Biology subjects

Baldo, F.

Publications and source records attributed to Baldo, F..

3 recordsLinked to original sources

bioRxiv2026

An amyloid-β/APP regulatory layer in human brown adipocyte recruitment identifies repurposable drugs for thermogenic fat expansion

Brown adipose tissue (BAT) increases energy expenditure but is scarce in adults, yet most strategies focus on activating existing thermogenic adipocytes rather than recruiting new ones. We integrate human single-nucleus transcriptomics with protein-interaction and knowledge-graph analyses to identify stage-specific, druggable programmes governing brown adipogenesis. This pipeline resolved four ordered transcriptional states and three transitions, revealing an amyloid-{beta}/APP regulatory layer and nominating APP as a central signalling hub. Most prioritised compounds altered differentiation or metabolic phenotype, several substantially. Phenserine (APP-lowering) and sacubitril (neprilysin inhibitor) promoted differentiation through distinct mechanisms and stages and could be combined sequentially for benefit. Phenserine increased differentiation across three human models and, in mice, expanded BAT mass and increased thermogenic capacity. Together, these findings reveal targetable control points in human brown adipocyte recruitment, nominate repurposable drugs for BAT expansion, and establish a generalisable framework coupling single-cell transcriptomics with network-based drug repurposing across staged biological systems.

cell biology↗

bioRxiv2024

Dissecting compounded hepatocyte injury in a model of MASLD progression from human induced pluripotent stem cells

Drug discovery for multifactorial diseases like metabolic dysfunction-associated steatotic liver disease (MASLD) remains challenging due to inadequate models and untargeted drug screenings. We combined stem-cell-based modeling with computational drug predictions identifying flavin pathways as therapeutic targets in MASLD. For disease stage-specific discovery, we established a MASLD testing model, compounding metabolic triggers to intensify mitochondrial crisis. In vitro injuries included adipo- and myokines, immune cell co-culture, and genomic risk factors. Benchmarking experiments revealed similarities with advanced human MASLD. To query therapeutic compounds, protein-protein-interaction networks, weighted gene co-expression, and knowledge graph-based analyses independently predicted flavin adenine dinucleotide (FAD) as an anti-MASLD factor. Dysregulated flavoproteomes in vitro and in vivo-in pediatric and adult MASLD patients- supported our flavin network-focused strategy. We established therapeutic FAD concentrations to mitigate metabolic injury and fibro-inflammation in human multicellular liver organoids and other assays. We enhanced therapeutic FAD effects through genetic mitochondrial biogenic augmentation and identified orally available flavo-active compounds--including Aspirin--restoring mitochondrial respiration. Our study demonstrates how integrating stem cell-derived disease modeling with computed drug predictions can expedite therapeutic discovery.

cell biology↗

bioRxiv2023

Rare but not absent: the Inverted Mitogenomes of Deep-Sea Hatchetfish

Mitochondrial genomes are by definition compact and structurally stable over aeons. This generalized perception results from a vertebrate-centric vision, as very few types of mtDNA rearrangements have been described in vertebrates. By combining a panel of sequencing approaches, including short- and long-reads, we show that species from a group of illusive marine teleosts, the deep-sea hatchetfish (Stomiiforms: Sternoptychidae), display a myriad of new mtDNA structural arrangements. We show a never reported inversion of the coding direction of protein-coding genes (PGG) coupled with a strand asymmetry nucleotide composition reversal directly related to the strand location of the Control Region (which includes the heavy strand replication origin). An analysis of the 4-fold redundant sites of the PCGs, in thousands of vertebrate mtDNAs, revealed the rarity of this phenomenon, only found in 9 fish species, five of which are deep-sea hatchetfish. Curiously, in Antarctic notothenioid fishes (Trematominae), where a single PCG inversion (the only other record in fish) is coupled with the inversion of the Control Region, the standard asymmetry is disrupted for the remaining PCG but not yet reversed, suggesting a transitory state in this species mtDNA. Together, our findings hint that a relaxation of the classic vertebrate mitochondrial structural stasis, observed in Sternoptychidae and Trematominae, promotes disruption of the natural balance of asymmetry of the mtDNA. Our findings support the long-lasting hypothesis that replication is the main molecular mechanism promoting the strand-specific compositional bias of this unique and indispensable molecule.

genomics↗