Biology subjects

Young, E. J.

Publications and source records attributed to Young, E. J..

8 recordsLinked to original sources

bioRxiv2025

Early overactivation of non-muscle myosin II during adaptation to combined BRAF and MEK inhibitors in dedifferentiating cutaneous melanomas

Cutaneous melanoma is a very aggressive type of skin cancer with remarkable phenotypic plasticity that contributes to adaptation and resistance to targeted therapies against the MAPK pathway. Previous research described that non-muscle myosin II (NMII) of the actomyosin cytoskeleton, which is essential for cell migration and metastasis, is overactivated in BRAF inhibitor-resistant melanomas. Since the combination of BRAF and MEK inhibitors (BMi) is the current standard of care, we investigated if and how NMII activity is regulated during adaptation to BMi. Here, we find that most dedifferentiating BMi-resistant melanomas overactivate NMII compared to their parental counterparts. NMII activity generally increases during the first 2 weeks of BMi treatment, and it is followed by elevated total NMII levels due partly to transcriptional modulation. Although ERK activity rebounds with similar kinetics, NMII overactivation is not prevented by ERK inhibition but by blockade of ROCK. In melanomas that hyperdifferentiate during adaptation to BMi, NMII activity is not increased upon BMi treatment due, in part, to MITF. We also find that co-targeting NMII along BMi in some melanomas reduces survival of drug-tolerant persister cells, which would delay the development of resistance. Therefore, our study identifies elevated NMII activity as a potential marker of adaptation to MAPK in some melanoma subpopulations, and also provide an approach to delay the emergence of resistance to MAPK-targeted therapy.

cancer biology↗

bioRxiv2024

Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential

Non-muscle myosin II (NMII), a molecular motor that regulates critical processes such as cytokinesis and neuronal synaptic plasticity, has substantial therapeutic potential. However, translating this potential to in vivo use has been hampered by the lack of selective tools. The most prototypical non-selective inhibitor, blebbistatin inactivates both NMII and cardiac myosin II (CMII), a key regulator of heart function. Using rational drug design, we developed a series of NMII inhibitors that improve tolerability by selectively targeting NMII over CMII, including MT-228, which has excellent properties such as high brain penetration and efficacy in preclinical models of stimulant use disorder, which has no current FDA-approved therapies. The structure of MT-228 bound to myosin II provides insight into its 17-fold selectivity for NMII over CMII. MT-228s broad therapeutic window opens the door to new disease treatments and provides valuable tools for the scientific community, along with promising leads for future medication development. HighlightsO_LIResearch suggests numerous indications, from axon regeneration and cancer, would benefit from a small molecule inhibitor of non-muscle myosin II, a molecular motor that regulates the actin cytoskeleton. C_LIO_LICurrent chemical probe options are very limited and lack sufficient safety for in vivo C_LIO_LIstudies, which we show is primarily due to potent inhibition of cardiac myosin II. C_LIO_LIRational design that focused on improving target selectivity over the pan-myosin II inhibitor, blebbistatin, led to the identification of MT-228, a small molecule inhibitor with a wide therapeutic window. C_LIO_LIHigh-resolution structure of MT-228 bound to myosin II reveals that selectivity results from a different positioning compared to blebbistatin and an important sequence difference between cardiac and non-muscle myosin II in the inhibitor binding pocket. C_LIO_LIA single administration of MT-228 shows long-lasting efficacy in animal models of stimulant use disorder, a current unmet and rapidly escalating need with no FDA-approved treatments. C_LI

cell biology↗

bioRxiv2024

MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma

We have identified a NMIIA and IIB-specific small molecule inhibitor, MT-125, and have studied its effects in GBM. MT-125 has high brain penetrance and retention and an excellent safety profile; blocks GBM invasion and cytokinesis, consistent with the known roles of NMII; and prolongs survival as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor significantly improves survival in orthotopic GBM models over either drug alone, and in the case of sunitinib, markedly prolongs survival in [~]40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM. HighlightsO_LIMT-125 is a highly specific small molecule inhibitor of non-muscle myosin IIA and IIB, is well-tolerated, and achieves therapeutic concentrations in the brain with systemic dosing. C_LIO_LITreating preclinical models of glioblastoma with MT-125 produces durable improvements in survival. C_LIO_LIMT-125 stimulates PDGFR- and MAPK-driven signaling in glioblastoma and increases dependency on these pathways. C_LIO_LICombining MT-125 with an FDA-approved PDGFR inhibitor in a mouse GBM model synergizes to improve median survival over either drug alone, and produces tumor free, prolonged survival in over 40% of mice. C_LI

cancer biology↗

bioRxiv2023

Efficient coding explains neural response homeostasis and stimulus-specific adaptation

In the absence of adaptation, the average firing rate of neurons would rise or drop when changes in the environment make their preferred stimuli more or less prevalent. However, by adjusting the responsiveness of neurons, adaptation can yield firing rate homeostasis and stabilise the average rates of neurons at fixed levels, despite changes in stimulus statistics. In sensory cortex, adaptation is typically also stimulus specific, in that neurons reduce their responsiveness to over-represented stimuli, but maintain or even increase their responsiveness to stimuli far from over-represented ones. Here, we present a normative explanation of firing rate homeostasis grounded in the efficient coding principle. Specifically, we show that this homeostasis can arise when neurons adapt their responsiveness to optimally mitigate the effect of neural noise on population coding fidelity, at minimal metabolic cost. Unlike previous efficient coding theories, we formulate the problem in a computation-agnostic manner, enabling our framework to apply far from the sensory periphery. We then apply this general framework to Distributed Distributional Codes, a specific computational theory of neural representations serving Bayesian inference. We demonstrate how homeostatic coding, combined with such Bayesian neural representations, provides a normative explanation for stimulus-specific adaptation, widely observed across the brain, and how this coding scheme can be accomplished by divisive normalisation with adaptive weights. Further, we develop a model within this combined framework, and, by fitting it to previously published experimental data, quantitatively account for measures of stimulus-specific and homeostatic adaption in the primary visual cortex.

neuroscience↗

bioRxiv2023

The entropy of resting-state neural dynamics is a marker of general cognitive ability in childhood

1Resting-state network activity has been associated with the emergence of individual differences across childhood development. However, due to the limitations of time-averaged representations of neural activity, little is known about how cognitive and behavioural variability relates to the rapid spatiotemporal dynamics of these networks. Magnetoencephalography (MEG), which records neural activity at a millisecond timescale, can be combined with Hidden Markov Modelling (HMM) to track the spatial and temporal characteristics of transient neural states. We applied HMMs to resting-state MEG data from (n = 46) children aged 8-13, who were also assessed on their cognitive ability and across multiple parent-report measures of behaviour. We found that entropy-related properties of participants resting-state time-courses were positively associated with cognitive ability. Additionally, cognitive ability was positively correlated with the probability of transitioning into HMM states involving fronto-parietal and somatomotor activation, and negatively associated with a state distinguished by default-mode network suppression. We discuss how using dynamical measures to characterise rapid, spontaneous patterns of brain activity can shed new light on neurodevelopmental processes implicated in the emergence of cognitive differences in childhood. Significance StatementThere is increasing evidence that the function of resting-state brain networks contributes to individual differences in cognition and behaviour across development. However, the relationship between dynamic, transient patterns of switching between resting-state networks and neurodevelopmental diversity is largely unknown. Here, we show that cognitive ability in childhood is related to the complexity of resting-state brain dynamics. Additionally, we demonstrate that the probability of transitioning into and remaining in certain states of brain network activity predicts individual differences in cognitive ability.

neuroscience↗

bioRxiv2020

Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor

Myosin IIs, actin-based motors that utilize the chemical energy of ATP to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite therapeutic potential for muscle disorders, no SkMII-specific inhibitor has been reported and characterized. Here we present the discovery, synthesis and characterization of "skeletostatins", novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity within the myosin IIs for SkMII. In addition, the skeletostatins bear improved potency, solubility and photostability, without cytotoxicity. Based on its optimal in vitro profile, Skeletostatin 1s in vivo tolerability, efficacy and pharmacokinetics were determined. Skeletostatin 1 was well-tolerated in mice, impaired motor performance, and had an excellent muscle to plasma ratio. Skeletostatins are useful probes for basic research and a strong starting point for drug development.

pharmacology and toxicology↗

bioRxiv2019

Methamphetamine learning induces persistent nonmuscle myosin II-dependent spine motility in the basolateral amygdala

Nonmuscle myosin II inhibition (NMIIi) in the basolateral amygdala (BLA) selectively disrupts memories associated with methamphetamine (METH) days after learning, without retrieval. However, the molecular mechanisms underlying this selective vulnerability remain poorly understood. A known function of NMII is to transiently activate dendritic spine actin dynamics with learning. Therefore, we hypothesized that METH-associated learning perpetuates NMII-driven actin dynamics in dendritic spines, leading to an extended window of vulnerability for memory disruption. Two-photon imaging of actin-mediated spine motility in neurons from memory-related structures, BLA and CA1, revealed a persistent increase in spine motility after METH-associated learning that was restricted to BLA neurons. METH-induced changes to BLA spine dynamics were reversed by a single systemic injection of an NMII inhibitor. Thus, a perpetual form of NMII-driven spine actin dynamics in BLA neurons may contribute to the unique susceptibility of METH-associated memories.

neuroscience↗

bioRxiv2018

Protein Gradients on the Nucleoid Position the Carbon-fixing Organelles of Cyanobacteria

In BriefWe describe a novel positioning system that utilizes the cyanobacterial nucleoid to segregate, transport and equidistantly position the carbon-fixation machinery (carboxysomes).\n\nSummaryCarboxysomes are protein-based bacterial organelles that encapsulate a key enzyme of the Calvin-Benson-Bassham cycle. Previous work has implicated a ParA-like protein (hereafter McdA) as important for spatially organizing carboxysomes along the longitudinal axis of the model cyanobacterium Synechococcus elongatus PCC 7942. Yet, how self-organization of McdA emerges and contributes to carboxysome positioning is unknown. Here, we show that a small protein, termed McdB, localizes to carboxysomes through interactions with carboxysome shell proteins to drive emergent oscillatory patterning of McdA on the nucleoid. Our results demonstrate that McdB directly interacts to stimulate McdA ATPase activity, and indicate that carboxysome-dependent McdA depletion zone formation on the nucleoid is required for directed motion of carboxysomes towards increased concentrations of McdA. We propose that McdA and McdB are a new class of self-organizing proteins that follow a Brownian-ratchet mechanism, challenging the cytoskeletal model of organelle transport, for equidistant positioning of carboxysomes in cyanobacteria. These results have broader implications for understanding spatial organization of protein mega-complexes and organelles in bacteria more broadly.

microbiology↗