Biology subjects

Thomas, M. H.

Publications and source records attributed to Thomas, M. H..

7 recordsLinked to original sources

bioRxiv2026

Computationally Optimized H1 and H3 Hemagglutinin Messenger RNA Vaccines Confer Broad Protective Immunity Against Modern Influenza Viruses

The hemagglutinin (HA) glycoprotein of seasonal influenza viruses undergoes continual antigenic drift, contributing to vaccine mismatch and reduced effectiveness of strain-specific seasonal vaccines. Although vaccination remains the most effective strategy for preventing influenza disease, conventional egg-based vaccine production requires several months and may not keep pace with viral evolution. Messenger RNA (mRNA) vaccines offer a promising alternative because they can be rapidly updated to encode emerging antigens and are manufactured through a scalable, cell-free process that avoids propagation associated adaptations. To address the challenges of antigenic drift and vaccine mismatch, we combined mRNA vaccine technology with Computationally Optimized Broadly Reactive Antigens (COBRA) to develop broadly protective influenza HA vaccines. These COBRA H1 and H3 mRNA HA vaccines elicited robust antigen-specific IgG, hemagglutination inhibition (HAI), and neutralizing antibody responses against diverse historical and contemporary influenza strains in cohorts of influenza naive and pre-immune mice. Vaccination also induced strong cellular immunity, characterized by the expansion of antigen-specific antibody and cytokine secreting cells. These responses were further enhanced in animals with pre-existing influenza immunity, as demonstrated by an increased frequency of IFN-{gamma} producing cells recognizing conserved HA stalk-based peptides. Together, these findings demonstrate that COBRA HA encoding mRNA vaccines can effectively leverage immunological memory while expanding responses to conserved HA epitopes, supporting improved protection against antigenically drifted strains. Thus, the combination of broadly reactive COBRA HA antigens with a rapidly adaptable and manufacturable mRNA platform represents a promising strategy for next-generation influenza vaccination.

immunology↗

bioRxiv2025

Transcriptional Dysregulation in the Hippocampus of a murine model for Parkinson's Disease Cognition Impairment is Driven by Sex, Age, and Alpha-synuclein overexpression

Cognitive impairment is the most common and detrimental, but understudied non-motor symptom of Parkinsons disease (PD). Neuropathologically, it is associated with alpha-synuclein (Syn) misfolding and synapse loss in hippocampus and prefrontal cortex, leading to cognition loss and ultimately dementia. The molecular underpinnings of PD-associated cognitive dysfunction are unknown. In the present study, longitudinal gene expression profiling was performed to characterise molecular hippocampal alterations in a transgenic mouse overexpressing E46K mutated Syn, a model of early PD with loss of synaptophysin, a proxy marker of cognition, in hippocampus and cortex. Comparing 4 different ages of mice from both sexes showed that hippocampal gene expression changes were sexually dimorphic and strongly modulated by age and Syn overexpression. Pathways that emerged across different comparisons were connected to a variety of neuronal functions, collagen synthesis/remodelling, cellular stress, and inflammatory responses. The findings indicate that sex and age are essential covariates to consider when studying PD-associated cognitive decline. The uncovering of early events leading to disease in an animal model is an essential step toward prognostic biomarker identification and early interventions, which may have implications for monitoring, and for timing of therapeutic approaches.

neuroscience↗

bioRxiv2022

Dietary fibre deprivation and bacterial curli exposure shift gut microbiome and exacerbate Parkinson's disease-like pathologies in an alpha-synuclein-overexpressing mouse

The microbiome-gut-brain axis has been proposed as a pathogenic path in Parkinsons disease (PD). Dietary driven dysbiosis and reduced gut barrier function could facilitate the interaction of toxic external or internal factors with the enteric nervous system, where PD could start. Amyloid bacterial protein such as curli can act as seed to corrupt enteric -synuclein and lead to its aggregation. Misfolded -synuclein can propagate to and throughout the brain. Here, we aimed at understanding if fibre deprivation and amyloidogenic protein curli could, individually or together, exacerbate the phenotype in both enteric and central nervous systems of a transgenic mouse overexpressing wild-type human -synuclein. We analysed the gut microbiome, motor behaviour, gastrointestinal and brain pathologies in these mice. Our findings show that external interventions, akin to unhealthy life habits in humans, can exacerbate PD-like pathologies in mice. We believe that our results shed light on how lifestyle affects PD progression.

neuroscience↗

bioRxiv2020

Strain- and age-dependent features of the nigro-striatal circuit in three common laboratory mouse strains, C57BL/6J, A/J, and DBA/2J - Implications for Parkinson's disease modeling

Mouse models have been instrumental in understanding genetic determinants of aging and its crucial role in neurodegenerative diseases. However, few studies have analyzed the evolution of the mouse brain over time at baseline. Furthermore, mouse brain studies are commonly conducted on the C57BL/6 strain, limiting the analysis to a specific genetic background. In Parkinsons disease, the gradual demise of nigral dopaminergic neurons mainly contributes to the motor symptoms. Interestingly, a decline of the dopaminergic neuron function and integrity is also a characteristic of physiological aging in some species. Age-related nigro-striatal features have never been studied in mice of different genetic backgrounds. In this study, we analyze the morphological features in the striatum of three common mouse strains, C57BL/6J, A/J, and DBA/2J at 3-, 9- and 15 months of age. By measuring dopaminergic markers, we uncover age-related changes that differ between strains and evolve dynamically over time. Overall, our results highlight the importance of considering background strain and age when studying the murine nigro-striatal circuit in health and disease. HighlightsO_LIStudy of the integrity of the nigro-striatal circuit in C57BL/6J, A/J, and DBA/2J at different ages C_LIO_LIAge related evolution of essential features of nigral dopaminergic neurons differ between strains C_LIO_LIConsider background strain and age is crutial to study the nigrostriatal circuit in health and disease C_LI

neuroscience↗

bioRxiv2020

Quantitative trait locus mapping identifies Col4a6 as a novel regulator of striatal dopamine level and axonal branching in mice.

The features of dopaminergic neurons (DAns) of nigrostriatal circuitry are orchestrated by a multitude of yet unknown factors, many of them genetic. Genetic variation between individuals at baseline can lead to differential susceptibility to and severity of diseases. As decline of DAns, a characteristic of Parkinsons disease, heralds a significant decrease in dopamine level, measuring dopamine can reflect the integrity of DAns. To identify novel genetic regulators of the integrity of DAns, we used the Collaborative Cross (CC) mouse strains as model system to search for quantitative trait loci (QTLs) related to dopamine levels in the dorsal striatum. The dopamine levels in dorsal striatum varied greatly in the eight CC founder strains, and the differences were inheritable in 32 derived CC strains. QTL mapping in these CC strains identified a QTL associated with dopamine level on chromosome X containing 393 genes. RNA-seq analysis of the ventral midbrain of two of the founder strains with large striatal dopamine difference (C57BL/6J and A/J) revealed 24 differentially expressed genes within the QTL. The protein-coding gene with the highest expression difference was Col4a6, which exhibited a 9-fold reduction in A/J compared to C57BL/6J, consistent with decreased dopamine levels in A/J. Publicly available single cell RNA-seq data from developing human midbrain suggests that Col4a6 is highly expressed in radial glia-like cells and neuronal progenitors, indicating possible involvement in neurogenesis. Interestingly, the lowered dopamine levels were accompanied by reduced striatal axonal branching of striatal DAns in A/J compared to C57BL/6J. Because Col4a6 is known to control axogenesis in non-mammal model organisms, we hypothesize that different dopamine levels in mouse dorsal striatum are due to differences in axogenesis induced by varying COL4A6 levels during neural development.

neuroscience↗

bioRxiv2020

Single nuclei chromatin profiles of ventral midbrain reveal cell identity transcription factors and cell type-specific gene regulatory variation

Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility such as Parkinsons disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression. We report 20 658 single nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Our dataset provides an extensive resource to study gene regulation in mesencephalon.

genomics↗

bioRxiv2020

Pituitary Tumor Transforming Gene 1 orchestrates gene regulatory variation in mouse ventral midbrain during aging

BackgroundDopaminergic neurons in the midbrain are of particular interest due to their role in diseases such as Parkinsons disease and schizophrenia. Genetic variation between individuals can affect the integrity and function of dopaminergic neurons but the DNA variants and molecular cascades modulating dopaminergic neurons and other cells types of ventral midbrain remain poorly defined. Three genetically diverse inbred mouse strains -- C57BL/6J, A/J, and DBA/2J -- differ significantly in their genomes (~7 million variants), motor and cognitive behavior, and susceptibility to neurotoxins. ResultsTo further dissect the underlying molecular networks responsible for these variable phenotypes, we generated RNA-seq and ChIP-seq data from ventral midbrains of the 3 mouse strains. We defined 1000-1200 transcripts that are differentially expressed among them. These widespread differences may be due to altered activity or expression of upstream transcription factors. Interestingly, transcription factors were significantly underrepresented among the differentially expressed genes, and only one TF, Pttg1, showed significant differences among all strains. The changes in Pttg1 expression were accompanied by consistent alterations in histone H3 lysine 4 trimethylation at Pttg1 transcription start site. The ventral midbrain transcriptome of three-month-old C57BL/6J congenic Pttg1-/- mutants was only modestly altered, but shifted towards that of A/J and DBA/2J in nine-month-old mice. Principle component analysis identified the genes underlying the transcriptome shift and deconvolution of these bulk RNA-seq changes using midbrain single cell RNA-seq data suggested that the changes were occurring in several different cell types, including neurons, oligodendrocytes, and astrocytes. ConclusionTaken together, our results show that Pttg1 contributes to gene regulatory variation between mouse strains and influences mouse midbrain transcriptome during aging.

genomics↗