Biology subjects

Vujic, A.

Publications and source records attributed to Vujic, A..

5 recordsLinked to original sources

bioRxiv2026

Spatial imprints of emergent cardiomyocyte states in the pressure-overloaded heart

Resilience to cardiac stress is essential for health, yet the relationship between cardiomyocyte (CM) stress response and local microenvironment remains unclear. Here, we combined MERFISH spatial transcriptome profiling with Cellouette, an improved cell segmentation method, to determine CM-microenvironment relationships in a mouse model of ventricular pressure overload. We report the shape, transcription profile, spatial organization, and physical connectivity for >400,000 cells across stressed and healthy tissues. Under stress, CMs adopted a spectrum of emergent transcriptional states, with advanced states marked by a metabolic and pro-fibrotic shift. To discover CM-environment relationships, we performed a network analysis of physical cell connectivity combined with cell-type-specific profiling. We found that pro-fibrotic CM progression was tightly linked to distinct local microenvironments, and CM metabolic shifts could be inferred from transcriptional patterns in neighboring non-CM cells, revealing microenvironmental imprints of disease. We thus provide a resource for understanding the heterogeneity of outcome during cardiac pressure overload. HighlightsO_LICellouette provides accurate segmentation for single-cell spatial transcriptomics in cardiac tissue. C_LIO_LIPressure overload creates spatial gradients of cardiomyocyte pro-fibrotic states. C_LIO_LICardiomyocyte pro-fibrotic progression is linked to changes in local cell composition and gene expression. C_LIO_LITranscriptional states of non-muscle cells predict metabolic state of adjacent cardiomyocytes. C_LI

genomics↗

bioRxiv2025

Experimental enhancement of structural heterogeneity in forest landscapes promotes multidimensional hoverfly diversity.

O_LIThe homogenization of temperate forests due to intensive management has led to biodiversity loss at local and landscape scales, threatening species persistence and ecosystem functions. However, experimental evidence on how structural heterogeneity among forest patches influences diversity at the landscape scale is lacking. Here, we test whether enhancing structural heterogeneity, via diverse deadwood enrichment and canopy gap creation treatments (Enhancement of Structural Beta Complexity, ESBC), can increase hoverfly diversity within landscapes, and elucidate the contributions of local (-) diversity enrichment and turnover ({beta}-diversity) to this effect. C_LIO_LIWe conducted a large-scale forest experiment in 11 regions across Germany. Each region included two districts, representing small forest landscapes. In one district, we implemented patches with ESBC treatments, while in the other, serving as the control, we established patches without ESBC. Hoverflies were sampled in three seasonal intervals and across, in total, 234 forest patches (50 x 50 m) using pan traps. We applied a new integrative meta-analytic framework that incorporates sample completeness to quantify taxonomic, functional, and phylogenetic diversity (TD, FD, PD) using Hill numbers at , {beta}, and {gamma} scales. C_LIO_LIAll three {gamma}-diversity dimensions - TD, FD, and PD - were significantly higher in structurally heterogeneous forest landscapes than in homogeneous ones. The strongest effects were observed for TD, indicating functional and phylogenetic redundancy among species. Effect sizes declined with increasing order of Hill numbers, suggesting that rare species benefit most from structural heterogeneity. C_LIO_LIIn most regions, {gamma}-diversity gains were driven by increases in -diversity rather than {beta}-diversity, highlighting the importance of interventions to increase local structural complexity. However, several regions also showed elevated {beta}-diversity, indicating context-dependent effects of spatial heterogeneity. C_LIO_LIOur results provide the first experimental evidence that enhancing structural heterogeneity at the landscape scale can restore multi-dimensional insect diversity in temperate forests. They underscore the management value of ESBC as a scalable tool to restore biodiversity, increase ecological resilience, and counteract biotic homogenization in production forests. C_LI

ecology↗

bioRxiv2024

Altered systemic bioenergetic reserve in chronic kidney disease predisposes hearts to worse functional outcomes

BackgroundCardiovascular mortality in chronic kidney disease (CKD) remains disproportionately high, yet the mechanisms linking renal dysfunction to cardiac vulnerability are incompletely understood. Uraemic cardiomyopathy is increasingly recognised as a systemic metabolic disease, but the contribution of multi-organ bioenergetic failure in cardiac dysfunction is poorly defined. HypothesisCKD induces metabolic remodelling across peripheral organs (liver, skeletal muscle, and kidneys) depleting systemic bioenergetic reserve, compromising cardiometabolic flexibility and stress resilience. MethodsUsing CKD models of different aetiologies in rats (glomerulosclerosis by partial nephrectomy and interstitial fibrosis by adenine diet) we investigated cardiac and systemic metabolic remodelling. ResultsIrrespective of aetiology, renal insufficiency resulted in cardiac dysfunction including impaired functional recovery after 25-minutes ischaemia. 1H NMR metabolomic analysis revealed perturbations of systemic metabolism in CKD were more severe than cardiometabolic changes with alterations of skeletal muscle, liver, and kidney metabolism indicating reduced systemic bioenergetic reserve. This pre-clinical observation was recapitulated in human CKD patients where phosphorus magnetic resonance spectroscopy assessment of exercising lower leg muscle identified bioenergetic deficiencies preventing maximal force generation. Thus, both heart and skeletal muscles in CKD have impaired response to metabolic stress. ConclusionsCKD induces multi-organ metabolic failure that limits the hearts ability to meet energetic demands under stress. This study identifies systemic bioenergetic collapse as a contributing factor to uraemic cardiomyopathy, thus targeting peripheral organ metabolism may represent a novel therapeutic strategy to improve cardiac outcomes in CKD. Key learning pointsO_ST_ABSWhat Was KnownC_ST_ABSCKD significantly increases cardiovascular risk, but the cause of heart failure in these patients is largely attributed to cardiac pathology alone whilst the potential contribution of systemic metabolic dysfunction remains unexplored. What This Study AddsUtilising clinical and pre-clinical approach we show that CKD triggers widespread metabolic dysfunction in the liver, skeletal muscle, and kidney, depleting the systemic bioenergetic reserve and impairing the hearts ability to handle metabolic stress. Potential ImpactThese findings show uraemic cardiomyopathy is a multi-organ metabolic disease and targeting peripheral metabolic dysfunction could offer a new therapeutic strategy to enhance cardiac resilience by restoring systemic energy balance.

physiology↗

bioRxiv2023

A transient modified mRNA encoding Myc and Cyclin T1 induces cardiac regeneration and improves cardiac function after myocardial injury

Cardiac injury, such as myocardial infarction (MI), results in permanent loss of cardiomyocytes and in many cases heart failure. Transgenic expression of the pro-proliferative transcription factor Myc and Cyclin T1 can drive substantial adult cardiomyocyte proliferation to replace lost cardiomyocytes. Herein, we show that Myc and Cyclin T1 induced cardiomyocyte proliferation leads to myocardial repair and functional (long-term) recovery post-MI in mice. To provide a more translational approach, we developed modified mRNA (modRNA) encoding Myc-Ccnt1 as a transient and non-integrating strategy for regeneration. One dose of Myc-Ccnt1 modRNA is sufficient to transiently drives cardiomyocyte proliferation in human pluripotent stem cell-derived cardiomyocytes and a mouse MI model, where it leads to better heart function. Using single nuclei sequencing and proteomics, we show this was functionally mediated by transcriptional activation of cell-cycle regulating genes, which ultimately results in mitosis and cytokinesis of cardiomyocytes. Collectively, these findings indicate that Myc-Ccnt1 modRNA has the potential to be an effective regenerative therapeutic.

molecular biology↗

bioRxiv2022

Functional substitutions of amino acids that differ between GDF11 and GDF8 impact skeletal development and skeletal muscle.

Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGF{beta} family proteins that interact with nearly identical signaling receptors and antagonist proteins. However, GDF11 appears to activate SMAD2/3 in vitro and in vivo more potently than GDF8. The ligands possess divergent structural properties, whereby substituting unique GDF11 amino acids into GDF8 enhanced activity of the resulting chimeric GDF8. We investigated potentially distinct endogenous activities of GDF11 and GDF8 in vivo by genetically modifying their mature signaling domains. Full recoding of the GDF8 mature domain to that of GDF11 yielded mice lacking GDF8, with GDF11 levels [~]50-fold higher than normal, and exhibiting modestly decreased muscle mass, with no apparent negative impacts on health or survival to adulthood. Substitution of two specific amino acids in the fingertip region of GDF11 with the corresponding GDF8 residues resulted in prenatal axial skeletal transformations, consistent with Gdf11-deficient mice, without apparent perturbation of skeletal or cardiac muscle development or homeostasis. These experiments uncover distinctive features between the GDF11 and GDF8 mature domains in vivo and identify specific requirement for GDF11 in early-stage skeletal development. Summary StatementReplacement of amino acids unique to GDF11 and GDF8 into the native locus of the other ligand yields measurable, differential skeletal and muscle phenotypes, revealing distinct features between the ligands.

developmental biology↗