Biology subjects

Menezes, R.

Publications and source records attributed to Menezes, R..

5 recordsLinked to original sources

bioRxiv2025

Mitochondrial Dysfunction in Endothelial Cells Drives Greater Vascular Impairment in Females with Diabetes-Associated Peripheral Artery Disease

BackgroundWomen with peripheral artery disease (PAD) experience poorer clinical outcomes than men, particularly in the setting of diabetes. However, the mechanistic basis for these sex- specific disparities remains unclear. MethodsHere, we investigated endothelial cell (EC) function(s) in diabetes-associated PAD, with a focus on sex differences. Limb tissues from patients with diabetes and chronic limb-threatening ischemia (CLTI) undergoing amputation, and a diabetes mouse model of hindlimb ischemia (HLI), were assessed for vasodilatory capacity, angiogenesis, oxidative stress and changes to expression of mitochondrial complex genes. ECs exposed to a hyperglycemic environment in vitro were assessed for mitochondrial function. The therapeutic potential of the mitochondrial-targeted antioxidant MitoQ was investigated. ResultsECs from females with diabetes-associated PAD have altered responses compared to males. Specifically, limb vessels and skeletal muscle from females exhibit reduced arterial relaxation, angiogenesis and increased oxidative stress in response to HLI in mice, and in tissues from patients. Single-cell RNA sequencing of murine limbs revealed marked suppression of EC mitochondrial complex genes in females with diabetes. Female human ECs exposed to high glucose had reduced respiration, reduced expression of mitochondrial genes and increased oxidative stress. Remarkably, MitoQ restored arterial relaxation and the angiogenic response in female diabetes- associated PAD. ConclusionOur findings uncover a striking sex-specific vulnerability involving oxidative stress and mitochondrial dysfunction in EC health in diabetes-associated PAD. These results highlight the need for sex-specific therapeutic strategies in diabetic PAD, which might include mitochondrial targeted antioxidant strategies.

pathology↗

bioRxiv2025

Urolithin B reduces the aggregate load of islet amyloid polypeptide in Caenorhabditis elegans

The progressive loss of pancreatic {beta}-cells is one of the defining features of Type 2 Diabetes Mellitus (T2DM), and is thought to be driven by the aggregation of islet amyloid polypeptide (IAPP). This highly amyloidogenic pancreatic hormone is co-secreted with insulin, and its elevated secretion can lead to toxic fibrillar aggregation. Despite numerous studies focusing on understanding the molecular mechanisms of IAPP aggregation, few therapeutic strategies exist to counter its toxicity. Urolithin B is a natural metabolite derived from the digestion and intestinal microbiota action on ellagitannin-rich foods. This compound was suggested to counteract IAPP aggregation and toxicity in silico and in yeast models expressing human IAPP. In this study, we focused on the protective potential of urolithin B using our previously characterised transgenic Caenorhabditis elegans IAPP-GFP model. We report that urolithin B reduces the levels of insoluble IAPP-GFP in the body wall muscle cells, while the mitochondrial association of IAPP-GFP remains unaltered. We show that the C. elegans model exhibits a reduced lifespan compared to controls, providing in vivo evidence of the toxic effects associated with IAPP-GFP expression. The lifespans of IAPP-GFP versus control animals were differentially modulated by urolithin B treatment, suggesting an interplay between the metabolite and IAPP-GFP mediated toxicity. To further elucidate the mode of action of urolithin B, we conducted in vitro assays and found no evidence of direct interaction with lipid-associated IAPP, suggesting that its effects are not mediated by interference with IAPP-membrane interactions. These results pave the way for further therapeutic developments targeting IAPP aggregation in T2DM.

biochemistry↗

bioRxiv2025

The range-resident logistic model: a new framework to formalize the population-dynamics consequences of range residency

Individual movement is critical in shaping population dynamics. However, existing frameworks linking these two processes often rely on unrealistic assumptions or numerical simulations. To address this gap, we introduce the range-resident logistic model, an easy-to-simulate and mathematically tractable extension of the spatial logistic model that incorporates empirically supported range-resident movement. Our framework unifies non-spatial and (sessile) spatial formulations of the logistic model as limiting cases. Between these regimes, the long-term population size depends nonlinearly on home-range size and spatial distribution. Neglecting range residency can hence lead to under- or overestimating population carrying capacity. To better understand these results, we also introduce a novel crowding index that depends on movement parameters and can be estimated from tracking data. This index captures the influence of spatial structure on population size, and serves as a robust predictor of abundance. The range-resident logistic model is thus a unifying framework bridging movement and population ecology.

ecology↗

bioRxiv2023

A chromatin-associated regulator of RNA Polymerase III assembly at tRNA genes revealed by locus-specific proteomics

Transcription of tRNA genes by RNA Polymerase III (RNAPIII) is tightly regulated by signaling cascades in response to nutrient availability. The emerging notion of differential tRNA gene regulation implies the existence of additional regulatory mechanisms. However, tRNA gene-specific regulatory factors have not been described. For that reason, we decoded the proteome of a single native tRNA gene locus in yeast. We observed dynamic reprogramming of the core RNAPIII transcription machinery upon nutrient perturbation. In addition, we identified Fpt1, a protein of unknown function. Fpt1 uniquely occupied tRNA genes but its occupancy varied and correlated with the efficiency of RNAPIII eviction upon nutrient perturbation. Decoding the proteome of a tRNA gene in the absence of Fpt1 revealed that Fpt1 promotes eviction of RNAPIII. Cells without Fpt1 also showed impaired shutdown of ribosome biogenesis genes upon nutrient perturbation. Our findings provide support for a chromatin-associated mechanism required for RNAPIII eviction from tRNA genes and for tuning an integrated physiological response to changing metabolic demands. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/534528v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1b2ef53org.highwire.dtl.DTLVardef@7e6234org.highwire.dtl.DTLVardef@1614b5borg.highwire.dtl.DTLVardef@9a4933_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2019

Isothermal Digital Detection Of MicroRNA Using Background-Free Molecular Circuit

MicroRNA, a class of transcripts involved in the regulation of gene expression, are emerging as promising disease-specific biomarkers accessible from tissues or bodily fluids. However, their accurate quantification from biological samples remains challenging. We report a sensitive and quantitative microRNA method using an isothermal amplification chemistry adapted to a droplet digital readout. Building on molecular programming concepts, we design DNA circuit that converts, threshold, amplifies and report the presence of a specific microRNA, down to the femtomolar concentration. Using a leak-absorption mechanism, we were able to suppress non-specific amplification, classically encountered in other exponential amplification reactions. As a result, we demonstrate that this isothermal amplification scheme is adapted to digital counting of microRNA: by partitioning the reaction mixture into water-in-oil droplets, resulting in single microRNA encapsulation and amplification, the method provides absolute target quantification. The modularity of our approach enables to repurpose the assay for various microRNA sequences.

molecular biology↗