Biology subjects

Haigh, J.

Publications and source records attributed to Haigh, J..

4 recordsLinked to original sources

bioRxiv2026

Thalamic Nuclei Functional Controllability Accounts for Cognitive Impairment in Multiple Sclerosis Over and Above Structural Damage

BackgroundThe thalamus has emerged as a key region involved in cognitive dysfunction in multiple sclerosis (MS). While previous studies have identified associations between thalamic structural damage, altered functional connectivity, and cognitive performance, the specific contributions of individual thalamic nuclei and the added value of integrating structural and functional metrics remain poorly understood. MethodsT1-weighted MRI, diffusion MRI, resting-state fMRI, and neuropsychological data were collected from 102 individuals with MS and 27 healthy controls. Thalamic grey matter volume, white matter microstructural integrity, and functional controllability were calculated for each nucleus and compared between individuals with MS and healthy controls, as well as between MS cognitive subgroups. Partial Spearman correlations were used to examine the relationship between imaging metrics across the three modalities, and also between imaging metrics and cognitive performance in MS. Sparse canonical correlation analysis models were used to examine the covariance between thalamic imaging metrics and cognitive performance in MS. ResultsWidespread atrophy and microstructural damage were observed across all thalamic nuclei in individuals with MS, regardless of cognitive status. In contrast, alterations in functional controllability were more spatially specific, primarily affecting the medial dorsal anterior nuclei, and were most pronounced in cognitively impaired individuals. These functional controllability metrics were independent of grey matter volume, white matter integrity, and lesion load. Combining thalamic functional controllability with structural metrics yielded a stronger association with cognitive performance in MS than either modality alone. ConclusionThis study provides novel evidence that functional controllability in the thalamus, particularly within the medial dorsal anterior nuclei, plays a critical role in cognitive impairment in MS. By applying a network control framework, our findings offer a dynamic systems perspective that extends beyond traditional connectivity analyses, capturing the thalamuss role in supporting flexible cognitive transitions. The integration of structural and functional controllability metrics enhances the ability to characterise individual differences in cognitive performance and may inform future efforts to identify biomarkers of cognitive dysfunction in MS.

neuroscience↗

bioRxiv2023

Modeling Braf-induced thyroid cancer development and drug screening using pluripotent stem cell-derived organoids

Thyroid cancer is the most common endocrine malignancy and several genetic events have been described to promote the development of thyroid carcinogenesis. Besides the effects of specific mutations on thyroid cancer development, the molecular mechanisms controlling tumorigenesis, tumor behavior, and drug resistance are still largely unknown. Cancer organoids have been proposed as a powerful tool to study aspects related to tumor development and progression and appear promising to test individual responses to therapies. Here, using mESC-derived thyroid organoids, we developed a BrafV637E- inducible model able to recapitulate the features of papillary thyroid cancer in vitro. Overexpression of the murine BrafV637E mutation, equivalent to BrafV600E in humans, rapidly triggers to MAPK activation, cell dedifferentiation, and disruption of follicular organization. BrafV637E-expressing organoids show a transcriptomic signature for p53, focal adhesion, ECM-receptor interactions, EMT, and inflammatory signaling pathways. Finally, PTC-like thyroid organoids were used for drug screening assays. The combination of MAPK and PI3K inhibitors reversed BrafV637E oncogene-promoted cell dedifferentiation while restoring thyroid follicle organization and function in vitro. Our results demonstrate that pluripotent stem cells-derived thyroid cancer organoids can mimic tumor development and features while providing an efficient tool for testing novel targeted therapies.

cancer biology↗

bioRxiv2021

Parallel functional testing identifies enhancers active in early postnatal mouse brain

Enhancers are cis-regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput functional screening of candidate DNA sequences for enhancer activity. Tissue-specific screening of in vivo enhancer function at scale has the potential to greatly expand our understanding of the role of non-coding sequences in development, evolution, and disease. Here, we adapted a self-transcribing regulatory element MPRA strategy for delivery to early postnatal mouse brain via recombinant adeno-associated virus (rAAV). We identified and validated putative enhancers capable of driving reporter gene expression in mouse forebrain, including regulatory elements within an intronic CACNA1C linkage disequilibrium block associated with risk in neuropsychiatric disorder genetic studies. Paired screening and single enhancer in vivo functional testing, as we show here, represents a powerful approach towards characterizing regulatory activity of enhancers and understanding how enhancer sequences organize gene expression in normal and pathogenic brain development.

neuroscience↗

bioRxiv2020

Piggybacking on the Cholera Toxin: Identification of a Toxoid-binding Protein as an Approach for Targeted Delivery of Proteins to Motor Neurons

A significant unmet need exists for the delivery of biologic drugs such as polypeptides or nucleic acids, to the central nervous system (CNS) for the treatment and understanding of neurodegenerative diseases. Naturally occurring toxoids have been considered as tools to meet this need. However, due to the complexity of tethering macromolecular drugs to toxins, and the inherent dangers of working with large quantities of recombinant toxin, no such route has been successfully exploited. Developing a method where toxoid and drug can be assembled immediately prior to in vivo administration has the potential to circumvent some of these issues. Using a phage-display screen, we identified two antibody mimetics, Anti-Cholera Toxoid Affimer (ACTA) -A2 and ACTA-C6 that non-covalently associate with the non-binding face of the cholera toxin B-subunit. In a first step toward the development of a non-viral motor neuron drug-delivery vehicle, we show that Affimers can be selectively delivered to motor neurons in vivo.

biochemistry↗