Biology subjects

O'Sullivan, J. D.

Publications and source records attributed to O'Sullivan, J. D..

4 recordsLinked to original sources

bioRxiv2025

Differential effects of neurodegenerative disorders on verbal creative idea generation and its cognitive cornerstones

Clinical research has documented a heterogeneous effect of neurodegenerative disorders on creativity. Some disorders are associated with impaired creative performance, while others may preserve, or even enhance, it. However, the underlying cognitive mechanisms that give rise to the heterogeneous behavioural manifestations remain poorly understood. From a theory-driven approach, we conducted a neuropsychological investigation to examine how frontotemporal lobar degeneration (FTLD), and Alzheimer's Disease (AD) differentially affected the cognitive mechanisms underlying creative thought (semantic cognition, episodic memory, executive control functions). In parallel, we assessed participants' verbal creative idea generation performance using the ideational fluency task (also known as the Alternate Uses Task). We analysed data from 24 individuals with FTLD [clinical consensus diagnosis corticobasal syndrome (CBS: n=20) or progressive supranuclear palsy (PSP: n=4)], 24 individuals with clinical consensus diagnosis AD, and 24 healthy individuals. We reached four major conclusions. First, while both disease groups exhibited deficits in controlled semantic retrieval and executive control functions, only participants with AD exhibited degradation in semantic representations and episodic memory. Second, both disease groups generated fewer responses in both typical and creative conditions across objects that were context-free - i.e., associated with multiple contexts (e.g., brick) and context-bound -i.e., associated with a dominant context (e.g., table knife). Third, when given a context-free object prompt, the ability to generate novel responses appeared to be preserved in participants with FTLD, which contrasted with an impaired ability when prompted to give creative uses for the context-bound object. Fourth, participants with AD produced similar levels of response novelty for both context-free and context-bound objects. From a clinical-cognitive neuroscience perspective, this study demonstrates that distinct cognitive profiles resulting from different neurodegenerative conditions yield differential effects on creative thought. As the first study to show that the contextual information of semantic stimuli can mediate the novelty of verbal responses, we suggest that future research should carefully examine how this factor influences creative task performance.

neuroscience↗

bioRxiv2024

Mitochondrial dynamics regulate cell size in the developing cochlea

In multicellular tissues, cell size and shape are intricately linked with physiological function. In the vertebrate auditory organ, the neurosensory epithelium develops as a mosaic of sensory hair cells (HCs), and their glial-like supporting cells (SCs), which have distinct morphologies at different frequency positions along its tonotopic long axis. In the chick cochlea, the basilar papilla (BP), proximal (high-frequency) HCs are larger than their distal (low-frequency) counterparts, a morphological feature essential for frequency tuning. Mitochondrial dynamics, which constitute the equilibrium between fusion and fission, regulate differentiation and functional refinement across a variety of cell types. We investigate this a potential mechanism for cell size regulation in developing HCs. Using live imaging in intact BP explants, we identify distinct remodelling of mitochondrial networks in proximal compared to distal HCs. Manipulating mitochondrial dynamics in developing HCs alters their normal morphology along the proximal-distal (tonotopic) axis. Inhibition of the mitochondrial fusion machinery decreased proximal HC size, whilst promotion of fusion increased the distal HC size. We identify mitochondrial dynamics as a key regulator of HC size and morphology in developing inner ear epithelia. Summary StatementMitochondrial remodelling drives developmental changes in cell size in the auditory sensory epithelium. Our data reveal a fundamental mechanism regulating cell size and frequency-place coding in the developing cochlea.

developmental biology↗

bioRxiv2022

Gradients in cellular metabolism regulate development of tonotopy along the chick cochlea.

In vertebrates with elongated auditory organs, mechanosensory hair cells (HCs) are organised such that complex sounds are broken down into their component frequencies along the proximal-to-distal long (tonotopic) axis. Acquisition of frequency-specific morphologies at the appropriate positions along the chick cochlea, the basilar papilla (BP), requires that nascent HCs determine their tonotopic positions during development. The complex signalling within the auditory organ between the developing HC and its local niche along the axis is currently poorly understood. Here we apply NAD(P)H fluorescence lifetime imaging (FLIM) to reveal metabolic gradients along the tonotopic axis of the developing BP. Re-shaping these gradients during development, by inhibiting different branch points of cytosolic glucose catabolism, alters normal morphogen signalling and abolishes tonotopic patterning, normalising the graded differences in hair cell morphology along the BP. These findings highlight a causal link between morphogen signalling and metabolic reprogramming in specifying tonotopic identity in developing auditory HCs.

developmental biology↗

bioRxiv2020

Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites - Trichuris muris, Brugia malayi and Heligmosomoides polygyrus

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics. Author summaryAround a billion people are infected by the soil transmitted helminths Ascaris, hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and against Schistosoma mansoni, a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.

pharmacology and toxicology↗