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Davis, C.

Publications and source records attributed to Davis, C..

At least 19 recordsLinked to original sources

Predicting curvature evolution on biological surfaces from clinical imaging-derived area dilation: a closed-form interpretable framework

Curvature evolution on a deforming surface is governed by the full change in the surface metric, but on biological surfaces captured by serial three-dimensional imaging, only the local area change is observable. The loss of the shear component leaves prediction of curvature evolution underdetermined from imaging alone. On the thoracic aorta, where curvature change marks disease progression, we derive a closed-form equation that predicts the change in integrated Gaussian curvature from the area dilation and initial geometry. The equation combines a conformal term in the area dilation with a leading anisotropy correction from the initial geometry. These two analytic levels, augmented by multi-scale spatial features at neighboring regions and a graph neural network trained on residuals, form a four-level nested predictor. On a synthetic aortic geometry under prescribed isotropic expansion, the equation recovers the analytic coefficient exactly. Across a continuum from pure expansion to pure shear, it holds R2 [≥] 0.71. On 236 paired thoracic aortic surfaces spanning dissection, aneurysm, traumatic injury, and non-pathologic controls, the equation recovers within-surface curvature change patterns with per-patient median Pearson [Formula] and pooled R2 = +0.238 [+0.225, +0.250], matching the graph neural network on the same inputs. The residual is a direct measurement of how far the observed growth field departs from conformality. HighlightsO_LIClosed-form equation predicts aortic curvature change from paired computed tomography scans. C_LIO_LIRecovers analytic predictions exactly on synthetic aortic geometries. C_LIO_LIAnisotropy proxy holds R2 [≥] 0.71 from pure expansion to pure shear. C_LIO_LICoefficients tie to geometric mechanisms ensuring interpretability. C_LIO_LIAnisotropy term, computable from one CT, is twice as large on diseased aortas. C_LI

bioengineering↗

Phosphoregulated SMCR8-FIP200 interaction connects the ALS/FTD-linked C9orf72 complex to autophagy initiation and mitochondrial quality control

Hexanucleotide (GGGGCC) repeat expansions in the non-coding region of C9ORF72 are a major genetic cause of ALS/FTD and reduce C9orf72-SMCR8-WDR41 complex levels, but how this contributes to autophagy-lysosome dysfunction and previously reported mitochondrial quality-control defects in C9ORF72-ALS/FTD remains unclear. Here we identify a direct interaction between SMCR8 and the FIP200 subunit of the ULK1/2 autophagy initiation complex, mediated by two FIP200-interacting region (FIR) motifs in a disordered SMCR8 loop. Phosphorylation of these motifs by ULK1/2 or TBK1 strengthens binding and promotes ULK1/2 complex association in cells. Stabilising the SMCR8-FIP200 interaction suppresses Parkin-dependent mitophagy, whereas both stabilisation and weakening impair deferiprone-induced mitophagy, while leaving bulk autophagy, lysophagy and ivermectin-induced mitophagy largely intact. These findings define a regulated C9orf72-ULK1/2 axis and provide a mechanistic framework by which repeat-expansion-associated reduction in C9orf72 complex abundance may contribute to previously observed mitochondrial quality-control defects in C9ORF72-ALS/FTD.

cell biology↗

Dirty mice better recapitulate key features of mRNA vaccine immunogenicity observed in humans

Although specific pathogen free (SPF) mice have traditionally been used to test candidate vaccines, recent work has demonstrated that "dirty" mice with broad microbial exposure more appropriately recapitulate human immune responses. Using a model where lab mice are co-housed with pet store mice, we modeled SARS-CoV-2 mRNA vaccine responses in dirty and traditional SPF models. We found that dirty mice show reduced serum spike-binding antibody titers after prime and require a second booster dose to reach SPF-level spike antibody titers. Additionally, spike antibodies showed faster waning in dirty mice through 5 months post-vaccination, and neutralizing activity of these antibodies were reduced against Omicron variants, directly comparable with observations in humans. We further investigated the seasonality and consistency of pathogens in cohoused mice, and the impact of serial microbial exposure on our animal model system. We found that pathogen exposure and T cell activation remained consistent over time, and that a single co-housing event was sufficient to provide broad microbial exposure. This work demonstrates that the dirty mouse co-housing system is a promising, translationally representative approach to screen candidate mRNA vaccines for efficacy and durability prior to human clinical trials. Significance statementThe development of mRNA vaccines during the COVID-19 pandemic dramatically reduced hospitalization and death rates for infected individuals. However, booster vaccinations were required to achieve full efficacy, and protection waned over time. Our research leveraged a "dirty" mouse model to test whether SARS-CoV-2 mRNA vaccinations in animals with previous microbial exposure better modelled human immune responses. We found that dirty mice require a booster vaccination for full efficacy and experienced waning serum antibody titer over time. We propose this approach as a future model for robust preclinical mRNA vaccine testing.

immunology↗

ZNF423 depletion induces the integrated stress response and represents a potential vulnerability in NF1-associated MPNST

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited systemic therapies and represent the leading cause of mortality for individuals with neurofibromatosis type 1 (NF1). Malignant progression can reactivate developmental precursor programs that are largely absent from normal nerve and benign tumors, creating tumor-selective vulnerabilities. Zinc finger protein 423 (ZNF423; also known as OAZ/ROAZ) is a developmentally regulated transcription factor that delays olfactory precursor differentiation and has been implicated in B-cell malignancy. Here, we asked whether ZNF423 is reactivated and functionally required in NF1-associated MPNST. In genetically defined models, Nf1 loss reduced Zfp423 in a benign tumor cell-of-origin context, whereas combined Nf1 and Cdkn2a loss induced marked Zfp423 upregulation during transformation. ZNF423 depletion impaired DNA synthesis and proliferation, induced DNA damage signaling, and activated the integrated stress response (ISR), increasing sensitivity to cytotoxic agents. In an orthotopic MPNST model, shRNA-mediated suppression of ZNF423 reduced tumor initiation in vivo; however, tumors that eventually emerged showed restoration of ZNF423 expression. ZNF423 is developmentally restricted in the peripheral nerve lineage yet elevated in MPNST, with single-cell analyses of patient nerve sheath tumors revealing localized expression restricted to malignant cells rather than SOX10-positive benign tumor cells. These data identify ZNF423 as a putative malignant biomarker, a potential dependency in NF1-MPNST, and nominate downstream stress and genome maintenance pathways as cooperative therapeutic vulnerabilities. STATEMENT OF SIGNIFICANCEZNF423 is a developmentally restricted transcription factor selectively reactivated in NF1-associated malignant peripheral nerve sheath tumors. Targeted ablation triggers the integrated stress response, impairs DNA synthesis, sensitizes cells to chemotherapy and PARP inhibition, and restricts in vivo growth. ZNF423 represents a candidate biomarker and therapeutic vulnerability in this aggressive sarcoma.

cancer biology↗

A structural and regulatory framework for Atg9-containing vesicle formation and their Atg1-dependent remodelling during autophagy initiation

Autophagy is a complex intracellular degradation pathway that depends on the coordinated interplay between the core autophagy machinery and diverse membrane sources to drive the de novo formation of double-membrane vesicles, known as autophagosomes. Golgi-derived Atg9-containing vesicles are essential for this process, delivering membranes to the pre-autophagosomal structure (PAS). These vesicles contain the transmembrane proteins Atg9 and Atg27 and the peripheral membrane protein Atg23; however, the nature, function, and regulation of their interactions remain poorly understood. Here, we systematically dissect the molecular interactions between Atg9, Atg23 and Atg27, and uncover their regulation in space and time. The bipartite binding mode by which Atg23 engages Atg9 provides a structural model for how Atg23 promotes vesicle budding. Furthermore, Atg1-dependent phosphorylation of Atg9 remodels its interactions with Atg23 and Atg27 at the PAS to support autophagy initiation. Together, these findings establish a molecular and regulatory framework for the earliest steps of autophagy.

biochemistry↗

Serological evidence of SARS-CoV-2 infection in red and fallow deer in Great Britain.

SARS-CoV-2 is the viral agent of COVID-19 disease in humans and has been shown to infect a wide range of mammals, including white-tailed deer in North America and fallow deer in the Republic of Ireland. There are six species of deer in the UK which inhabit both urban and rural areas, providing a broad interface for human-deer interaction. Little is known if British deer species act as a reservoir for zoonotic spread of consequence to human health. Here, we report a high seroprevalence of SARS-CoV-2 neutralising antibodies in British deer, adding native red deer to the list of susceptible species. 62% of fallow and 25% of red deer sampled between 2024 and 2025 from one British deer park were positive for SARS-CoV-2 infection by serology. Data suggest that deer may function as permissive, reservoir-capable hosts and highlight the risks of anthroponosis and zoonosis from unregulated human-deer contact. While there is currently no evidence to suggest that these viruses are persisting within deer populations in Great Britain, the animal origins of SARS-CoV-2 highlight the importance of appropriate and limited interactions with wildlife, to minimise transmission risks and safeguard both animal and human health.

microbiology↗

RIPK1 regulates beta-cell fate via actions on gene expression and kinase signaling in a mouse model of beta-cell self-reactivity

Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic {beta}-cells, insulin insufficiency, and hyperglycemia. Receptor interacting protein kinase 1 (RIPK1) is a multifunctional regulator of cell fate with kinase and scaffolding functions, and we previously identified RIPKs as regulators of {beta}-cell cytotoxicity in vitro. Here we report that Ripk1 expression is increased in islets from aged non-obese diabetic (NOD) mice and {beta}-cells from T1D donors, suggesting that RIPK1 may drive cytokine- and autoimmune-mediated {beta}-cell demise in T1D. Using NIT-1 {beta}-cells derived from NOD mice, we observed that TNF+IFN{gamma} increase RIPK1 phosphorylation, caspase 3/7 activity, and cell death. In contrast, this cytotoxicity was blocked with small molecule RIPK1 inhibition or in Ripk1 gene-edited (Ripk1{Delta}) {beta}-cells. Co-labeling of caspase 3/7 activation and cell death in single cells revealed protection from caspase-dependent and -independent forms of death in Ripk1{Delta} cells. RNAseq uncovered differential cell death-, immune-, and identity-related gene expression, and kinome profiling identified changes in MAPK, Eph, JAK, and other kinase activity associated with protection from cell death in RIPK1 deficient {beta}-cells. Furthermore, in vitro co-culture assays and in vivo adoptive transfer experiments revealed that NIT-1 Ripk1{Delta} cells were protected from autoimmune destruction by splenocytes isolated from diabetic NOD mice. Collectively, our findings indicate that RIPK1 promotes {beta}-cell demise in response to cytokine and autoimmune stress via actions on gene expression and kinase signaling. Therapeutics targeting RIPK1 may provide novel opportunities for prevention or treatment of autoimmune diabetes.

cell biology↗

Loss of DAXX induces alternative lengthening of telomeres (ALT)-associated hallmarks in prostate cancer cells in a context-specific manner

BackgroundThe histone chaperone complex, consisting of the death domain-associated protein (DAXX) and the alpha-thalassemia/mental retardation X-linked protein (ATRX), plays a pivotal role in maintaining chromatin through the deposition of the histone variant H3.3. Mutations leading to loss of ATRX or DAXX function are linked to the non-telomerase, alternative lengthening of telomeres (ALT) phenotype in certain cancers. Engineered ATRX mutations have previously been found to induce features of ALT in prostate cancer cell lines, notably in LAPC-4, but not in CWR22Rv1. This study determined the impact of DAXX mutations on ALT-associated characteristics in CWR22Rv1 and LAPC-4. MethodologyMutations were induced in CWR22Rv1 and LAPC-4 cells by targeting exon 2 of DAXX using the CRISPR-Cas9 genome editing strategy. The resulting mutant clones were then evaluated for ALT-associated characteristics, including the presence of ALT-associated PML bodies (APBs), C-circles, telomere length heterogeneity, and a lack of telomerase activity. ResultsFour CWR22Rv1 DAXX mutant clones (DAXXMut1-4) and five LAPC-4 clones (DAXXMut1-5) were evaluated. In CWR22Rv1, DAXXMut1, DAXXMut2, and DAXXMut4 were true knockout clones with frameshift mutations in both copies, while CWR22Rv1 DAXXMut3 had a frameshift mutation in one copy and an in-frame mutation in the other. Protein expression was undetectable in all the CWR22Rv1 clones, including CWR22Rv1 DAXXMut3. In LAPC-4, DAXXMut1 was a true knockout, while DAXXMut2, DAXXMut3, DAXXMut4, and DAXXMut5 clones had at least one in-frame mutation. Among these LAPC-4 clones, only DAXXMut1 had undetectable protein by western blotting. ALT-associated characteristics such as APBs, C-circles, and telomere length heterogeneity were observed only in CWR22Rv1 DAXXMut4. All the clones maintained telomerase activity, regardless of whether ALT-associated hallmarks were observed. ImplicationsThe CWR22Rv1 and LAPC-4 DAXX mutant clone models provide useful tools for future studies on telomere maintenance mechanisms and DAXX-related biology, particularly in prostate cancer.

cancer biology↗

Phase Separation Oppositely Modulates G-quadruplex and i-Motif DNA Folding in the Nuclei of Living Cells

G-quadruplexes and i-motifs are non-canonical DNA structures that are important not only as targets of gene regulation in cancer therapy, but also as nanotools with biomedical applications. However, their apparent in vitro stabilities and dynamics cast doubt upon their physiological relevance and utility in vivo. Here we investigate folding of the thrombin-binding aptamer G-quadruplex and the TAA(C5TAA)4 i-motif. We use fast relaxation imaging, which couples fluorescence microscopy with laser-induced temperature jumps, to quantify the stability and dynamics of FRET-labelled constructs in vitro and in the nuclei of living cells. Our work suggests that the stability and kinetics of i-motif and G-quadruplex DNA are carefully tuned by phase separation to fit the seconds-to-minutes timescales of key regulatory processes inside cells. Taken together, our findings underscore the importance of studying the folding of DNA structures under near-physiological conditions to their mechanistic understanding as well as for the development of DNA-targeted drugs. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/661982v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@e76eedorg.highwire.dtl.DTLVardef@23aefforg.highwire.dtl.DTLVardef@b6117aorg.highwire.dtl.DTLVardef@135736a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

Leukocyte-type 12/15-lipoxygenase is essential for timely inflammation-resolution and effective tissue regeneration following skeletal muscle injury

Unlike traditional anti-inflammatory therapies which may interfere with musculoskeletal tissue repair, pharmacological administration of specialized pro-resolving lipid mediators (SPMs) can promote timely resolution of inflammation while stimulating skeletal muscle regeneration. Despite this, the potential role of endogenous inflammation-resolution circuits in skeletal muscle injury and repair remains unknown. Here, we investigated the effect of whole-body knockout of leukocyte-type 12/15-lipoxygenase (12/15-LOX) on acute inflammation and regeneration following skeletal muscle injury in mice. Prior to muscle injury, Alox15-/- mice displayed lower intramuscular concentrations of 12/15-LOX-derived lipid mediators than wild type (WT) mice, and this was associated with chronic low-grade muscle inflammation. Alox15-/- mice mounted an exaggerated acute immune response to sterile skeletal muscle injury which was associated with a local imbalance of pro-inflammatory vs. pro-resolving lipid mediators. During the regenerative phase, Alox15-/- mice displayed defects in myogenic gene expression, myofiber size, and myonuclear accretion. Mechanistically, bone marrow-derived macrophages (M[FE]) obtained from Alox15-/- mice produced less 12/15-LOX-derived lipid mediators and this was associated with impaired M2 polarization. Isolated myogenic progenitor cells also produced many LOX metabolites in response to long chain polyunsaturated fatty acid (LC-PUFA) supplementation, including bioactive SPMs. Alox15-/- myoblasts were both impaired in their ability to produce SPMs and were insensitive to the stimulatory effect of LC-PUFAs on in vitro myogenesis. These data show that the 12/15-LOX pathway is essential for timely resolution of acute inflammation and direct determination of myogenic progenitor cell fate following skeletal muscle injury.

developmental biology↗

Mechanistic studies of autophagic cargo recruitment and membrane expansion through in vitro reconstitution

Autophagy is a highly conserved catabolic pathway to remove deleterious cytosolic material to maintain cellular homeostasis and cell survival. Upon autophagy induction, a unique double-membraned structure, called a phagophore, forms and expands into a cup shape to engulf these cytosolic substrates. ATG8 proteins are covalently conjugated to autophagic membranes by lipidation of phosphatidylethanolamine (PE) and are thought to localise on both sides of the phagophore membrane. ATG8 conjugated on the inner membrane of the phagophore recruits autophagy cargo receptors, such as p62. To recapitulate events on the inner membrane, we used giant unilamellar vesicles (GUVs) as a model membrane and encapsulated proteins of interest inside GUVs, thus generating a membrane platform to which ATG8 proteins could be localised on the inner leaflet of the vesicles. We reconstituted WIPI2b-directed and cargo-directed ATG8 lipidation inside the GUVs and revealed distinct roles of WIPI2b and p62 in initiating the ATG conjugation cascade. Furthermore, we showed that p62 or p62 droplets were recruited to the inner membrane of the GUVs though interaction with membrane-bound ATG8s. Using a bead-based membrane expansion assay, we demonstrated a redistribution and local enrichment of membrane-bound ATG8s across the membrane upon interaction with p62 and p62 droplets. Our study provides novel model systems to investigate the interactions on the inner membrane of the phagophore and reveals fundamental molecular insights into phagophore membrane bending. This process is directed by ATG8-cargo interaction, during which cargo receptors concentrate ATG8 proteins on the inner surface of the phagophore membrane.

biochemistry↗

Mapping histological and functional maturation of human endocrine pancreas across early postnatal periods

Human endocrine cell differentiation and islet morphogenesis play critical roles in determining islet cell mass and function, but the events and timeline of these processes are incompletely defined. To better understand early human islet cell development and maturation, we collected 115 pediatric pancreata and mapped morphological and spatiotemporal changes from birth through the first ten years of life. Using quantitative analyses and a combination of complementary tissue imaging approaches, including confocal microscopy and whole-slide imaging, we developed an integrated model for endocrine cell formation and islet architecture, including endocrine cell type heterogeneity and abundance, endocrine cell proliferation, and islet vascularization and innervation. We also assessed insulin and glucagon secretory profiles in isolated islet preparations from pediatric donors aged 2 months to 10 years and found a temporal difference in the maturation of insulin secretion compared to glucagon secretion. This comprehensive summary of postnatal and pediatric pancreatic islet development provides a framework for future studies and integration of emerging genetic and genomic data related to islet biology and diabetes risk.

developmental biology↗

Heterogeneous endocrine cell composition defines human islet functional phenotypes

Phenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers, enabling the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes, analyzed using this pipeline, highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While and {beta} cell composition influenced insulin and glucagon secretory traits, the abundance of {delta} cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and {beta} cell replacement therapy.

physiology↗

The V-ATPase/ATG16L1 axis is controlled by the V1H subunit

Defects in organellar acidification indicate compromised or infected compartments. Recruitment of the autophagy-related ATG16L1 complex to pathologically de-acidified compartments targets ubiquitin-like ATG8 molecules to perturbed membranes. How this process is coupled to pH gradient disruption is unclear. Here, we reveal a direct role for the V1H subunit of the V-ATPase proton pump in recruiting ATG16L1. The interaction between V1H and ATG16L1 occurs within assembled V-ATPases, but not dissociated V1 complexes. This selectivity allows recruitment to be coupled to changes in V-ATPase assembly that follow pH dissipation. Cells lacking V1H undergo canonical macroautophagy but are unable to recruit ATG16L1 in response to influenza infection or ionophore drugs. We identify a loop within V1H that mediates ATG16L1 binding, which is absent in a neuronal isoform of V1H. Thus, V1H controls ATG16L1 recruitment in response to proton gradient dissipation, suggesting that the V-ATPase acts autonomously as a cell-intrinsic damage sensor.

molecular biology↗

Temperature elevation synergises with and enhances the type-I IFN-mediated restriction of MPXV

Fever is an evolutionary conserved host pro-inflammatory immune response that governs the regulation of multiple biological processes to control the outcome of infection. In January 2022, the World Health Organization (WHO) reported a global outbreak in mpox cases with a high incidence of human-to-human transmission. A frequent prodromal symptom of monkeypox virus (MPXV) infection is fever, with a febrile temperature range of 38.3 to 40.5 {degrees}C. However, the outcome of temperature elevation on MPXV infection remains poorly defined. Here, we isolated a circulating strain of MPXV from a patient who presented with fever (38.5 {degrees}C) and rash from the 2022 outbreak. Genomic sequencing identified this isolate to belong to the epidemic Clade IIb.B1. Transcriptomic analysis of infected cells demonstrated this virus to induce a strong IL6 pro-inflammatory immune response, consistent with a role for this pyrogen in the regulation of fever. We identify host-cell temperature at both physiological skin (33 {degrees}C) and clinical febrile temperatures (38.5 and 40 {degrees}C) to be a key determinant in the outcome of infection through the differential regulation of MPXV transcription and associated amplitude of host cytokine response to infection. Incubation of infected cells at 38.5 or 40 {degrees}C led to a restriction or ablation in MPXV replication, respectively. Importantly, this thermal inhibition was reversible upon temperature downshift to 37 {degrees}C without detriment to viral replication fitness. Co-stimulation of the type-I interferon (IFN) response led to a dose- and temperature-dependent inhibition in MPXV replication that restricted the re-establishment of infection upon temperature downshift and withdrawal of IFN as an immune stimulus. Our data identify febrile temperatures associated with mpox disease to be a critical component of the host pro-inflammatory immune response to infection which can synergise with the type-I IFN response to enhance the host-cell mediated restriction of MPXV.

microbiology↗

Context and Attention Shape Electrophysiological Correlates of Speech-to-Language Transformation

To transform speech into words, the human brain must accommodate variability across utterances in intonation, speech rate, volume, accents and so on. A promising approach to explaining this process has been to model electroencephalogram (EEG) recordings of brain responses to speech. Contemporary models typically invoke speech categories (e.g. phonemes) as an intermediary representational stage between sounds and words. However, such categorical models are typically hand-crafted and therefore incomplete because they cannot speak to the neural computations that putatively underpin categorization. By providing end-to-end accounts of speech-to-language transformation, new deep-learning systems could enable more complete brain models. We here model EEG recordings of audiobook comprehension with the deep-learning system Whisper. We find that (1) Whisper provides an accurate, self-contained EEG model of speech-to-language transformation; (2) EEG modeling is more accurate when including prior speech context, which pure categorical models do not support; (3) EEG signatures of speech-to-language transformation depend on listener-attention.

neuroscience↗

A strict requirement in proteasome substrates for spacing between ubiquitin tag and degradation initiation elements

Proteins are typically targeted to the proteasome for degradation through the attachment of ubiquitin chains and the proteasome initiates degradation at a disordered region within the target protein. Yet some proteins with ubiquitin chains and disordered regions escape degradation. Here we investigate how the position of the ubiquitin chain on the target protein relative to the disordered region modulates degradation and show that the distance between the two determines whether a protein is degraded efficiently. This distance depends on the type of the degradation tag and is likely a result of the separation on the proteasome between the receptor that binds the tag and the site that engages the disordered region.

biochemistry↗

Maresin 1 Repletion Improves Muscle Regeneration After Volumetric Muscle Loss

The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and improved myogenesis, leading to enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.

physiology↗