence, it
remains unclear how PAX6 and SOX2 influence each other at the molecular
level and how sensitive their stoichiometry is during ocular development.
In this thesis I investigated the dynamic interplay between PAX6/SOX2 and
chromatin in live cells, at the molecular level. I compared wild-type protein
function with pathogenic missense variants using advanced fluorescence
microscopy techniques and assessed how these mutations quantitatively and
qualitatively affected molecular behaviour. My results showed that both SOX2
and PAX6 pathogenic missense mutants display differential subnuclear
localisation, as well as altered protein-protein and protein-chromatin
interactions, linking molecular diffusion to pathogenic phenotype in humans.
More importantly, I identified a novel role of SOX2 in stabilising PAX6-
chromatin complexes in live cells, providing further insight into the complex
and dynamic relation of PAX6 and SOX2 in ocular tissue specification,
maintenance and development
Novel strategies for the modulation and investigation of memories in the hippocampus
Disruptions of the memory systems in the brain are linked to the manifestation of many neuropsychiatric diseases such as Alzheimer’s disease, depression, and post-traumatic stress disorder. The limited efficacy of current treatments necessities the development of more effective therapies. Neuromodulation has proven effective in a variety of neurological diseases and could be an attractive solution for memory disorders. However, the application of neuromodulation requires a more detailed understanding of the network dynamics associated with memory formation and recall. In this work, we applied a combination of optical and computational tools in the development of a novel strategy for the modulation of memories, and have expanded its application for interrogation of the hippocampal circuitry underlying memory processing in mice.
First, we developed a closed-loop optogenetic stimulation platform to activate neurons implicated in memory processing (engram neurons) with a high temporal resolution. We applied this platform to modulate the activity of engram neurons and assess memory processing with respect to synchronous network activity. The results of our investigation support the proposal that encoding new information and recalling stored memories occur during distinct epochs of hippocampal network-wide oscillations.
Having established the high efficacy of the modulation of engram neurons’ activity in a closed-loop fashion, we sought to combine it with two-photon imaging to enable high spatial resolution interrogation of hippocampal circuitry. We developed a behavioral apparatus for head-fixed engram modulation and the assessment of memory recall in immobile animals. Moreover, through the optimization of dual color two-photon imaging, we improved the ability to monitor activity of neurons in the subfields of the hippocampus with cellular specificity. The platform created here will be applied to investigate the effects of engram reactivation on downstream projections targets with high spatial and cell subtype specificity.
Following these lines of investigations will enhance our understanding of memory modulation and could lead to novel neuromodulation treatments for neurological disorders associated with memory malfunctioning
Managing global virtual teams in the London FinTech industry
Today, the number of organisations that are adopting virtual working arrangements has exploded, and the London FinTech industry is no exception. During recent years, FinTech companies have increasingly developed virtual teams as a means of connecting and engaging geographically dispersed workers, lowering costs, and enabling greater speed and adaptability.
As the first study in the United Kingdom regarding global virtual team management in the FinTech industry, this DBA research seeks answers to the question, “What makes for the successful management of a global virtual team in the London FinTech industry?”. Straussian grounded-theory method was chosen as this qualitative approach lets participants have their own voice and offers some flexibility. It also allows the researcher to have preconceived ideas about the research undertaking.
The research work makes the case for appreciating the voice of people with lived experiences. Ten London-based FinTech Managers with considerable experience running virtual teams agreed to take part in this study. These Managers had spent time working at large, household-name firms with significant global reach, and one had recently become founder and CEO of his own firm, taking on clients and hiring contract staff from around the world. At least eight of the other participants were senior ‘Heads’ of various technology teams and one was a Managing Director working at a ‘Big Four’ consultancy. They had all (and many still did) spent years running geographically distributed teams with members as far away as Pacific Asia and they were all keen to discuss that breadth of experience and the challenges they faced.
Results from these in-depth interviews suggested that there are myriad reasons for a global virtual team, from providing 24 hour, follow-the-sun service to locating the most cost-effective resources with the highest skills. It also confirmed that there are unique challenges to virtual management and new techniques are required to help navigate virtual managers through them.
Managing a global virtual team requires much more than the traditional management competencies. Based on discussion with the respondents, a set of practical recommendations for global virtual team management was developed and covered a wide range of issues related to recruitment and selection, team building, developing standard operating procedures, communication, motivation, performance management, and building trust
Identification of Hindbrain Neural Substrates for Motor Initiation in the hatchling Xenopus laevis Tadpole
Animal survival profoundly depends on the ability to detect stimuli in the environment, process them and respond accordingly. In this respect, motor responses to a sensory stimulation evolved into a variety of coordinated movements, which involve the control of brain centres over spinal locomotor circuits. The hatchling Xenopus tadpole, even in its embryonic stage, is able to detect external sensory information and to swim away if the stimulus is considered noxious. To do so, the tadpole relies on well-known ascending sensory pathway, which carries the sensory information to the brain. When the stimulus is strong enough, descending interneurons are activated, leading to the excitation of spinal CPG neurons, which causes the undulatory movement of swimming. However, the activation of descending interneurons that marks the initiation of motor response appears after a long delay from the sensory stimulation. Furthermore, the long-latency response is variable in time, as observed in the slow-summating excitation measured in descending interneurons. These two features, i.e. long-latency and variability, cannot be explained by the firing time and pattern of the ascending sensory pathway of the Xenopus tadpole. Therefore, a novel neuronal population has been proposed to lie in the hindbrain of the tadpole, and being able to 'hold' the sensory information, thus accounting for the long and variable delay of swim initiation. In this work, the role of the hindbrain in the maintenance of the long and variable response to trunk skin stimulation is investigated in the Xenopustadpole at developmental stage 37/38. A multifaceted approach has been used to unravel the neuronal mechanisms underlying the delayed motor response, including behavioural experiments, electrophysiology analysis of fictive swimming, hindbrain extracellular recordings and imaging experiments. Two novel neuronal populations have been identified in the tadpole's hindbrain, which exhibit activation patterns compatible with the role of delaying the excitation of the spinal locomotor circuit. Future work on cellular properties and synaptic connections of these newly discovered populations might shed light on the mechanism of descending control active at embryonic stage. Identifying supraspinal neuronal populations in an embryonic organism could aid in understanding mechanisms of descending motor control in more complex vertebrates
Uso de las histonas circulantes y sus modificaciones post-traduccionales como biomarcadores en sepsis y shock séptico
La sepsis es una afección potencialmente mortal causada por una respuesta anormal del huésped a una infección, produciendo respuestas fisiológicas alteradas que dañan los propios tejidos del paciente y pueden provocar disfunción orgánica e incluso la muerte. Asimismo, algunos pacientes sépticos progresan a shock séptico, caracterizado por alteraciones circulatorias, celulares y metabólicas sustanciales que aumentan el riesgo de mortalidad. A pesar de que la sepsis se caracteriza por un mal funcionamiento del sistema inmunológico, lo que a su vez conduce a una respuesta inmune alterada e inmunosupresión, la alta complejidad de la fisiopatología de la sepsis requiere una mayor investigación para comprender las respuestas inmunes que ocurren durante la sepsis. Asimismo, las histonas extracelulares circulantes han ganado relevancia como mediadores citotóxicos en la sepsis, ya que actúan como patrones moleculares asociados a daño, que inducen estrés oxidativo y activan el inflamasoma NLRP3. Estos mecanismos median la activación de la piroptosis, un mecanismo de muerte celular programada que produce inflamación mediante la expresión de IL-18, IL-1β and IL-1α. Sin embargo, a pesar de la evidencia de activación del inflamasoma en las células inmunes durante la sepsis, se desconoce si las histonas extracelulares son capaces de activar los inflamasomas endoteliales y sus consecuencias. En este trabajo destacamos el papel previamente desconocido de las histonas extracelulares, mediando la activación del inflamasoma NLRP3 y la piroptosis en las células endoteliales, contribuyendo a la disfunción endotelial y la desregulación de la respuesta inmune mediada por el endotelio. Asimismo, también demostramos cómo la acetilación de histonas disminuye la activación de la piroptosis. Además, demostramos que la piroptosis se produce en pacientes con shock séptico y los niveles de histonas circulantes se correlacionan con la expresión de citoquinas proinflamatorias y citoquinas piroptóticas, la liberación de factores de adhesión endotelial y la gravedad de la enfermedad. Proponemos la piroptosis mediada por histonas como un nuevo objetivo para desarrollar intervenciones clínicas. De manera similar, hemos analizado las respuestas inmunorelacionadas que ocurren durante las primeras etapas de la sepsis con el objetivo de proporcionar nuevos datos comparando las cantidades de citoquinas, inmunomoduladores y otros mediadores endoteliales en pacientes críticamente enfermos no sépticos, sépticos y de shock séptico. Nuestro enfoque ayudará a caracterizar rápidamente las respuestas inmunes alteradas en pacientes sépticos y de shock séptico ingresados en la Unidad de Cuidados Intensivos. Finalmente analizamos el papel de la metilación del ADN en el control del sistema inmune séptico. Nuestros resultados demostraron el papel central de la metilación del ADN modulando la respuesta molecular en los pacientes de shock séptico y contribuyendo a la inmunosupresión, a través de la alteración de los patrones de metilación de los promotores de IL-10 y TREM-2.Sepsis is a life-threatening condition caused by an abnormal host response to an infection that produce altered physiological responses which damages own tissues of the patient and can result in organ dysfunction and in some cases death. Likewise, a subset of septic patients progresses to septic shock, characterized by substantial circulatory, cellular and metabolic abnormalities, which substantially increase the risk of mortality. Sepsis is characterized by a malfunction of the immune system and it can lead to an altered immune response and immunosuppression. Moreover, the high complexity of the pathophysiology of sepsis requires of further investigation to characterize the immune responses in sepsis and septic shock. Likewise, circulating extracellular histones have gained relevance as cytotoxic mediators in sepsis pathophysiology, since they act as damage-associated molecular patterns, which induce oxidative stress and activate NLRP3 inflammasome. Subsequently, inflammasome mediates pyroptosis activation, a programmed cell death mechanism that produces inflammation through the release of IL-18, IL-1β and IL-1α. However, despite inflammasome activation may occur in immune cells during sepsis, it is unknown if this process also takes place in endothelial cells and particularly whether extracellular histones are capable of activating endothelial inflammasomes and their consequences. In this work we highlight a previously unknown role for extracellular histones, that mediates the activation of NLRP3 inflammasome and pyroptosis in endothelial cells by contributing to endothelial dysfunction and the dysregulation of the immune response mediated by endothelium. Likewise, we demonstrated how histone acetylation decreases pyroptosis activation. Furthermore, we show how pyroptosis occurs in septic shock patients and how circulating histone levels correlate with the expression of pro-inflammatory and pyroptotic cytokines, the release of endothelial adhesion factors and septic shock severity. We propose histone-mediated pyroptosis as a new target to develop clinical interventions. Similarly, we have analyzed the immune-related responses occurring during the early stages of sepsis with the aim of providing new data by comparing the amounts of cytokines, immune modulators and other endothelial mediators in critically-ill non-septic patients, septic and septic shock patients. Our approach will help to rapidly characterize the altered immune responses in septic and septic shock patients admitted in the Intensive Care Unit. Finally, we also analyzed the role of DNA methylation in the control of septic immune system. Our results demonstrated the central role of DNA methylation modulating the molecular response in septic shock patients and contributing to immunosuppression, through the alteration of DNA methylation patterns of IL-10 and TREM2 promoters
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