Biology subjects

Haynes, C.

Publications and source records attributed to Haynes, C..

9 recordsLinked to original sources

bioRxiv2026

Wasting is essential: cachexia is driven by a wound-healing adaptation

Background: Several explanations have been given for why cachexia occurs in the presence of severe acute wounds and chronic diseases. None of these explanations address the scope of clinical settings in which cachexia has been observed, nor do they account for the failure of nutritional support to reverse cachexia. We hypothesize that induced muscle wasting (IMW) is an adaptation to support wound healing, and when a wound does not heal, prolonged IMW leads to cachexia. Methods: To evaluate this hypothesis, we developed a mathematical model of IMW. In this model, we compared the time needed for wound healing when IMW was present and when it was inhibited. We also measured the relationship between the pathogen growth rate and final patient muscle mass for chronic diseases such as cancer and tuberculosis, demonstrating the onset of cachexia. Finally, we simulated the effects of nutritional support and contrasted the outcomes of when IMW was present and when it was inhibited. Results: Acute wound healing was ~2-6 times longer without IMW than with IMW. For chronic wounds, steady-state muscle mass strongly depended on the growth rate of the pathogenic agent. Inhibiting IMW was more effective at preventing acute muscle mass loss than nutritional support, and the benefit of nutritional support was enhanced by inhibiting IMW. Nutritional support also increased the speed of healing acute wounds when IMW was inhibited. For cancer with high growth rate, giving nutritional support alone had a negligible effect on steady-state muscle mass. But when IMW was inhibited, muscle mass loss was attenuated. With IMW inhibition, nutritional support with the normal diet was able to abrogate muscle mass loss entirely. Conclusions: Inhibiting IMW slows the healing of acute wounds, supporting our hypothesis that IMW is an adaptation to support rapid wound healing. Our experiments demonstrate that nutritional support is insufficient to prevent severe muscle mass loss while IMW continues. But when IMW is inhibited, nutritional support restores normal levels of muscle mass for both acute and chronic wounds, as well as increasing the rate of wound healing. Discovering and developing methods to inhibit IMW for clinical use will be essential to restore patient muscle mass, ease suffering, and reduce mortality.

systems biology↗

bioRxiv2026

Epithelial Reprogramming and Transition during Pulmonary Bioengineering

Recent research has emphasized the critical role of cell state transitions in tissue homeostasis. In lung biology, transitional cells are recognized as a feature of tissue-scale processes during both normal physiology and disease. The precise way that transitional cell states emerge and are regulated remains to be determined. Engineered tissues, built in a laboratory through bioengineering approaches, allow detailed study of cellular states that are not commonly found in native biology, and allow opportunities to directly induce and manipulate cellular transitions. The following study explores and characterizes epithelial cell states that emerge via cellular reprogramming in a tissue engineering context. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/701406v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1d456f3org.highwire.dtl.DTLVardef@1989ba5org.highwire.dtl.DTLVardef@127dd7org.highwire.dtl.DTLVardef@3dd7a_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

A Tunable Pulmonary Organoid Model Demonstrates Compositionally Driven Epithelial Plasticity and Immune Polarization

Summary/AbstractAberrant epithelial regeneration and immune remodeling are hallmarks of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), COPD, and post-viral syndromes. Yet how cellular context shapes these trajectories remains unresolved. We present a tunable, primary rat-derived lung organoid model that systematically varies immune, epithelial, and mesenchymal inputs to reveal how composition alone dictates epithelial plasticity and macrophage polarization. Across organoid conditions that varied by relative starting lineage ratios, we observed the spontaneous emergence of disease-relevant transitional cell states, including Sox9+ stressed progenitors, RAS-like intermediates, and hillock-like cells, alongside distinct macrophage activation profiles. In mesenchyme-rich contexts, epithelial-immune-mesenchymal crosstalk appeared to reinforce inflammatory signaling and stabilize transitional persistence, while immune-dominant inputs favored ATI-like repair and squamous remodeling. Hillock-like cells displayed context-specific polarization and expressed immune-regulatory genes, suggesting a role as epithelial orchestrators that help calibrate inflammatory response during regeneration. Connectomic analysis via NICHES revealed that regenerative outcomes were associated with dynamic multicellular signaling networks that integrate stress sensing, immune coordination, and epithelial resilience. This platform provides a tractable system for modeling milieu-specific repair and regenerative mechanisms and could inform therapeutic strategies aimed at redirecting epithelial fate in chronic lung disease.

bioengineering↗

bioRxiv2025

Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans

The mitochondrial unfolded protein response (UPRmt), which promotes mitochondrial proteostasis and biogenesis is regulated by the transcription factor ATFS-1. In C. elegans, impaired atfs-1 expression perturbs mitochondrial function and slows development. Here, via an RNAi suppressor screen, we found that inhibition of the nuclear hormone receptor NHR-180 increases mitochondrial function and the rate of development in atfs-1(null) worms. NHR-180 is activated during mitochondrial dysfunction and induces transcription of genes required for protein synthesis on cytosolic and mitochondrial ribosomes. Importantly, the NHR-180 ligand binding domain interacts with AMP, which results in increased protein synthesis potentially to promote mitochondrial biogenesis and recovery from transient mitochondrial perturbations. However, NHR-180 exacerbates the mitochondrial dysfunction caused by mutations in genes required for oxidative phosphorylation. Consistent with these findings, we found that inhibition of the S6 kinase homolog RSKS-1 also increased mitochondrial function in atfs-1(null) worms. Importantly, treatment with an S6 kinase inhibitor also increased respiration and mtDNA content in mammalian ATF5-knockout cells and OXPHOS-deficient models, suggesting that translation regulation is a conserved, targetable approach for restoring mitochondrial function in disease.

developmental biology↗

bioRxiv2024

Optimized recess design in artificial structures dramatically enhances coral settlement and survival

The worldwide decline of coral reefs, driven by climate change and local stressors, demands new, scalable restoration approaches. Coral larvae offer significant potential for reef recovery, as a single coral colony can release millions of offspring, with almost all larvae dying before finding a suitable habitat. Building upon an iterative design process, incorporating a gradient of sizes and angles based on larval settlement preferences observed in nature, we developed and tested seven 3D-printed settlement module designs, proposed to enhance coral larvae habitat. We studied the settlement and survival of coral larvae on the settlement modules integrating these designs and adjacent reef structures in K[a]neohe Bay over one year. Helix recesses dramatically outperformed other structural features, increasing settlement by [~]80-fold and post-settlement survival over a year by 20-50-fold compared to control modules. In contrast to natural reef substrates, settlement on modules with helix recesses increased by [~]70-fold. We identified the recess dimensions and light levels preferred as settlement habitat. In a parallel tank experiment, we explored the impacts of hydrodynamics on the settlement and survival of Montipora capitata larvae on modules with helix recesses. We found that settlement was more pronounced under high-flow conditions, suggesting a crucial role of micro-scale hydrodynamics in entraining settling corals. These findings highlight the potential of helix recesses to significantly improve early coral recruitment, a critical bottleneck in reef restoration. By integrating these structures into artificial reefs and coastal infrastructure, our approach offers an innovative, scalable, and cost-effective solution to enhance reef resilience and accelerate ecosystem recovery in a changing ocean.

ecology↗

bioRxiv2022

Mitochondrial genome recovery by ATFS-1 is essential for development following starvation

Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) number and leads to aging-related phenotypes. Here, we demonstrate that the bZIP protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPRmt), is required to promote growth and establish a functional germline following prolonged starvation. Surprisingly, we found that the recovery of mtDNA copy number and development following starvation required mitochondrial-localized ATFS-1 but not its nuclear transcription activity. Lastly, we found that the insulin-like receptor DAF-2, functions upstream of ATFS-1 to modulate mtDNA content. We demonstrate that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content partly mediated by mitochondrial-localized ATFS-1. Combined, our data indicate the importance of the UPRmt in recovering mitochondrial mass and suggests that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion following starvation.

cell biology↗

bioRxiv2020

ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1

Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

physiology↗

bioRxiv2020

Degradation of ATFS-1 by LONP-1 promotes deleterious mitochondrial genome heteroplasmy

The accumulation of deleterious mitochondrial genomes ({Delta}mtDNAs) underlies inherited mitochondrial diseases and contributes to the aging-associated decline in mitochondrial function. In heteroplasmic cells, oxidative phosphorylation (OXPHOS) function declines as the population of {Delta}mtDNAs increase relative to wildtype mtDNAs. In response to mitochondrial perturbations, the bZIP protein ATFS-1 induces a transcription program to promote the recovery of mitochondrial function. Paradoxically, ATFS-1 is also required to maintain {Delta}mtDNAs in heteroplasmic worms. However, the mechanism(s) by which ATFS-1 promotes {Delta}mtDNA accumulation relative to wildtype mtDNAs is unclear. Here, we show that mitochondrial-localized ATFS-1 binds almost exclusively to {Delta}mtDNAs in heteroplasmic worms. Moreover, we demonstrate that mitochondrial ATFS-1 promotes the preferential binding of the mtDNA replicative polymerase (POLG) to {Delta}mtDNAs. Interestingly, inhibition of the mtDNA-bound protease LONP-1 increased ATFS-1 and POLG binding to wildtype mtDNAs. Furthermore, LONP-1 inhibition in C. elegans and human cybrid cells improved the heteroplasmy ratio and restored OXPHOS function. Our findings suggest that ATFS-1 promotes mtDNA replication by recruiting POLG to mtDNA in a manner that is antagonized by LONP-1. We speculate that this mechanism promotes the repair and expansion of the mitochondrial network by synchronizing mtDNA replication with UPRmt activation driven by nuclear ATFS-1 activity. However, this repair mechanism cannot resolve OXPHOS defects in mitochondria harboring {Delta}mtDNAs, resulting in an accumulation of ATFS-1 in dysfunctional mitochondria and constitutive replication of {Delta}mtDNAs.

cell biology↗

bioRxiv2018

A legacy role for DNA binding of Lon protects against genotoxic stress

DNA binding proteins are essential for cellular life, but persistently bound complexes have toxic consequences. Here we show that the proteotoxic responsive bacterial protease Lon clears proteins from DNA to promote genotoxic stress resistance. Purified Lon binds DNA and degrades neighboring bound proteins, while a fully active DNA-blind Lon variant does not. This variant can degrade substrates as normal during unstressed growth, complements pleotropic phenotypes of {Delta}lon, including proteotoxic resilience, but remains sensitive to genotoxic stresses and fails to degrade proteins efficiently during DNA damage. Transposon sequencing reveals that {Delta}lon is vulnerable to loss of protein-DNA eviction factors and we use dynamic nucleoid occupancy profiling to show that chromosome-wide protein turnover relies on Lon DNA binding. Finally, disrupting Lon binding to mitochondria genomes also results in genotoxic stress sensitivity, consistent with the bacterial ancestry of this organelle. We propose that clearance of persistent proteins from DNA by Lon originated in free-living -proteobacteria and maintained during the evolution of mitochondria. SummaryDNA binding by the Lon protease protects against genotoxic damage in a manner preserved from bacteria to mitochondria.

microbiology↗