Gods and Monsters: Classical Allusion and the Jacobites

The myths and legends of the classical world provided a wealth of material that Scottish Jacobites exploited to signal support for, and spread messages about, the exiled Stuarts. Dr Calum Cunningham and Dr Alan Montgomery delve into these clandestine allusions in architecture, text and material cultur

Charles III: the difficult legacy and political significance of the new king’s name

First paragraph: On the day of Queen Elizabeth II’s death, the former Prince of Wales was proclaimed King Charles III. Although it’s been known for decades that Charles would succeed his mother, there were rumours that he might, once king, choose the name George due to the contentious legacies of Kings Charles I and Charles II.https://theconversation.com/charles-iii-the-difficult-legacy-and-political-significance-of-the-new-kings-name-19038

Gods and Monsters: Classical Allusion and the Jacobites

The myths and legends of the classical world provided a wealth of material that Scottish Jacobites exploited to signal support for, and spread messages about, the exiled Stuarts. Dr Calum Cunningham and Dr Alan Montgomery delve into these clandestine allusions in architecture, text and material cultur

Charles III: the difficult legacy and political significance of the new king’s name

First paragraph: On the day of Queen Elizabeth II’s death, the former Prince of Wales was proclaimed King Charles III. Although it’s been known for decades that Charles would succeed his mother, there were rumours that he might, once king, choose the name George due to the contentious legacies of Kings Charles I and Charles II

The Stuarts in Italy, 1766–1807: A Court in Perpetual Pretence

Taking its cues from the conclusions of Edward Corp in The Stuarts in Italy, 1719–1766: A Royal Court in Permanent Exile, this article considers the evolution of the princely court held by the two final Stuart claimants, Charles Edward and Henry Benedict Stuart. It surveys the dénouement of this court from the deposed Catholic dynasty’s loss of de jure recognition of sovereignty in 1766 to the death of its last representative in 1807. By analysing the Stuarts’ interactions with the Papacy and European monarchies amid their ongoing struggle to uphold the appearance of royalty, it argues that the changing nature of their court emerged as a significant and distinctive nexus of cultural and symbolic meaning. The court of the exiled Stuarts from 1766 to 1807 emphasised the character, prerogatives and status of retreating Ancien Régime kingship in the decades preceding the French Revolution, during the years of its existence and in the Napoleonic era that followed

Lawful sovereignty: the political criminalisation and decriminalisation of Jacobitism, 1688–1788

Following the Revolution of 1688–89 and the exile of the Catholic Stuarts, Jacobitism was a socio-political alternative to the constitutional and religious settlements established in its aftermath. Propaganda campaigns favouring the royal dynasties at the centre of this ideological conflict remained fundamental as it developed. The Jacobites’ failure to recognise the Williamite and Hanoverian monarchs, regimes and the laws enacted in their names resulted in a swathe of mass criminality. It included considerable sedition and a near-universal association with high treason. This political irritant continued to subsist, and in the wake of the Treaty of Union of 1707, the Jacobite movement became the ideological challenger to the nascent British state. This thesis examines the Scottish, English (at times, Irish) and British states’ responses to the incendiary Jacobite threat beyond the battlefield. Successive administrations’ actions formed an overarching programme of political criminalisation and decriminalisation that lasted for around one hundred years, from 1688 to 1788. It looks at four thematic aspects of state weaponry employed on the Jacobites across several decades: ideology, policy, legislation and punishment. Doing so reveals that these mechanisms were inextricably entwined, and research has focused on materials relating to these themes, primarily those of a political and legislative nature. They include state papers and cabinet correspondence, policy-related memoranda, statutory public legislation and applicable punishment data. It assesses the policy formation, implementation and reformation required to tackle the ‘Jacobite problem’. The institution of a formidable legislative framework shows that the authorities regarded it as a severe danger. Their approach towards punishment involved a delicate balancing act between affording much clemency alongside a raft of ruthless retribution and cautionary warnings. The results suggest a significant amount of politico-legal precedent and institutional memory influenced the collective administrative response to, but also the evolution of, the Jacobite movement. It argues that a state-sanctioned political criminalisation programme was essential to obliterate all facets of Jacobitism

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.

BACKGROUND: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. METHODS: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. FINDINGS: Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). INTERPRETATION: ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. FUNDING: UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy

Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)–associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder. Huang et al. report the first functional validation of candidate pathological variants in RBBP5. We present three truncating p.(K244Nfs*6), p.(W254*), p.(R307*) and two missense p.(T232I), p.(E296D) variants found de novo in affected individuals sharing phenotypes including microcephaly and short stature. RBBP5 is a core member of the COMPASS complex responsible for H3 lysine 4 methylation to activate developmental target genes (COMPASS complex adapted from Namitz et al., 2023). Differentiation of neural stem cells in humans and neuroblasts in Drosophila is conserved allowing for the study of neural development in the fly model organism (neural stem cell/neuroblast differentiation diagram adapted from Kim and Hirth, 2009). We used overexpression and rescue experiments to characterize the missense variants in the fly. Neural progenitor populations were evaluated in the larval brain and tissue specific phenotypes were quantified using adult eye and wing morphology studies. We identify that the truncating and missense variants are loss-of-function alleles. As additional patients are identified, the full phenotypic spectrum of RBBP5-related disorders will be elucidated. Created with Biorender.com. [Display omitted