33,478 research outputs found
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Engineering protein toxins to modulate the intracellular trafficking of biologics into exosomes for third order drug targeting
The successful use of mRNA as a vaccine to limit the effects of COVID-19 has highlighted the potential of RNA based drugs. However, the use of small interfering (si)RNA (or antisense oligonucleotides (ASOs)) as therapeutics remains limited by the availability of safe and robust drug delivery technology that can deliver intact RNA to the cytosol of tissues beyond the liver or muscle. New knowledge regarding the regulation of intracellular compartmentalisation associated with membrane trafficking has led to the identification of new problems and opportunities within the field of drug delivery. One of the technologies that has emerged is the use of attenuated toxins for the cytosolic delivery of macromolecules. Unlike charged lipids or synthetic polymers, these molecules do not display charge limited PKPD or toxicity profiles intimately linked to their ability to mediate transfection. Anthrax toxin uses intraluminal vesicles (ILVs) as an intermediary compartment en route to the cytosol of mammalian cells. These ILVs can be subsequently secreted as exosomes and herein is an opportunity to load selected nucleic acid or protein drugs into exosomes. Exosomes loaded in this manner have the potential to transport bioactive payloads across intercellular space to their target, whilst protecting their luminal cargo from hydrolytic enzymes or from the host’s immune response before effecting cytosolic delivery. Following such a rationale, engineering biology may provide a valuable platform for third order drug targeting and facilitate the intracellular delivery of RNA drugs to cells and tissues beyond striated muscle and the liver
Building body identities - exploring the world of female bodybuilders
This thesis explores how female bodybuilders seek to develop and maintain a viable sense of self despite being stigmatized by the gendered foundations of what Erving Goffman (1983) refers to as the 'interaction order'; the unavoidable presentational context in which identities are forged during the course of social life. Placed in the context of an overview of the historical treatment of women's bodies, and a concern with the development of bodybuilding as a specific form of body modification, the research draws upon a unique two year ethnographic study based in the South of England, complemented by interviews with twenty-six female bodybuilders, all of whom live in the U.K. By mapping these extraordinary women's lives, the research illuminates the pivotal spaces and essential lived experiences that make up the female bodybuilder. Whilst the women appear to be embarking on an 'empowering' radical body project for themselves, the consequences of their activity remains culturally ambivalent. This research exposes the 'Janus-faced' nature of female bodybuilding, exploring the ways in which the women negotiate, accommodate and resist pressures to engage in more orthodox and feminine activities and appearances
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Co-design As Healing: Exploring The Experiences Of Participants Facing Mental Health Problems
This thesis is an exploration of the healing role of co-design in mental health. Although co-design projects conducted within mental health settings are rising, existing literature tends to focus on the object of design and its outcomes while the experiences of participants per se remain largely unexplored. The guiding research question of this study is not how we design things that improve mental health, but how co-designing, as an act, might do so.
The thesis presents two projects that were organized in collaboration with the mental health charity Islington Mind and the Psychosis Therapy Project (PTP) in London.
The project at Islington Mind used a structured design process inviting participants to design for wellbeing. A case study analysis provides insights on how participants were impacted, summarizing key challenges and opportunities.
The design at PTP worked towards creating a collective brief in an emergent fashion, finally culminating in a board game. The experiences of participants were explored through Interpretative Phenomenological Analysis (IPA), using semi-structured interview data. The analysis served to identify key themes characterising the experience of co-design such as contributing, connecting, thinking and intentioning. In addition, a mixed-methods analysis of questionnaires and interview data exploring participants' wellbeing, showed that all participants who engaged fairly consistently in the project improved after the project ended, although some participants' scores returned to baseline six months later.
Reflecting on both projects, an approach to facilitation within mental health is outlined, detailing how the dimensions of weaving and layered participation, nurturing mattering and facilitating attitudes interlace. This contribution raises awareness of tacit dimensions in the practice of facilitation, articulating the nuances of how to encourage and sustain meaningful and ethical engagement and offering insights into a range of tools. It highlights the importance of remaining reflexive in relation to attitudes and emotions and discusses practical methodological and ethical challenges and ways to resolve them which can be of benefit to researchers embarking on a similar journey.
The thesis also offers detailed insights on how methodologies from different fields were integrated into a whole, arguing for transparency and reflexivity about epistemological assumptions, and how underlying paradigms shift in an interdisciplinary context.
Based on the overall findings, the thesis makes a case for considering design as healing (or a designerly way of healing), highlighting implications at a systems, social and individual level. It makes an original contribution to our understanding of design, highlighting its healing character, and proposes a new way to support mental health. The participants in this study not only had increased their own wellbeing through co-designing, but were also empowered and contributed towards healing the world. Hence, the thesis argues for a unique, holistic perspective of design and mental health, recognizing the interconnectedness of the individual, social and systemic dimensions of the healing processes that are ignited
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Meaning-Making Practices of Emergent Arabic–English Bilingual Kindergarten Children in Cairo
The number of British Schools in the Middle East and North Africa (MENA) region is growing. The National Curriculum of England is used by an increasing number of such schools. As well as exporting a culturally-specific curriculum, these schools usually adopt an ideology of monolingualism, thus potentially limiting communication for emergent bilinguals and failing to acknowledge the multiple ways of meaning-making.
Current studies of translanguaging are moving the focus to multimodal forms of communication as a resource for thinking and communicating (GarcÃa and Wei 2014, Wei 2018). Building on the work of Kress (1997, 2010) I explore pre-school emergent bilinguals’ wider signifying practices and create an analytical framework, which I call MMTL (multimodal translanguaging), used as a lens to illustrate meaning-making.
Valley Hill in Cairo, Egypt is a British school which encourages ‘English-only’ as the medium of instruction in the kindergarten. Using a case study methodology, this research explores the meaning-making practices of eight emergent bilingual children aged 3–4 during child-initiated play, later reduced to four in the thesis to provide a detailed multimodal analysis. The principal aim is to explore their speech, gaze, gesture, and their engagement (layout/position) with artefacts during play.
The findings of this study suggest that although there is an ‘English-only’ approach, these young emergent bilingual children are meaning-making in a variety of ways. Children are translanguaging but it is never in isolation from other modes of communication. Emergent bilinguals use a range of modes to mediate their understanding and communication with others. They use gesture, gaze, and artefacts alongside translingual practices to move meaning across to more accessible modes, enabling communication and understanding. The implications for schools should be to embrace such hybrid practices and for teachers to be more responsive to young children’s meaning-making to enable learning
What is the importance of sperm subpopulations?
.The study of sperm subpopulations spans three decades. The origin, meaning, and practical significance, however, are less clear. Current technology for assessing sperm morphology (CASA-Morph) and motility (CASA-Mot) has enabled the accurate evaluation of these features, and there are many options for data classification. Subpopulations could occur as a result of the stage of development of each spermatozoon in the subpopulation. Spermatogenesis might contribute to the production of these subpopulations. Insights from evolutionary biology and recent molecular research are indicative of the diversity among male gametes that could occur from unequal sharing of transcripts and other elements through cytoplasmic bridges between spermatids. Sperm cohorts exiting the gonads would contain different RNA and protein contents, affecting the spermatozoon physiology and associations with the surrounding environmental milieu. Subsequently, these differences could affect how spermatozoa interact with the environmental milieu (maturation, mixing with seminal plasma, and interacting with the environmental milieu, or female genital tract and female gamete). The emergence of sperm subpopulations as an outcome of evolution, related to the reproductive strategies of the species, genital tract structures, and copulatory and fertilization processes. This kind of approach in determining the importance of sperm subpopulations in fertilization capacity should have a practical impact for conducting reproductive technologies, inspiring and enabling new ways for the more efficient use of spermatozoa in the medical, animal breeding, and conservation fields. This manuscript is a contribution to the Special Issue in memory of Dr. Duane GarnerS
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
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
Studies of strategic performance management for classical organizations theory & practice
Nowadays, the activities of "Performance Management" have spread very broadly in actually every part of business and management. There are numerous practitioners and researchers from very different disciplines, who are involved in exploring the different contents of performance management. In this thesis, some relevant historic developments in performance management are first reviewed. This includes various theories and frameworks of performance management. Then several management science techniques are developed for assessing performance management, including new methods in Data Envelopment Analysis (DEA) and Soft System Methodology (SSM). A theoretical framework for performance management and its practical procedures (five phases) are developed for "classic" organizations using soft system thinking, and the relationship with the existing theories are explored. Eventually these results are applied in three case studies to verify our theoretical development. One of the main contributions of this work is to point out, and to systematically explore the basic idea that the effective forms and structures of performance management for an organization are likely to depend greatly on the organizational configuration, in order to coordinate well with other management activities in the organization, which has seemingly been neglected in the existing literature of performance management research in the sense that there exists little known research that associated particular forms of performance management with the explicit assumptions of organizational configuration. By applying SSM, this thesis logically derives some main functional blocks of performance management in 'classic' organizations and clarifies the relationships between performance management and other management activities. Furthermore, it develops some new tools and procedures, which can hierarchically decompose organizational strategies and produce a practical model of specific implementation steps for "classic" organizations. Our approach integrates popular types of performance management models. Last but not least, this thesis presents findings from three major cases, which are quite different organizations in terms of management styles, ownership, and operating environment, to illustrate the fliexbility of the developed theoretical framework
The empty space in abstract photography: a psychoanalytical perspective
The aim of the research that this thesis is based on is to explore the theoretical problems raised by the concept of photographic abstraction. These consist in the tension between the two aspects of the photographic sign, the indexical and iconic, and are examined in the context of the particular exploration of the empty space in abstract photography which I have pursued through my practice. The investigation draws mainly upon the psychoanalytic theory of transitional phenomena as proposed by Winnicott, as well as other art theories (Deleuze & Guattari, Ehrenzweig, Fer, Fuller, Greenberg, Joselit, Kuspit, Leider, Worringer) of abstraction. It explores the relationship of the abstract photographic image to notions of exteriority and interiority as these relate to the transition from the unconscious to conscious reality. The development of this research suggests the psychoanalytical concept of potential space as a contribution to an aesthetic model of abstraction. This concept is employed as a methodological tool in the development of the practical work and creates a framework for its interpretation. The concept of potential space is based on Winnicott's ideas around "playing with the real" in an intermediate area of experience between the internal and external reality, where creativity originates as a zone of fictive play that facilitates the subject's journey from "what is subjectively conceived of' to "what is objectively perceived. " The outcome of this investigation constitutes the production of a series of photographs describing an empty abstract space, one that is invested with a psychic dimension that produces the effect of ambiguity between its representational and abstract readings. It provides a redefinition of abstraction in a space of tension between the iconic and indexical aspects of the sign and opens up the space of abstraction in photography as one in which the relationship between inner and outer reality can be performed and can become a space of action and intervention
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