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"Woods, Angela"
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Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines
mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency.
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Journal Article
Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.
Journal Article
The limits of narrative: provocations for the medical humanities
This paper aims to (re)ignite debate about the role of narrative in the medical humanities. It begins with a critical review of the ways in which narrative has been mobilised by humanities and social science scholars to understand the experience of health and illness. I highlight seven dangers or blind spots in the dominant medical humanities approach to narrative, including the frequently unexamined assumption that all human beings are ‘naturally narrative’. I then explore this assumption further through an analysis of philosopher Galen Strawson's influential article ‘Against Narrativity’. Strawson rejects the descriptive claim that “human beings typically see or live or experience their lives as a narrative” and the normative claim that “a richly Narrative outlook is essential to a well-lived life, to true or full personhood”. His work has been taken up across a range of disciplines, but its implications in the context of health and illness have not yet been sufficiently discussed. This article argues that ‘Against Narrativity’ can and should stimulate robust debate within the medical humanities regarding the limits of narrative, and concludes by discussing a range of possibilities for venturing ‘beyond narrative’.
Journal Article
Experiences of felt presence in first episode psychosis
Felt presence (FP) – sensing another person without clear sensory evidence – has been described in psychosis for over a century but rarely studied due to challenges in recognition and assessment. Recently FP has been identified as a transdiagnostic phenomenon and highlighted by people with lived experience of psychosis as a clinical priority. Here we describe FP presentation in a first-episode psychosis sample and report preliminary associations with affect, gender, and psychopathology.
Journal Article
Activation of Yeast Snf1 and Mammalian AMP-Activated Protein Kinase by Upstream Kinases
The Snf1/AMP-activated protein kinase (AMPK) family plays fundamental roles in cellular responses to metabolic stress in eukaryotes. In humans, AMPK regulates lipid and glucose metabolism and has been implicated in such metabolic disorders as diabetes and obesity and in cardiac abnormalities. Snf1 and AMPK are the downstream components of kinase cascades, but the upstream kinase(s) have remained elusive. We have here identified three yeast kinases, Pak1p, Tos3p, and Elm1p, that activate Snf1 kinase in vivo. Triple deletion of the cognate genes causes a Snf-mutant phenotype and abolishes Snf1 catalytic activity. All three kinases phosphorylate recombinant Snf1p on the activation-loop threonine. Moreover, Tos3p phosphorylates mammalian AMPK on the equivalent residue and activates the enzyme, suggesting functional conservation of the upstream kinases between yeast and mammals. We further show that the closely related mammalian LKB1 kinase, which is associated with Peutz-Jeghers cancer-susceptibility syndrome, phosphorylates and activates AMPK in vitro. Thus, the identification of the yeast upstream kinases should facilitate identification of the corresponding, physiologically important mammalian upstream kinases.
Journal Article
AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue
Obesity results from a chronic imbalance between energy intake and energy output but remains difficult to prevent or treat in humans. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an important regulator of energy homeostasis
1
–
3
and is a molecular target of drugs used for the treatment of metabolic diseases, including obesity
4
,
5
. Here we show that mice expressing a gain-of-function AMPK mutant
6
display a change in morphology of subcutaneous white adipocytes that is reminiscent of browning. However, despite a dramatic increase in mitochondrial content, Ucp1 expression is undetectable in these adipocytes. In response to a high-fat diet (HFD), expression of skeletal muscle–associated genes is induced in subcutaneous white adipocytes from the gain-of-function AMPK mutant mice. Chronic genetic AMPK activation results in protection against diet-induced obesity due to an increase in whole-body energy expenditure, most probably because of a substantial increase in the oxygen consumption rate of white adipose tissue. These results suggest that AMPK activation enriches, or leads to the emergence of, a population of subcutaneous white adipocytes that produce heat via Ucp1-independent uncoupling of adenosine triphosphate (ATP) production on a HFD. Our findings indicate that AMPK activation specifically in adipose tissue may have therapeutic potential for the treatment of obesity.
AMPK is a master regulator of cellular metabolism. Here the authors show that a constitutively active AMPK mutation protects mice fed a high-fat diet from obesity by increasing energy expenditure in subcutaneous white adipocytes, possibly as a result of the emergence of a hitherto-unknown type of adipocyte.
Journal Article
The ripple effects of suicide: a personal account of dealing with the death of an adult sibling
Purpose
The purpose of this paper is to offer an opinion piece that documents the experience of losing an adult sibling to suicide and explores the experience of personal and family grief.
Design/methodology/approach
This narrative is written from an autoethnographic perspective and uses the current evidence base to support a personal reflection.
Findings
This paper identifies the complex nature of bereavement following death from suicide and considers those factors that support more positive outcomes for those grieving.
Research limitations/implications
This piece focuses on autoethnographic data but is supported by findings from the wider evidence base.
Practical implications
The importance of seeking positives as part of the healing process when processing complex grief.
Social implications
Disclosure has been identified as an important part of processing complex grief associated with suicide bereavement and yet suicide remains a taboo subject for many.
Originality/value
This autoethnographic piece details the experience of dealing with a sibling suicide and the importance of creating the opportunity for positive reflection to process complex grief.
Journal Article
The Edinburgh Companion to the Critical Medical Humanities
This is the first volume to comprehensively introduce the ways in which interdisciplinary thinking across the humanities and social sciences might contribute to, critique and develop medical understanding of the human individually and collectively.
eBook
Acylated-acyl carrier protein stabilizes the Pseudomonas aeruginosa WaaP lipopolysaccharide heptose kinase
Phosphorylation of
Pseudomonas aeruginosa
lipopolysaccharide (LPS) is important for maintaining outer membrane integrity and intrinsic antibiotic resistance. We solved the crystal structure of the LPS heptose kinase WaaP, which is essential for growth of
P
.
aeruginosa
. WaaP was structurally similar to eukaryotic protein kinases and, intriguingly, was complexed with acylated-acyl carrier protein (acyl-ACP). WaaP produced by
in vitro
transcription-translation was insoluble unless acyl-ACP was present. WaaP variants designed to perturb the acyl-ACP interaction were less stable in cells and exhibited reduced kinase function. Mass spectrometry identified myristyl-ACP as the likely physiological binding partner for WaaP in
P
.
aeruginosa
. Together, these results demonstrate that acyl-ACP is required for WaaP protein solubility and kinase function. To the best of our knowledge, this is the first report describing acyl-ACP in the role of a cofactor necessary for the production and stability of a protein partner.
Journal Article