Biology subjects

Molina, C.

Publications and source records attributed to Molina, C..

13 recordsLinked to original sources

bioRxiv2026

Photographic age gap is associated with frailty and predicts survival in laboratory mice

Ageing studies in mice need biomarkers that are cheap, non-invasive and repeatable. We asked how much of a mouse's age can be read from an ordinary photograph, and whether the part that cannot be explained by age carries biological information. We assembled 2,846 photographs of 1,292 mice (four strains, 1 to 34 months old) from seven facilities and predicted age with a frozen self-supervised vision model (DINOv2) and a ridge regression, always tested on facilities the model had never seen. Absolute age transferred poorly between facilities (median absolute error 138 days), because each facility's photographs carried an offset. Relative age transferred well: among mice photographed in the same session, the older mouse was predicted older in 65% of pairs, rising above 95% for age differences over 500 days, and the later photograph of the same mouse was predicted older in 63% of repeat pairs. Sex, in comparison, was inferred more reliably (87%). Mice predicted older than their age were frailer (+0.12 SD per 100 days) and had shorter survival (hazard ratio 1.14 per 100 days), and fourth generation (G4) telomerase-deficient mice looked 151 days older than their wild-type controls. Routine photographs therefore carry a real biological age signal that can be read at no extra cost, best used to compare mice photographed together.

systems biology↗

bioRxiv2025

Private QTLs and the Genetic Architecture of Hierarchical Size Traits: From Body Size to Sex-Specific Plasticity

Sex-specific size plasticity (SSP) is the phenomenon whereby the size of one sex is more environmentally sensitive than the other, and is thought to underlie the developmental regulation and evolution of sexual size dimorphism (SSD). Sex-specific plasticity is a higher order phenotype that emerges due to the effect of the environment and sex on core growth regulatory mechanisms. Genetic variation in SSP necessarily requires sex- and environment-specific variation in growth, yet the developmental-genetic mechanisms enabling such context-dependent size variation remain poorly understood. Using a genome-wide association study (GWAS) and functional validation in Drosophila melanogaster, we dissected the genetic architecture of body size, size plasticity, SSD, and SSP across 196 isogenic lineages. We find that each phenotype is governed by largely non-overlapping sets of loci, with most candidate variants lying outside canonical growth pathways. Instead, size trait are shaped by "private QTLs", whose effects are limited to specific sex, trait, or environmental contexts. Functional knockdown of selected candidate genes for SSP revealed that while most did not affect SSP directly, many influenced body size, SSD, and size plasticity, in a manner consistent with their nested phenotypic relationships. Together, our results suggest that context-dependent alleles in genes peripheral to core growth regulatory pathways drive variation in SSD and SSP, offering a mechanistic explanation for their evolutionary lability and highlighting the role of private QTLs in structuring complex trait architecture. Significance StatementSexual size dimorphism (SSD), the differences in body size between females and males, is highly variable among species and yet the developmental genetic mechanisms that generate it and drive its evolution remain elusive. Our work reveals a modular genetic architecture underlying SSD in Drosophila melanogaster, showing that variation in body size, its sex-specific plasticity, and the resulting SSD are controlled by largely non-overlapping, context-dependent loci. This finding provides critical insight into how complex morphological differences between the sexes are genetically organized, allowing for the flexible and independent evolution of hierarchical traits.

evolutionary biology↗

bioRxiv2025

Clonal Expansion of Alveolar Fibroblast Progeny Drives Pulmonary Fibrosis

Pulmonary fibrosis has been called a fibroproliferative disease but the functional importance of proliferating fibroblasts to pulmonary fibrosis has not been systematically examined. In response to alveolar injury, resting alveolar fibroblasts differentiate into fibrotic fibroblasts that express high levels of collagens. However, what role, if any, proliferation plays in the accumulation of fibrotic fibroblasts remains unclear. Through EdU incorporation, genetic lineage tracing, and single cell RNA sequencing, we resolve the proliferation dynamics of lung fibroblasts during post-injury fibrogenesis. Our data show substantial DNA replication in progeny of alveolar fibroblasts in two models of pulmonary fibrosis. By genetically labeling individual cells, we observe clonal expansion of alveolar fibroblast descendants principally in regions of fibrotic remodeling. The transcriptome of proliferating fibroblasts closely resembles that of fibrotic fibroblasts, suggesting that fibroblasts can first differentiate into fibrotic fibroblasts and then proliferate. Genetic ablation of proliferating fibroblasts and selective inhibition of cytokinesis in alveolar fibroblast descendants significantly mitigates pulmonary fibrosis and rescues lung function. Furthermore, fibroblasts in precision-cut lung slices from human fibrotic lungs exhibit higher proliferation rates than those in non-diseased lungs. This work establishes fibroblast proliferation as a critical driver of pulmonary fibrosis and suggests that specifically targeting fibroblast proliferation could be a new therapeutic strategy for fibrotic diseases.

cell biology↗

bioRxiv2025

Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma

Melanoma, the most lethal form of skin cancer, is commonly associated by mutations in the BRAF gene, particularly BRAFV600E, which drives tumor proliferation via ERK1/2 signaling cascade. While BRAF inhibitors initially demonstrate efficacy, therapeutic resistance remains a significant challenge. Emerging evidence implicates the cAMP signaling pathway, particularly the cAMP response element-binding protein (CREB) and its repressor, Inducible cAMP Early Repressor (ICER), in melanoma progression and drug resistance. ICER, a transcriptional repressor regulated via Ras/MAPK-mediated phosphorylation and ubiquitination, is degraded in melanoma, undermining its tumor-suppressive role. In a brafV600E; p53(loss of function) transgenic zebrafish (Danio rerio) model, we investigated the role of a ubiquitin-resistant ICER mutant (S35-41A-ICER) in tumor progression. Transgenic fish expressing S35-41A-ICER exhibited extended survival and reduced tumor invasiveness compared to wild-type ICER. RNA sequencing revealed dysregulation of CREB/CREM targets and compensatory pathways, including Rap1 and PI3K/AKT signaling, as well as candidate gene targets of ICER regulation, including the Protein Kinase A catalytic subunit prkacaa. Our findings suggest that a ubiquitin resistant ICER mitigates melanoma progression and represses oncogenic pathways in a brafV600E melanoma context. Summary StatementThis study shows that ubiquitin-resistant ICER mutant suppresses melanoma progression, prolongs survival in brafV600E zebrafish, revealing its potential as a tumor suppressor and therapeutic target in melanoma resistance.

cancer biology↗

bioRxiv2025

Environmental, Developmental, and Genetic Conditions Shaping Monarch Butterfly Migration Behavior

Monarch butterflies in North America migrate south each autumn, but the mechanisms that initiate their migratory flight remain incompletely understood. We investigated environmental, developmental, and genetic factors that contribute to directional flight by testing summer and autumn-generation monarchs in three flight simulators: two at ground level (with and without wind blockage) and a novel balloon-based system that raised butterflies 30 meters into the air. Monarchs reared under autumn-like conditions in a growth chamber during the summer were also tested to explore the influence of developmental cues. Autumn generation monarchs demonstrated significant southwestern flight orientation, observed exclusively in the balloon simulator, underscoring the importance of high-altitude flight for migratory behavior. Summer generation monarchs reared under autumn-like conditions displayed southward orientation, larger wing sizes, and partial reproductive diapause, indicating specific seasonal environmental cues that are sufficient to induce migratory traits. In contrast, a lab line of monarchs reared in captivity since 2016 exhibited diminished wing size and reduced orientation ability, even when raised outdoors in the autumn, consistent with a loss of migratory traits in the absence of migration. Surprisingly, butterflies in the balloon simulator tended to orient upwind, which suggests that wind may also serves as a directional cue during migration. These findings highlight the critical roles of altitude, wind, and environmental cues in monarch migration and validate the balloon flight simulator as a powerful tool for studying migratory behavior. This research advances our understanding of the initiation of monarch migration and informs strategies for conservation efforts amidst environmental change.

animal behavior and cognition↗

bioRxiv2024

Importin-β specific nuclear transport defects recapitulate phenotypic and transcriptional alterations seen in neurodegeneration

Defects in Nucleocytoplasmic transport have been implicated as an important neurodegenerative pathway in ALS/FTD. Here, we show that a NemfR86S mutation results in the disruption of NCT both in vitro and in vivo. These disruptions are specific to Importin-{beta} nuclear import, and result in the nuclear loss and cytoplasmic gain of NEMF, Importin-{beta}, and TDP-43. We show that a transient nuclear import block is capable of inducing the mis-localization of TDP-43 and is associated with altered transcriptional expression of ALS, FTD, and AD/ARD genes. Taken together, these findings show that disrupted Importin-{beta} nuclear import, whether through genetic forms such as Nemf mutations, or through pharmacological inhibition, is the primary driver of TDP-43 pathology, disease-related transcriptional alterations, and neurodegeneration.

neuroscience↗

bioRxiv2023

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGF{beta}) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGF{beta} signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGF{beta} signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFb signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.

physiology↗

bioRxiv2022

An international scholastic network to generate LexA enhancer-trap lines for Drosophila

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and eleven insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science.

genetics↗

bioRxiv2022

p16High senescence restricts totipotent potential during somatic cell reprogramming

The discovery of four factor (4F)-induced reprogramming of somatic cells into induced pluripotent stem (iPS) cells has revolutionized the fields of cell and regenerative biology. In contrast, the feasibility of a direct conversion of somatic cells into a totipotent state defined as the ability to produce all cell types of an organism, including extraembryonic tissues, is not well established. Using genetic and chemical approaches to manipulate senescent cells, here we found that removal of p16High cells resulted in 4F-induced reprogramming of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the 2-cell (2C) embryonic state, readily formed implantation-competent blastocyst-like structures, blastoids, and following morula aggregation, contributed to embryonic and extraembryonic lineages in E12.5 embryos. We identified senescence-dependent regulation of nicotinamide N-methyltransferase (NNMT) as a key mechanism controlling the S-adenosyl-O_SCPLOWLC_SCPLOW-methionine (SAM) levels during 4F-induced reprogramming that was required for expression of the 2C genes and acquisition of an extraembryonic potential. Our results show that the presence of p16High senescent cells, high NNMT and low SAM limit cell plasticity during 4F-reprogramming, while their modulation could help to achieve the highest state of stem cell potency, totipotency.

cell biology↗

bioRxiv2021

A thermostable oral SARS-CoV-2 vaccine induces mucosal and protective immunity

An ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be well accepted by the population and have a simple logistic chain. To fulfill these criteria, we developed a thermostable, orally administered vaccine that can induce a robust mucosal neutralizing immune response. We used our platform based on retrovirus-derived enveloped virus-like particles (e-VLPs) harnessed with variable surface proteins (VSPs) from the intestinal parasite Giardia lamblia, affording them resistance to degradation and the triggering of robust mucosal cellular and antibody immune responses after oral administration. We made e-VLPs expressing various forms of the SARS-CoV-2 Spike protein (S), with or without membrane protein (M) expression. We found that prime-boost administration of VSP-decorated e-VLPs expressing a pre-fusion stabilized form of S and M triggers robust mucosal responses against SARS-CoV-2 in mice and hamsters, which translate into complete protection from a viral challenge. Moreover, they dramatically boosted the IgA mucosal response of intramuscularly injected vaccines. We conclude that our thermostable orally administered e-VLP vaccine could be a valuable addition to the current arsenal against SARS-CoV-2, in a stand-alone prime-boost vaccination strategy or as a boost for existing vaccines.

immunology↗

bioRxiv2020

Early-life nutrition interacts with developmental genes to shape the brain and sleep behavior in Drosophila melanogaster

The mechanisms by which the genotype interacts with nutrition during development to contribute to the variation of complex behaviors and brain morphology of adults are not well understood. Here we use the Drosophila Genetic Reference Panel to identify genes and pathways underlying these interactions in sleep behavior and mushroom body morphology. We show that early-life nutritional restriction has genotype-specific effects on variation in sleep behavior and brain morphology. We mapped genes associated with sleep sensitivity to early-life nutrition, which were enriched for protein-protein interactions responsible for translation, endocytosis regulation, ubiquitination, lipid metabolism, and neural development. By manipulating the expression of candidate genes in the mushroom bodies and all neurons, we confirm that genes regulating neural development, translation and insulin signaling contribute to the variable response of sleep and brain morphology to early-life nutrition. We show that the interaction between differential expression of candidate genes with nutritional restriction in early life resides in the mushroom bodies or other neurons, and that these effects are sex specific. Natural variation in genes that control the systemic response to nutrition and brain development and function interact with early-life nutrition in different types of neurons to contribute to the variation of brain morphology and adult sleep behavior.

genetics↗

bioRxiv2019

Instability of cooperation in finite populations

Evolutionary game theory has been developed primarily under the implicit assumption of an infinite population. We rigorously analyze a standard model for the evolution of cooperation (the multi-player snowdrift game) and show that in many situations in which there is a cooperative evolutionarily stable strategy (ESS) if the population is infinite, there is no cooperative ESS if the population is finite (no matter how large). In these cases, contributing nothing is a globally convergently stable finite-population ESS, implying that apparent evolution of cooperation in such games is an artifact of the infinite population approximation. The key issue is that if the size of groups that play the game exceeds a critical proportion of the population then the infinite-population approximation predicts the wrong evolutionary outcome (in addition, the critical proportion itself depends on the population size). Our results are robust to the underlying selection process.

evolutionary biology↗

bioRxiv2019

Selection may oppose invasion, yet favour fixation: consequences for evolutionary stability

Models of evolution by natural selection often make the simplifying assumption that populations are infinitely large. In this infinite population limit, rare mutations that are selected against always go extinct, whereas in finite populations they can persist and even reach fixation. Nevertheless, for mutations of small phenotypic effect, it is widely believed that in sufficiently large populations, if selection opposes the invasion of rare mutants, then it also opposes their fixation. Here, we identify circumstances under which infinite-population models do or do not accurately predict evolutionary outcomes in large, finite populations. We show that there is no population size above which considering only invasion generally suffices: for any finite population size, there are situations in which selection opposes the invasion of mutations of arbitrarily small effect, but favours their fixation. This is not an unlikely limiting case; it can occur when fitness is a smooth function of the evolving trait, and when the selection process is biologically sensible. Nevertheless, there are circumstances under which opposition of invasion does imply opposition of fixation: in fact, for the n-player snowdrift game (a common model of cooperation) we identify sufficient conditions under which selection against rare mutants of small effect precludes their fixation--in sufficiently large populations--for any selection process. We also find conditions under which--no matter how large the population--the trait that fixes depends on the selection process, which is important because any particular selection process is only an approximation of reality.

evolutionary biology↗