Biology subjects

Kee, R.

Publications and source records attributed to Kee, R..

3 recordsLinked to original sources

bioRxiv2025

Ampyrone (4-Aminoantipyrine) is a Direct Agonist of Human Tyrosinase and Potential Therapeutic for Oculocutaneous Albinism and Disorders of Hypopigmentation.

Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a unique human TYR construct, high-throughput screening, and computational analysis techniques, we identified ampyrone as a TYR activator. Ampyrone increased the in vitro catalytic activity of the intramelanosomal domain of human TYR (hTYR) and its hypomorphic variant, P406L, a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both wild-type and OCA1B human melanocytes, as well as 3-dimension (3D) human skin cultures. Our results reveal ampyrone as a lead compound for first-in-class TYR activators, potentially accelerating the discovery of novel therapies for patients with genetic and acquired diseases of hypopigmentation.

pharmacology and toxicology↗

bioRxiv2025

Spatial transcriptomics of compartmentalised inflammation in a natural disease multiple sclerosis cohort.

Compartmentalised inflammation is a poorly understood aspect of multiple sclerosis (MS) that is associated with worse outcomes and represents an important therapeutic target. To gain deeper insight into compartmentalised inflammation, we have taken the approach of digital spatial profiling of the whole human transcriptome in areas of perivascular and meningeal inflammation and tertiary lymphoid-like structures (TLS) in MS central nervous system tissue. Critically, we had access to rare archival tissue obtained before the era of disease-modifying therapies, representing a natural history of disease. This analysis has identified differentially expressed genes in TLS compared to meningeal or perivascular inflammation. Pathway analysis highlighted that TLS signalling is dominated by B cell activity including active antibody secretion. Our data demonstrated the diversity of immunoglobulins and the prominence of IgG3- and IgG4-secreting cells in TLS. Intriguingly, pathway analysis suggests TLS may be hubs for viral (re)activation which warrants further investigation. These findings provide insight into the function of TLS in MS disease pathogenesis and reveal unique immune signatures that may support biomarker development to predict which patients harbour TLS in life.

neuroscience↗

bioRxiv2025

A Complexity-Science Framework for Studying Flow: Using Media to Probe Brain-Phenomenology Dynamics

Consciousness spans a range of phenomenological experiences, from effortless immersion to disengaged monotony, yet how such phenomenology emerges from brain activity is not well understood. Flow, a phenomenological experience frequently elicited by interactive media, has drawn attention for its links to performance and wellbeing, but existing neural accounts rely on single region or small network analyses that overlook the brains distributed and dynamic nature. Complexity science offers tools that capture brain-wide dynamics, but this approach has rarely been applied to flow or to its natural comparisons: boredom and frustration. Consequently, it remains unclear whether tools drawn from complexity science can objectively discriminate between these phenomenological experiences while also clarifying their neural basis. To address this uncertainty, we induced each phenomenological experience with a difficulty-titrated video game during functional magnetic resonance imaging and collected concurrent behavioral and self-report data. Our complex systems analyses revealed that flow, in this experimental setup, shows an inverse relationship to global entropy with moderate explanatory power, and is not explained by either synchronization or metastability, whereas boredom and frustration exhibit different configurations of brain-dynamics metrics. Notably, these findings integrate previously separate prefrontal and network-synchrony observations within a single dynamical systems framework and identify complexity-based markers with the potential to map the neural underpinnings of media-related benefits.

neuroscience↗