Neurodegenerative diseases represent one of the main public health issues in our western societies and one of the greatest challenges in drug development. Prevention policies have become essential to address these issues: primary prevention to prevent disease onset by acting on actionable risk factors, or secondary prevention to slow disease progression with very early therapeutic interventions, ideally at pre-symptomatic stages. Key to the implementation of such prevention measures is the identification of at-risk patients, at the point of care, and preferably long before disease onset. Our project, LeMeReND, proposes to use electronic health records (EHR) to identify biomedical risk factors through studying previous diagnoses (preclinical comorbidities), drug prescription, clinical care usage, and biological test results. This analysis will use longitudinal data in EHR registries including millions of patients who have been followed for at least 10 years before diagnosis in 4 different healthcare systems: Australia, France, the UK and Sweden and across 4 therapeutic areas: Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies and motor neuron diseases. We will identify the biomedical risk factors that are common to these diseases and the ones differentiating them. We will stratify patients based on the progression profile of their exposure to the set of risk factors, in order to design tailored primary prevention measures. We will also design a screening tool which will give each patient a propensity score to develop one of these neurodegenerative diseases. Such a tool could be deployed at the point of care to prioritise at-risk individuals for further inclusion in secondary prevention trials. We will evaluate the economic and social benefits of this new generation of precision prevention measures. We will study the public acceptability of a secondary-prevention effort, among the French population, and the feasibility of its implementation in primary care practices in France, Australia, and Sweden. Eventually, we will progress our understanding of the genetic and imaging markers of the disorders by studying the identified prodromal biomedical factors, using the UK BioBank and GWAS summary statistics. This will progress our understanding of the pathological processes which result in an increased risk to develop a specific neurodegenerative disease. LeMeReND gathers a multidisciplinary research group with a leading expertise in epidemiology, statistics and machine learning, in particular for the analysis of longitudinal EHR data. Partners have demonstrated a strong track record on neurodegenerative diseases (Sweden, France, Australia), analyses of large-scale data including neuroimaging (France), genetics (Australia), longitudinal modelling (Sweden, France), and machine learning (Australia, France). An expert team in health economics and health policy complements the consortium. LeMeReND will therefore provide invaluable insights to inform health policies and highlight possible new therapeutic targets. It will provide unique screening tools to facilitate the large-scale recruitment of patients in secondary prevention trials.

There are many physical disabilities with a neurological origin, such as stroke and spinal cord injuries, that significantly impact a person’s mobility, physical capacity, stamina, or dexterity. In the era of personalized medicine, optimizing the treatment of these physical disabilities requires: i) accessing direct information on the neural commands that are sent to the muscles, and ii) integrating this knowledge into the development and assessment of rehabilitation and neurotechnology aimed at restoring movement. The breakthrough of our approach lies in changing the level at which we observe the control of movement, i.e., shifting focus from the level of whole muscles to the spinal (alpha) motor neurons. To achieve this, we will combine the use of dense grids of surface electromyographic (EMG) electrodes with algorithms that decode the firing activity of spinal motor neurons. By unravelling the “neural code” for movement generation, we will address critical gaps in our understanding of the control of movement in health and disease. Building on recent work from our team, we will decode the activity of large populations of motor neurons from different muscles. We will identify motor neuron synergies, defined as functional groups of motor neurons that share inputs from various supraspinal, spinal and sensory sources. In this translational project, we will examine the structure and plasticity of these synergies in both healthy controls and patients with neurological impairments (stroke, spinal cord injury). We will also enhance the electrode design to facilitate the transfer of these methods into clinical settings. Our project is structured into independent research work packages (WP), where the progression of one is not contingent on the outcomes of another: - Aim of WP 1: To identify motor neuron synergies that controls the lower limb during tasks with different mechanical and neural constraints. Hypothesis: The activity of motor neurons can be explained by the combination of robust motor neuron synergies that would define a control space with much lower dimensions than the number of recruited motor neurons. - Aim of WP 2: To determine whether motor neuron synergies can be modified in the short- and long-term by biofeedback training. We will test the hypothesis that it is possible to dissociate the activity of motor neurons represented in the same synergy after several days of training; and conversely, it is possible to dissociate the activity of motor neurons represented in different synergies with minimal training. - Aim of WP 3: To determine whether (a) motor neuron synergies differ between stroke survivors and controls; (b) changes in synergies over the course of a rehabilitation program correlate with recovery. Based on changes in neuronal connectivity at the brain level and the observed coactivation, we will test the hypotheses that (a) synergies are disorganized in stroke survivors, and (b) they can provide biomarkers of recovery. - Aim of WP 4: (a) To describe motor neuron synergies in patients with spinal cord injury who have undergone a tendon transfer, (b) to determine whether changes in synergies correlate with the improvement in active elbow extension. Hypotheses: (a) over the course of rehabilitation, motor neurons innervating the transferred muscle and its previous agonists are progressively represented in distinct synergies, and (b) the extent of these changes is correlated with the improvement in active elbow extension. - Aim of WP 5: To improve the design of the grid of surface EMG electrodes to identify larger samples of motor neurons, especially in females Hypothesis: The differences in the number of identified motor neurons between males and females are primarily attributed to variations in fat layer thickness and innervation ratio (size of the motor units). The methodological and theoretical frameworks developed in this project will set the path for future ambitious clinical studies.

EVENTS aims to investigate both the positive and negative impacts of endogenous viral elements (EVEs) on plant metabolism. EVEs are viral sequences that are integrated in the genomes of their hosts. In plants, most characterized EVEs originate from viruses in the families Caulimoviridae and Geminiviridae, which have DNA genomes, following passive horizontal gene transfer (HGT). Members of the project team recently showed that DNA from ancestral viruses in the family Caulimoviridae were captured within the genomes of a wide range of angiosperms, including economically important crops (rice, sorghum, citrus, grape, apple, pear, strawberry, eucalyptus, poplar, tomato, potato, cucumber, cotton). A new genus, tentatively named Florendovirus, was proposed to accommodate these viruses. Several endogenous florendoviruses could potentially be replication competent and, therefore, infective, although this hypothesis has not yet been tested. Different members of the project team have also discovered new geminivirus-like elements (EGVs) in the genome of yams and demonstrated that these EGVs represent transcriptionally active endogenous geminiviral sequences that may be functionally expressed in their respective host plants. Building on this pioneering work, EVENTS focuses on the role of caulimovirid and geminivirid EVEs in virus evolution and their functions in plants. EVENTS will create automated computational tools to search for these EVEs in plant genomes and will implement these tools in a large-scale plant EVE discovery program, providing access to viral sequences that were integrated millions to tens of millions of years ago. These EVEs will be used to reconstruct accurate time-scaled evolutionary histories of entire viral lineages across unprecedented time-spans, helping to refine predictive models of viral emergence. EVENTS will investigate the contributions of caulimovirid and geminivirid EVEs to viral diversity. A range of antigenic and molecular detection tools will be created and used to screen germplasm collections and collected samples for viral particles and infective genomes of as yet undescribed geminiviruses and florendoviruses with EVE counterparts. Graft experiments will be carried out to confirm infective status. The project will also explore synergistic interactions between endogenous viruses and exogenous viruses encoding suppressors of silencing, in order to investigate the role of silencing in the regulation of EVE gene expression in plants. The contribution of caulimovirid and geminivirid EVEs to genetic and epigenetic regulation of plant gene expression will be investigated in silico through the systematic search for fused (viral/plant) open reading frames, alternative promoters, intron splicing sites and premature terminations of transcription. Immunological and molecular approaches will be designed and used to search for and characterize EVE-derived proteins and/or RNAs expressed in host plants. Experimental approaches using recombinant infective viral clones expressing EVE sequences will be designed and implemented to evaluate potential antiviral resistance in plants conferred by EVEs acting as natural viral transgenes. By developing novel integrated and multidisciplinary approaches to illuminate the diversity of EVEs in plant genomes, their roles in viral evolution, their functions and potentially beneficial roles within their host plants, EVENTS stands at the forefront of an emerging research field. We anticipate that the project will contribute significantly to societal issues such as the control of viral diseases and the advancement of plant biotechnology. EVENTS brings together leading groups with complementary expertise in virology, bioinformatics and molecular systematics working in France, South Africa and Australia. Partners have a proven record of collaboration and joint publications that demonstrate their ability to meet project goals and deliver results in ground-breaking research domains.