Bohm and Einstein-Sasaki Metrics, Black Holes and Cosmological Event Horizons

We study physical applications of the Bohm metrics, which are infinite sequences of inhomogeneous Einstein metrics on spheres and products of spheres of dimension 5 <= d <= 9. We prove that all the Bohm metrics on S^3 x S^2 and S^3 x S^3 have negative eigenvalue modes of the Lichnerowicz operator and by numerical methods we establish that Bohm metrics on S^5 have negative eigenvalues too. We argue that all the Bohm metrics will have negative modes. These results imply that higher-dimensional black-hole spacetimes where the Bohm metric replaces the usual round sphere metric are classically unstable. We also show that the stability criterion for Freund-Rubin solutions is the same as for black-hole stability, and hence such solutions using Bohm metrics will also be unstable. We consider possible endpoints of the instabilities, and show that all Einstein-Sasaki manifolds give stable solutions. We show how Wick rotation of Bohm metrics gives spacetimes that provide counterexamples to a strict form of the Cosmic Baldness conjecture, but they are still consistent with the intuition behind the cosmic No-Hair conjectures. We show how the Lorentzian metrics may be created ``from nothing'' in a no-boundary setting. We argue that Lorentzian Bohm metrics are unstable to decay to de Sitter spacetime. We also argue that noncompact versions of the Bohm metrics have infinitely many negative Lichernowicz modes, and we conjecture a general relation between Lichnerowicz eigenvalues and non-uniqueness of the Dirichlet problem for Einstein's equations.Comment: 53 pages, 11 figure

Priorities for mitigating greenhouse gas and ammonia emissions to meet UK policy targets

Agriculture is essential for providing food and maintaining food security while concurrently delivering multiple other ecosystem services. However, agricultural systems are generally a net source of greenhouse gases and ammonia. They, therefore, need to substantively contribute to climate change mitigation and net zero ambitions. It is widely acknowledged that there is a need to further reduce and mitigate emissions across sectors, including agriculture to address the climate emergency and emissions gap. This discussion paper outlines a collation of opinions from a range of experts within agricultural research and advisory roles following a greenhouse gas and ammonia emission mitigation workshop held in the UK in March 2022. The meeting identified the top mitigation priorities within the UK’s agricultural sector to achieve reductions in greenhouse gases and ammonia that are compatible with policy targets. In addition, experts provided an overview of what they believe are the key knowledge gaps, future opportunities and co-benefits to mitigation practices as well as indicating the potential barriers to uptake for mitigation scenarios discussed

Greenhouse gas and ammonia emission mitigation priorities for UK policy targets

Acknowledgements Many thanks to the Association of Applied Biologist’s for organising and hosting the ‘Agricultural greenhouse gases and ammonia mitigation: Solutions, challenges, and opportunities’ workshop. This work was supported with funding from the Scottish Government’s Strategic Research Programme (2022-2027, C2-1 SRUC) and BBSRC (BBS/E/C/000I0320 and BBS/E/C/000I0330). We also acknowledge support from UKRI694 BBSRC (United Kingdom Research and Innovation-Biotechnology and Biological Sciences 695 Research Council; United Kingdom) via grants BBS/E/C/000I0320 and BBS/E/C/000I0330. and Rothamsted Research's Science Initiative Catalyst Award (SICA) supported by BBSRC.Peer reviewedPublisher PD

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Evaluating genetic markers and neurobiochemical analytes for fluoxetine response using a panel of mouse inbred strains

RationaleIdentification of biomarkers that establish diagnosis or treatment response is critical to the advancement of research and management of patients with depression.ObjectiveOur goal was to identify biomarkers that can potentially assess fluoxetine response and risk to poor treatment outcome.MethodsWe measured behavior, gene expression, and the levels of 36 neurobiochemical analytes across a panel of genetically diverse mouse inbred lines after chronic treatment with water or fluoxetine.ResultsGlyoxylase 1 (GLO1) and guanine nucleotide-binding protein 1 (GNB1) mostly account for baseline anxiety-like and depressive-like behavior, indicating a common biological link between depression and anxiety. Fluoxetine-induced biochemical alterations discriminated positive responders, while baseline neurobiochemical differences differentiated negative responders (p < 0.006). Results show that glial fibrillary acidic protein, S100 beta protein, GLO1, and histone deacetylase 5 contributed most to fluoxetine response. These proteins are linked within a cellular growth/proliferation pathway, suggesting the involvement of cellular genesis in fluoxetine response. Furthermore, a candidate genetic locus that associates with baseline depressive-like behavior contains a gene that encodes for cellular proliferation/adhesion molecule (Cadm1), supporting a genetic basis for the role of neuro/gliogenesis in depression.ConclusionWe provided a comprehensive analysis of behavioral, neurobiochemical, and transcriptome data across 30 mouse inbred strains that has not been accomplished before. We identified biomarkers that influence fluoxetine response, which, altogether, implicate the importance of cellular genesis in fluoxetine treatment. More broadly, this approach can be used to assess a wide range of drug response phenotypes that are challenging to address in human samples.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2574-z) contains supplementary material, which is available to authorized users

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Mouse genetic models of cardiovirulent coxsackievirus B3 infection

Coxsackievirus B3 (CVB3) is a relatively common cause of infection. Infection by coxsackieviruses is typically mild and resolves quickly without lasting complications. In a subset of individuals, coxsackievirus infection can be severe, leading to permanent damage of vital organs or even death. The mouse presents an ideal model to study natural variation in response CVB3 infection as human isolates of CVB3 productively infect the mouse, and lead to similar pathologies as found in humans. Inbred strains of mice respond differently to CVB3 infection, therefore the genetic background of the host can determine susceptibility to CVB3 infection. We hypothesize that interrogation of genetically determined susceptibility to CVB3 infection will help to identify genes whose direct involvement in control of CVB3 was previously unsuspected. To characterize the contribution of host genetics to coxsackievirus, we screened a panel of recombinant congenic strains (RCS) generated from susceptible A/J and C57BL/6 progenitors. While most C57BL/6 background (BcA) strains were more susceptible than C57BL/6, BcA86 in particular was particularly susceptible to early lethality and hepatic necrosis. A segregating [BcA86xC57BL/10]F2 mapping cross led to the identification of a locus on distal chromosome 13 controlling liver damage during coxsackieviral hepatitis. Previously through the analysis of a segregating we detected the Vms1 (viral myocarditis susceptibility) locus on distal chromosome 3. Vms1 controls viral replication, inflammation and necrosis within the heart during CVB3 infection. We have further refined this locus in additional mapping crosses and congenic lines of mice. We have also determined that Vms1 controls viral replication before inflammation becomes evident within the heart. The cardiac specific kinase Tnni3k is a candidate gene for Vms1. We found that overexpression of TNNI3K greatly enhanced necrosis and inflammation in the heart following CVB3 infection. Furthermore, we found increased viral replication and gene expression and changes within isolated cardiomyocytes, indicating TNNI3K is implicated in a heart specific immune pathway. Altogether, our results provide new functional insight into the host determinants of pathogenesis following infection with coxsackievirus B3.Les virus Coxsackie du groupe B3 (CVB3) sont retrouvés partout dans le monde et il y a une prévalence saisonnière. L'infection par CVB3 se manifeste de manière différente selon les personnes. Certains individus ne développent pas de maladies cliniquement apparentes et guérissent spontanément, tandis que d'autres risquent de développer des complications plus sévères comme des affections cardiaques, des hépatites où des atteintes du système nerveux central. Les cas les plus graves peuvent entraîner la mort du sujet. La souris de laboratoire constitue un modèle idéal pour étudier les mécanismes inhérents à ces formes diverses des maladies induites par l'infection. En effet, des lignées des souris consanguines peuvent être infectées expérimentalement avec des souches humaines du virus CVB3. Les lignés des souris présentant un large spectre des signes cliniques indique que la constitution génétique des individus infectés est un facteur déterminant dans la gravité de l'infection. Nous avons donc formulé l'hypothèse que l'investigation des facteurs génétiques étant à l'origine de la réponse de l'hôte à l'infection par CVB3 devrait nous conduire à identifier des gènes et des mécanismes moléculaires directement impliqués dans le contrôle de cette infection dont on n'aurait pas eu connaissance dans le passé.Dans le but de mieux cerner la contribution des facteurs génétiques de l'hôte dans l'évolution de l'infection par CVB3, nous avons utilisé une approche de cartographie génétique. En ce sens, nous avons examiné une collection des lignées de souris recombinantes consanguines (RCS) issues des lignées parentales A/J et C57BL/6. Nous avons constaté que la plupart des lignées BcA (dont le fonds génétique est majoritairement issu de la lignée C57BL/6) présentaient une susceptibilité accrue en comparaison à C57BL/6. Dû à son taux précoce de mortalité, la lignée BcA86 a été particulièrement visée. En ayant recours à un croisement (BcA86 x C57BL/10)F2 il nous a été possible de détecter un locus dans la région distale du chromosome 13 liée à la sévérité des lésions du foie pendant l'hépatite coxsackievirale. Une étude préalable de liaison génétique, nous avait permis de mettre en évidence le locus Vms1 (viral myocarditis susceptibility) dans la région distale du chromosome 3. Le locus Vms1 est responsable du niveau de la réplication virale, de la nécrose du myocarde et de l'infiltration cellulaire que l'on observe dans le cœur des souris infectées par CVB3. En étudiant des lignées de souris consomiques ainsi qu'en réalisant de nouveaux croisements entre souris sensibles et souris résistantes, nous avons élaboré une cartographie fine de l'intervalle critique contenant le locus Vms1. Aussi avons-nous pu constater que le contrôle de la multiplication virale par Vms1 précède l'infiltration des cellules inflammatoires dans les tissus cardiaques.Le gène Tnni3k code pour une kinase dont l'expression étant spécifique aux cellules cardiaques apparaît comme un gène candidat de choix pour le locus Vms1. En comparant avec les souris normales, nous avons trouvé que la surexpression du gène Tnni3k dans des souris transgéniques leur confère un phénotype de nécrose et d'inflammation extrêmes du tissu cardiaque suite à l'infection par CVB3. Nous avons également établi que l'infection des cardiomyocytes isolés à partir de ces mêmes souris provoque un accroissement de la réplication du virus CVB3 ainsi qu'un profil d'expression unique des gènes inflammatoires. Les résultats ainsi obtenus ont mis en lumière que la kinase TNNI3K est impliquée dans un circuit de signalisation immunitaire propre au cœur. Ainsi, pris dans leur ensemble, nos travaux apportent des nouvelles voies pour la compréhension du déterminisme génétique de l'hôte dans la sensibilité aux infections par CVB3 ainsi qu'une meilleure connaissance de la pathogénèse de ce virus dévastateur

Immunogenetics of Virus Pathogenesis

Identification of the genetic component of infectious disease susceptibility is an area of intense investigation, which, as presented in this chapter, can provide clues to fundamental questions about virus pathogenesis and the diversity, redundancy, and specialization of host mechanisms against infection. The chapter addresses some methodological approaches of the identification of susceptibility genes to virus infection. It talks about genetic control of virus entry into the host cell. Infection with mouse coronavirus has served as a model to understand the viral and immunological determinants of coronavirus disease, including severe acute respiratory syndrome. Parvovirus B19, a significant human pathogen that causes fetal loss and severe disease in immunocompro‐mised patients, is classified as an erythrovirus due to its ability to infect red blood cell precursors of the bone marrow. Noroviruses or Norwalk‐like viruses are the leading cause of viral acute gastroenteritis in humans. The chapter deals with genetic control of interferon (IFN)‐mediated immunity in viral infection. An important consequence of type I IFN secretion is the activation of natural killer (NK) cells, a central component of the innate response against virus infection. It also discusses major histocompatibility complex (MHC) I alleles and TCR repertoire which can influence CD81 t responses and outcomes after viral infection. Pathogens are considered one of the most powerful forces shaping the evolution of the human genome. Numerous studies have shown that genes or loci involved in host defense against infection present signs of positive or negative selection