Biology subjects

Wood, T. R.

Publications and source records attributed to Wood, T. R..

6 recordsLinked to original sources

bioRxiv2025

Multi-modal screening for synergistic neuroprotection of extremely preterm brain injury

Preterm brain injury affects both white and grey matter, including altered cortical development and gyrification, with associated neurodevelopmental sequelae such as cerebral palsy and learning deficits. The preterm brain also displays regionally heterogeneous responses to both injury and treatment, supporting the need for drug combinations to provide global neuroprotection. We developed an extremely preterm-equivalent organotypic whole hemisphere (OWH) slice culture injury model using the gyrencephalic ferret brain to probe treatment mechanisms of promising therapeutic agents and their combination. Regional and global responses to injury and treatment were assessed by cell death quantification, machine learning-augmented morphological microglia assessments, and digital transcriptomics. Using two promising therapeutic agents, azithromycin (Az) and erythropoietin (Epo), we show minimal neuroprotection by either therapy alone, but evidence of synergistic neuroprotection by Az*Epo both globally and regionally. This effect of Az*Epo involved emergent augmentation of transcriptomic responses to injury related to neurogenesis and neuroplasticity and downregulation of transcripts involved in cytokine production, inflammation, and cell death. This study supports the use of the ferret OWH slice culture model to provide a powerful high-throughput platform to examine combinations of therapeutics for extremely preterm brain injury.

neuroscience↗

bioRxiv2025

Nicotinamide-loaded Peptoid Nanotubes for Energy Regeneration in Acute Brain Injury

Acute brain injuries such as perinatal asphyxia, stroke, and traumatic brain injury result in ischemia, oxidative stress, excitotoxicity, and inflammation, leading to a depletion of ATP, the brains cellular energy store. Nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular homeostasis, is crucial for energy regeneration and DNA repair in post-injury recovery. However, the therapeutic benefits of NAD+ and its precursors, such as nicotinamide (NAM), are limited by the complexity of their metabolic pathways and challenges in effective cell-specific intracellular delivery. Therefore, cellular delivery strategies are needed to capture the potential of an NAD+-regenerating therapeutic approach. In this study, we introduce a nanopeptoid delivery strategy to replenish cellular redox state and energy production in the acutely injured brain. By self-assembling peptoids into tubular structures, we created biocompatible NAM-conjugated peptoid nanotubes (NAM-PNTs) that vary in tubular length. NAM-PNTs demonstrated significant therapeutic benefits by enhancing cell viability and replenishing intracellular ATP levels within 24 hours of treatment in oxygen-glucose deprived (OGD) BV-2 cells. In organotypic brain slices, NAM-PNT treatment promoted glial proliferation, reduced pro-inflammatory cytokine levels, and increased anti-inflammatory cytokines after OGD, an ex vivo model of hypoxia-ischemia. A single systemic dose of NAM-PNTs also reduced brain tissue loss and improved neuropathology after hypoxia-ischemia in term-equivalent rats. These findings highlight the strong therapeutic potential of NAM-PNTs for cell-specific targeted delivery and energy restoration in the acutely injured neonatal brain. In the neonatal brain injury field, this is the first demonstration of a novel nanoparticle platform development from first principles design and synthesis to in vitro screening and then demonstration of efficacy in vivo.

bioengineering↗

bioRxiv2022

Distinct molecular profile of the chick Organizer as a stem zone during axial elongation

The vertebrate Organizer plays a crucial role in defining the main axes of embryo: it neuralizes the surrounding ectoderm, and is the site of emigration for cells making axial and paraxial mesendoderm during elongation. The chick Organizer becomes a stem zone at the onset of elongation: it stops recruiting cells from the neighbouring ectoderm, and generates all its derivatives from the small number of resident cells it contains at the end of gastrulation stages. Nothing is known about the molecular identity of this stem zone. Here, we specifically labelled long-term resident cells of the Organizer, and compared their RNA-seq profile to that of the neighbouring cell populations. Screening by RT-PCR and in situ hybridisation identified four genes (WIF1, PTGDS, ThPO and UCKL1), which are upregulated only in the Organizer region when it becomes a stem zone, and remain expressed there during axial elongation. In experiments specifically labelling the resident cells of the mature Organizer, we show that only these cells express these genes. These findings molecularly define the Organizer as a stem zone, and offer a key to understanding how this zone is set up, the molecular control of its cells behaviour, and the evolution of axial growth zones.

developmental biology↗

bioRxiv2021

Neurodevelopmental clustering of gene expression identifies lipid metabolism genes associated with neuroprotection and neurodegeneration.

APOE variants present the strongest association with sporadic Alzheimers Disease. APOE is also highly expressed during neurodevelopment in the Central Nervous System (CNS) and has been shown to be neuroprotective in infancy and gestation. We explored other lipid metabolism genes to determine whether they show a similar neurodevelopmental expression trajectory and are associated with neurodegeneration. APOE was by far the most highly expressed of the lipid metabolism genes in the CNS. Two other genes, Apolipoprotein C1 (APOC1) Glutamate-Ammonia Ligase (GLUL--also known as glutamine synthetase), co-clustered with Apolipoprotein E (APOE) in its developmental trajectory in late gestation through early childhood. These three genes highlight brain structures and developmental time-windows distinct from other lipid metabolism genes. In the CNS they are primarily expressed in astrocytes and are implicated in neuroprotection and neurodegeneration.

neuroscience↗

bioRxiv2019

Using synthetic datasets to better understand and explain health outcomes associated with common single nucleotide polymorphisms

Due to decreasing costs and a move towards \"personalised medicine\", the use of direct-to-consumer genetic analyses is increasing. Both consumers and healthcare practitioners must therefore be able to understand the true disease risks associated with common genetic single nucleotide polymorphisms (SNPs). However, most population studies of common SNPs only provide average (+/-error) phenotypic or risk descriptions for a given genotype, which hides the true heterogeneity of the population and reduces the ability of an individual to determine how they themselves might truly be effected. Here, we describe the use of synthetic datasets generated from descriptive phenotypic data published on common SNPs associated with obesity, elevated fasting blood glucose, and methylation status. Using both simple statistical theory and full graphical representation of the generated data, we show that single common SNPs are associated with a less than 10% likelihood of effecting final phenotype, even in homozygotes. The significant heterogeneity in the data, as well as the baseline disease risk of Western populations suggests that most disease risk is dominated by the effect of the modern environment.

genetics↗

bioRxiv2019

Tissue Mechanics Determines Cell Fate in the Axial Stem Zones

Most embryos and regenerating tissues grow by the action of stem zones. Two epithelial stem zones drive axial elongation in amniotes: the mature organizer generates mesoderm, the neuralised ectoderm around it extends the neuraxis. Bipotential progenitors were also shown to exist. How are these stem cell populations organised and what controls the cell fate of bipotential progenitors? We use direct, in vivo imaging of these stem cells in the chick. We find that progenitors of single and dual fates are mingled in a small region between the specialised stem zones. Divergent tissue movements surround this region. When transplanted downstream of these flows, cells from the region of mixed fates adopt the molecular identity and behaviour of the target stem zone, irrespective of their normal fate. Thus, multipotent cells serve to separate the specialized stem zones, instead of a classical boundary. We propose their fate is determined extrinsically by morphogenetic shearing.

developmental biology↗