Osteoarthritis has a considerable heritable component, with GWAS variants residing in non-coding sequences near chondrocyte genes; loci which likely became evolutionarily optimized during bipedal knee formation. To explore this relationship, we epigenetically profiled joint chondrocytes, revealing evidence of selection and constraint on human knee-specific regulatory elements. These elements also overlap osteoarthritis loci, with risk variants contributing to disease heritability by altering constrained sequences. Using these findings we then describe a causal enhancer variant present in half the world’s population, showing that it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of anatomy to its pathogenesis.

The training day is run by members of the Malaria Atlas Project (MAP) and is aimed at introducing geographic information systems (GIS) and statistical techniques to analyse spatial data. The event is open to BDI, NDPH and NDM researchers and students & no prior knowledge is required. The morning session (Seminar Room 0) will introduce you to: - key objectives and fundamental concepts of analysing spatial data - the MAP’s library of covariates and malaria model outputs - the basics of spatial modelling, spatial prediction, and communicating uncertainty - advanced spatial modelling techniques developed by MAP In the afternoon we offer three practical sessions at different levels that focus on different steps in the analysis of spatial data: - spatial data operations using ArcGIS software [novice] (BDI L1 Ax) - spatial modelling with INLA (R package) [intermediate] (BDI LG 0 Seminar Room) - advanced spatial modelling with TMB (R package) [advanced] (BDI L2 Ax) To register, please visit https://oxford.onlinesurveys.ac.uk/spatialanalysis Please note that we strongly encourage participants to sign up for both the morning session as well as to one of the practical sessions in the afternoon. Once a session is fully booked and you would like to be added to the waiting list, please contact sarah.laseke@ndph.ox.ac.uk. For details on the schedule, see the programme attached.

Intracellular lipopolysaccharide (LPS) from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11 causing pyroptotic cell death, IL-1 processing, and lethal septic shock. How caspase-11 drives these downstream signaling events is largely unknown. Here we show that Gasdermin-D (Gsdmd) is essential for caspase-11-dependent pyroptosis and IL-1 maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice linked Gsdmd to the intracellular LPS response. Macrophages from Gsdmd–/– mice generated by gene targeting also exhibited defective pyroptosis and IL-1 secretion induced by cytoplasmic LPS or Gram-negative bacteria. In addition, Gsdmd–/– mice were protected from a lethal dose of LPS. Mechanistically, caspase-11 cleaved Gsdmd and the N-terminal Gsdmd fragment promoted both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify Gsdmd as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacterial infection. At the meeting I’ll give an update on the discovery of an additional mediator of pyroptosis: IRF2, a transcriptional factor that drives the expression of Gsdmd. In it’s absence cells and mice are resistant to LPS challenge. In sum we have defined a new pathway for LPS responsiveness that may have therapeutic potential.

Vishva has made some of the biggest discoveries uncovering the biology of TNF and Caspase-mediated cell death pathways and the complex interplay between cell death and inflammation at the molecular level. Attached is the summary of Vishva’s research interests with selected publications.

The ability to sense and respond to danger appropriately is critical for maintaining immune homeostasis. Inflammasomes are supra-molecular protein complexes that sense danger signals both from microbes and tissue damage, and initiate an inflammatory response through activation of the protease caspase-1 and subsequent release of interleukin(IL)-1β and IL-18. Dysregulation of inflammasomes contributes to the progression of chronic disease such as Alzheimer’s disease, COPD, or Rheumatoid Arthritis. In this seminar we will discuss our latest work on the molecular mechanisms that control inflammasome activation in macrophages, especially the contribution of posttranslational modifications to this process.

The ability to profile the expression profile, genome and epigenome of individual cells is transforming our ability to answer questions about cell type heterogeneity, cell fate decisions in early development and the regulation of variability in gene expression levels. In this presentation, I will discuss some of the computational methods we have developed to analyse such data and discuss their application in the context of early mammalian development. I will also discuss how we are integrating information about genetic differences between individuals into our analyses.

Clinical genetic testing approaches typically focus on the ~1.5% of the genome that codes directly for protein, and where deciphering the effect of an individual variant is relatively straightforward. Using this strategy, however, ~50% of rare disease is genetically unexplained. A critical portion of the remaining genomic sequence has important roles in regulating protein expression, however, prioritising likely disease-relevant variants and regions in this non-coding sequence presents a considerable challenge. 5’untranslated regions (5’UTRs) are encoded directly upstream of protein-coding regions and regulate both the stability of the mRNA and the rate at which it is translated into protein. Using 15,708 whole genome sequenced individuals from the Genome Aggregation Database (gnomAD) and cohorts of disease patients, we systematically explored the deleteriousness of variants in 5’UTRs. This analysis identifies a subset of 5’UTR variants that result in reduced protein translation and lead to dominant human disease.

The Ethox Centre and Wellcome Centre for Ethics and Humanities at the Nuffield Department of Population Health, University of Oxford, look forward to welcoming you from 12th-14th September 2019 to the 36th EACME conference in Oxford, on the theme of Rethinking Ethics in 21st Century Europe. About the conference: Just as thinking in medical ethics has shaped medicine and medical sciences, developments in medicine and new technologies have also been shaping medical ethics since its beginning. Clinical and research practices have always had to be rethought and norms redefined in response to biomedical advances and social change. Developments in ethics, society and medicine are inseparable. In the 20th Century, bioethics responded to developments in medical research, life extending treatments, assisted reproduction and to changing social attitudes to medical practitioners and paternalism. Through the development of concepts such as those of informed consent, confidentiality, minimal risk, duties of care and the idea of independent review of research, the 20th Century played an important role in ensuring that developments in medicine respected patients and commanded public trust. The emerging questions concerned boundaries of medical intervention or scientific research and respect for the patient or research participants. Despite the valuable contributions made by 20th Century bioethics, in recent years, however, new challenges are being presented by advances in neuroscience, big data, genomics and global connectedness, and by their convergence. Personalised medicine and big data approaches are changing the focus of medicine and increasingly blur boundaries between clinical interventions and research activities. These developments raise important questions about the extent to which 20th Century ethics is fit for purpose. We currently observe a shift in research agendas and a redefinition of normative as well as national boundaries in Europe, and beyond. These changes raise the question as to whether medical ethics in the 21st century needs to revisit its principles and approaches. Do we need to rethink bioethics for the 21st Century? The 2019 EACME conference in Oxford will respond to a pressing need for ethics, humanities and social sciences research on these new challenges. The annual EACME conference presents an open platform for research contributions and debate about ethical issues in health care practices, policies, and medical sciences as well as new approaches in clinical ethics, research ethics and ethics teaching. Read more https://www.ethox.ox.ac.uk/opportunities/EACME2019

how a cell dies—not simply whether it dies—is a key determinant of the innate and adaptive immune response that follows. We use engineered forms of cell death proteins and knockout mouse models to understand how different forms of cell death occur, and to compare the immune response triggered by each in vivo in the context of infection, cancer, and autoimmunity. Specific questions currently under investigation include: What are the determinants of the immune response to necroptotic cells? Necroptosis is a form of cellular suicide involving both lytic cell death and the production of inflammatory cytokines. We are investigating how these two immunogenic events are linked, in both engineered cellular models and viral infection. How does pathogen sensing engage cell death? Activation of innate immune pattern-sensing pathways such as the Toll-like receptors, RIG-I-like receptors, NOD-like receptors or the cGAS-STING pathway can trigger immune cytokine production. These pathways can also lead to apoptosis, pyroptosis, or necroptosis, depending on the cell and tissue context in which they occur. We study the causes and consequences of these cell death programs. Are there death-independent roles of the cell death machinery? (Yes, there are.) Mice lacking necroptotic effector proteins are highly susceptible to multiple types of viral infection. Surprisingly however, in some cases this susceptibility is not due to a failure to trigger cell death, but rather to non-death functions of these proteins in innate immune signaling. How does activation of inflammatory cell death alter models of cancer and autoimmunity? Promoting inflammation and an immune response to dying cells may be beneficial in the context of infection or cancer, but an overexuberant immune response to dying cells can lead to autoimmunity. We have created engineered cell death effectors that allow us to induce specific forms of cell death in vivo. We are applying these systems to models of tumorigenesis, type-I diabetes, and lupus.

Mesenchymal stem/stromal cells (MSC) are probably amongst the most promising cell-based reagents for immunomodulation. Their potent immunosuppressive action, which is not antigen specific and does not require MHC compatibility, has successfully been exploited in immune mediated ailments with dramatic clinical benefits. However, the incomplete understanding of the underlying mechanisms has hindered their best clinical use. We have recently identified a mechanism of action that can finally reconcile the complexity of MSC immunomodulation and resolve the paradox of their long-term in vivo activity despite the lack of engraftment. We will discuss the implications of these findings on biomarker development and novel therapeutic approaches. Biography: Prof Francesco Dazzi has been working on the biology and clinical applications of cellular therapies in haemopoietic stem cell transplantation for the last 20 years. He obtained an MD and a PhD at Padua University Medical School (Italy), and subsequently trained as a Haematologist at Verona University and at the Royal Postgraduate Medical School (London, UK). He was appointed Senior Lecturer and then Professor in Stem Cell biology at Imperial College in 2005. In 2014 he moved to King’s College London where he is Professor of Regenerative and Haematological Medicine and leads Cellular Therapies for Kings’ Health Partners. Francesco pioneered a large and highly successful cellular immunotherapy programme for leukaemia and characterised the immunosuppressive effects of mesenchymal stromal cells (MSC). His team successfully tested MSC in pre-clinical models and the work has formed the basis of UK wide clinical studies.

Sexually transmitted infections are on the rise throughout the developed world, and this likely reflects changing behavioural and technological factors in a post-HIV world, resulting in a perfect epidemiological storm. However, many bacterial STIs are chronically understudied, with limited work being done to understand how these pathogens spread and evolve. In some cases this reflects an inability to efficiently culture the causative bacteria, making genomic and biological analysis challenging. At the Sanger Institute, we have been driving the development of direct sequencing approaches for the study of difficult to culture organisms such as Treponema pallidum, causative agent of syphilis, and are now applying this to large clinical cohorts of patients from around the world. In this talk, I will show how we are using these genomic tools to understand STI epidemiology and transmission dynamics, using examples from recent and ongoing syphilis and gonorrhoea studies.

We study axon degeneration and its roles in neurodegenerative disease. One focus is proteins regulating the degeneration of injured axons (‘Wallerian degeneration'), which we have linked into a molecular pathway. Disease models involving similar mechanisms include several of peripheral neuropathies, Parkinson’s disease, glaucoma, motor neuron disease and multiple sclerosis. We aim to completely characterize the Wallerian pathway, identify human diseases associated with it and develop drugs to modify it. A second major interest is axonal pathology in Alzheimer’s disease. Using a new organotypic hippocampal slice culture model, we are studying the earliest pathogenic events in amyloid pathology and their dependence on Abeta and tau. We are collaborating on ALS, traumatic brain injury, neuropathic pain and white matter damage in Alzheimer’s disease. Finally, we have a developing interest in roles that rare axonal disease genes could play in axon survival in more common disorders.

UK Biobank 15:30 Dietary assessment - Aurora Perez-Cornago 15:45 Nutritional biomarkers: analyses of urinary sodium reproducibility, and association with blood pressure - Jennifer Carter 16:00 Red and processed meat: outcome-wide analyses - Keren Papier EPIC 16:15 Protein food substitutions and risk of ischaemic heart disease - Tammy Tong Million Women Study 16:30 Diet quality and total mortality - Anika Knuppel China Kadoorie Biobank 16:45 Diet and cardiometabolic health - Huaidong Du 17:00 Close

Introducing newborn screening services for Sickle Cell Disease in Sub-Saharan Africa (SSA) is proved to be the most cost effective approach to reducing morbidity and mortality associated with the disease. In view of that some countries in SSA are embarking on establishing and piloting newborn screening programs for Sickle Cell Disease complemented with comprehensive care services. While these initiatives are commendable, it is imperative to address context-relevant factors that could limit realization of optimal benefits of establishing the screening programs. In this study we used the pilot newborn screening program for Sickle Cell Disease in Tanzania as a platform to understand ethical, socio-cultural and resource based implication of implementing the program in Sub-Saharan Africa. In the first paper, we analyzed the effects of gender norms in the settings before and after newborn screening for Sickle Cell Disease and its influence on the quality of care of the child. In the second paper we highlighted sustainability approaches adapted by the implementers to sustain implementation of the program activities in resource constrained environment.

As part of the WIMM Careers Seminar series, Andrew will outline his move from neurobiology to data science.

Discover unusual objects and assemble your own cabinet of curiosities. Drop-in, ages 5–13

Diseases of immunity cause much illness in the developed world – on one hand we are beset by a range of antibiotic resistance bacterial infections, while on the other hand our immune systems are responsible for many the common diseases of ageing – heart disease, stroke and COPD. Understanding the regulation of innate immune cells, neutrophils and macrophages, in infection and inflammation will help us tune the immune system to the exact level needed to cope with the current level of threat. More host defence to fight antibiotic resistant organisms; less host defence to prevent lung damage in response to environmental pollutants. To improve our understanding, I have set up a model system in which the genes controlling regulation of innate immune cell function can be identified. The model I have chosen is the Zebrafish, which is both genetically manipulable and transparent, leading to easy visualisation of immune cells during infection and inflammation. This model allows me to test the ability of a range of candidate genes to influence host-pathogen interaction and the resolution of inflammation, and additionally to screen for novel genes involved in this process. At the same time, I can see every immune cell during the whole of an infection or an inflammatory episode, where necessary imaging intracellular signalling events in real-time. The small size of our model also lends itself to drug screening and this has identified several potential new therapies for immune disease. I will discuss how this model has informed our understanding of inflammation, sharing new data on regulation of neutrophil function in vivo.

Two of the key successes of genomic epidemiology and routine sequencing for public health microbiology are monitoring of outbreaks and source attribution. Since 2014, Public Health England (PHE) have used routine whole genome sequencing for all clinical isolates of Salmonella and Shiga toxigenic Escherichia coli (STEC) for those exact purposes. This has generated a huge breadth of data, to date there are >100,000 gastrointestinal pathogens that have been sequenced at PHE. However, large datasets of sequenced pathogens are not unique anymore and many institutions and universities are generating their own large microbial genomics datasets. What is unique about this dataset is the detailed metadata and epidemiological information that is also stored alongside it in PHE’s Gastro Data Warehouse from real clinical cases of patients in the UK. Enhanced surveillance of foodborne pathogens means that each sequenced case of STEC and Salmonella also has collected information about the region of the case, any recent foreign travel of the patient and also what virulence factors were associated with the strain. Here we present work on the use of this wealth of associated metadata in conjunction with the publicly available sequencing data to train random forest algorithms on kmer count data to predict the country that the strain is likely to have originated from for newly generated sequences. This will enable a fully automated method to reproduce source attribution but also monitor international outbreaks. This will build on the two successes of genomic epidemiology in a natural progression to automation of it, that will have the potential to democratize genomic epidemiology by extending its usability to unskilled practitioners not trained in phylogenetics or bioinformatics.

Androgen receptor (AR) signalling is essential to nearly all prostate cancers. Any alterations to AR-mediated transcription can have a profound effect on prostate carcinogenesis and tumour growth. Yet despite this importance, many critical aspects of AR activity are poorly understood. Specifically, there is a stark contrast between the number of AR binding sites on DNA (tens of thousands) and androgen-driven gene transcription (hundreds). Functional validation of these AR binding sites (ARBS) is required to better understand prostate cancer growth and development. To characterize how AR induces transcription, we systematically tested the enhancer activity at every clinical ARBS with a novel massively multi-parallel enhancer assay. Interestingly, only 7% of ARBS were found to be AR-mediated enhancers. Demonstrating the importance of this functional approach, these enhancers could not be readily identified by descriptive techniques including epigenetic ChIPseq or DNA accessibility. Further, we observed that a large number of ARBS were constitutively active enhancers that were not affected by AR binding. In preliminary experiments we show that these constitutive enhancers work in concert with androgen-inducible enhancers. Finally combining these results with clinical whole genome sequencing and chromosomal confirmation capture methodologies we identified and validated specific somatic mutations at enhancer sites that may act as potential driver mutations. Using multiple functional genomic approaches, this work provides the first “map” of AR enhancers and their target genes.

Talk titles: Juliane Obst (ODDI), 'Using iPSC-macrophages to study the role of PLCγ2 in regulating TREM2-mediated responses’ Gian Filippo Ruda (Brennan Group), 'SGC-BRC Translational Science updates’

External speakers will be coming to talk to the Medical Stats team and anyone else who is interested in: Routinely collected healthcare data GP access and appointment scheduling Reasons for consultations in primary care Improving patient experiences in primary care Alternative modes of primary care consultations Opening access to help manage demand: dichotomy or opportunity? askmyGP is a system designed to allow patients to submit their issues to their GPs more easily and 24/7. By providing GPs with workflow management and a variety of communication options, it allows practices to provide a quicker and more tailored response to those submissions and gives practices analysis tools (including patient feedback) to paint a picture of how well they are doing. Ian Barratt and Steve Black from GP Access Ltd will explain the philosophy underpinning askmyGP and the data now available for research purposes (over 800k requests and 26k items of patient feedback submitted since September 2018). The system is currently running at ~100k submissions and 3k items of feedback each month).

The innate immune system provides the first line of defense against infections by rapidly recognizing and eliminating invading microbes. An important component of innate immunity are pattern recognition receptors, which are sensors that constantly monitor the extracellular and intracellular space of host cells for molecules of bacterial origin. Once the presence of bacteria is detected, these sensors initiate an inflammatory response. A subset of these pattern recognition receptors initiates the assembly of cytosolic multi-protein complexes called inflammasomes. The inflammasome complex is a large filamentous assembly formed by progressive oligomerization of receptors and adaptor proteins and serves as an activation platform for inflammatory caspases, a group of cysteine proteases. The prototypic caspase activated by canonical inflammasomes in caspase-1, which control the release of cytokines like IL-1b. Uncontrolled activation of the inflammasome by gain-of-function mutations or sterile inflammatory triggers is an underlying cause of many (auto-) inflammatory diseases. By characterizing new players and regulatory mechanism that control complex assembly and downstream signaling, we aim at identifying new targets for therapeutic modulation of inflammasome activity.