Biology subjects

Thomas, E. A.

Publications and source records attributed to Thomas, E. A..

5 recordsLinked to original sources

bioRxiv2026

Acute hypoxia induces transient olfactory dysfunction through olfactory epithelial degeneration and bulbar mitochondrial stress in zebrafish

Hypoxic-ischemic injury is a major cause of olfactory dysfunction, yet the cellular and morphological mechanisms underlying this sensory loss remain poorly understood. Here, we investigated the structural, cellular, and functional effects of acute hypoxic exposure on the olfactory system of adult zebrafish (Danio rerio) of both sexes, a model organism with remarkable neuroregenerative capacity. Fish were subjected to 15 minutes of acute severe hypoxia (0.8 mg/L dissolved oxygen) and assessed at 1 and 5 days post-hypoxia (dph). We evaluated olfactory function by means of cadaverine-evoked aversive behavioral assays. Structural and morphological integrity and inflammation of the olfactory epithelium (OE) and olfactory bulb (OB) were characterized using immunohistochemistry, histological stainings, and a 2,3,5-triphenyltetrazolium chloride (TTC) colorimetric assay. Acute hypoxic exposure impaired olfactory-mediated behaviors without affecting locomotion or exploratory behavior. In the peripheral OE, hypoxia caused neurodegeneration, disruption of the nasal mucus layer, and robust leukocytic infiltration. We observed reduced mitochondrial dehydrogenase activity in the olfactory bulb (OB) along with reactive astrogliosis. Olfactory function recovered by 5 days, coinciding with full restoration of OE morphology, and supported by a strong proliferative response. These findings reveal a coordinated degenerative and regenerative response to hypoxia across the olfactory axis, with implications for understanding hypoxia-induced sensory loss and neural repair. SIGNIFICANCEThis work addresses an important gap in knowledge regarding the mechanisms linking hypoxic insult and olfactory dysfunction. By using adult zebrafish, an extraordinarily regenerative vertebrate, it also provides insight into neuronal repair and regenerative processes supporting olfactory recovery. The novelty of our study resides in that, to our knowledge, there are no studies that provide a comprehensive characterization of the effects of hypoxia in the olfactory system across molecular, histological, and functional levels. These findings advance our understanding of hypoxia-induced sensory neurodegeneration and regeneration, and highlight the zebrafish olfactory system as a powerful model for investigating neural repair mechanisms relevant to hypoxic-ischemic brain injury.

neuroscience↗

bioRxiv2024

Structural regeneration and functional recovery of the olfactory system of zebrafish following brain injury

Olfactory dysfunction is a common outcome of brain injuries, negatively affecting quality of life. The mammalian nervous system has limited capacity for spontaneous olfactory recovery, making it challenging to study olfactory regeneration and recovery in adults. In contrast, zebrafish are an ideal model for such studies due to its extensive and lifelong regenerative abilities. In this work, we describe a model of excitotoxic injury in the olfactory bulb using quinolinic acid (QA) lesions in adult zebrafish. We observed extensive neurodegeneration in both the olfactory bulb and olfactory epithelium, including a reduction of bulbar volume, neuronal death, and impaired olfactory function. Recovery mechanisms involved tissue remodeling, cell proliferation, neurogenesis, leading to full restoration of olfactory function by 21 days. This study provides a model to further investigate the effects of excitotoxicity on olfactory dysfunction, and highlights zebrafishs remarkable regenerative abilities, providing insights into potential therapeutic strategies for restoring olfactory function following brain injuries.

neuroscience↗

bioRxiv2024

Considerations for Cell Type Heterogeneity in Pediatric Salivary DNA Methylation Analyses: Comparison of Reference Panels & Stratification by Estimated Cell TypeProportion

Saliva is widely used in biomedical population research, including epigenetic analyses to investigate gene-environment interplay and identify biomarkers. Its minimally invasive collection procedure makes it ideal for studies in pediatric populations. Saliva is a heterogenous tissue composed of immune and buccal epithelial cells (BEC). Amongst the many epigenetic marks, DNA methylation (DNAm) is the most studied in human populations. Given DNAms integral role to cellular differentiation and maintenance, DNAm profiles are often highly cell type (CT)-specific and CT composition can drive salivary DNAm associations with environments or health as well as epigenetic age acceleration (EAA), discrepancy between chronological age and biological age derived from DNAm. To address this, reference-based CT deconvolution and statistically adjustment with estimated CT in DNAm analyses have become a common practice. However, it remains unclear how different CT reference panels--constructed from adult versus pediatric samples--affect DNAm results. Additionally, whether DNAm and EAA associations in saliva primarily originate from immune cells or BECs, or if they persist across saliva samples despite varying CT proportions, has yet to be examined. The current study used salivary DNAm samples obtained from 529 children (mean age=7.26 years, SD=0.26 years) in a community-based cohort, the Family Life Project. Our results highlighted the impact of estimated CT discrepancies across child and adult reference panels on DNAm associations. Upon stratifying the salivary DNAm samples into three subsamples--primarily BECs, primarily immune cells, and an approximately equal mix of both, we found significantly different EAAs across stratified samples when CT proportions were not accounted for. In both the context of DNAm and EAA associations, we detected stronger effects of cotinine concentrations, a tobacco smoke-exposure biomarker, in the subsample with primarily immune cells. We discussed the implications of our findings for the interpretation and replication of epigenetic research involving pediatric saliva samples.

bioinformatics↗

bioRxiv2024

Parallel neuroinflammatory pathways to cerebrovascular injury and amyloid-beta in Alzheimer's disease

ImportanceWhile the hallmark pathologies of amyloid-beta (A{beta}) and tau in Alzheimers disease (AD) are well documented and even part of the definition, upstream neuroinflammation is thought to play an important role but remains poorly understood. ObjectivesWe tested whether two distinct neuroinflammatory markers are associated with cerebrovascular injury and A{beta}, and whether these markers are associated with plasma phosphorylated tau (pTau) concentration, medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits. We examined neuroinflammatory markers plasma YKL-40 and GFAP, due to previous conflicting evidence relating YKL-40 and GFAP to AD pathogenic markers. DesignCross-sectional data from a community observational study (Biomarker Exploration in Aging, Cognition, and Neurodegeneration - BEACoN) were included. SettingAll participants were enrolled in a single site, at University of California, Irvine. Participants126 participants were included if they had at least one of the following measures available: neuropsychological data, MRI, A{beta}-PET, or plasma. ExposuresPlasma YKL-40 and plasma glial fibrillary acidic protein (GFAP) levels. Main outcomes and measuresWhite matter hyperintensity (WMH) volume, 18F-florbetapir (FBP) PET mean SUVR, plasma phosphorylated tau (pTau-217) concentration, MTL cortical thickness, hippocampal volume, and memory function assessed by Rey Auditory Verbal Learning Test. Using path analysis, we tested whether higher plasma YKL-40 and GFAP are associated with WMH and A{beta}, and whether these converge to downstream markers of tauopathy, MTL neurodegeneration, and memory deficits. ResultsIn older adults without dementia (N=126, age=70.60+6.29, 62% women), we found that higher plasma YKL-40 concentration was associated with greater WMH volume, while higher plasma GFAP concentration was related to increased FBP SUVR. Further, higher plasma GFAP, WMH and FBP SUVR were independently associated with increased pTau-217. In turn, plasma pTau-217 was associated with reduced MTL cortical thickness and hippocampal volume. Subsequently, only reduced hippocampal volume was related to lower memory function. Conclusions and RelevanceNeuroinflammatory markers contribute to parallel pathways of cerebrovascular injury and A{beta}, which converge to tau-associated neurodegeneration and memory deficits in older adults. These observations underscore the need for a more comprehensive approach to developing an AD framework and treatment strategies. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow does neuroinflammation impact downstream features of cerebrovascular injury and amyloid-beta (A{beta}) in Alzheimers disease? FindingsIn this study of 126 older adults without dementia, we found evidence for two distinct neuroinflammatory pathways that lead to neurodegeneration and memory deficits. One path involves plasma YKL-40 and its impact on cerebrovascular injury, as measured by white matter hyperintensities (WMH) on MRI scans. The other involves plasma glial fibrillary acidic protein (GFAP) and its impact on A{beta} deposition measured via 18F-florbetapir (FBP) PET. Both pathways converged on tauopathy, measured by plasma pTau-217, which was associated with lower medial temporal lobe (MTL) cortical thickness and hippocampal volume, and consequently, memory deficits. MeaningInflammation acts on Alzheimers disease mechanisms via multiple distinct and parallel pathways which converge downstream onto neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/616579v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@2d3c39org.highwire.dtl.DTLVardef@1ccc453org.highwire.dtl.DTLVardef@6d40bdorg.highwire.dtl.DTLVardef@b543cb_HPS_FORMAT_FIGEXP M_FIG C_FIG Credit: BioRender was used to help create this graphical abstract.

neuroscience↗

bioRxiv2024

Salivary metabolomics in the family environment: A large-scale study investigating oral metabolomes in children and their parental caregivers

Human metabolism is complex and dynamic, and is impacted by genetics, diet, health, and countless inputs from the environment. Beyond the genetics shared by family members, cohabitation leads to shared microbial and environmental exposures. Furthermore, metabolism is affected by factors such as inflammation, environmental tobacco smoke (ETS) exposure, metabolic regulation, and exposure to heavy metals. Metabolomics represents a useful analytical method to assay the metabolism of individuals to find potential biomarkers for metabolic conditions that may not be phenotypically obvious or represent unknown physiological processes. As such, we applied untargeted LC-MS metabolomics to archived saliva samples from a racially diverse group of elementary school-aged children and their caregivers collected during the "90-month" assessment of the Family Life Project. We assayed a total of 1,425 saliva samples of which 1,344 were paired into 672 caregiver/child dyads. We compared the metabolomes of children (N = 719) and caregivers (N = 706) within and between homes, performed population-wide "metabotype" analyses, and measured associations between metabolites and salivary biomeasures of inflammation, antioxidant potential, ETS exposure, metabolic regulation, and heavy metals. Dyadic analyses revealed that children and their caregivers have largely similar salivary metabolomes. Although there were differences between the dyads at the individual levels of analysis, dyad explained most (62%) of the metabolome variation. At a population level of analysis, our data clustered into two large groups, indicating that people likely share most of their metabolomes, but that there are distinct "metabotypes" across large sample sets. Lastly, individual differences in several metabolites - which were putative oxidative damage-associated or pathological markers - were significantly correlated with salivary measures indexing inflammation, antioxidant potential, ETS exposure, metabolic regulation, and heavy metals. Implications of the effects of family environment on metabolomic variation at the population, dyadic, and individual levels of analyses for health and human development are discussed.

systems biology↗