Polygenic Prediction of Recurrent Events after Early-Onset Myocardial Infarction

Background: Myocardial infarction (MI) is a complex disease caused by both lifestyle and genetic factors. This study aims to investigate the predictive value of genetic risk, in addition to traditional cardiovascular risk factors, for recurrent events following early-onset MI. Methods: The Italian Genetic Study of Early-Onset Myocardial Infarction is a cohort study enrolling patients with MI before 45 years. Monogenic variants causing familial hypercholesterolaemia were identified and a coronary artery disease polygenic score (PGS) was calculated. Ten-fold cross-validated Cox proportional hazards models were fitted sequentially including all clinical variables, the PGS, and monogenic variants on the composite outcome of cardiovascular death, recurrent MI, stroke or revascularization. Results: During a 19.9-year follow-up, 847 (50.7%) patients experienced recurrent events. Each 1-SD higher PGS was associated with a 21% higher hazard of recurrent events (HR 1.21, 95%CI 1.13-1.31, p=4.04x10-6). Except for secondary prevention, PGS was the strongest determinant of recurrent event risk (C-index 0.56, 95%CI 0.54-0.58) compared to clinical risk factors. Overall, predictive performance of clinical risk factors (C-index 0.69, 95%CI 0.67-0.71) improved after adding the PGS (C-index 0.69, 95%CI 0.68-0.71 p=0.006). When dividing the population by PGS quintiles, the highest fifth had a 57% higher hazard of recurrent events than the lowest fifth (HR 1.57, 95%CI 1.26-1.96, p=5.57x10-5). Conclusions: When compared to other clinical risk factors, PGS was the strongest predictor of event recurrence among patients with an early-onset MI. Though the discriminative power of recurrent event prediction in this cohort was modest, the addition of PGS significantly improved discrimination

Dual regulation of inositol 1,4,5-trisphosphate receptors by inositol 1,4,5-trisphosphate and phosphatidylinositol 4,5-bisphosphate

Ca2+ is a universal and effective intracellular messenger, which holds a central role in the regulation of a vast array of cellular processes. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are key signal integrators, which transform extracellular stimuli into intracellular Ca2+ signals. Only immobilised IP3Rs, licensed by association with KRas-induced actin-interacting protein (KRAP), can respond through IP3-mediated Ca2+ release. These licensed IP3Rs are tethered on actin near membrane contact sites (MCS) between the endoplasmic reticulum (ER) and plasma membrane (PM), where store-operated Ca2+ entry (SOCE) takes place. Uncovering the mechanisms that govern IP3R regulation is an essential element in understanding the spatial and temporal patterns of Ca2+ signalling. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a minor, but functionally diverse lipid at the PM. In the canonical Ca2+ signalling cascade, activation of PM-resident receptors such as G-protein coupled receptors (GPCRs) causes phospholipase C (PLC) to hydrolyse PI(4,5)P2, producing inositol 1,4,5-trisphosphate (IP3) which diffuses through the cytoplasm to IP3Rs, enabling Ca2+ release from the ER. The stimulus intensity governs the amount of IP3 produced and in consequence, the extent of IP3R activation, starting from brief, localised Ca2+ puffs, and progressing to cell-wide global Ca2+ waves. Tight control of the transition from local to global Ca2+ signals is central to the downstream consequences of receptor activation. PI(4,5)P2, with its essential roles in F-actin nucleation and formation of the SOCE complex at ER-PM MCS, is thus a potential regulator of IP3R activity in addition to its role in providing IP3. Towards exploring possible additional roles of PI(4,5)P2 in regulating Ca2+ signalling via IP3Rs, I have assessed three strategies for selective depletion of PI(4,5)P2 at the PM: pharmacological inhibition of the synthesis of phosphatidylinositol 4-phosphate (PI(4)P), the precursor of PI(4,5)P2, gene silencing of the 5-kinases that convert PI(4)P to PI(4,5)P2, and expression of a rapamycin-inducible heterodimerization system that allows translocation of a PI(4,5)P2-specific 5-phosphatase (herein referred to as the ‘’5-PTASE system’’) to the PM. Pharmacological or siRNA-mediated inhibition of the relevant kinases in the PI(4,5)P2 metabolic cycle did not successfully attenuate Ca2+ signals in response to histamine in HeLa cells, suggesting that PLC-sensitive PI(4,5)P2 pools remain available after treatment. On the contrary, I have shown that the 5-PTASE system caused global depletion of PI(4,5)P2 at the PM using a genetically encoded, PI(4,5)P2-selective fluorescent sensor, and showed that Ca2+ signals in response to histamine in HeLa cells were attenuated. The method thereby allows acute and near-complete depletion of PM-associated PI(4,5)P2. Using the validated 5-PTASE system for PM PI(4,5)P2 depletion, and uniform delivery of i-IP3 to the cytosol via uncaging of the exogenously supplied photolabile caged ci-IP3, revealed that PI(4,5)P2 depletion significantly reduced the frequency of Ca2+ puffs in HeLa and HEK293 cells without affecting puff amplitude or kinetics. PI(4,5)P2 regulation was confirmed to extend to all three IP3R subtypes. As PI(4,5)P2 depletion may lead to reduction of basal IP3 levels, I employed two complementary approaches to assess whether a loss of basal IP3 is responsible for the reduced Ca2+ puff frequency. Reducing basal IP3 levels by inhibiting PLC activity with U73122 or by overexpressing cytosolic IP3 kinase C (IP3KC) did not reduce the frequency of Ca2+ puffs evoked by photolysis of ci-IP3. I conclude that PI(4,5)P2 regulates IP3R activity in parallel to providing IP3. As PI(4,5)P2 levels at the PM are dynamically controlled during signalling when PI(4,5)P2 is consumed to produce IP3, I developed methods to uncouple stimulation of GPCRs that evoke IP3 formation from delivery of IP3 to IP3Rs while retaining opportunities to stimulate IP3Rs directly. I expressed IP3KC to intercept endogenous IP3 and photolyzed ci-IP3 to enable independent activation of GPCRs and delivery of i-IP3 to IP3Rs. Activation of H1 receptors in HeLa cells or M3 muscarinic receptors in HEK293 cells in the presence of IP3KC reduced the frequency of Ca2+ puffs evoked exogenously by photolysis of ci-IP3 without affecting puff amplitude or kinetics. This inhibition was entirely mediated by PI(4,5)P2 depletion. PI(4,5)P2 depletion significantly reduced the likelihood of Ca2+ puffs progressing to a global Ca2+ signal, but once the transition threshold was reached, the amplitude of the global signal was indistinguishable in the presence and absence of PI(4,5)P2. PI(4,5)P2 depletion did not affect the subcellular distribution of IP3Rs. I suggest that PI(4,5)P2 primes IP3Rs to respond to IP3 by partially occupying the receptor’s IP3-binding site. Increasing PI(4,5)P2 levels in the PM did not further activate IP3Rs, suggesting that basal PI(4,5)P2 achieves the maximal effect. It is unclear whether this occurs with all IP3-binding sites occupied by PI(4,5)P2 or whether physical barriers constrain the number of sites that can be occupied. My results establish that PI(4,5)P2 primes IP3Rs to respond, and that as GPCRs stimulate IP3 formation they also deplete PI(4,5)P2, relieving this priming stimulus and resetting IP3R sensitivity. Dual regulation of IP3Rs by PI(4,5)P2 and IP3 through GPCRs thus controls the transition from local to global Ca2+ signals

Improving Hateful Meme Detection through Retrieval-Guided Contrastive Learning

Hateful memes have emerged as a significant concern on the Internet. Detecting hateful memes requires the system to jointly understand the visual and textual modalities. Our investigation reveals that the embedding space of existing CLIP-based systems lacks sensitivity to subtle differences in memes that are vital for correct hatefulness classification. We propose constructing a hatefulness-aware embedding space through retrieval-guided contrastive training. Our approach achieves state-of-the-art performance on the HatefulMemes dataset with an AUROC of 87.0, outperforming much larger fine-tuned large multimodal models. We demonstrate a retrieval-based hateful memes detection system, which is capable of identifying hatefulness based on data unseen in training. This allows developers to update the hateful memes detection system by simply adding new examples without retraining - a desirable feature for real services in the constantly evolving landscape of hateful memes on the Internet

The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics.

A genomic database of all Earth's eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP

A Manuscript of the Arabian Nights and Its Journey to Cambridge

Abstract Cambridge University Library holds an Arabic manuscript of The Thousand and One Nights (Ms Qq.106–109). The library records it as entering the collection in 1819 and codicological evidence shows that the manuscript was copied in Cairo in the early 19th century. This paper discusses the complex narrative of its acquisition, including the roles played by prominent travellers and collectors. The significance of the text of the ‘Nights’ and its popularity in England and Europe are also examined as are the factors that made the Arabic text of this work much sought-after at the time. The influence of the contemporary political situation, the conditions of travel in the Middle East, and the individuals involved with the text’s acquisition are described, focusing on those with a Cambridge connection. A detailed analysis of the activities and twists of fate resulting in the acquisition of this particular manuscript are traced in contemporary sources.</jats:p

Visual mismatch negativity in Parkinson's psychosis and potential for testing treatment mechanisms.

Acknowledgements: We thank the CRISP (patient representation) group for support and advice during the inception of this study and all our participants for taking part in the research and their partners for their support on the study days. We thank AstraZeneca UK for providing the study drug. We also thank Robin Carhart–Harris for advice on the psilocybin study and Dag Aarsland for his support with the development of important study ideas. We thank Stephanie Stephenson for training the study researchers with clinical trials procedures and for her support throughout the duration of the study; and we thank Caroline Woolridge for her support with study logistics and ethics applications. We thank Dr Daniel van Wamelen and Dr Claudia Lazcano Ocampo for their help with the study. We thank Simon Hill for the contribution to the EEG task and recording setup. We thank Paulo Silva for the contribution to the EEG task programming. We also wish to thank Dr Maria Teresa Pascarelli for helpful advice on EEG analysis. We thank Glynis Ivin and David Taylor South London and Maudsley pharmacy for their support. We thank the KCL Clinical Research Facility staff for their support with the study and the CRF director Elka Giemza. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.Funder: National Institute for Health and Care Research; doi: https://doi.org/10.13039/501100000272Funder: Maudsley Biomedical Research Centre; doi: https://doi.org/10.13039/100019418Funder: Department of Health and Social Care; doi: https://doi.org/10.13039/501100000276Psychosis and visual hallucinations are a prevalent non-motor symptom of Parkinson's disease, negatively affecting patients' quality of life and constituting a greater risk for dementia. Understanding neural mechanisms associated to these symptoms is instrumental for treatment development. The mismatch negativity is an event-related potential evoked by a violation in a sequence of sensory events. It is widely considered an index of sensory change-detection. Reduced mismatch negativity response is one of the most replicated results in schizophrenia and has been suggested to be a superior psychosis marker. To understand whether this event-related potential component could be a similarly robust marker for Parkinson's psychosis, we used electroencephalography with a change-detection task to study the mismatch negativity in the visual modality in 20 participants with Parkinson's and visual hallucinations and 18 matched Parkinson's participants without hallucinations. We find that visual mismatch negativity is clearly present in participants with Parkinson's disease without hallucinations at both parieto-occipital and frontal sites, whereas participants with Parkinson's and visual hallucinations show reduced or no differences in the two waveforms, confirming the sensitivity of mismatch negativity to psychosis, even within the same diagnostic group. We also explored the relationship between hallucination severity and visual mismatch negativity amplitude, finding a negative correlation between visual hallucinations severity scores and visual mismatch negativity amplitude at a central frontal and a parieto-occipital electrodes, whereby the more severe or complex (illusions, formed visual hallucinations) the symptoms the smaller the amplitude. We have also tested the potential role of the serotonergic 5-HT2A cascade in visual hallucinations in Parkinson's with these symptoms, following the receptor trafficking hypothesis. We did so with a pilot study in healthy controls (N = 18) providing support for the role of the Gi/o-dependent pathway in the psychedelic effect and a case series in participants with Parkinson's and visual hallucinations (N = 5) using a double-blind crossover design. Positive results on psychosis scores and mismatch amplitude add further to the potential role of serotonergic modulation of visual hallucinations in Parkinson's disease

Reduced brain connectivity underlying value-based choices and outcomes in stimulant use disorder.

BACKGROUND: Patients with stimulant use disorder (SUD) show impairments when making value-based choices that are associated with disruptions in neural processing across brain networks. Making optimal choices requires learning from outcomes to update knowledge and further optimise ongoing behaviour. The optimal functioning of neural systems that underpin the ability to make favourable choices is an essential component for life functioning, and successful recovery in patients with SUD. Therefore, we sought to investigate the neural processes that underpin value-based choices in SUD patients. We hypothesise that patients with SUD have reduced functional connectivity while making financial choices during a probabilistic reinforcement learning task. METHODS: We investigated connectivity associated with loss and reward value-based choices and their outcomes in patients with SUD and healthy control participants during a pharmacological magnetic resonance imaging study. Participants received a single dose of a dopamine receptor agonist, pramipexole, and a dopamine receptor antagonist, amisulpride, in a randomised, double-blind, placebo-controlled, balanced, crossover design. Functional task-related connectivity was analysed taking a whole brain connectomics approach to identify networks that are differentially modulated by dopaminergic receptor functioning. RESULTS: SUD patients showed widespread reductions in connectivity during both reward and loss value-based choices and outcomes, which were negatively correlated with the duration of stimulant drug use. Disturbances to functional brain connectivity in SUD patients during task performance were not modulated acutely by either amisulpride or pramipexole. CONCLUSIONS: Reductions in brain connectivity, particularly when making value-based choices and processing outcomes, may underlie learning impairments in SUD patients. Given that acute dopaminergic modulation did not improve brain connectivity impairments in SUD patients, it is likely that alternative treatments are needed.The authors thank all volunteers for their participation in this study. This work was partly funded by GlaxoSmithKline (RG45422) and the NIHR Cambridge Biomedical Research Centre and conducted within the Behavioural and Clinical Neuroscience Institute (BCNI). The views expressed are those of the authors and not the NIHR, the NHS, or the Department of Health and Social Care. The authors are also grateful to Dorothy Langton and her family for their support of our work

Evaluation of the effectiveness of the Indian government's policies to strengthen health warning labels on smokeless tobacco products: findings from the 2010-2019 Tobacco Control Project India Surveys.

Peer reviewed: TruePublication status: PublishedFunder: Healis Sekhsaria Institute for Public HealthBACKGROUND: Smokeless tobacco (SLT) packaging in India had a single symbolic (a scorpion) health warning label (HWL) in 2009 covering 40% of the front surface. In 2011, it was replaced with four pictorial images. In 2016, HWLs were enlarged to 85% on the front and back. This study aimed to assess the effectiveness of the old (symbolic and smaller images) and larger HWLs. METHODS: Data were from the Tobacco Control Project India Survey and included respondents who used SLT in Wave 1 (2010-2011, n=5911), Wave 2 (2012-2013, n=5613) and Wave 3 (2018-2019, n=5636). Using a repeated-measures design, weighted logistic regression models assessed whether there were changes in seven HWL effectiveness measures within the domains of awareness, salience, cognitive and behavioural responses. A cohort design was employed to test whether HWL effectiveness in Waves 1 and 2 was associated with quitting SLT in Waves 2 and 3, respectively. RESULTS: The 2011 HWL revision did not result in any significant changes in HWL effectiveness. There was no significant change in HWL awareness and salience after larger HWLs were introduced in 2016, but respondents were more likely to consider SLT health risks (Wave 2=17.9%, Wave 3=33.6%, p<0.001) and quitting SLT (Wave 2=18.9%, Wave 3=36.5, p<0.001). There was no change in HWLs stopping SLT use (Wave 2=36.6%, Wave 3=35.2%, p=0.829); however, respondents were more likely to avoid looking at HWLs (Wave 2=10.1%, Wave 3=40.2%, p<0.001). Effectiveness of older, symbolic and smaller pictorial HWLs was not associated with quitting SLT. DISCUSSION: There was no significant change in HWL effectiveness following the revision from a symbolic to a pictorial image, but enlarging pictorial images resulted in some improved cognitive and behavioural effects. Results suggested wear-out of HWL salience and that the effectiveness of warnings depends on both their design and time since implementation

Research Data Supporting "Revealing Ion Adsorption and Charging Mechanisms in Layered Metal-Organic Framework Supercapacitors with Solid-State NMR"

Experimental data supporting "Revealing Ion Adsorption and Charging Mechanisms in Layered Metal-Organic Framework Supercapacitors with Solid-State NMR". This dataset contains the raw data used to produce the following figures in the manuscript and supplementary information: - Main text figures 1 - 6. - SI figures S1 - 19 'README' text files are included in some subfolder containing detailed metadata on the experiment

Displacive Jahn-Teller Transition in NaNiO2.

Below its Jahn-Teller transition temperature, TJT, NaNiO2 has a monoclinic layered structure consisting of alternating layers of edge-sharing NaO6 and Jahn-Teller-distorted NiO6 octahedra. Above TJT where NaNiO2 is rhombohedral, diffraction measurements show the absence of a cooperative Jahn-Teller distortion, accompanied by an increase in the unit cell volume. Using neutron total scattering, solid-state Nuclear Magnetic Resonance (NMR), and extended X-ray absorption fine structure (EXAFS) experiments as local probes of the structure we find direct evidence for a displacive, as opposed to order-disorder, Jahn-Teller transition at TJT. This is supported by ab initio molecular dynamics (AIMD) simulations. To our knowledge this study is the first to show a displacive Jahn-Teller transition in any material using direct observations with local probe techniques.This work was supported by the Faraday Institution (FIRG001, FIRG017, FIRG024, FIRG060). L.A.V.N-C acknowledges a scholarship EP/R513180/1 to pursue doctoral research from the UK Engineering and Physical Sciences Research Council (EPSRC) and additional funding from the Cambridge Philosophical Society. J.M.A.S. acknowledges support from the EPSRC Cambridge NanoCDT, EP/L015978/1. A.L.G. acknowledges European Research Council (ERC) funding under grant 788144. The authors acknowledge Oak Ridge National Laboratory, a United States Department of Energy Office of Science User Facility, for use of the NOMAD instrument at the Spallation Neutron Source (experiment IPTS25164). We acknowledge the European Synchrotron Radiation Facility for provision of beam time on BM23 (experiment CH6437). We acknowledge I11 beamline at the Diamond Light Source, UK, for the synchrotron XRD measurement done under BAG proposal (the data presented in this work under CY34243; essential preliminary data from CY28349). Calculations were performed using the Sulis Tier 2 HPC platform hosted by the Scientific Computing Research Technology Platform at the University of Warwick (EP/T022108/1)