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"Fletcher, Emma"
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Structures of RecBCD in complex with phage-encoded inhibitor proteins reveal distinctive strategies for evasion of a bacterial immunity hub
Following infection of bacterial cells, bacteriophage modulate double-stranded DNA break repair pathways to protect themselves from host immunity systems and prioritise their own recombinases. Here, we present biochemical and structural analysis of two phage proteins, gp5.9 and Abc2, which target the DNA break resection complex RecBCD. These exemplify two contrasting mechanisms for control of DNA break repair in which the RecBCD complex is either inhibited or co-opted for the benefit of the invading phage. Gp5.9 completely inhibits RecBCD by preventing it from binding to DNA. The RecBCD-gp5.9 structure shows that gp5.9 acts by substrate mimicry, binding predominantly to the RecB arm domain and competing sterically for the DNA binding site. Gp5.9 adopts a parallel coiled-coil architecture that is unprecedented for a natural DNA mimic protein. In contrast, binding of Abc2 does not substantially affect the biochemical activities of isolated RecBCD. The RecBCD-Abc2 structure shows that Abc2 binds to the Chi-recognition domains of the RecC subunit in a position that might enable it to mediate the loading of phage recombinases onto its single-stranded DNA products.
Journal Article
Feminist art activisms and artivisms
The first volume in the new Plural series, this publication seeks to critically dissect the term 'activism,' which today seems to have become a catchword for any woman's empowerment through the arts, and reveal the diversity of practices and realities that it comprises. Presenting a range of critical insights, perspectives, and practices from artists, activists, and academics, it reflects on the role of feminist interventions in the field of contemporary art, the public sphere, and politics. In the process, it touches upon broader questions of cultural difference, history, class, economic standing, ecological issues, and sexual orientation, as well as the ways in which these intersect.
Book
Psychosocial factors associated with overdose subsequent to Illicit Drug use: a systematic review and narrative synthesis
Background and aims
Psychological and social status, and environmental context, may mediate the likelihood of experiencing overdose subsequent to illicit drug use. The aim of this systematic review was to identify and synthesise psychosocial factors associated with overdose among people who use drugs.
Methods
This review was registered on Prospero (CRD42021242495). Systematic record searches were undertaken in databases of peer-reviewed literature (Medline, Embase, PsycINFO, and Cinahl) and grey literature sources (Google Scholar) for work published up to and including 14 February 2023. Reference lists of selected full-text papers were searched for additional records. Studies were eligible if they included people who use drugs with a focus on relationships between psychosocial factors and overdose subsequent to illicit drug use. Results were tabulated and narratively synthesised.
Results
Twenty-six studies were included in the review, with 150,625 participants: of those 3,383–4072 (3%) experienced overdose. Twenty-one (81%) studies were conducted in North America and 23 (89%) reported polydrug use. Psychosocial factors associated with risk of overdose (
n
= 103) were identified and thematically organised into ten groups. These were: income; housing instability; incarceration; traumatic experiences; overdose risk perception and past experience; healthcare experiences; perception of own drug use and injecting skills; injecting setting; conditions with physical environment; and social network traits.
Conclusions
Global rates of overdose continue to increase, and many guidelines recommend psychosocial interventions for dependent drug use. The factors identified here provide useful targets for practitioners to focus on at the individual level, but many identified will require wider policy changes to affect positive change. Future research should seek to develop and trial interventions targeting factors identified, whilst advocacy for key policy reforms to reduce harm must continue.
Journal Article
Opioid prescribing is rising in many countries
Chronic pain strategies must be embedded within broader efforts to tackle deprivation
Journal Article
Differential modulation of feedforward inhibition reflects topographic organization in the olfactory system
The nervous system flexibly processes information under different conditions. To do this, neural networks frequently rely on uniform expression of modulatory receptors by distinct classes of neurons to fine tune the computations supported by each neuronal class. Here, we explore an alternate organization in which one population of neurons in the olfactory system of
Drosophila
expresses all of the receptors for the modulator serotonin. We find extensive, heterogeneous receptor co-expression by ventral projection neurons (v-PNs), with many receptor combinations present. Despite overlap in glomerular innervation of v-PNs expressing each serotonin receptor, their axon terminals innervate largely distinct zones within a higher order olfactory region. Serotonin differentially modulates odor-evoked responses of v-PNs with distinct receptor expression and these v-PNs synapse upon separate sets of third order olfactory neurons. This functional organization implies that serotonin differentially modulates the responses of v-PNs that participate in divergent, downstream olfactory circuits.
Jonaitis et al demonstrate that serotonin differentially modulates feedforward inhibitory neurons in the olfactory system of Drosophila which likely reflects odor categorization in higher order brain regions.
Journal Article
Perceptions, barriers, and career priorities among prospective medical school applicants in Scotland
Background
Total medical school applicant numbers in the UK are steadily declining. This is a particular problem in the devolved nations including Scotland, where the number of local applicants has not increased in line with the expansion of medical school places. This study aims to understand how prospective Scottish-domiciled medical school applicants perceive medical careers and the NHS, the potential barriers to medical school and which factors are most important when making careers decisions, including whether these factors differ depending on demographic background.
Methods
An online cross-sectional survey was delivered to prospective medical school applicants in S5 and S6 (the last two years of secondary education) Scotland during the 2024–2025 UCAS application cycle. Students were invited to participate if they were considering or have considered medicine as a career in the past. Chi-squared analysis was performed to identify differences in responses by demographics.
Results
There were 416 respondents, representing a quarter of the Scottish-domiciled students who applied to medicine during the 2024-25 cycle. There are demonstrable differences in career priorities and perceptions of working as a doctor by ethnicity, sex and widening participation (WP) status. Respondents held generally negative views about the demanding and inflexible nature of working within the NHS, although identified positives such as being able to give back to the community and the variety of work. The majority of respondents had been discouraged from applying to medicine by at least one person, usually due to difficulties in the working lives of doctors, rather than barriers in the application process.
Conclusions
Prospective applicants have concerns about working conditions and careers after graduation which may be impacting their decision on whether to apply for medicine. This necessitates coordinated efforts from medical schools, NHS trusts and other stakeholders to improve the perceptions of doctors and NHS careers generally. The survey will be delivered UK-wide in the 2025-26 application round, to shed light on whether these patterns are seen across the four nations.
Journal Article
Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency
Mevalonate kinase deficiency (MKD) is characterized by recurrent fevers and flares of systemic inflammation, caused by biallelic loss-of-function mutations in MVK. The underlying disease mechanisms and triggers of inflammatory flares are poorly understood because of the lack of in vivo models. We describe genetically modified mice bearing the hypomorphic mutation p.Val377Ile (the commonest variant in patients with MKD) and amorphic, frameshift mutations in Mvk. Compound heterozygous mice recapitulated the characteristic biochemical phenotype of MKD, with increased plasma mevalonic acid and clear buildup of unprenylated GTPases in PBMCs, splenocytes, and bone marrow. The inflammatory response to LPS was enhanced in compound heterozygous mice and treatment with the NLRP3 inflammasome inhibitor MCC950 prevented the elevation of circulating IL-1[beta], thus identifying a potential inflammasome target for future therapeutic approaches. Furthermore, lines of mice with a range of deficiencies in mevalonate kinase and abnormal prenylation mirrored the genotype-phenotype relationship in human MKD. Importantly, these mice allowed the determination of a threshold level of residual enzyme activity, below which protein prenylation is impaired. Elevated temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and the defective prenylation in vitro and in vivo, highlighting increased body temperature as a likely trigger of inflammatory flares.
Journal Article
Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages
Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.
Journal Article
Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants
Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.
Journal Article