Biology subjects

Leon, L.

Publications and source records attributed to Leon, L..

5 recordsLinked to original sources

bioRxiv2025

DINOcell: Learning Generalizable Perturbation Effects through Self-Distillation

AO_SCPLOWBSTRACTC_SCPLOWPredicting cellular responses to therapeutics is a promising approach for novel target discovery. However, state-of-the-art computational models designed to predict perturbation effects struggle to generalize and outperform simple baselines. We present DINOcell, a weakly supervised framework that adapts self-distillation to single-cell transcriptomics for predicting perturbation effects. We demonstrate that DINOcell outperforms baselines in predicting the effects of single gene perturbations. Furthermore, DINOcell accurately predicts non-additive effects of combination perturbations, indicating its capacity to model complex genetic interactions. Finally, we show that DINOcell learns representations that capture biological signals and is a promising, generalizable approach for in silico perturbation modeling, providing a valuable tool for accelerating therapeutic target discovery.

bioinformatics↗

bioRxiv2024

Tunable differentiation of human CD4+ and CD8+ T cells from pluripotent stem cells

SummaryAllogeneic T cell therapies are a highly desirable option to circumvent the cost and complexity of using autologous T cells to treat diseases. Allogeneic CD8+ T cells can be made from pluripotent stem cells (PSCs), but deriving CD4+ T cells from PSCs remained a significant challenge. Using feeder-and serum-free conditions, we found that CD4+ versus CD8+ T cell commitment from PSCs can be controlled by fine-tuning the dynamics of Notch and T cell receptor signaling delivered to CD4+CD8+ double positive T cells. Notch signaling negatively impacts CD4+ T cell commitment, and its timed removal allows generation of clonally-diverse and expandable CD4+ T cells from PSCs. The resulting CD4+ T cells respond to cytokine-mediated polarization by differentiating into Th1, Th2, or Th17 cells, recapitulating canonical helper cell function. These findings represent a significant step towards using PSC-derived CD4+ T cells as a low cost, off-the-shelf, cell therapy.

bioengineering↗

bioRxiv2024

Genomic Insights Guiding Personalized First-Line Immunotherapy Response in Lung and Bladder Tumors

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, particularly in advanced non-small cell lung cancer (NSCLC) and muscle-invasive bladder cancer (MIBC). However, identifying reliable predictive biomarkers for ICI response remains a significant challenge. In this study, we analyzed real-world cohorts of advanced NSCLC and MIBC patients treated with ICIs as first-line therapy. Tumor samples underwent Whole Genome Sequencing (WGS) to identify specific somatic variants and assess tumor mutational burden (TMB). Additionally, mutational signature extraction and pathway enrichment analyses were performed to uncover the underlying mechanisms of ICI response. We also characterized HLA-I haplotypes and investigated LINE-1 retrotransposition. Distinct mutation patterns were identified in patients who responded to treatment, suggesting potential biomarkers for predicting ICI effectiveness. In NSCLC, tumor mutational burden (TMB) did not differ significantly between responders and non-responders, while in MIBC, higher TMB was linked to better responses. Specific mutational signatures and HLA haplotypes were associated with ICI response in both cancers. Pathway analysis showed that NSCLC responders had active inflammatory and immune pathways, while non-responders had pathways such related to FGFR3 and neural crest differentiation associated to resistance mechanisms. In MIBC, responders had alterations in DNA repair, leading to more neoantigens and a stronger ICI response. Importantly, for the first time, we found that LINE-1 activation was positively linked to ICI response, especially in MIBC. These findings reveal promising biomarkers and mechanistic insights, offering a new perspective on predicting ICI response and opening up exciting possibilities for more personalized immunotherapy strategies in NSCLC and MIBC.

genomics↗

bioRxiv2023

The Small GTPase Rab7 Regulates Release of Mitochondria in Extracellular Vesicles in Response to Lysosomal Dysfunction

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

physiology↗

bioRxiv2021

Characterization of an Agarophyton chilense oleoresin containing PPARγ natural ligands with insulin-sensitizing effects in a C57BL/6J mouse model of diet-induced obesity and antioxidant activity in Caenorhabditis elegans.

The biomedical potential of the edible red seaweed Agarophyton chilense (former Gracilaria chilensis) has not been explored. Red seaweeds are enriched in polyunsaturated fatty acids and eicosanoids, which are known natural ligands of the PPAR{gamma} nuclear receptor. PPAR{gamma} is the molecular target of thiazolidinediones (TZDs), drugs used as insulin sensitizers to treat type 2 diabetes mellitus. TZDs medical use is limited due to undesired side effects, the fact that it has triggered the search for partial agonists without the TZDs side effects. We produced A.chilense oleoresin (Gracilex(R)) that induces the activation of PPAR{gamma} without inducing adipocyte differentiation, similar to PPAR{gamma} partial agonists. In a model of high-fat diet-induced obesity in male mice, we showed that treatment with Gracilex(R) improves insulin sensitivity, normalizing altered glucose and insulin parameters. Gracilex(R) was enriched in palmitic acid, arachidonic acid, oleic acid, and lipophilic antioxidants such as {beta}-carotene and tocopherols. Gracilex(R) possesses antioxidant activity in vitro (CUPRAC) and increased the antioxidant capacity in vivo in Caenorhabditis elegans. These findings support the idea that Gracilex(R) is an excellent source of healthy lipids targeting PPAR{gamma} with antioxidant activity and a high nutraceutical value.

physiology↗