Biology subjects

Cordero, M.

Publications and source records attributed to Cordero, M..

7 recordsLinked to original sources

bioRxiv2026

Pushing for survival: Spatial intermixing and indirect resistance enable collective growth

The survival of bacterial communities depends on complex dynamics at molecular, cellular, and ecosystem levels. Understanding antibiotic resistance requires a broader community context, as emergent dynamics can lead to unexpected outcomes, such as the persistence of susceptible populations or community collapse. We capture these behaviors by integration of microscopy and mathematical modeling to understand how bacterial interactions and spatial organization shape bacteriostatic antibiotic resistance in a two-strain community. We show that local chloramphenicol detoxification and mechanical pushing shape bacterial coexistence and spatial organization, promoting the survival and growth of otherwise susceptible bacteria. Additionally, the timing of antibiotic administration critically determines the growth dynamics, co-existence, local diversity of susceptible and resistant bacteria, and overall community resistance. Together, these insights highlight how community-level interactions fundamentally reshape antibiotic responses and open new avenues to understand and control bacterial resilience. SIGNIFICANCE STATEMENTAntibiotic resistance is usually treated as a property of individual bacterial strains, yet bacteria typically grow in dense, spatially structured communities where physical interactions matter. We find that under bacteriostatic (growth pausing) antibiotic stress, resistant bacteria can create highly localized protective environments that allow sensitive cells to survive and proliferate. This protection arises not only from antibiotic detoxification, but also from growth-driven mechanical pushing that maintains close cell-cell proximity. As a result, antibiotic tolerance emerges as a collective, spatially dependent property rather than an intrinsic trait of single cells. These findings show that spatial organization, physical forces, and treatment timing can strongly reshape therapy outcomes, with implications for how resistance is understood and managed in microbial communities.

biophysics↗

bioRxiv2026

Combinatorial base editing couples disease correction with lineage amplification in hematopoietic stem and progenitor cells

First-generation genome editing therapies have largely focused on correcting or compensating for pathogenic variants. However, as these approaches enter the clinic, emerging biological constraints limit maximal therapeutic impact. Because globin genes are activated late during erythroid differentiation, genome-corrected hematopoietic stem and progenitor cells (HSPCs) gain little selective advantage in the bone marrow. Here, we establish a strategy that links therapeutic genome edits to an erythroid fitness-enhancing allele to amplify the output of clinically relevant cells. We develop a multiplex base editing strategy that couples fetal hemoglobin (HbF) reactivation with erythroid lineage expansion. Introduction of a naturally occurring erythropoietin receptor truncation (tEPOR) associated with benign erythrocytosis increased erythroid cell production without impairing viability or differentiation. Combinatorial editing of tEPOR together with the BCL11A erythroid enhancer and HBG1/2 promoters in healthy donor, sickle cell disease, and {beta}-thalassemia HSPCs synergistically increased erythroid proliferation and HbF expression beyond single base-edited or Casgevy-treated controls. Multiplex base-edited HSPCs retained long-term lineage repopulation and engraftment capacity in vivo, establishing a modular strategy that pairs disease correction with lineage amplification to improve therapeutic potency.

cell biology↗

bioRxiv2025

Integrated single-nuclei and spatial transcriptomic profiling of human sacrococcygeal teratomas reveals heterogeneity in cellular composition and X-chromosome inactivation

Sacrococcygeal teratomas (SCTs) are the most common neonatal tumors, yet their cellular origins, clinical stratification, and sex bias-occurring three times more in XX than XY individuals--remain poorly understood. To address these gaps, we examined six postnatal (one male and five female) and two prenatal (both female) SCTs by single nuclei RNA-seq and spatial transcriptomics. We identified five broad cellular lineages in SCTs: stroma, epithelia, endothelia, neuroectoderm, and immune. The transcriptomes and lineage compositions showed significant heterogeneity, which offer a framework for future molecular stratification. SCTs are thought to originate from and be propagated by pluripotent cells, notably however, we did not detect these populations. Among female tumors, a subset of cells exhibited biallelic expression of X-linked genes, consistent with X-inactivation failure or reactivation of the once inactivated X-chromosome. These biallelic cells were enriched for developmental and neuronal programs, whereas cells with single-allelic X-chromosome preferentially expressed immune-related genes. Biallelic X-chromosome activation, which can occur only in female cells, may result in transcriptomic features that favor survival of tumor cells, contributing to the sex bias of SCTs. Our findings reveal a link between X-chromosome inactivation and SCT cell identity, suggesting that X-dosage dysregulation may influence SCT heterogeneity and immune landscape.

cancer biology↗

bioRxiv2025

In utero lipid nanoparticle delivery achieves robust editing in hematopoietic stem cells.

Efficient delivery of genome editing reagents to hematopoietic stem cells (HSCs) has limited the development of in vivo gene editing therapies for hematologic disease. Here, we exploit developmental hematopoiesis to enable HSC targeting using clinically scalable lipid nanoparticles (LNPs). During fetal development, HSCs reside in the liver, a tissue that is efficiently accessed by LNPs. We show that in utero delivery of LNPs carrying Cre recombinase or CRISPR-Cas9 components results in transfection and genome editing of bona fide long-term repopulating HSCs. Edited HSCs maintain multilineage reconstitution capacity following transplantation, demonstrating preserved stem cell function. Comparative studies reveal that both fetal and early neonatal delivery permit HSC editing, with greater efficiency during fetal liver hematopoiesis. We further identify an LNP formulation that enhance HSC targeting and enable robust neonatal HSC editing without antibody-mediated targeting. Finally, combined delivery of Cas9 via LNPs and a repair template via adeno-associated virus in neonatal mice enables in vivo homology-directed repair in multiple tissues. Together, these findings establish the perinatal period as a therapeutic window for in vivo HSC genome editing and provide a scalable strategy for treating severe early-onset hematologic diseases.

cell biology↗

bioRxiv2024

Cell aspect ratio is a mechanical winning strategy in microbial competition

Bacterial competition shapes community architecture, yet a universally conserved determinant remains elusive. We show that cell aspect ratio -a simple morphological feature- confers a competitive advantage. Using growth-based range expansion experiments, we show that longer bacteria conquer the expanding front, even when initially in minority. Using an agent-based model of dividing bacteria, to isolate the effect of aspect ratio, we reveal that the takeover mechanism is collective alignment: groups of locally aligned bacteria form "nematic arms" bridging the central region of the colony to the expanding front. Once at the front, bacteria align parallel to it and block shorter bacteria from access to nutrients and space. We confirm this observation with single-cell experiments and further generalise our findings by introducing a generic continuum model of alignment-dominated competition, explaining both experimental and cell-based model observations. Moreover, we extend our predictions to spherical range expansions and confirm the competitive advantage, even though the effect is less pronounced than in surface-attached colonies. Our results uncover a simple, yet hitherto overlooked, mechanical mechanism determining the outcome of bacterial competition, which is potentially ubiquitous among various bacteria. Current advances in genetic engineering enable aspect ratio tuning as a mechanism with broad implications for biofilm control.

biophysics↗

bioRxiv2022

Motility mediates satellite formation in confined biofilms

Bacteria have spectacular survival capabilities and can spread in many, vastly different environments. For instance, when pathogenic bacteria infect a host, the cells expand through proliferation and squeezing through narrow pores and elastic matrices. However, the exact role of surface structures and matrix elasticity in colony expansion and morphogenesis is still largely unknown. Here we show how satellite colonies emerge around biofilms embedded in semi-soft agar in controlled in vitro assays. We tested how extra-cellular structures - important for biofilm formation and motility - control this morphology. Moreover, we identify the range of extra-cellular matrix elasticity, where this morphology is possible. When paralleled with mathematical modelling, our results demonstrate that satellite formation allows bacterial communities to spread faster. We anticipate that this strategy is important to speed up expansion in various environments while retaining the close interactions and protection provided by the community.

biophysics↗

bioRxiv2019

Specific domains of early parenting, their heritability and differential association with adolescent behavioural and emotional disorders and academic achievement

BackgroundVariations in parenting across large populations have rarely been described. It also remains unclear which specific domains of parenting are important for which specific offspring developmental outcomes. The study describes different domains of early parenting behaviours, their genetic heritability, and then determines the extent to which specific domains of parenting are associated with later offspring outcomes.\n\nMethodsParenting behaviours (birth to 3 years) were extracted from self-reported questionnaires administered to 12,358 mothers from the UK-based birth cohort study, the Avon Longitudinal Study of Parents and Children, and modelled as a latent factor using Confirmatory Factor Analysis. Genetic heritability and correlations between parenting factors were estimated using wide complex trait analysis. Offspring emotional, behavioural and academic outcomes were assessed at age 16 years using the self-reported Short Mood and Feelings Questionnaire, the Development and Well-Being Assessment, and grades achieved in national English Language examination.\n\nResultsThree parenting factors were derived: parental enjoyment, conflictual relationships and stimulation; all showed low genetic heritability. There was no evidence of associations between parenting factors and offspring depressed mood. Stimulation was associated with better English grades after controlling for maternal education (standardised {beta}=0.058, p=0.007), and enjoyment was negatively associated with English grades ({beta}=-0.082, p=0.002). Conflictual relationships were associated with higher risk of offspring behavioural disorders after controlling for behavioural problems at age 3 years ({beta}=0.227, p=0.007). Higher enjoyment reduced the association between conflict and behavioural problems (interaction term {beta}=0.113, p<0.001).\n\nConclusionsWe found evidence for predictive specificity of early parenting domains for offspring outcomes in adolescence. Early stimulation, unlike enjoyment, promoted later educational achievement. Conflictual relationships were associated with greater risk of behavioural problems, buffered by increased enjoyment. These findings hold implications for parenting interventions, guiding their focus according to specificity of parenting domains and their long-term outcomes in children.

epidemiology↗