Biology subjects

Dalan, R.

Publications and source records attributed to Dalan, R..

6 recordsLinked to original sources

bioRxiv2026

Gut Roseburia hominis-derived 10-hydroxystearic acid alleviates metabolic disorder by restoring hepatic fatty acid metabolism

Metabolic disorders and health-promoting dietary interventions represent complementary contexts of metabolic impairment and improvement, providing an opportunity to identify gut microbial taxa associated with both disease status and dietary response. Here, we integrated five independent human cohorts spanning metabolic disorders and dietary interventions and identified Roseburia hominis as a gut microbial taxon that consistently decreased in metabolic disorders and increased after dietary interventions. Beyond species abundance, strain-level genetic variation in R. hominis provided additional information for distinguishing metabolic disorder status and stratifying cardiometabolic severity. Integration of phenotype-associated variants with circulating metabolomics prioritized ohyA, encoding an oleate hydratase, as a candidate functional determinant linking R. hominis genetic variation to host metabolic heterogeneity. An ohyA-based genetic burden score was associated with adverse cardiometabolic traits and changed longitudinally during dietary intervention, while circulating metabolites statistically accounted for part of the associations between ohyA variants and host phenotypes. Functional experiments demonstrated that R. hominis OhyA protein converts oleic acid to 10-hydroxystearic acid (10-HSA), whereas an OhyA carrying five prioritized missense substitutions showed markedly impaired enzymatic activity. In high-fat diet-fed mice, 10-HSA attenuated body-weight gain, improved glucose homeostasis and insulin sensitivity, and reduced dyslipidemia and hepatic steatosis. Multi-omics profiling revealed limited remodeling of the gut microbiota but pronounced hepatic transcriptional and metabolic responses, characterized by activation of PPAR-associated lipid-metabolic pathways, altered fatty-acid oxidation and desaturation, and remodeling of hepatic lipid composition. Together, these findings establish a diet-responsive R. hominis-OhyA-10-HSA axis linking microbial variation to host metabolic dysfunction and show that 10-HSA can improve metabolic health in mice.

microbiology↗

bioRxiv2026

Gut microbial phenylalanine metabolism contributes to MASLD in a dietary protein-dependent manner

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly a third of adults worldwide, yet how diet shapes the microbiota's contribution remains unclear. In a diet-induced mouse model varying protein content independently of caloric intake, microbiota depletion ameliorated hepatic steatosis and liver injury under protein- sufficient but not protein-restricted conditions. Caecal and plasma metabolomics implicated microbial phenylalanine catabolism and its host conjugates phenylacetylglutamine (PAGln) and phenylacetylglycine (PAGly). PAGln supplementation exacerbated steatosis and liver injury without altering body weight, adiposity or glucose homeostasis. Individual-antibiotic perturbation with metagenomics linked bacterial phenylalanine catabolic capacity to disease severity, and in gnotobiotic mice, genetic disruption of bacterial phenylalanine-to-phenylacetic acid conversion lowered circulating conjugates and attenuated steatosis and fibrosis. In a human cohort, circulating PAGln was selectively elevated in cardiometabolic MASLD. These findings identify dietary protein availability as a modifier of the contribution of microbial phenylalanine metabolism to MASLD and highlight PAGln as a microbiota-derived metabolite that exacerbates hepatic disease.

microbiology↗

bioRxiv2026

The Proposed Bone Post-Arterial Type R Capillaries Resolve into Venous and Fatty Acid-Handling Endothelial Cells

Endothelial specialization is increasingly recognized as a fundamental regulator of tissue homeostasis, yet the cellular diversity of the skeletal vasculature remains incompletely resolved. Here, we integrate large-scale single-cell transcriptomics, cross-tissue comparisons, and imaging to comprehensively define endothelial heterogeneity across the skeleton. Our analyses demonstrate that the proposed post- arterial "type R" endothelial population is not a distinct endothelial subtype but instead comprises canonical venous endothelial cells and fatty acid-handling endothelial state. RNA velocity supports a venous continuum, while the proposed type R markers FMO2, and AQP7 lack both endothelial and skeletal specificity. The fatty acid-handling endothelial state, characterized by Lpl and Cd36 is conserved across multiple skeletal sites and non-skeletal tissues, indicating a general endothelial metabolic programme. Within bone, this endothelial state expands following high-fat diet and is suppressed during injury. Together, these findings redefine skeletal endothelial heterogeneity and establish the proposed type R population as part of a venous continuum.

cell biology↗

bioRxiv2025

Degeneration and Impaired Resilience of Skull Bone and Hematopoietic Bone Marrow

Bone marrow health is central to transplantations, blood formation, and cancer progression. However, the bone marrow niche deteriorates with age, impairing haematopoietic stem cell function. Contrary to a recent report1 suggesting skull marrow resists ageing, our multi-laboratory investigation reveals the opposite: the skull marrow is among the vulnerable sites of age-related decline. Ageing skull niches consistently show loss of mesenchymal and osteoprogenitors, suppression of angiogenic and lymphatic programs, adipocyte accumulation, vascular senescence, DNA replication stress, mitochondrial dysfunction, cellular senescence, and heightened inflammation. Proteomic profiling further highlights this vulnerability, demonstrating that vertebral niches--unlike the skull--are relatively spared from these ageing hallmarks. Together, these convergent datasets overturn the notion of skull-specific resilience and instead establish the skull marrow as a fragile, degenerating environment. These findings redefine marrow ageing and highlight the skull as a critical, clinically relevant target for sustaining blood and immune health and reducing vulnerability to haematological disease.

cell biology↗

bioRxiv2025

Sirtuin 1 is an endogenous NETosis inhibitor that becomes dysfunctional in diabetes

Neutrophils release their chromatin with toxic granular proteins as neutrophil extracellular traps (NETs) when activated. Diabetes exacerbates NET formation (NETosis), resulting in tissue damage and diabetic complications such as non-healing wounds. How diabetes predisposes neutrophils to NETosis remains unclear. Herein, we found that pharmacological inhibition or siRNA-knockdown of sirtuin 1 (SIRT1) increased NETosis in neutrophils of healthy humans and mice, unveiling SIRT1 as an endogenous suppressor of NETosis. In contrast, SIRT1 inhibition did not cause further increase in NETosis in neutrophils of diabetic patients and mice, indicative of SIRT1 dysfunction in disease state. Indeed, SIRT1 activity was significantly lower in neutrophils of diabetic individuals, accompanied by a concomitant increase in the activity of peptidylarginine deiminase 4 (PAD4), a key enzyme that mediates NETosis. PAD4 was co-detected with SIRT1 immunoprecipitated from HL-60-derived neutrophils cultured in basal glucose; such co- immunoprecipitation was absent in cells with high-glucose exposure, suggesting that hyperglycemia disrupts the SIRT1-PAD4 interaction. SIRT1 activators restored the SIRT1-PAD4 interaction and normalized the exacerbated NETosis and PAD4 activity in diabetes and hyperglycemia. This study reveals a novel regulatory role of SIRT1 on PAD4 activity. Revitalizing SIRT1 can be a new preventive or therapeutic strategy for combating NET-mediated inflammation in diabetes and beyond.

cell biology↗

bioRxiv2023

Isolating Small Extracellular Vesicles from Small Volumes of Blood Plasma using size exclusion chromatography and density gradient ultracentrifugation: A Comparative Study

Small extracellular vesicles (sEVs) are heterogeneous biological vesicles released by cells under both physiological and pathological conditions. Due to their potential as valuable diagnostic and prognostic biomarkers in human blood, there is a pressing need to develop effective methods for isolating high-purity sEVs from the complex milieu of blood plasma, which contains abundant plasma proteins and lipoproteins. Size exclusion chromatography (SEC) and density gradient ultracentrifugation (DGUC) are two commonly employed isolation techniques that have shown promise in addressing this challenge. In this study, we aimed to determine the optimal combination and sequence of SEC and DGUC for isolating sEVs from small plasma volumes, in order to enhance both the efficiency and purity of the resulting isolates. To achieve this, we compared sEV isolation using two combinations: SEC-DGUC and DGUC-SEC, from unit volumes of 500 l plasma. Both protocols successfully isolated high-purity sEVs; however, the SEC-DGUC combination yielded higher sEV protein and RNA content. We further characterized the isolated sEVs obtained from the SEC-DGUC protocol using flow cytometry and mass spectrometry to assess their quality and purity. In conclusion, the optimized SEC-DGUC protocol is efficient, highly reproducible, and well-suited for isolating high-purity sEVs from small blood volumes.

bioengineering↗