Boosting with variant-matched or historical mRNA vaccines protects against Omicron infection in mice.

The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.

SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness.

A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity1. This principle has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation. Here we show that mRNA-1273 induces potent neutralizing antibody responses to both wild-type (D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a phase III trial to evaluate its efficacy.

The Recovery Narrative: Politics and Possibilities of a Genre.

Recovery is now widely acknowledged as the dominant approach to the management of mental distress and illness in government, third-sector and some peer-support contexts across the United Kingdom and elsewhere in the Anglophone Global North. Although narrative has long been recognised in practice and in policy as a key "technology of recovery," there has been little critical investigation of how recovery narratives are constituted and mobilised, and with what consequences. This paper offers an interdisciplinary, critical medical humanities analysis of the politics and possibilities of Recovery Narrative, drawing literary theoretical concepts of genre and philosophical approaches to the narrative self into conversation with the critiques of recovery advanced by survivor-researchers, sociologists and mad studies scholars. Our focus is not on the specific stories of individuals, but on the form, function and effects of Recovery Narrative as a highly circumscribed kind of storytelling. We identify the assumptions, lacunae and areas of tension which compel a more critical approach to the way this genre is operationalised in and beyond mental health services, and conclude by reflecting on the possibilities offered by other communicative formats, spaces and practices.

Hearing spiritually significant voices: A phenomenological survey and taxonomy.

Whereas previous research in the medical humanities has tended to neglect theology and religious studies, these disciplines sometimes have a very important contribution to make. The hearing of spiritually significant voices provides a case in point. The context, content and identity of these voices, all of which have typically not been seen as important in the assessment of auditory-verbal hallucinations (AVHs) within psychiatry, are key to understanding their spiritual significance. A taxonomy of spiritually significant voices is proposed, which takes into account frequency, context, affect and identity of the voice. In a predominantly Christian sample of 58 people who reported having heard spiritually significant voices, most began in adult life and were infrequent experiences. Almost 90% reported that the voice was divine in identity and approximately one-third were heard in the context of prayer. The phenomenological characteristics of these voices were different from those in previous studies of voice hearing (AVHs). Most comprised a single voice; half were auditory; and a quarter were more thought-like (the rest being a mixture). Only half were characterful, and one-third included commands or prompts. The voices were experienced positively and as meaningful. The survey has implications for both clinical and pastoral work. The phenomenology of spiritually significant voices may be confused with that of psychopathology, thus potentially leading to misdiagnosis of normal religious experiences. The finding of meaning in content and context may be important in voice hearing more widely, and especially in coping with negative or distressing voices.

Protein kinase A negatively regulates VEGF-induced AMPK activation by phosphorylating CaMKK2 at serine 495.

Activation of AMP-activated protein kinase (AMPK) in endothelial cells by vascular endothelial growth factor (VEGF) via the Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) represents a pro-angiogenic pathway, whose regulation and function is incompletely understood. This study investigates whether the VEGF/AMPK pathway is regulated by cAMP-mediated signalling. We show that cAMP elevation in endothelial cells by forskolin, an activator of the adenylate cyclase, and/or 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterases, triggers protein kinase A (PKA)-mediated phosphorylation of CaMKK2 (serine residues S495, S511) and AMPK (S487). Phosphorylation of CaMKK2 by PKA led to an inhibition of its activity as measured in CaMKK2 immunoprecipitates of forskolin/IBMX-treated cells. This inhibition was linked to phosphorylation of S495, since it was not seen in cells expressing a non-phosphorylatable CaMKK2 S495C mutant. Phosphorylation of S511 alone in these cells was not able to inhibit CaMKK2 activity. Moreover, phosphorylation of AMPK at S487 was not sufficient to inhibit VEGF-induced AMPK activation in cells, in which PKA-mediated CaMKK2 inhibition was prevented by expression of the CaMKK2 S495C mutant. cAMP elevation in endothelial cells reduced basal and VEGF-induced acetyl-CoA carboxylase (ACC) phosphorylation at S79 even if AMPK was not inhibited. Together, this study reveals a novel regulatory mechanism of VEGF-induced AMPK activation by cAMP/PKA, which may explain, in part, inhibitory effects of PKA on angiogenic sprouting and play a role in balancing pro- and anti-angiogenic mechanisms in order to ensure functional angiogenesis.

'I've learned I need to treat my characters like people': Varieties of agency and interaction in Writers' experiences of their Characters' Voices.

Writers often report vivid experiences of hearing characters talking to them, talking back to them, and exhibiting independence and autonomy. However, systematic empirical studies of this phenomenon are almost non-existent, and as a result little is known about its cause, extent, or phenomenology. Here we present the results of a survey of professional writers (n = 181) run in collaboration with the Edinburgh International Book Festival. Participants provided detailed descriptions of their experiences of their characters in response to a phenomenological questionnaire, and also reported on imaginary companions, inner speech and hallucination-proneness. Qualitative analysis indicated that the phenomenology of the experience of agentive characters varied in terms of the characters' separateness from the writer's self and the kinds of interaction this did or did not allow for. We argue that these variations can be understood in relation to accounts of mindreading and agency tracking which adopt intuitive as opposed to inferential models.

A linguistic approach to the psychosis continuum: (dis)similarities and (dis)continuities in how clinical and non-clinical voice-hearers talk about their voices.

Introduction: "Continuum" approaches to psychosis have generated reports of similarities and differences in voice-hearing in clinical and non-clinical populations at the cohort level, but not typically examined overlap or degrees of difference between groups. Methods: We used a computer-aided linguistic approach to explore reports of voice-hearing by a clinical group (Early Intervention in Psychosis service-users; N = 40) and a non-clinical group (spiritualists; N = 27). We identify semantic categories of terms statistically overused by one group compared with the other, and by each group compared to a control sample of non-voice-hearing interview data (log likelihood (LL) value 6.63+=p < .01; effect size measure: log ratio 1.0+). We consider whether individual values support a continuum model. Results: Notwithstanding significant cohort-level differences, there was considerable continuity in language use. Reports of negative affect were prominent in both groups (p < .01, log ratio: 1.12+). Challenges of cognitive control were also evident in both cohorts, with references to "disengagement" accentuated in service-users (p < .01, log ratio: 1.14+). Conclusion: A corpus linguistic approach to voice-hearing provides new evidence of differences between clinical and non-clinical groups. Variability at the individual level provides substantial evidence of continuity with implications for cognitive mechanisms underlying voice-hearing.

Mutations Reducing In Vitro Susceptibility to Novel LpxC Inhibitors in Pseudomonas aeruginosa and Interplay of Efflux and Nonefflux Mechanisms.

Upregulated expression of efflux pumps, lpxC target mutations, LpxC protein overexpression, and mutations in fabG were previously shown to mediate single-step resistance to the LpxC inhibitor CHIR-090 in P. aeruginosa Single-step selection experiments using three recently described LpxC inhibitors (compounds 2, 3, and 4) and mutant characterization showed that these mechanisms affect susceptibility to additional novel LpxC inhibitors. Serial passaging of P. aeruginosa wild-type and efflux pump-defective strains using the LpxC inhibitor CHIR-090 or compound 1 generated substantial shifts in susceptibility and underscored the interplay of efflux and nonefflux mechanisms. Whole-genome sequencing of CHIR-090 passage mutants identified efflux pump overexpression, fabG mutations, and novel mutations in fabF1 and in PA4465 as determinants of reduced susceptibility. Two new lpxC mutations, encoding A214V and G208S, that reduce susceptibility to certain LpxC inhibitors were identified in these studies, and we show that these and other target mutations differentially affect different LpxC inhibitor scaffolds. Lastly, the combination of target alteration (LpxCA214V) and upregulated expression of LpxC was shown to be tolerated in P. aeruginosa and could mediate significant decreases in susceptibility.

Defects in Efflux (oprM), ß-Lactamase (ampC), and Lipopolysaccharide Transport (lptE) Genes Mediate Antibiotic Hypersusceptibility of Pseudomonas aeruginosa Strain Z61.

Antibiotic hypersensitive bacterial mutants (e.g., Escherichia coliimp) are used to investigate intrinsic resistance and are exploited in antibacterial discovery to track weak antibacterial activity of novel inhibitor compounds. Pseudomonas aeruginosa Z61 is one such drug-hypersusceptible strain generated by chemical mutagenesis, although the genetic basis for hypersusceptibility is not fully understood. Genome sequencing of Z61 revealed nonsynonymous single-nucleotide polymorphisms in 153 genes relative to its parent strain, and three candidate mutations (in oprM, ampC, and lptE) predicted to mediate hypersusceptibility were characterized. The contribution of these mutations was confirmed by genomic restoration of the wild-type sequences, individually or in combination, in the Z61 background. Introduction of the lptE mutation or genetic inactivation of oprM and ampC genes alone or together in the parent strain recapitulated drug sensitivities. This showed that disruption of oprM (which encodes a major outer membrane efflux pump channel) increased susceptibility to pump substrate antibiotics, that inactivation of the inducible ß-lactamase gene ampC contributed to ß-lactam susceptibility, and that mutation of the lipopolysaccharide transporter gene lptE strongly altered the outer membrane permeability barrier, causing susceptibility to large antibiotics such as rifampin and also to ß-lactams.

Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.

Folliculin (FLCN) is a tumor-suppressor protein mutated in the Birt-Hogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive loss-of-function variant of Fnip1 Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells. FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK. Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium, whereas AMPK-dependent unc-51-like autophagy activating kinase 1 (ULK1) phosphorylation and autophagy were increased in FNIP1-deficient B-cell progenitors. These data support a role for FNIP1 as a negative regulator of AMPK.

Determinants of Antibacterial Spectrum and Resistance Potential of the Elongation Factor G Inhibitor Argyrin B in Key Gram-Negative Pathogens.

Argyrins are natural products with antibacterial activity against Gram-negative pathogens, such as Pseudomonas aeruginosa, Burkholderia multivorans, and Stenotrophomonas maltophilia We previously showed that argyrin B targets elongation factor G (FusA). Here, we show that argyrin B activity against P. aeruginosa PAO1 (MIC = 8 µg/ml) was not affected by deletion of the MexAB-OprM, MexXY-OprM, MexCD-OprJ, or MexEF-OprN efflux pump. However, argyrin B induced expression of MexXY, causing slight but reproducible antagonism with the MexXY substrate antibiotic ciprofloxacin. Argyrin B activity against Escherichia coli increased in a strain with nine tolC efflux pump partner genes deleted. Complementation experiments showed that argyrin was effluxed by AcrAB, AcrEF, and MdtFX. Argyrin B was inactive against Acinetobacter baumannii Differences between A. baumannii and P. aeruginosa FusA proteins at key residues for argyrin B interaction implied that natural target sequence variation impacted antibacterial activity. Consistent with this, expression of the sensitive P. aeruginosa FusA1 protein in A. baumannii conferred argyrin susceptibility, whereas resistant variants did not. Argyrin B was active against S. maltophilia (MIC = 4 µg/ml). Spontaneous resistance occurred at high frequency in the bacterium (circa 10-7), mediated by mutational inactivation of fusA1 rather than by amino acid substitutions in the target binding region. This strongly suggested that resistance occurred at high frequency through loss of the sensitive FusA1, leaving an alternate argyrin-insensitive elongation factor. Supporting this, an additional fusA-like gene (fusA2) is present in S. maltophilia that was strongly upregulated in response to mutational loss of fusA1.

On shame and voice-hearing.

Hearing voices in the absence of another speaker-what psychiatry terms an auditory verbal hallucination-is often associated with a wide range of negative emotions. Mainstream clinical research addressing the emotional dimensions of voice-hearing has tended to treat these as self-evident, undifferentiated and so effectively interchangeable. But what happens when a richer, more nuanced understanding of specific emotions is brought to bear on the analysis of distressing voices? This article draws findings from the 'What is it like to hear voices' study conducted as part of the interdisciplinary Hearing the Voice project into conversation with philosopher Dan Zahavi's Self and Other: Exploring Subjectivity, Empathy and Shame to consider how a focus on shame can open up new questions about the experience of hearing voices. A higher-order emotion of social cognition, shame directs our attention to aspects of voice-hearing which are understudied and elusive, particularly as they concern the status of voices as other and the constitution and conceptualisation of the self.

Critical medical humanities: embracing entanglement, taking risks.

What can the medical humanities achieve? This paper does not seek to define what is meant by the medical humanities, nor to adjudicate the exact disciplinary or interdisciplinary knowledges it should offer, but rather to consider what it might be capable of doing. Exploring the many valences of the word 'critical', we argue here for a critical medical humanities characterised by: (i) a widening of the sites and scales of 'the medical' beyond the primal scene of the clinical encounter; (ii) greater attention not simply to the context and experience of health and illness, but to their constitution at multiple levels; (iii) closer engagement with critical theory, queer and disability studies, activist politics and other allied fields; (iv) recognition that the arts, humanities and social sciences are best viewed not as in service or in opposition to the clinical and life sciences, but as productively entangled with a 'biomedical culture'; and, following on from this, (v) robust commitment to new forms of interdisciplinary and cross-sector collaboration. We go on to introduce the five other articles published in this special issue of the journal, reflecting on the ways in which collaboration and critique are articulated in their analyses of immunology, critical neuroscience, toxicity, global clinical labour, and psychological coercion and workfare. As these articles demonstrate, embracing the complex role of critical collaborator--one based on notions of entanglement, rather than servility or antagonism--will, we suggest, develop the imaginative and creative heterodox qualities and practices which have long been recognised as core strengths of the medical humanities.

Spiritually significant hallucinations: a patient-centred approach to tackle epistemic injustice.

SUMMARY: This article uses three fictitious case vignettes to raise questions and educate on how clinicians can appropriately approach patients experiencing spiritually significant hallucinations. Religious hallucinations are common but are not pathognomonic of mental illness. They are often intimate experiences for the patient that raise complex questions about psychopathology for clinicians. When assessing a patient with religious hallucinations it is important that clinicians hold at the centre that person's personal experience and create a safe space in which they are listened to and epistemic injustices are avoided. Involvement of chaplaincy services is important not just to support the patient but also to ensure that as clinicians we seek support in understanding the religious nature of these experiences.

AMP-activated protein kinase: new regulation, new roles?

The hydrolysis of ATP drives virtually all of the energy-requiring processes in living cells. A prerequisite of living cells is that the concentration of ATP needs to be maintained at sufficiently high levels to sustain essential cellular functions. In eukaryotic cells, the AMPK (AMP-activated protein kinase) cascade is one of the systems that have evolved to ensure that energy homoeostasis is maintained. AMPK is activated in response to a fall in ATP, and recent studies have suggested that ADP plays an important role in regulating AMPK. Once activated, AMPK phosphorylates a broad range of downstream targets, resulting in the overall effect of increasing ATP-producing pathways whilst decreasing ATP-utilizing pathways. Disturbances in energy homoeostasis underlie a number of disease states in humans, e.g. Type 2 diabetes, obesity and cancer. Reflecting its key role in energy metabolism, AMPK has emerged as a potential therapeutic target. In the present review we examine the recent progress aimed at understanding the regulation of AMPK and discuss some of the latest developments that have emerged in key areas of human physiology where AMPK is thought to play an important role.

The voice-hearer.

BACKGROUND: For 25 years, the international Hearing Voices Movement and the U.K. Hearing Voices Network have campaigned to improve the lives of people who hear voices. In doing so, they have introduced a new term into the mental health lexicon: "the voice-hearer." AIMS: This article offers a "thick description" of the figure of "the voice-hearer." METHOD: A selection of prominent texts (life narratives, research papers, videos and blogs), the majority produced by people active in the Hearing Voices or consumer/survivor/ex-patient movements, were analysed from an interdisciplinary medical humanities perspective. RESULTS: "The voice-hearer" (i) asserts voice-hearing as a meaningful experience, (ii) challenges psychiatric authority and (iii) builds identity through sharing life narrative. While technically accurate, the definition of "the voice-hearer" as simply "a person who has experienced voice-hearing or auditory verbal hallucinations" fails to acknowledge that this is a complex, politically resonant and value-laden identity. CONCLUSIONS: The figure of "the voice-hearer" comes into being through a specific set of narrative practices as an "expert by experience" who challenges the authority and diagnostic categories of mainstream psychiatry, especially the category of "schizophrenia."

The Long or the Post of It? Temporality, Suffering, and Uncertainty in Narratives Following COVID-19.

Long COVID affects millions of individuals worldwide but remains poorly understood and contested. This article turns to accounts of patients' experiences to ask: What might narrative be doing both to long COVID and for those who live with the condition? What particular narrative strategies were present in 2020, as millions of people became ill, en masse, with a novel virus, which have prevailed three years after the first lockdowns? And what can this tell us about illness and narrative and about the importance of literary critical approaches to the topic in a digital, post-pandemic age? Through a close reading of journalist Lucy Adams's autobiographical accounts of long COVID, this article explores the interplay between individual illness narratives and the collective narrativizing (or making) of an illness. Our focus on temporality and suffering knits together the phenomenological and the social with the aim of opening up Adams's narrative and ascertaining a deeper understanding of what it means to live with the condition. Finally, we look to the stories currently circulating around long COVID and consider how illness narratives-and open, curious, patient-centered approaches to them-might shape medicine, patient involvement, and critical medical humanities research.

Corpus linguistics and clinical psychology: Investigating personification in first-person accounts of voice-hearing.

Triangulating corpus linguistic approaches with other (linguistic and non-linguistic) approaches enhances "both the rigour of corpus linguistics and its incorporation into all kinds of research" (McEnery & Hardie, 2012:227). Our study investigates an important area of mental health research: the experiences of those who hear voices that others cannot hear, and particularly the ways in which those voices are described as person-like. We apply corpus methods to augment the findings of a qualitative approach to 40 interviews with voice-hearers, whereby each interview was coded as involving 'minimal' or 'complex' personification of voices. Our analysis provides linguistic evidence in support of the qualitative coding of the interviews, but also goes beyond a binary approach by revealing different types and degrees of personification of voices, based on how they are referred to and described by voice-hearers. We relate these findings to concepts that inform therapeutic interventions in clinical psychology.

AMPK activation protects against prostate cancer by inducing a catabolic cellular state.

Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK) is a master regulator of metabolism, although its role in PCa remains unclear. Here, we show that genetic and pharmacological activation of AMPK provides a protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1α expression, leading to catabolic metabolic reprogramming of PCa cells. This catabolic state is characterized by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation, and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network involved in cell cycle regulation that is inhibited by AMPK activation. Strikingly, we show a correlation between this gene network and PGC1α gene expression in human PCa. Taken together, our findings support the use of AMPK activators for clinical treatment of PCa to improve patient outcome.

Domain-based mRNA vaccines encoding spike protein N-terminal and receptor binding domains confer protection against SARS-CoV-2.

With the success of messenger RNA (mRNA) vaccines against coronavirus disease 2019, strategies can now focus on improving vaccine potency, breadth, and stability. We designed and evaluated domain-based mRNA vaccines encoding the wild-type spike protein receptor binding domain (RBD) or N-terminal domain (NTD) alone or in combination. An NTD-RBD-linked candidate vaccine, mRNA-1283, showed improved antigen expression, antibody responses, and stability at refrigerated temperatures (2° to 8°C) compared with the clinically available mRNA-1273, which encodes the full-length spike protein. In BALB/c mice administered mRNA-1283 as a primary series, booster, or variant-specific booster, similar or greater immune responses from viral challenge were observed against wild-type, beta, delta, or omicron (BA.1) viruses compared with mRNA-1273-immunized mice, especially at lower vaccine dosages. K18-hACE2 mice immunized with mRNA-1283 or mRNA-1273 as a primary series demonstrated similar degrees of protection from challenge with SARS-CoV-2 Delta and Omicron variants at all vaccine dosages. These results support clinical assessment of mRNA-1283, which has now entered clinical trials (NCT05137236).