NIHRDataInsights/HRCSData huggingface dataset:
Title: Implementing an innovative electronic registry in a new regional intensive care network to improve quality of care and establish a platform for clinical trials in resource-limited settings in Asia
Funder: Wellcome Trust

Abstract: The project is the second in a portfolio of joint projects with Wei/come and Oxford Tropical Network that aim to reduce mortality and morbidity from critical illness. This project's primary objective in phase 1 is to network a large number of ICUs in the Southeast and South Asia regions by implementing a setting-adapted, real-time, clinician-led electronic registry. The information captured through the registry will directly benefit patient care by evaluating the quality of care currently delivered in each ICU (and enable recognition of the bottlenecks to quality care delivery) and provide a platform for quality improvement interventions and clinical trials within the network. (phase 2). This project unites with the proposal led by OUCRU to evaluate technology innovations in critical care. Collaborating countries include: Bangladesh, India, Laos, Malaysia, Nepal, Pakistan, Sri Lanka, Thailand and Vietnam. The resulting internationaiiCU network will enable high impact multi-site evaluation of setting-adapted interventions to improve critical care delivery and patient outcomes.

Lay abstract: This 3-year project will establish a novel intensive care unit (ICU) network of 42 ICUs over 9 countries in South and Southeast Asia. Activities within the network consist of 3 work packages (WPs). WP1 will implement a purpose developed electronic ICU registry across the network, which will capture in real time patient information on disease category and diagnosis, physiological parameters, treatment interventions, and patient outcome measures. WP2 will assess ICU performance in the participating ICUs. This assessment will use quantitative data captured by the electronic registry. In addition this will include a qualitative assessment based on an agreed list of quality indicators reflecting minimum standards for quality ICU care and an assessment of barriers and enablers of quality ICU care, mainly using semi-structured interviews and focus group discussions. WP3 will develop, facilitate and evaluate a series of locally led quality improvement (QI) interventions. Workshops will provide local QI teams with training in quality improvement methodology and meetings will be organised to meet quality improvement experts and exchange learning experiences. In addition WP3 will prepare sites for the planned clinical studies for the next phase of the ICU Flagship programme. The key goals of the project are: 1. Provide a model for improving ICU performance in resource-limited settings in Asia, 2. Implement the electronic registry and 3. Create an ICU network for large clinical trials.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing a centre for Biomedicine, Self and Society
Funder: Wellcome Trust

Abstract: Our vision is to build the foundation for an internationally recognised Centre for Biomedicine, Self and Society that combines novel integrative social science and humanities research with innovative approaches to collaboration, stakeholder and public engagement. This discretionary award will support development work to: build our research portfolio and networks, including ‘proof of concept’ exemplar projects; mature a leadership team to take us to the next stage; create a vibrant research community of interdisciplinary scholars at all levels; and, develop innovative knowledge exchange and public engagement opportunities for a long term transformation in biomedicine and society relationships. Anchored through five key themes - Beyond bodies, Beyond disease; Beyond the global, Beyond the legal and Beyond engagement – we will produce new evidence through novel conceptual frameworks and modes of analysis that transcend disciplines and actively engage with stakeholders. Cross cutting work will be stimulated through a core project on data and data practices and through a responsive strand to meet emergent challenges. Translation and engagement will be integrated throughout the five years, to support the development of a cutting edge programme of collaborative, creative and critical engagement with publics, scientists, health care professionals and those in the creative and other industries.

Lay abstract: No Data Entered

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of spliceosome remodeling and splice site selection during the catalytic stage of mammalian pre-mRNA splicing
Funder: Wellcome Trust

Abstract: The spliceosome produces mRNAs in two sequential transesterifications – branching and exon ligation. The post-branching C complex is remodeled by the ATPase Prp16 into the C* complex. Prp16 allows binding of the exon ligation factors Cactin and FAM32A, which stabilise docking of the 3’-splice site (3’SS) at the active site. While in yeast Prp18 is constitutively bound to C* spliceosomes, in humans Prp18 and other exon ligation factors of unknown function appear to engage the C* spliceosome in a transcript-specific manner. Here, I will reconstitute the C to C* transition in vitro in mammals and use biochemistry and cryo-electron microscopy to isolate and visualize novel intermediates and dissect the structural mechanisms by which Cactin, FAM32A, Prp18, and additional exon ligation factors cooperate to promote Prp16-mediated remodeling and to ensure correct 3’SS choice. In parallel, iCLIP studies will reveal where these exon ligation factors bind across all human pre-mRNAs and how RNA sequences around the splice sites determine the association of subsets of factors on specific pre-mRNAs. This work will elucidate how Prp16 drives remodeling of the human catalytic spliceosome and will investigate whether exon ligation factors regulate alternative splicing in a sequence-specific manner while proofreading 3'SS recognition during exon ligation.

Lay abstract: During gene expression, DNA is transcribed into pre-messenger RNAs (pre-mRNAs), which are spliced through the excision of non-coding regions to produce mRNAs with continuous protein-coding information. Splicing is performed by the spliceosome – a dynamic assembly of RNA and proteins. Many proteins influence the conformation of the spliceosome during splicing catalysis and determine how a single gene produces multiple mRNAs through alternative splicing. I aim to use electron microscopy and biochemistry to visualise at the molecular level how mammalian splicing proteins bind to and remodel the spliceosome to ensure correct splicing of different pre-mRNAs. I will use sequencing approaches to investigate how RNA sequence determines which proteins bind to, and affect splicing of, specific pre-mRNAs across all human transcripts. These experiments will reveal how human spliceosomes produce mRNAs correctly and will determine whether alternative splicing is regulated during the catalytic stage by proteins that influence splicing of subsets of pre-mRNAs.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural insight into the mechanisms of lysosomal the control of cell proliferation and DNA damage response that are central to cancer cell growth.
Funder: Cancer Research UK

Abstract: Background In metazoan cells, both signalling pathways and ancient nutrient and stress response pathways are frequently mutated in cancers or resistance to cancer therapy. Three phosphoinositide 3-kinase (PI3K) family enzyme complexes have linked roles in cancer cells: nutrient sensing mTORC1, autophagic and endocytic associated PI3K VPS34 complexes and complexes of the DNA damage response (DDR) kinase ATM. This network enables growth and proliferation as well as response to stress. Constitutively activated mTORC1 signaling is associated with cancers and resistance to cancer therapies. The Ras superfamily of G proteins RHEB and Rag GTPases activate mTORC1, and our work focuses on mTORC1 oncogenic mutants in complexes with oncogenic Rags, the Ragulator and RHEB that upregulate the pathway. The mTORC1 inhibitory subunit DEPTOR is also dysregulated in many cancer cells. The mTORC1 is activated downstream of the class III PI3K, VPS34, and, in turn, mTORC1 modulates the activity of VPS34 complexes. VPS34 complex I is a key component of autophagy that cancers use as a survival response. The PI3K-like protein kinase ATM is recruited to sites of DNA damage where it is activated to initiate DNA damage response (DDR) signaling. Activated ATM also has cytosolic roles, including formation of a phospho-ATM and mTOR signalosome that confers cell survival due to stress induced by anti-cancer therapies. Aims Structures, kinetics and dynamics of mTORC1 in complexes with Rags, RHEB and DEPTOR are vital to understanding how cancers modulate mTORC1. We will characterise mTORC1 pathways reconstituted with their regulators in vitro on lysosomal mimics. We will also reconstitute and characterize Rag assemblies with two alternate effectors, the transcription factor TFEB and Galectin-8, which protect cancer cells from therapy-mediated stress. We will determine how membrane-coupled Rabs and mTORC1 phosphorylation regulate VPS34 assemblies. This is essential to understand how complex I is regulated in autophagy and how VPS34 complex II interacts with LC3-associated phagosomes and endocytic compartments containing receptor tyrosine kinases that signal in human cancers. We will determine mechanisms of ATM activation in a DDR complex (ATM/MRN/DNA) as well as characterize the redox-activated ATM that downregulates mTORC1 in the cytosol. Methods We will analyse structures and functions of enzyme complexes reconstituted on vesicles. Our approach involves single-article cryo-EM, electron cryo-tomography (Cryo-ET) and X-ray structures as well as biochemistry and hydrogen/deuterium exchange mass spectrometry (HDX-MS). How the results of this research will be used Understanding mechanisms of regulation of mTORC1, VPS34 and ATM will facilitate new therapeutic approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Deciphering Notch signalling dynamics in vivo
Funder: Wellcome Trust

Abstract: To make and organize different tissues, cells must decipher information from developmental signalling pathways. Transmitting this information accurately, so that cell-surface signals are translated into correct transcriptional responses, is of critical importance but how this is achieved mechanistically remains a major question. We propose to answer this focussing on the Notch pathway. Dosage and dynamics of Notch activity are fundamentally important for developmental decisions and tissue homeostasis and their mis-regulation underlies many diseases including cancers. Our ability to image events in real time within living fly embryos gives us a powerful system to investigate dynamic properties of Notch signalling in physiological conditions. Our overall goal is to decipher temporal, quantitative and mechanistic principles that govern how Notch activity is read by target enhancers in the living animal. Using cutting-edge strategies for measuring transcription responses and complexes we will address: (i) how Notch signals are decoded in real time in vivo, (ii) what mechanisms/partners are required to accurately transduce Notch signals, (iii) what roles tissue geometry and forces play in shaping signalling dynamics. Answers will provide new insights for manipulating Notch in a controlled way, enabling strategies for altering cell fates or for treating diseases driven by aberrant Notch signalling.

Lay abstract: To make and organize tissues, cells need to communicate with each other and to correctly decipher the information they receive –mistakes are at the root of many inherited diseases and cancers. We focus on the Notch pathway, which provides key information during tissue development and maintenance. A critical end-result from Notch activity is that genes are turned on; our goal is to discover how this occurs accurately in developing animals. Using fly embryos as a model, we will visualize events in real time, directly measuring gene activities on a cell-by-cell basis to explore their response. We will then examine and model the effects when we perturb different steps to learn how cells accurately perceive Notch signals to make appropriate decisions. By giving new insights for manipulating Notch signals in a controlled way, our resuts may offer strategies for regulating stem cells or for treating diseases driven by incorrect Notch signalling.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Next Generation Data Formats for BioImaging
Funder: Wellcome Trust

Abstract: Bioimaging measures the structure, constitution and dynamics of molecules, cells, tissues and organisms in biological systems. Data are often GBytes or Tbytes in size, cover space, time and other dimensions, include complex metadata that describe experimental setups, acquisition parameters and analytic outputs and are stored in 100s of different proprietary file formats. The scale and complexity of these data are a consistent, unsolved block to researchers making their bioimaging data public and FAIR, despite the fact that open data sharing and publication are mandated by the Wellcome and many other funding agencies. OME is a globally recognised, open source bioimage data specification and software project (https://www.openmicroscopy.org). Since 2002, OME's OME-TIFF file format and Bio-Formats file translation library have served as the global de facto standard for accessing bioimage data, but the capabilities of these tools will soon be surpassed by the growing volume and complexity of bioimaging datasets. We propose to build next generation bioimage file formats, flexible data models, data linkages and transfer tools to serve the needs of the rapidly evolving bioimaging community and feed new public data repositories and databases. The software will be liberally licensed to allow adoption across the research and industrial bioimaging communities.

Lay abstract: Biological microscopy has always involved “imaging”: images were initially hand drawn and with the advent of light-sensitive film, recorded and then reproduced on paper, but these recordings were difficult to use for scientific measurements. However, the application of digital detectors to microscopy and the rapid growth of computerised automation has spawned massive growth in the use of digital imaging in basic and clinical research. Unfortunately, our current generation of data formats and software tools are incapable of handling, sharing or publishing these new Big Image Data. To ensure imaging will continue to grow and contribute to discoveries in the biological and clinical sciences, we propose to develop new, scalable data formats and software that are open source and available for anyone to adopt and use. These new technologies will enable new ways of sharing, publishing and driving new discoveries with Big Image Data.

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: A multi-contrast X-ray nanoscope for multidisciplinary research
Funder: Wellcome Trust

Abstract: We are seeking to acquire the resources to develop a unique X-ray 3D nanoscope. We will need: custom-source, isolation, manipulators, custom-detector, radiation-safe enclosure, two PDRAs (hardware- and software-focussed) and 1year system engineer for the transition to the long-term maintenance/management of the instrument. We plan to build a nano-resolution multi-contrast 3D scanner with transformative potential across diverse disciplines, including cellular structural biology, pathology, musculoskeletal and respiratory medicine, tissue engineering and child health. This will create a multi-user tool, benefitting researchers across multiple specialties. The simultaneous attainment of nano-scale resolution, unprecedented scale range (six orders of magnitude,5cm/50nm), multi-contrasts and a wide energy range will make the X-ray nanoscope proposed here a unique non-destructive 3D imaging tool. Its key advancements will be ultra-high-resolution zoom-ins on intact samples, whose entire structure is measured at a lower resolution, combined with multi-contrast modes arising from phase effects. A simple analogy of this new X-ray tomography paradigm is the way we navigate digital maps. We use coarse resolution at large scales, blowing-up in precise locations of interest. Both capabilities must be concurrently present: it would not be useful to navigate large areas at highest resolution (lost in space) and having only coarse resolution would lack invaluable insights.

Lay abstract: We propose a technology development leading to a new paradigm in three-dimensional volumetric imaging. This new concept has an analogy in the way we navigate digital maps, where we use a coarse resolution to move efficiently over large areas, then blow up specific locations to visualise details of interest. We plan to use X-rays, for their ability to propagate through thick and opaque samples and quantitatively measure their three-dimensional internal structure. X-ray microscopy techniques were pioneered at synchrotron facilities, where they have led to significant breakthroughs in many diverse areas of science. Our aim is to develop a table-top instrument, easily deployable in a standard laboratory, which enables quantitative imaging of label-free samples across a vast range of scales. This will bridge the resolution gap between other well-established microscopy techniques, such as electron and visible light microscopy, and become a platform catalysing collaborative projects among scientists from diverse backgrounds.

Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: EMDB: dealing with the cryo-EM data deluge
Funder: Wellcome Trust

Abstract: Decades of research (rewarded with the 2017 Nobel Prize in Chemistry) have led to revolutionary developments in the field of cryo-electron microscopy (cryo-EM), with further improvements underway (phase plates, robotics). The Wellcome Trust and other funders have recognised the importance of cryo-EM and made substantial investments in infrastructure. These developments together cause a vast increase in the amount and diversity of experimental data emanating from molecular and cellular structural studies. EMDB (Electron Microscopy Data Bank), maintained by EMBL-EBI with international partners, is the single global archive of 3D cryo-EM reconstructions. This project will address major archiving challenges caused by the rapid growth of the cryo-EM field. Its aims are: 1. Handling the increasing volume, complexity and diversity of EM data depositions. 2. Data enrichment and validation - by enriching EMDB entries with biological annotations, expanding the volume of biologically-annotated segmentations in EMDB by exploiting crowd-sourcing initiatives and machine-learning techniques and developing and maintaining validation tools and resources for EMDB. 3. Enabling effective use of EMDB data - by developing new and improved web-based resources for searching, analysing and visualising EMDB data and developing tools and resources that facilitate the use of EMDB data by other bioinformatics resources.

Lay abstract: Biology at the molecular level is intimately related to the 3D atomic structure of biological molecules. Structural biology, the study of 3D molecular structure, requires sophisticated equipment and structure determination is often a time and resource-intensive process. Public archiving of the produced data is well-established and crucial for promoting its further use. Decades of research (rewarded with the 2017 Nobel Prize in Chemistry) have led to revolutionary developments in cryo-electron microscopy (cryo-EM), making it a leading technique in structural biology. This has led to a vast increase in the amount, complexity and diversity of experimental data from cryo-EM studies. EMDB (Electron Microscopy Data Bank) is the single global archive of 3D cryo-EM reconstructions. In this project we want to address archiving challenges associated with the rapid expansion of the cryo-EM field and develop resources to make it easier for specialists and non-specialists to exploit EMDB data.

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Oocyte-specific pathways that compensate for lack of centrosomes
Funder: Wellcome Trust

Abstract: Frequent mis-segregation of chromosomes in human oocytes during meiosis is a major cause of infertility, miscarriages and birth defects such as Down syndrome. Chromosome segregation is mediated by a bipolar spindle. Centrosomes are the main organisers of the mitotic spindle, but are lost from oocytes of most animals including humans and Drosophila. The absence of centrosomes poses a unique question: how does an oocyte assemble and maintain a single bipolar spindle during meiosis without centrosomes? Using Drosophila, we discovered that oocytes have meiosis-specific pathways that compensate for the lack of centrosomes. These pathways are poorly understood compared to those shared with mitosis. Our overall goal is to define the molecular mechanism and regulation of the oocyte-specific pathways we have discovered, by combining in vivo and in vitro approaches. Specifically, we will molecularly dissect the two key oocyte-specific pathways crucial for spindle microtubule assembly and bipolarity. Furthermore, we will uncover regulatory mechanisms that remodel the molecular architecture of the bipolar spindle during programmed arrest, and that drive oocyte-specific chromosome clustering essential for forming a single spindle without centrosomes. Considering the conservation between human and Drosophila oocytes, our finding will provide unique insights into how human oocytes segregate and mis-segregate chromosomes.

Lay abstract: Transmitting genetic information carried by DNA from generation to generation is most fundamental for life. Genes are carried on chromosomes and a sophisticated machinery mediates their accurate transmission. However, there is a high incidence of errors in chromosome transmission to human eggs. As a result, 10-30% of all human eggs have an incorrect number of chromosomes. This is a major cause of infertility, miscarriages and birth defects, such as Down syndrome. Despite the medical implications, the molecular and genetic basis of this process is still not understood. The machinery to transmit chromosomes to egg cells is distinct from the ones in other cells of the body, but little is known about this specialised machinery. We aim to find out how this machinery is built and maintained using fruit flies as a model system, by taking advantage of similarities between humans and flies. We discovered new pathways important for building and maintaining this specialised machinery. I propose to investigate how these pathways work at the molecular level, and reveal why they are used only for transmitting chromosomes to eggs. Our studies may provide unique insights into how errors occur in chromosome tranmission during female reproduction.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE