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Smith, C. E.

Publications and source records attributed to Smith, C. E..

7 recordsLinked to original sources

Digital twins of upright stance reveal mechanistic bifurcations underlying Parkinsonian sway phenotypes

How the central nervous system maintains upright stance--and why this capability collapses in Parkinsons disease (PD)--remains a fundamental open question in computational neuroscience. A primary barrier is a severe topological degeneracy between observable sway kinematics (z-space) and latent neural control policies (-space), causing radically distinct control strategies to mask as identical sway patterns. Here, we establish a dynamical digital twin framework bridging empirical sway time series with mechanistic physical models. Assimilating a large cohort (N = 1, 038) into an intermittent control model via Bayesian inference, we construct a bidirectional mapping (z {leftrightarrow} ) that unmasks these hidden dynamics. We prove that healthy stance is universally governed by flexible intermittent control near an optimal intermittency ratio ({rho} {approx} 0.5), whereas PD progression reflects a structural regression toward rigid continuous control ({rho} [->] 1). Crucially, parameter topology in -space reveals that neural control policies reside on a folded low-dimensional manifold separated by a distinct parameter gap; attractor bifurcation analysis demonstrates that a catastrophic tipping point is embedded within this void, proving that parkinsonian postural breakdown is driven by a discontinuous dynamical phase transition rather than continuous control decay. By unmasking hidden disease severity beneath degenerate sway phenotypes, our framework reframes parkinsonian motor failure as an attractor bifurcation on a neural control manifold, providing a modern computational realization of the classical "dynamical disease" paradigm. SignificancePostural collapse in Parkinsons disease presents a profound neurobiological paradox: cellular degeneration progresses continuously over decades, yet clinical motor failure strikes as a sudden, catastrophic collapse. We resolve this paradox by demonstrating that motor breakdown is not a passive decay of control resources, but a discontinuous dynamical phase transition (attractor bifurcation) triggered when underlying neural control policies cross a latent parameter gap. By unmasking "phenotypic degeneracy"--where radically different neural control strategies produce identical body sway--our digital twin framework redefines neurodegenerative motor failure as a qualitative regime shift in complex control dynamics, offering a universal paradigm for predicting catastrophic transitions in neurological disorders.

neuroscience↗

Predicting Sex-Specific Antiarrhythmic Strategies for Atrial Fibrillation through a Regression-Guided Computational Modeling Pipeline

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a major contributor to stroke, heart failure, and mortality worldwide. Although AF affects both men and women at a similar rate, accumulating experimental and clinical evidence indicates that its underlying mechanisms, disease progression, and treatment responses differ by sex. However, current antiarrhythmic drug development and clinical management of AF remains largely sex neutral, likely contributing to limited efficacy and increased adverse effects. To address this gap, we developed a computational drug-screening pipeline based on experimentally constrained, sex-specific human atrial cardiomyocyte models to predict and evaluate sex-specific pharmacological strategies for AF. The pipeline integrates multivariable regression with mechanistic modeling to systematically test multi-target combinations of ion channel inhibitors and Ca2+ handling modulators and identify interventions that reduce arrhythmia vulnerability by restoring sex-specific electrophysiological and Ca2+ handling properties toward normal sinus rhythm (nSR). Application of this approach revealed a greater number of successful inhibitory drug combinations in males than in females. In males, optimal recovery to nSR primarily required inhibition of Na+ and K+ channels to prolong repolarization and refractoriness, increase Ca2+ transient amplitude (CaTAmp), and reduce susceptibility to action potential duration (APD) alternans. In females, modulation of Ca2+-related pathways was additionally required to suppress delayed afterdepolarizations (DADs). Forward single-cell simulations confirmed the predictions of the drug-analysis pipeline, demonstrating recovery of APD, CaTAmp, and arrhythmia vulnerability indices without introducing instabilities. Importantly, extension of these interventions to two-dimensional atrial tissue simulations demonstrated that sex-specific drug strategies reduce vulnerability to triggered activity, while suppression of reentry was most effective when combined with partial recovery of cell-cell coupling. Our results establish a multiscale computational pipeline for identifying sex-informed, multi-target antiarrhythmic therapies, amenable to experimental validation and translation to the clinic. Clinical PerspectiveO_ST_ABSWhat is KnownC_ST_ABSO_LIAtrial fibrillation arises from multiple interacting multiscale mechanisms, which limit the effectiveness of single-target therapies. C_LIO_LICurrent single-target antiarrhythmic drugs for atrial fibrillation show more limited efficacy and higher adverse event rates in women than in men C_LI What the Study AddsO_LIThis study demonstrates that effective pharmacologic strategies require different combinations of ion channel and calcium handling modulation in males versus females with persistent (chronic) atrial fibrillation. C_LIO_LIIn males, coordinated Na+ and K+ channel inhibition most effectively improves electrical stability, whereas in females additional targeting of Ca2+ handling is required to suppress triggered activity. C_LIO_LISex-specific multi-target drug strategies including partial recovery of intercellular coupling suppress triggered activity and reentry in atrial tissue while preserving conduction. C_LI

pharmacology and toxicology↗

Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate

Cell fate transitions require signal-induced chromatin derepression, yet mechanisms governing transitions from repressed to active chromatin states are poorly understood. We discover, at fate-defining genes across immune cell types, a signal-induced histone code, and describe domains of H3 serine 28 phosphorylation (H3S28ph) spanning architectural features, often coincident with repressive H3 lysine 27 trimethylation (H3K27me3). Employing biophysical, single cell, and functional approaches to study signal-induced cell differentiation in the immune system, we uncover epigenomic transitions and cell fate choices precipitated by histone phosphorylation (H3ph). Mechanistically, H3ph overrides Polycomb Repressive Complex 2 (PRC2) chromatin repression, biophysically disrupts polynucleosome compaction, and promotes loss of H3K27me3, while increasing activating H3K27 acetylation and H3K36 dimethylation to drive domain interactivity and stabilize transcription. We demonstrate the activity of H3ph in several cell fate transitions and illuminate biophysical mechanisms enabling rapid signal-activated chromatin derepression, processes with general relevance for cellular differentiation and activation.

immunology↗

Peptide nanoparticles for systemic mRNA delivery in rodents and non-human primates

The therapeutic potential of mRNA is vast, and yet translating this potential into effective treatments requires overcoming significant challenges of achieving safe and efficient delivery. This process is hampered by biological barriers that limit cellular uptake, degrade exposed mRNA, and thus necessitate effective endosomal escape to reach the cytoplasm. To address these challenges, we developed a hPep peptide-based nanoparticle (PNP) system that encapsulates mRNA, forming stable and biocompatible particles, which are rapidly taken up by the cells and enable efficient mRNA delivery across various cell culture models. Following systemic administration in mice, lead hPep3/mRNA PNPs achieve broad mRNA expression across multiple tissues, including the lungs, liver, and spleen, and enable effective mRNA delivery to the central nervous system upon local administration. Furthermore, we established a high-yield ([≥]70%) microfluidics-based protocol to scale up the production of well-defined, sterile hPep3/mRNA PNP formulations (approximately 70 nm, PDI around 0.170). Most importantly, in a proof-of-concept study in nonhuman primates (NHPs), we demonstrate that hPep PNPs loaded with human erythropoietin (hEPO) mRNA induce dose-dependent expression of hEPO protein in monkey serum, reaching up to 10 ng/ml at 1.0 mg/kg dose, following both single and repeated administration, while remaining systemically well-tolerated. These findings underscore the potential of hPep peptide-based nanoparticles as a versatile platform for mRNA delivery across multiple tissues, highlighting their promise in advancing the development of mRNA therapeutics.

pharmacology and toxicology↗

Nucleosome context regulates chromatin reader preference

Chromatin is more than a simple genome packaging system, and instead locally distinguished by histone post-translational modifications (PTMs) that can directly change nucleosome structure and / or be "read" by chromatin-associated proteins to mediate downstream events. An accurate understanding of histone PTM binding preference is vital to explain normal function and pathogenesis, and has revealed multiple therapeutic opportunities. Such studies most often use histone peptides, even though these cannot represent the full regulatory potential of nucleosome context. Here we apply a range of complementary and easily adoptable biochemical and genomic approaches to interrogate fully defined peptide and nucleosome targets with a diversity of mono or multivalent chromatin readers. In the resulting data, nucleosome context consistently refined reader binding, and multivalent engagement was more often regulatory than simply additive. This included abrogating the binding of the Polycomb group L3MBTL1 MBT to histone tails with lower methyl states (me1 or me2 at H3K4, H3K9, H3K27, H3K36 or H4K20); and confirmation that the CBX7 chromodomain and AT-hook-like motif (CD-ATL) tandem act as a functional unit to confer specificity for H3K27me3. Further, in vitro nucleosome preferences were confirmed by in vivo reader-CUT&RUN genomic mapping. Such data confirms that more representative chromatin substrates provide greater insight to biological mechanism and its disorder in human disease.

biochemistry↗

Acute sildenafil administration reduces susceptibility to induced atrial fibrillation in sheep

BackgroundSildenafil is a PDE5 inhibitor with a very good safety profile and animal models suggest it may be beneficial in the treatment of heart failure and ventricular fibrillation. Sildenafil has also been associated with a reduced incidence of atrial fibrillation (AF) in a retrospective observational study. We have therefore sought to determine whether sildenafil has a direct effect on atrial electrophysiology and resultant AF burden. MethodsInvasive electrophysiological studies were performed in 12 anaesthetised healthy adult female Welsh mountain sheep. Pacing protocols were performed in the right atrium before and after administration of an acute 10 mg intravenous bolus of sildenafil and the burden of AF assessed. ResultsSildenafil profoundly reduced the vulnerability to AF, decreasing AF duration (112.2 {+/-} 73.5 s vs. 3.3 {+/-} 1.4 s), the number of burst pacing inductions causing AF (90 % vs 70 %) and the complexity of AF. The antiarrhythmic effects of sildenafil were determined to be resultant of prolongation of both the atrial effective refractory period (146.9 {+/-} 7.2 ms vs 166.2 {+/-} 32.5 ms) and the atrial excitation wavelength (12.9 {+/-} 0.07 cm vs 15.0 {+/-} 0.07 cm) and resulted in a shallower restitution curve, reflected in a decreased magnitude of monophasic action potential alternans (0.09 {+/-} 0.001 mV vs 0.05 {+/-} 0.10 mV). ConclusionsIn the subjectively healthy atria of a highly translational model a strong antiarrhythmic effect upon acute sildenafil application was observed suggestive of a potential clinical benefit in AF.

physiology↗

LYMTACs: Chimeric Small Molecules Repurpose Lysosomal Membrane Proteins for Target Protein Relocalization and Degradation

Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a novel small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. To extend these findings, we show that oncogenic, membrane-associated KRASG12D protein can be tethered to RNF152, inducing KRAS relocalization to the lysosomal membrane, inhibiting downstream phospho-ERK signaling, and leading to lysosomal degradation of KRASG12D in a LYMTAC-dependent manner. Notably, potent cell killing could be attributed to the multi-pharmacology displayed by LYMTACs, which differentiates the LYMTAC technology from existing modalities. Thus, LYMTACs represent a proximity-based therapeutic approach that promises to expand the target space for challenging membrane proteins through targeted protein relocalization and degradation.

cancer biology↗