Biology subjects

Hunt, D. R.

Publications and source records attributed to Hunt, D. R..

6 recordsLinked to original sources

bioRxiv2026

Multi-omics Insight into Cardiac Myofibril Remodeling in Post-Prandial Burmese Pythons

Burmese pythons exhibit rapid cardiac remodeling in response to a dramatic increase in metabolic rate during digestion. Here, we performed single-myofibril mechanics measurements and myosin heavy chain metabolic assays to evaluate the impact of feeding on the cardiomyocyte sarcomere - the fundamental molecular unit of muscle contraction - using two experimental paradigms: normal feeding (one meal per month) and frequent feeding (eight meals per month). Myofibril tension and rate of relaxation increased during digestion in both paradigms, while frequent feeding was further associated with slower myofibril activation kinetics and faster myosin heavy chain ATP turnover. To identify molecular changes at the sarcomere and gain potential mechanistic insight, we performed multi-omics analyses. RNA sequencing identified increased expression of some sarcomere genes during digestion; however, proteomics analysis suggested a delay in sarcomere protein synthesis at the peak of remodeling, as expression of many sarcomere proteins decreased. Analysis of post-translational modifications (ubiquitinomics, phospho-proteomics, acetylomics) identified hundreds of significantly regulated sites on sarcomere proteins during digestion, including many on the tension-regulating titin and myosin heavy chain proteins. Our results detail the molecular underpinnings of cardiac remodeling in digesting Burmese pythons and suggest that natures solution for rapidly increasing cardiac contractility is a post-translational sarcomere tuning program.

molecular biology↗

bioRxiv2025

Cytoplasmic CaMKIIδ-B prevents myocardial recovery in heart failure

Restoration of cardiac function in patients with advanced heart failure is rare, and the molecular processes that regulate recovery are unknown. To identify potential mechanisms, we studied paired myocardial samples before and after left ventricular assist device therapy, where significant cardiac functional recovery occurred in [~]25% of patients. We found that expression of the nuclear B isoform of Ca2+/calmodulin-dependent protein kinase II{delta} (CaMKII{delta}-B) inversely correlated with recovery. Furthermore, increased phosphorylation near the CaMKII{delta}-B nuclear localization signal in non-responders prevented its auto-activation dependent nuclear translocation. Expression of a cytoplasm-restricted CaMKII{delta}-B in cardiomyocytes dramatically remodeled the phospho-proteome and impaired contractility, while a nuclear-competent version did not. Modulating CaMKII{delta} subcellular localization may thus represent a therapeutic strategy for advanced heart failure.

physiology↗

bioRxiv2025

First whole genome assembly of Python regius (ball python), a model of extreme physiological and metabolic plasticity

The study of nontraditional model organisms, particularly those exhibiting extreme phenotypes, offers unique insights into adaptive mechanisms of stress response and survival. Snakes, with their remarkable physiological, metabolic, and morphological adaptations, serve as powerful models for investigating these processes. Pythons are a unique model organism that have been studied for their extreme metabolic and physiological plasticity. To date, the Burmese python (Python bivittatus) is the only member of the Pythonidae family to have been sequenced. The low contiguity of this genome and rising challenges in obtaining Burmese pythons for study prompted us to sequence, assemble, and annotate the genome of the closely related ball python (Python regius). Using a hybrid sequencing approach, we generated a 1.45 Gb genome assembly with a contig N50 greater than 18 Mb and a BUSCO score of 98%, representing the highest quality genome to date for a member of the Pythonidae family. This assembly provides a valuable resource for studying snake-specific traits and evolutionary biology. Furthermore, it enables exploration of the molecular mechanisms underlying the remarkable cardiac and muscular adaptations in pythons, such as their ability to rapidly remodel organs following feeding and resist muscular atrophy during prolonged fasting. These insights have potential applications in human health, particularly in the development of therapies targeting cardiac hypertrophy and muscular atrophy.

genomics↗

bioRxiv2024

Digital Light Processing 3D Printing enables High Throughput Fabrication of Human Engineered Heart Tissues for Disease Modeling

3D in vitro engineered heart tissue (EHT) models recapitulate aspects of native cardiac physiology but are often limited by scalability, cost, and reproducibility. Here, we report a simple, one-step method for rapid ([~]minutes) fabrication of molds using digital light processing (DLP)-based 3D printing that support the formation of EHTs by human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with high reproducibility (>95% efficiency) and varied designs (e.g., length, aspect ratio). Compared to 2D iPSC-CMs, 3D EHTs display enhanced maturity, including increased expression of {beta}-oxidation genes, higher concentrations of sarcomeric myosins, improved sarcomere density and alignment, and enrichment of cardiac pathways (e.g., upregulation of sodium channels, action potentials, contraction). The technology is applied to model pathological cardiac hypertrophy in vitro, using either (i) acute adrenergic agonism or (ii) chronic culture within stiff hydrogel molds. Treated EHTs exhibit increased levels of pathology-associated gene expression and activation of signaling cascades involved in pathological remodeling compared to untreated controls or treated 2D iPSC-CMs. Thus, our method results in robust yet simpler, cheaper, and faster EHTs to study cardiac disease.

bioengineering↗

bioRxiv2024

A Conserved Mechanism of Cardiac Hypertrophy Regression through FoxO1

The heart is a highly plastic organ that responds to diverse stimuli to modify form and function. The molecular mechanisms of adaptive physiological cardiac hypertrophy are well-established; however, the regulation of hypertrophy regression is poorly understood. To identify molecular features of regression, we studied Burmese pythons which experience reversible cardiac hypertrophy following large, infrequent meals. Using multi-omics screens followed by targeted analyses, we found forkhead box protein O1 (FoxO1) transcription factor signaling, and downstream autophagy activity, were downregulated during hypertrophy, but re-activated with regression. To determine whether these events were mechanistically related to regression, we established an in vitro platform of cardiomyocyte hypertrophy and regression from treatment with fed python plasma. FoxO1 inhibition prevented regression in this system, while FoxO1 activation reversed fed python plasma-induced hypertrophy in an autophagy-dependent manner. We next examined whether FoxO1 was implicated in mammalian models of reversible hypertrophy from exercise and pregnancy and found that in both cases FoxO1 was activated during regression. In these models, as in pythons, activation of FoxO1 was associated with increased expression FoxO1 target genes involved in autophagy. Taken together, our findings suggest FoxO1-dependent autophagy is a conserved mechanism for regression of physiological cardiac hypertrophy across species. HIGHLIGHTSO_LIPost-prandial cardiac remodeling in Burmese pythons is associated with dynamic regulation of FoxO1 and autophagy. C_LIO_LIRegression of fed python plasma-induced hypertrophy in mammalian cardiomyocytes is FoxO1-dependent. C_LIO_LIActivation of FoxO1-dependent autophagy is a conserved feature of physiological hypertrophy regression in mammalian models. C_LI

physiology↗

bioRxiv2020

Chromatin Fiber Folding Represses Transcription and Loop Extrusion in Quiescent Cells

Determining the conformation of chromatin in cells at the nucleosome level and its relationship to cellular processes has been a central challenge in biology. We show that in quiescent yeast, widespread transcriptional repression coincides with the local compaction of chromatin fibers into structures that are less condensed and more heteromorphic than canonical 30-nanometer forms. Acetylation or substitution of H4 tail residues decompacts fibers and leads to global transcriptional de-repression. Fiber decompaction also increases the rate of loop extrusion by condensin. These findings establish a role for H4 tail-dependent local chromatin fiber folding in regulating transcription and loop extrusion in cells. They also demonstrate the physiological relevance of canonical chromatin fiber folding mechanisms even in the absence of regular 30-nanometer structures.

molecular biology↗