Biology subjects

Medina, J. M.

Publications and source records attributed to Medina, J. M..

8 recordsLinked to original sources

bioRxiv2026

Computationally Optimized H1 and H3 Hemagglutinin Messenger RNA Vaccines Confer Broad Protective Immunity Against Modern Influenza Viruses

The hemagglutinin (HA) glycoprotein of seasonal influenza viruses undergoes continual antigenic drift, contributing to vaccine mismatch and reduced effectiveness of strain-specific seasonal vaccines. Although vaccination remains the most effective strategy for preventing influenza disease, conventional egg-based vaccine production requires several months and may not keep pace with viral evolution. Messenger RNA (mRNA) vaccines offer a promising alternative because they can be rapidly updated to encode emerging antigens and are manufactured through a scalable, cell-free process that avoids propagation associated adaptations. To address the challenges of antigenic drift and vaccine mismatch, we combined mRNA vaccine technology with Computationally Optimized Broadly Reactive Antigens (COBRA) to develop broadly protective influenza HA vaccines. These COBRA H1 and H3 mRNA HA vaccines elicited robust antigen-specific IgG, hemagglutination inhibition (HAI), and neutralizing antibody responses against diverse historical and contemporary influenza strains in cohorts of influenza naive and pre-immune mice. Vaccination also induced strong cellular immunity, characterized by the expansion of antigen-specific antibody and cytokine secreting cells. These responses were further enhanced in animals with pre-existing influenza immunity, as demonstrated by an increased frequency of IFN-{gamma} producing cells recognizing conserved HA stalk-based peptides. Together, these findings demonstrate that COBRA HA encoding mRNA vaccines can effectively leverage immunological memory while expanding responses to conserved HA epitopes, supporting improved protection against antigenically drifted strains. Thus, the combination of broadly reactive COBRA HA antigens with a rapidly adaptable and manufacturable mRNA platform represents a promising strategy for next-generation influenza vaccination.

immunology↗

bioRxiv2025

An integrative framework identifies cooperative targeting of host pathways by tick salivary miRNAs

Ticks are ectoparasites that modulate host responses to sustain prolonged blood feeding, and in Ixodes ricinus, salivary microRNAs (miRNAs) represent promising candidates for manipulating host gene expression. Using phylogenetic footprinting combined with cooperative targeting analysis, we identified deeply conserved miRNA-mRNA interactions that appear essential for the tick lifecycle and its ability to parasitize diverse vertebrate hosts. Our findings show that conserved tick miRNAs can mimic host miRNAs by exploiting shared target sites on host transcripts, allowing them to modulate regulatory circuits critical during tick feeding. We identified twelve core salivary miRNAs--highly expressed and enriched in conserved target sites--that cooperatively target twenty-two human genes predominantly expressed in skin and neural tissues. This cooperative suppression converges on host hub genes like PDGFRA and NRG1, linking tick miRNA activity to MAPK and PI3K-AKT pathways that regulate immune defense, tissue repair, and sensory responses. Overall, our results demonstrate that I. ricinus miRNAs can synergistically disrupt host homeostasis, and they introduce a broadly applicable framework that leverages evolutionary conservation to detect meaningful cross-species miRNA-mRNA interactions. HighlightsThe study shows that tick miRNAs with Bilaterian node of origin mimic host miRNAs to exploit conserved target sites of host mRNAs. It demonstrates that these conserved tick miRNAs cooperatively repress key host defense and repair pathways. It introduces a framework that leverages evolutionary conservation to detect and explain functional, conserved cross-species miRNA-mRNA regulation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/692500v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@6eea0aorg.highwire.dtl.DTLVardef@1c739d2org.highwire.dtl.DTLVardef@a53910org.highwire.dtl.DTLVardef@1458544_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial condition influenced by the gut microbiome (GM). While previous studies have reported inconsistent associations between MASLD and key microbial clades using low-resolution 16S rRNA profiling, we employed high-resolution metagenomic sequencing and multi-marker taxonomic classification across three independent cohorts to identify robust microbial and functional signatures of MASLD. We consistently detected a depletion of Agathobacter rectalis, a known butyrate producer, in MASLD patients. Functionally, MASLD was characterized by a depletion of genes involved in butyrate and methane biosynthesis-particularly within the crotonyl-butyryl-CoA axis-alongside an enrichment of genes driving the production of endogenous alcohols such as ethanol and 1-propanol. Genes encoding these fermentative pathways, often organized in operons like pdu and tor, were more abundant in MASLD samples, indicating a potential shift toward alcohol-producing metabolism. These geno-metabolic changes were accompanied by a broader displacement of beneficial taxa and an increase in accessory gene content across the GM, underscoring the limitations of taxonomy-based disease associations. Many of the differentially abundant genes were also found on plasmids, suggesting that horizontal gene transfer contributes to strain-level metabolic variability relevant to MASLD progression. Our findings support a model in which GM-driven metabolic shifts-rather than taxonomic changes alone-play a central role in MASLD pathogenesis, highlighting the importance of functional and mobile genetic element (MGEs) profiling for uncovering mechanistic links between the microbiome and liver disease.

microbiology↗

bioRxiv2024

Long-term evolution reveals the role of the circadian cycle in the environmental adaptation of cyanobacteria

Circadian clocks synchronize internal cellular states with diurnal rhythms. Widespread in bacteria and eukaryotes, they regulate a variety of physiological processes, from hormone secretion in animals to carbon fixation in photosynthetic organisms. The adaptive role of circadian clocks is assumed to stem from their ability to anticipate environmental change, yet their impact on ecological adaptation remains unclear. Here, we use experimental evolution to study the interplay between fitness and circadian regulation in the model cyanobacterium Synechococcus elongatus PCC 7942. After 1,200 generations under continuous, high-intensity illumination, we obtained a strain that grew six times faster than its ancestral counterpart. Genome sequencing revealed three mutations fixed in the population, two of which replicated the fast-growing phenotype in the wild-type. A deletion in SasA, a key circadian regulator, was essential for fast growth. Transcriptomic and metabolomic analyses revealed that this mutation perturbed the rhythmicity of the cycle, while simultaneously locking the cell in a transcriptomic response to high intensity illumination. A comparison with another fast- growing isolate, UTEX 2973, showed convergent transcriptomic states despite different driving mutations. Our results indicate that the clock acts not only as a timekeeping device, but also as an adaptive mechanism to optimize growth across diverse ecological conditions.

microbiology↗

bioRxiv2024

Whole genome sequencing of four Ixodes species expands understanding of tick evolution

Ticks, hematophagous acari, pose a significant threat by transmitting various pathogens to their vertebrate hosts during feeding. Despite advances in tick genomics, high-quality genomes were lacking until recently, particularly in the genus Ixodes, which includes the main vectors of Lyme disease. Here, we present the complete genome sequences of four tick species, derived from a single female individual, with a particular focus on the European species Ixodes ricinus, achieving a chromosome-level assembly. Additionally, draft assemblies were generated for the three other Ixodes species, I. persulcatus, I. pacificus and I. hexagonus. The quality of the four genomes and extensive annotation of several important gene families have allowed us to study the evolution of gene repertoires at the level of the genus Ixodes and of the tick group. We have determined gene families that have undergone major amplifications during the evolution of ticks, while an expression atlas obtained for I. ricinus reveals striking patterns of specialization both between and within gene families. Notably, several gene family amplifications are associated with a proliferation of single-exon genes. The integration of our data with existing genomes establishes a solid framework for the study of gene evolution, improving our understanding of tick biology. In addition, our work lays the foundations for applied research and innovative control targeting these organisms.

genomics↗

bioRxiv2023

Limits to the spread of an obligate social cheater in the social amoeba Dictyostelium discoideum

Cooperation is widespread across life, but its existence can be threatened by exploitation. Social cheaters can be obligate, incapable of contributing to a necessary function, so that spread of the cheater leads to loss of the function. In the social amoeba Dictyostelium discoideum, obligate social cheaters cannot become dead stalk cells that lift spores up for dispersal, but instead depend on forming chimeras with fully functional altruistic individuals for forming a stalk. Obligate cheaters in D. discoideum are known to pay the cost of being unable to form fruiting bodies on their own. In this study we discovered that there are two additional costs that can apply to obligate cheaters. Even when there are wild-type cells to parasitize, the chimeric fruiting bodies that result have shorter stalks that are disadvantaged in spore dispersal. Furthermore, we found that obligate cheaters were overrepresented among spore cells in chimeras only when they were at low frequencies. Failure to develop into viable fruiting bodies on their own, negative frequency-dependent cheating, and shorter fruiting bodies represent three limits on obligate social cheating so it is not surprising that obligate cheaters have not been found in nature.

evolutionary biology↗

bioRxiv2021

Unbiased and UMI-informed sequencing of cell-free miRNAs at single-nucleotide resolution

Terminal nucleotidyl transferases are enzymes that add non-templated nucleotides to RNA molecules. In the case of microRNAs, this process was shown to be functionally relevant for their maturation process and generation of isomiRs with non-canonical mRNA targets. Deconvolution of these posttranscriptional modifications is challenging in particular for extracellular miRNAs that are considered as a target for minimally-invasive diagnostics. Massively parallel RNA sequencing is the only method that can truthfully reveal isomiR diversity in biological samples and determine relative quantities. Improvements aside, current small RNA sequencing strategies remain imprecise. We developed IsoSeek that diverges from these methods by making use of randomized 5- and 3-adapters combined with a 10N unique molecular identifier (UMI). Using synthetic miRNA and isomiR spike-in sets and testing depletion and RNA competition strategies in 7 sequencing rounds of >100 samples, we rigorously optimized and validated the technical accuracy of the IsoSeek method. In genetically-altered HEK293, we characterized the terminal uridylase (TUT4/TUT7) dependent miRNA uridylome and discovered extensive uridylation of disease-associated miRNAs. Notably, 3-uridylated isomiR profiles of plasma extracellular vesicles (EVs) rely on UMI-correction. Thus, IsoSeek advances our knowledge of cell-free miRNAs and supports development into non-invasive biomarkers.

genomics↗

bioRxiv2019

TAT-Cx43266-283 impairs metabolic plasticity in glioma stem cells in vitro and in vivo

Glioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years1. These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies2, 3, and exhibit metabolic plasticity to adapt to challenging environments4, 5. GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43266-283) that reduces tumour growth and increases survival in preclinical models6 via c-Src inhibition7. Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells8-10, we investigated the effect of TAT-Cx43266-283 on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43266-283 decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43266-283 reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43266-283 showed decreased levels of important targets for cancer therapy, such as HK-211, 12 and glucose transporter 3 (GLUT-3)13, evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43266-283 for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.

cancer biology↗