Biology subjects

Norton, E. S.

Publications and source records attributed to Norton, E. S..

3 recordsLinked to original sources

bioRxiv2023

Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM. HighlightsO_LIPeriventricular GBM is more malignant and disrupts neurogenesis in a rodent model. C_LIO_LICell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs. C_LIO_LINPCs induce upregulated CTSB expression in GBM, promoting tumor progression. C_LIO_LIGBM stalls neurogenesis and promotes NPC senescence via CTSB. C_LI

cancer biology↗

bioRxiv2020

Developmental Patterning of Irritability Enhances Prediction of Psychopathology in Pre-adolescence: Improving RDoC with Developmental Science

Research has demonstrated the transdiagnostic importance of irritability in psychopathology pathways but the contribution of developmentally-unfolding patterns has only recently been explored. To address this question, irritability patterns of 110 youth from a large and diverse early childhood cohort were assessed at preschool age and at school age ([~]2.5 years later) with a dimensional irritability scale designed to capture the normal:abnormal spectrum. Participants then returned at Pre-adolescence ([~]6 years later) for an assessment with a structured clinical interview (internalizing/externalizing symptoms) and a magnetic resonance imaging scan. When only preschool age irritability was considered, this was a transdiagnostic predictor of internalizing and externalizing symptoms. However, a model including both preschool and school age irritability provided a more nuanced picture. A high preschool and decreasing school age profile of irritability predicted elevated pre-adolescence internalizing symptoms, potentially reflecting emerging coping/internalizing behavior in pre-adolescence. In contrast, a stable irritability profile across these timepoints predicted increased pre-adolescence externalizing symptoms. Further, preschool irritability (a period of rapid growth) did not predict pre-adolescent gray matter volume abnormality, an indicator of transdiagnostic clinical risk. However, irritability at school age (when gray matter volume growth is largely finished) demonstrated an interactive effect among regions; increased school age irritability predicted reduced volume in pre-adolescence emotional regions (e.g., amygdala, medial orbitofrontal cortex) and increased volume in other regions (e.g., cerebellum). Expanding the impact of RDoCs approach yielding transdiagnostic phenotypes and multiple units of analysis, a developmentally informed approach provides critical new insights into the complex unfolding of mechanisms underlying emerging psychopathology.

developmental biology↗

bioRxiv2019

Putative protective neural mechanisms in pre-readers with a family history of dyslexia who subsequently develop typical reading skills

Developmental dyslexia is a learning disability characterized by difficulties in word reading. While the prevalence in the general public is around 10-12%, an increased prevalence of 40-60% has been reported for children with a familial risk. Neural atypicalities in the reading network have been observed in children with (FHD+) compared to without (FHD-) a family history of dyslexia, even before reading onset. Despite the hereditary risk, about half of FHD+ children develop typical reading abilities (FHD+Typical) but the underlying neural characteristics and the developmental trajectories of these favorable reading outcomes remain unknown. Utilizing a retrospective, longitudinal approach, this is the first study to examine whether potential protective neural mechanisms are present before reading onset in FHD+Typical. Functional and structural brain characteristics were examined in 69 pre-readers who subsequently developed typical reading abilities (35 FHD+Typical/34 FHD-Typical) using MRI/fMRI. Searchlight-based multivariate pattern analyses identified distinct activation patterns during phonological processing between FHD+Typical and FHD-Typical in right inferior frontal (RIFG) and left temporo-parietal (LTPC) regions. Hypoactivation in LTPC was further demonstrated in FHD+Typical compared to FHD-Typical, suggesting that this previously reported neural characteristic of dyslexia is primarily associated with familial risk. Importantly, FHD+Typical pre-readers exhibited higher activation in RIFG than FHD-Typical, which was associated with increased interhemispheric functional and structural connectivity. These results suggest that putative protective neural mechanisms are already established in FHD+Typical pre-readers and may therefore support their successful reading development. Further studies are needed to investigate the functional significance and developmental trajectories of these neural mechanisms as well as their enabling factors, which has the potential to inform the design of early preventative/remediation strategies.

neuroscience↗