A5082078926- Genetics and Neurodevelopmental Disorders
- Pluripotent Stem Cells Research
- Neuroscience and Neural Engineering
- Ion Transport and Channel Regulation
- Epilepsy research and treatment
- Congenital gastrointestinal and neural anomalies
- CRISPR and Genetic Engineering
- Intestinal Malrotation and Obstruction Disorders
- Neuroscience and Neuropharmacology Research
- Heart Failure Treatment and Management
- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- RNA regulation and disease
- Congenital heart defects research
- Amyotrophic Lateral Sclerosis Research
- Developmental Biology and Gene Regulation
- Genomics and Chromatin Dynamics
- Genomics and Rare Diseases
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Neural dynamics and brain function
- Tissue Engineering and Regenerative Medicine
- Advanced Memory and Neural Computing
- Neurogenesis and neuroplasticity mechanisms
- Renal and related cancers
Monash University
2009-2024
Florey Institute of Neuroscience and Mental Health
2017-2023
The University of Melbourne
2018-2023
Murdoch Children's Research Institute
2013-2018
Royal Children's Hospital
2013-2018
Monash Institute of Medical Research
2009
Integrating neurons into digital systems may enable performance infeasible with silicon alone. Here, we develop DishBrain, a system that harnesses the inherent adaptive computation of in structured environment. In vitro neural networks from human or rodent origins are integrated silico computing via high-density multielectrode array. Through electrophysiological stimulation and recording, cultures embedded simulated game-world, mimicking arcade game "Pong." Applying implications theory...
De novo variation in SCN2A can give rise to severe childhood disorders. Biophysical gain of function is seen some patients with early seizure onset developmental and epileptic encephalopathy (DEE). In these cases, targeted reduction expression could substantially improve clinical outcomes. We tested this theory by central administration a gapmer antisense oligonucleotide (ASO) targeting Scn2a mRNA mouse model DEE (Q/+ mice). Untreated Q/+ mice presented spontaneous seizures at P1 did not...
Background: Ischemia–reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, buildup acidic metabolites results decreased intracellular extracellular pH, which can reach as low 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic significantly affects function. Methods: We used genetic pharmacologic methods investigate role acid-sensing ion channel 1a (ASIC1a) IRI at cellular...
Abstract Background Multiple lines of evidence suggest possible impairment the glymphatic system in amyotrophic lateral sclerosis (ALS). To investigate this, we used vivo magnetic resonance imaging (MRI) to assess function early course disease a transgenic mouse with doxycycline (Dox)-controlled expression cytoplasmic human TDP-43 (hTDP-43ΔNLS), mimicking key pathology implicated ALS. Methods Adult and littermate monogenic control mice underwent longitudinal multimodal MRI one three weeks...
The caudal neural plate is a distinct region of the embryo that gives rise to major progenitor lineages developing central and peripheral nervous system, including crest floor cells. We show dual inhibition glycogen synthase kinase 3β activin/nodal pathways by small molecules differentiate human pluripotent stem cells (hPSCs) directly into preneuroepithelial population we named "caudal progenitors" (CNPs). CNPs coexpress mesoderm markers, and, share high similarities embryonic in their...
Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy migrating focal (EIMFS) is one the most severe these syndromes. De novo variants in ion channels, including gain-of-function KCNT1, which encodes for sodium activated potassium channel protein KNa1.1, have been found to play a major role etiology EIMFS. Here, we test potential precision therapeutic approach KCNT1-associated DEE...
Abstract Repressor element-1 silencing transcription factor (REST) is a transcriptional repressor involved in neurodevelopment and neuroprotection. REST forms complex with the corepressors, CoREST1, CoREST2, or CoREST3 (encoded by RCOR1 , RCOR2 RCOR3 respectively). Emerging evidence suggests that CoREST family can target unique genes independently of REST, various neural glial cell types during different developmental stages. However, there limited knowledge regarding expression function...
Vagal neural crest cells (VNCCs) arise in the hindbrain, and at (avian) embryonic day (E) 1.5 commence migration through paraxial tissues to reach foregut as chains of 1–2 days later. They then colonise rest gut a rostrocaudal wave. The migrating later resolve into ganglia enteric nervous system. In organ culture, E4.5 VNCCs resident (termed or ENCC) which have previously encountered vagal tissues, rapidly colonised aneural tissue large numbers cells. Within same timeframe, E1.5 not exposed...
An efficient delivery system is critical for the success of cell therapy. To deliver cells to a dynamic organ, biomaterial vehicle should mechanically match with non-linearly elastic host tissue. In this study, biomaterials have been fabricated from chemically crosslinked elastomeric poly(glycerol sebacate) (PGS) and thermoplastic poly(l-lactic acid) (PLLA) using core/shell electrospinning technique. The spun fibrous materials containing PGS core PLLA shell demonstrate J-shaped stress-strain...
Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to family secreted proteins expressed within normal cells. GKN2 expression frequently lost during GC progression, suggesting an inhibitory role; however, causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice investigate the functional impact loss in...
Abstract Squamous cell carcinoma antigen recognized by T cells 3 ( SART3 ) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in nine individuals presenting intellectual disability, global developmental delay and a subset of brain anomalies, together gonadal dysgenesis 46,XY individuals. Knockdown Drosophila orthologue reveals conserved role testicular neuronal development. Human induced...
The trial and error approach to epilepsy treatment has not changed for over a century but machine learning patient derived stem cells promise personalised more effective strategy, argue <b>Patrick Kwan colleagues</b>
<ns4:p>The avian enteric nervous system (ENS) consists of a vast number unusually small ganglia compared to other peripheral ganglia. Each ENS ganglion at mid-gestation has core neurons and shell mesenchymal precursor/glia-like neural crest (ENC) cells. To study cell ganglionation we isolated midgut cells by HNK-1 fluorescence-activated sorting (FACS) from E5 E8 quail embryos, E9 chick embryos. We performed cell-cell aggregation assays which revealed developmentally regulated functional...
Following fusion, embryonic stem cells (ESCs) are capable of reprogramming somatic in cell hybrids. It has also been shown that transcriptional changes can occur a heterokaryon, without nuclear hybridization. However, it is unclear whether these be sustained after the removal dominant nucleus. In this study, we analyze (ES)–somatic heterokaryons following ESCs We show ES–somatic fusion using tetraploid ESCs, heterokaryon reverted to an autologous diploid state by differential enucleation...
Abstract The clinical spectrum associated with SCN2A de novo mutations (DNMs) continues to expand and includes autism disorder or without seizures, in addition early late seizure onset developmental epileptic encephalopathies (DEEs). Recent biophysical studies on variants suggest that the majority of DEE DNMs cause gain function. Gain function SCN2A, principal sodium channel excitatory pyramidal neurons, would result heightened neuronal activity is likely underlie pathology seen patients....
Integrating neurons into digital systems to leverage their innate intelligence may enable performance infeasible with silicon alone, along providing insight the cellular origin of intelligence. We developed DishBrain , a system which exhibits natural by harnessing inherent adaptive computation in structured environment. In vitro neural networks from human or rodent origins, are integrated silico computing via high-density multielectrode array. Through electrophysiological stimulation and...
One-third of people with epilepsy continue to experience seizures despite treatment existing anti-seizure medications (ASMs). The failure modern ASMs substantially improve prognosis has been partly attributed overreliance on acute rodent models in preclinical drug development as they do not adequately recapitulate the mechanisms human epilepsy, are labor-intensive and unsuitable for high-throughput screening (HTS). There is an urgent need find human-relevant HTS identify novel compounds....
ABSTRACT Developmental and epileptic encephalopathies (DEE) are characterized by pharmacoresistant seizures with concomitant intellectual disability. Epilepsy of infancy migrating focal (EIMFS) is one the most severe these syndromes. De novo mutations in ion channels, including gain-of-function variants KCNT1 , have been found to play a major role etiology EIMFS. Here, we test potential precision therapeutic approach -associated DEE using gene silencing antisense oligonucleotide (ASO)...