A5017042137- Neonatal and fetal brain pathology
- Genetic Syndromes and Imprinting
- Neuroinflammation and Neurodegeneration Mechanisms
- Mitochondrial Function and Pathology
- Preterm Birth and Chorioamnionitis
- Epigenetics and DNA Methylation
- Genetics and Neurodevelopmental Disorders
- Gene expression and cancer classification
- Metabolism and Genetic Disorders
- Bioinformatics and Genomic Networks
- Muscle Physiology and Disorders
- Birth, Development, and Health
- Heat shock proteins research
- Infant Development and Preterm Care
- Cardiomyopathy and Myosin Studies
- Advanced Neuroimaging Techniques and Applications
- Congenital heart defects research
- Genetic Neurodegenerative Diseases
- S100 Proteins and Annexins
- Tissue Engineering and Regenerative Medicine
- Genetic Associations and Epidemiology
- Healthcare and Venom Research
- Folate and B Vitamins Research
- Health, Environment, Cognitive Aging
- Genetic and Kidney Cyst Diseases
Roche (Switzerland)
2018-2023
Novartis (United States)
2022
Novartis Institutes for BioMedical Research
2021
Novartis (Switzerland)
2021
St Thomas' Hospital
2013-2019
King's College London
2014-2019
Kings Health Partners
2017-2019
Boston Children's Hospital
2010
Harvard University
2010
Rudolf Steiner College
2007
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches characterize genetic regulation of pathophysiological in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, identify gene-regulatory genetically associated with that contains specialized, highly expressed transcriptional module encoding proconvulsive cytokines Toll-like...
Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory microglia in still-developing preterm-born infants associated with permanent neurological sequelae 9 million every year. Investigating regulators microglial across models neuroinflammation-mediated injury (mouse, zebrafish) and primary human mouse we found using analysis genes proteins that a reduction Wnt/β-catenin signalling necessary...
The subplate zone is a highly dynamic transient sector of the developing cerebral cortex that contains some earliest generated neurons and first functional synapses cortex. Subplate cells have important functions in early establishment maturation thalamocortical connections, as well development inhibitory cortical circuits sensory areas. So far no role has been identified for mature brain disease association subplate-specific genes not analyzed systematically. Here we present gene expression...
Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known involve neuroinflammation. In this study, we integrate human mouse molecular neuroimaging data investigate the role of microglia preterm white matter damage. Using model where encephalopathy prematurity is induced by systemic interleukin-1β administration, undertake gene network analysis microglial transcriptomic response injury,...
The aim of this study was to develop a simple reproducible method for the measurement apparent diffusion coefficient values in white matter preterm infants using diffusion-weighted imaging test hypothesis that elevated mean are associated with lower developmental quotient scores at 2 years' corrected age.We obtained 38 term-equivalent age who had no evidence overt cerebral pathology on conventional MRI. Mean level centrum semiovale were determined. children assessed standardized neurologic...
Abstract Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair expression, but they differ how neighboring genes on chromosome 15 at 15q11–q13 affected. evidence different subtypes present with clinical severity, systematic quantitative investigation lacking. Here we analyze natural history data large sample individuals AS ( n = 250, 848 assessments), including scales quantify...
The role of heritable factors in determining the common neurologic deficits seen after preterm birth is unknown, but characteristic phenotype neurocognitive, neuroanatomical, and growth abnormalities allows principled selection candidate genes to test hypothesis that genetic variation modulates risk for brain injury.
Abstract Angelman syndrome (AS) is a complex, heterogeneous, and life-long neurodevelopmental disorder. Despite the considerable impact on individuals caregivers, no disease-modifying treatments are available. To support holistic clinical management development of AS-specific outcome measures for studies, we conducted primary secondary research identifying symptoms with AS their unmet need. This qualitative adopted rigorous step-wise approach, aggregating information from published...
Preterm infants show abnormal structural and functional brain development, have a high risk of long-term neurocognitive problems. The molecular cellular mechanisms involved are poorly understood, but novel methods now make it possible to address them by examining the relationship between common genetic variability endophenotype. We addressed hypothesis that in Peroxisome Proliferator Activated Receptor (PPAR) pathway would be related development. employed machine learning an unsupervised,...
Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported results from FREESIAS study feasibility utility in-clinic at-home measures key AS symptoms. Methods Fifty-five individuals with...
Abstract Background The consequences of preterm birth are a major public health concern with high rates ensuing multisystem morbidity, and uncertain biological mechanisms. Common genetic variation may mediate vulnerability to the insult prematurity provide opportunities predict modify risk. Objective To gain novel therapeutic insights from integrated analysis magnetic resonance imaging data, informed by prior knowledge. Methods We apply our previously validated pathway‐based statistical...
Abstract Background Friedreich’s ataxia is an inherited, progressive, neurodegenerative disease that typically begins in childhood. Disease severity commonly assessed with rating scales, such as the modified Ataxia Rating Scale, which are usually administered clinic by a neurology specialist. Objective This study evaluated utility of home‐based, self‐administered digital endpoints children and unaffected controls their relationship to standard clinical scales. Methods In cross‐sectional 25...
Introduction Drug development for neurodegenerative diseases such as Friedreich’s ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been their small sample sizes follow up. TRACK-FA, longitudinal, multi-site, multi-modal natural history study, aims address these shortcomings enabling better understanding underlying pathology identifying...
Abstract Neuropsychiatric disease has polygenic determinants but is often precipitated by environmental pressures, including adverse perinatal events. However, the way in which genetic vulnerability and early-life adversity interact remains obscure. We hypothesised that extreme stress of prematurity would promote neuroanatomic abnormality individuals genetically vulnerable to psychiatric disorders. In 194 unrelated infants (104 males, 90 females), born before 33 weeks gestation (mean...
Summary Microglia of the developing brain have unique functional properties but how their activation states is regulated poorly understood. Inflammatory microglia in still-developing preterm born infants associated with permanent neurological sequelae 9 million every year. Investigating regulators microglial multiple models neuroinflammation-mediated injury and primary human we found that a reduction Wnt/β-catenin signalling necessary sufficient to drive an oligodendrocyte-injurious...
Objective: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of anti-myostatin adnectin RG6206 (BMS-986089) in a Phase 1b/2 study (NCT02515669) ambulatory boys with Duchenne muscular dystrophy (DMD). Background: Pharmacologic inhibition myostatin, negative regulator muscle growth, has been shown to increase skeletal mass several species, including humans. Design/Methods: Forty-three DMD, aged 5–10 years, were randomized receive weekly subcutaneous injections...
Objective: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of novel anti-myostatin adnectin RG6206 (BMS-986089) in a Phase 1b/2 study ambulatory boys with Duchenne muscular dystrophy (DMD; NCT02515669). Background: Pharmacologic inhibition myostatin, negative regulator muscle growth, has been shown to increase skeletal mass several species, including humans. is potent, previously inhibit myostatin activity healthy adults. Design/Methods: Forty-eight DMD, aged 5–10...
1. Abstract Background Neuropsychiatric disease has polygenic determinants but is often precipitated by environmental pressures, including adverse perinatal events. However, the way in which genetic vulnerability and early-life adversity interact remains obscure. Preterm birth associated with abnormal brain development psychiatric disease. We hypothesised that extreme stress of premature extra-uterine life could contribute to neuroanatomic abnormality genetically vulnerable individuals....