Biology subjects

Duran, A.

Publications and source records attributed to Duran, A..

8 recordsLinked to original sources

bioRxiv2026

A mathematical model for fitness effects on viral persistence

Persistent viral infections arise from complex interactions between viral replication, host cell responses, and ongoing viral evolution. A general framework linking viral fitness to persistence dynamics is lacking. Here, we develop for the first time a mathematical model of viral persistence that takes into consideration viral fitness variations. Essential to the model is the partition of the classical fitness parameter into three components: replicative, infective, and dispersal fitness. The model was initially inspired by a new experiment on hepatitis C virus (HCV) persistence, established in human hepatoma cells, also reported in this work. This experiment documents two strikingly different viral trajectories depending on the initial replicative fitness of the viral population used to establish persistence. The dynamical model describes the interactions among uninfected cells, infected cells, and infectious virions, and it incorporates, through a continuum, two alternative mechanisms of viral release from cells: budding and lysis. Analysis of the model reveals that viral fitness parameters organise infection outcomes into distinct dynamical regimes. Low replicative and dispersal fitness values lead to viral extinction, whereas high values enable persistence through either stable coexistence or recurrent infection waves. The space of fitness discloses a hierarchy among these parameters, with replicative and dispersal fitness being able to trigger important shifts in the outcome of the infection as opposed to infective fitness. The model identifies trade-offs between replication and dispersal that shape viral production and predicts slow dynamical regimes in which infection may persist despite low detectable viral loads. These dynamical transitions provide candidate mechanisms capable of generating the persistence patterns observed experimentally. Our results establish a computational framework linking multidimensional viral fitness to persistence dynamics and suggest general principles by which evolving RNA viruses transition between extinction (cell curing) and sustained persistence.

systems biology↗

bioRxiv2026

A dominant frontoparietal beta oscillatory brain state in the days after psilocybin and 5-MeO-DMT

Background. Serotonergic psychedelics show promise for treating psychiatric disorders, with symptom improvements lasting for weeks after a single dose. Clarifying the neural basis of these effects would benefit from an identification of empirical biomarkers of such lasting shifts in brain function. Resting state EEG offers a rapid (<5 minute), low-cost window into functional brain networks. However, connectivity is not static, but cycles between recurring semi-stable patterns that vary across frequency bands. Here we employed a dynamic function connectivity (dFC) framework to identify frequency-specific connectivity states and examine how they change in the weeks following psychedelic use. Methods. We collected resting-state EEG from individuals who had used one of two serotonergic psychedelic subclasses within the prior three weeks, psilocybin/LSD (typical; n=14) or 5-MeO-DMT (atypical; n=12), and age- and sex-matched controls (n=16). Frequency-band-specific spatial connectivity states (phase-lag index) were estimated across the full sample (5 per band). Groups were compared on proportion and dwell-time (per state) and state-to-state transitions. Results. A right frontoparietally-distributed beta synchrony state was dominant after both typical and atypical psychedelics use (proportion/dwell-time). This effect correlated with the number of days since using psychedelics. A globally-distributed theta-band state was prominent in recent users of typical psychedelics but occurred less often in atypical users. In contrast, neural entropy (Lempel-Ziv complexity; known to increase acutely during psychedelic dosing) was not altered in recent users of either subclass. Conclusion. These results reveal a beta-band signature of altered neural dynamics in the week following a psychedelic dose, consistent with a relaxation of brain network hierarchy after psychedelics.

neuroscience↗

bioRxiv2025

Clinical Trypanosoma cruzi isolates share a common antigen repertoire that is absent from culture adapted strains

BackgroundTrypanosoma cruzi causes Chagas disease, a poorly understood and clinically heterogeneous disease. Recent work has demonstrated that parasites adapted to laboratory conditions are genomically variable, but little is known of the extent of genomic diversity from clinically isolated specimens. MethodsIn this retrospective observational genomic study, we isolated 15 T. cruzi specimens from three clinical studies of Chagas disease, representing different clinical contexts. We sequenced the genome of each strain and used single nucleotide variant (SNV) based analyses to estimate parasite genetic lineage, genomic population structure, regions of copy number plasticity, and to identify gene conversion events. In addition, we generated and annotated whole genome assemblies of each isolate. From these assemblies, we compared the repertoires of genes encoding for highly virulent and variable proteins that have been implicated in disease pathogenesis. FindingsWe identified parasites from two genetic lineages in this collection of clinical isolates. Our analysis revealed evidence of genomic instability. Diversity-generating copy number variation was statistically enriched in regions encoding the virulence-associated multigene families, while diversity-eliminating gene conversion events were enriched in regions depleted of multigene family members. We also discovered a set of multigene family members that is present in all of the clinically isolated parasite genomes and absent from all of the lab adapted strains, regardless of parasite lineage. Multigene family repertoires were more conserved among field isolated specimens of the same genetic lineage than among culture adapted strains of the same genetic type. InterpretationThis study provides whole genome sequencing data for TcV parasites isolated from naturally infected human patients with Chagas disease for the first time. Our analysis of these genomes revealed substantial genomic instability, suggesting the parasite undergoes genomic change in response to the pressures imposed by the host environment. Moreover, we observed a set of virulence-associated genes that are present exclusively within clinical isolates and absent from lab-adapted strains, indicating a potential role for these genes in parasite survival in natural hosts. These findings highlight the limitations of genetic studies focused exclusively on lab-adapted parasite strains and provide insight into the genomic features of T. cruzi that are likely to be important for clinical infection.

microbiology↗

bioRxiv2024

SARS-CoV-2 B Epitope-Guided Neoantigen NanoVaccines Enhance Tumor-Specific CD4/CD8 T Cell Immunity Through B Cell Antigen Presentation

Current neoantigen cancer vaccines activate T cell immunity through dendritic cell /macrophage-mediated antigen presentation. It is unclear whether incorporating B cell-mediated antigen presentation into current neoantigen vaccines could enhance CD4/CD8 T cell immunity to improve their anticancer efficacy. We developed a SARS-CoV-2 B cell epitope-guided neoantigen peptide/mRNA cancer nanovaccines (BSARSTNeoAgVax) to improve anticancer efficacy by enhancing tumor-specific CD4/CD8 T cell antitumor immunity through B cell-mediated antigen presentation. BSARSTNeoAgVax crosslinked with B cell receptor, promoted SARS-CoV-2 B cell-mediated antigen presentation to tumor-specific CD4 T cells, increased tumor-specific follicular/non-follicular CD4 T cells, and enhanced B cell-dependent tumor-specific CD8 T cell immunity. BSARSTNeoAgVax achieved superior efficacy in melanoma, pancreatic, and breast cancer models compared to the current neoantigen vaccines. Our study provides a universal platform, SARS-CoV-2 B epitope-guided neoantigen nanovaccines, to improve anticancer efficacy against various cancer types by enhancing CD4/CD8 T cell antitumor immunity through viral-specific B cell-mediated antigen presentation.

immunology↗

bioRxiv2024

A lasting impact of serotonergic psychedelics on visual processing and behavior

Serotonergic psychedelics (e.g., psilocybin, LSD) have potential to treat psychiatric disorders, with therapeutic effects lasting days to weeks after a single dose. Prominent theories suggest that psychedelics have a lasting effect on hierarchical brain circuits, reducing top-down influence on information processing to facilitate an unbiased, bottom-up reassessment of the world, but direct and concrete evidence for such an effect is lacking. Here we directly tested this hypothesis in both humans and mice, assessing predictive processing in the fronto-visual system in the days after a single psychedelic exposure. Individuals who recently (<3 weeks) used 5-HT2AReceptor agonist psychedelics (psilocybin, LSD) were assessed via electroencephalography (EEG) and electrooculography recordings during a saccadic prediction task and compared to age- and sex-matched non-users. Compared to non-users, recent psychedelic users produced fewer fast saccades and less suppression of EEG delta/theta power to predictively presented stimuli, pointing to a disruption of predictive processing. These changes correlated with time since psychedelic use and were replicated in a second cohort taking a different serotonergic psychedelic (5-MeO-DMT). Direct recordings of primary visual cortex (V1) in mice administered psilocybin (1 mg/kg) evinced a similar loss of predictive suppression 24-hrs after the dose. This coincided with weakened top-down modulation of V1 from anterior cingulate area (ACa), a subregion of medial prefrontal cortex, along with clear spine growth in ACa neurons that project to V1. These results suggest that psychedelic-induced neural plasticity serves to reorganize feedback circuits in the cortex and relax top-down influence on bottom-up sensory processing - an effect that persists beyond the acute exposure period and may underlie a therapeutic window.

neuroscience↗

bioRxiv2021

Concerted modification of nucleotides at functional centers of the ribosome revealed by single-molecule RNA modification profiling

Nucleotides in RNA and DNA are chemically modified by numerous enzymes that alter their function. Eukaryotic ribosomal RNA (rRNA) is modified at more than 100 locations, particularly at highly conserved and functionally important nucleotides. During ribosome biogenesis, modifications are added at various stages of assembly. The existence of differently modified classes of ribosomes in normal cells is unknown because no method exists to simultaneously evaluate the modification status at all sites within a single rRNA molecule. Using a combination of yeast genetics and nanopore direct RNA sequencing, we developed a reliable method to track the modification status of single rRNA molecules at 37 sites in 18S rRNA and 73 sites in 25S rRNA. We use our method to characterize patterns of modification heterogeneity and identify concerted modification of nucleotides found near functional centers of the ribosome. Distinct, undermodified subpopulations of rRNAs accumulate upon loss of Dbp3 or Prp43 RNA helicases, suggesting overlapping roles in ribosome biogenesis. Modification profiles are surprisingly resistant to change in response to many genetic and acute environmental conditions that affect translation, ribosome biogenesis, and pre-mRNA splicing. The ability to capture single molecule RNA modification profiles provides new insights into the roles of nucleotide modifications in RNA function. HighlightsO_LImethod enabling single-molecule profiling of RNA modifications is developed and reveals heterogeneous classes of modified ribosomes. C_LIO_LIrRNA 2O methylation and pseudouridylation modifications are independent of each other. C_LIO_LIin functional centers of the ribosome are modified in a concerted fashion. C_LIO_LIof function for RNA helicases Dbp3 and Prp43 produce discrete overlapping subpopulations of incompletely modified ribosomes. C_LIO_LImodification profiles are resilient to rapidly changing nutrient conditions and perturbation of translation C_LI

molecular biology↗

bioRxiv2021

Psychomotor impairments and therapeutic implications revealed by a mutation linked with Infantile Parkinsonism-Dystonia

Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly-penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination through enhanced DAT surface expression via the lysosomal inhibitor chloroquine. Together, these studies shed light on how a DTDS-linked DAT mutation underlies DA dysfunction and, more broadly, the clinical phenotypes shared by DTDS and PD.

neuroscience↗

bioRxiv2020

Not so optimal: The evolution of mutual information in potassium voltage-gated channels

Potassium voltage-gated (Kv) channels need to detect and respond to rapidly changing ionic concentrations in their environment. With an essential role in regulating electric signaling, they would be expected to be optimal sensors that evolved to predict the ionic concentrations. To explore these assumptions, we use statistical mechanics in conjunction with information theory to model how animal Kv channels respond to changes in potassium concentrations in their environment. By estimating mutual information in representative Kv channel types across a variety of environments, we find two things. First, under a wide variety of environments, there is an optimal gating current that maximizes mutual information between the sensor and the environment. Second, as Kv channels evolved, they have moved towards decreasing mutual information with the environment. This either suggests that Kv channels do not need to act as sensors of their environment or that Kv channels have other functionalities that interfere with their role as sensors of their environment.

biophysics↗