Biology subjects

Prado, L.

Publications and source records attributed to Prado, L..

9 recordsLinked to original sources

bioRxiv2025

Categorical rhythmic priors in macaques

Rhythmic ability is a universal aspect of human cultures and sets the basis for musical rhythm perception and synchronization. While humans can synchronize movements to complex rhythms, it is unclear whether this capability extends to our primate ancestors. In this study, we explore whether primates can synchronize to complex rhythms and acquire rhythmic representations with generalizability akin to humans. Using controlled behavioral experiments, we provide evidence that monkeys not only can synchronize to short-long or long-short rhythms but also learn representations that generalize across a wide range of rhythm ratios and total durations. These results indicate ability to flexibly represent ratios within a relative timing framework is not exclusive to humans, but it is also present in monkeys. In addition, the produced intervals show a bias towards rhythmic categories. Notably, in an iterative tapping task, macaques and humans showed large priors for isochrony and integer ratios (2:1, 3:1). These results demonstrate a common biological foundation for rhythm synchronization in primates, extending our understanding of the shared cognitive mechanisms between primates and humans, and highlight the enormous potential of using monkeys to study the neurophysiological basis of complex rhythm perception.

neuroscience↗

bioRxiv2025

Staphylococcus aureus derived extracellular vesicles trigger multiple inflammatory pathways in host cells and deliver their RNA cargo following their internalization and lysis within late endosomes

Staphylococcus aureus is a major opportunistic Gram-positive pathogen whose virulence can be partly mediated by extracellular vesicles (EVs). These nanosized particles carry a diverse cargo and can play key roles in host-pathogen interactions. Here, we investigated the production, composition, and host cell interactions of EVs secreted by the methicillin-resistant S. aureus strain N315, one of the most widely studied clinical isolates. To mimic infection, EVs produced from RPMI supplemented with 10% LB were purified by size exclusion chromatography, and characterized by nanoparticle tracking analysis and electron microscopy. N315 EVs contained a diverse molecular cargo, selectively enriched, and including proteins, lipoproteins, DNA, RNA, lipoteichoic acid, and peptidoglycan. Protection assays and confocal microscopy confirmed the intravesicular localization of RNAs and proteins. N315 EVs were recognized by multiple host pattern recognition receptors (PPRs) in human MG-63 cells, located at the cell surface (TLR1, TLR2, TLR4, TLR6), within endosomes (TLR3, TLR7, TLR4) and in the cytoplasm (NOD2). EV exposure promoted the selective upregulation of these PRRs, activated the NF-{kappa}B and JAK/STAT signaling pathways, and induced the expression of pro-inflammatory cytokines such as IL1{beta}, IL6, and CXCL8. N315 EVs were internalized via a dynamin-dependent endocytosis mechanism and trafficked to late endosomes, where RNA cargo release occurred. Importantly, inhibition of EVs uptake altered cytokine gene expression, confirming that internalization is required for immunomodulation. This work provides a better understanding of the mechanisms of interaction of S. aureus EVs with host cells and sheds light on the fate of EVs and their cargo once internalized by cells. IMPORTANCEAntibiotic resistance, coupled with the limited discovery of new antimicrobial agents, poses a growing threat to public health. Staphylococcus aureus is one of the six highly virulent and antibiotic-resistant bacterial species responsible for both severe hospital- and community-acquired infections. This pathogen demonstrates a remarkable ability to adapt to diverse hosts and environments and to produce a broad arsenal of virulence factors. Gaining deeper insight into its pathogenic mechanisms and host interactions may reveal novel therapeutic targets and alternative treatment strategies. Over the past decade, a key advancement has been the identification of extracellular vesicle production by S. aureus and its critical role as a new secretion system for virulence factors. This study shed light on the immunogenic effect of EVs and their role as a vehicle for the delivery of their contents into host cells. These adjuvant-like properties open new avenues for research and potential intervention.

microbiology↗

bioRxiv2025

Flexible tapping synchronization in macaques: dynamic switching of timing strategies within rhythmic sequences

The ability to synchronize bodily movements with regular auditory rhythm across a broad range of tempos underlies humans capacity for playing music and dancing. This capability is prevalent across human cultures but relatively uncommon among non-human species. Recent research indicates that monkeys can predictively synchronize to regular, isochronous metronomes, exhibiting a preference for visual rather than auditory sequences. In this study, we trained macaques to perform a visual synchronization tapping task, testing their synchronization abilities over a wide tempo range and characterizing their precision and accuracy in timing intervals throughout rhythmic sequences. Additionally, we investigated whether the macaques employed priors or error correction strategies to maintain synchrony with the metronome. Our findings demonstrate that, following sufficient training, macaques exhibit a remarkable capability to synchronize across diverse tempos. Through an inference model analysis, we identified two distinct timing control strategies used by the macaques: an initial strong regression-to-the-mean effect transitioning dynamically into a more precise error correction approach at their preferred tempo. These results provide compelling evidence that primates possess sophisticated rhythmic timing mechanisms, effectively leveraging internal and external cues to regulate their tapping behavior according to task demands. NEW & NOTEWORTHYWe trained macaques in a visual synchronization tapping task and using an inference model we found that they are highly precise and accurate in their rhythmic performance. The model also captured a dynamic switch in behavior. At the beginning of the task, the monkeys used their prior knowledge about the interval statistics and then switched to an error correction mechanism to generate intervals depending on the previously produced duration.

neuroscience↗

bioRxiv2024

Monkeys have rhythnm

Synchronizing movements to music is one of the hallmarks of human culture whose evolutionary and neurobiological origins remain unknown. The ability to synchronize movements requires 1) detecting a steady rhythmic pulse, or beat, out of a stream of complex sounds, 2) projecting this rhythmic pattern forward in time to predict future input, and 3) timing motor commands in anticipation of predicted future beats. Here, we demonstrate that the macaque is capable of synchronizing taps to a subjective beat in real music, and even spontaneously chooses to do so over alternative strategies. This contradicts the influential "vocal learning hypothesis" that musical beat synchronization is only possible in species with complex vocalizations such as humans and some songbirds. We propose an alternative view of musical beat perception and synchronization ability as a continuum onto which a wider range of species can be mapped depending on their ability to perform and coordinate the general abilities listed above through association with reward.

neuroscience↗

bioRxiv2023

CD38 regulates ovarian function and fecundity via NAD+ metabolism

Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD+ levels. However, the mechanisms underlying this loss of ovarian NAD+ are unclear. Here, we show that CD38, a NAD+ consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD+ levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD+ metabolism and establishing the ovarian reserve, a critical process that dictates a females reproductive lifespan.

developmental biology↗

bioRxiv2023

Different time encoding strategies within the medial premotor areas of the primate

The measurement of time in the subsecond scale is critical for many sophisticated behaviors, yet its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the neural activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing. During interval categorization, we found that preSMA encodes a subjective category limit by reaching a peak of activity at a time that divides the set of test intervals into short and long. We also observed neural signals associated with the category selected by the subjects and the reward outcomes of the perceptual decision. On the other hand, we have studied the behavioral and neurophysiological basis of rhythmic timing. First, we have shown in different tapping tasks that macaques are able to produce predictively and accurately intervals that are cued by auditory or visual metronomes or when intervals are produced internally without sensory guidance. In addition, we found that the rhythmic timing mechanism in MPC is governed by different layers of neural clocks. Next, the instantaneous activity of single cells shows ramping activity that encode the elapsed or remaining time for a tapping movement. In addition, we found MPC neurons that build neural sequences, forming dynamic patterns of activation that flexibly cover all the produced interval depending on the tapping tempo. This rhythmic neural clock resets on every interval providing an internal representation of pulse. Furthermore, the MPC cells show mixed selectivity, encoding not only elapsed time, but also the tempo of the tapping and the serial order element in the rhythmic sequence. Hence, MPC can map different task parameters, including the passage of time, using different cell populations. Finally, the projection of the time varying activity of MPC hundreds of cells into a low dimensional state space showed circular neural trajectories whose geometry represent the internal pulse and the tapping tempo. Overall, these findings support the notion that MPC is part of the core timing mechanism for both single interval and rhythmic timing, using neural clocks with different encoding principles, probably to flexibly encode and mix the timing representation with other task parameters.

neuroscience↗

bioRxiv2023

A Gamma-adapted recombinant subunit vaccine induces broadly neutralizing antibodies against SARS-CoV-2 variants and protects mice from SARS-CoV-2 infection.

The COVID-19 pandemic continues with the emergence of successive new variants of concern (VOC). One strategy to prevent breakthrough infections is developing safe and effective broad-spectrum vaccines. Here, we present preclinical studies of a RBD recombinant vaccine candidate derived from the Gamma SARS-CoV-2 variant adjuvanted with alum. Gamma RBD-derived antigen elicited better neutralizing antibody and T cell responses than formulation containing ancestral RBD antigen. The Gamma-adapted subunit vaccine elicited a long-lasting antibody response with cross-neutralizing activity against different VOC including the Omicron variant. Additionally, Gamma variant RBD-adapted vaccine elicited robust T cells responses with induction of Th1 and CD8+ T cell responses in spleen and lung. Vaccine-induced immunity protected K18-hACE2 mice from intranasal challenge with SARS-CoV-2 increasing survival, reducing body weight loss and viral burden in the lungs and brain. Importantly, the subunit vaccine demonstrated a potent effect as heterologous booster of different vaccine platforms including the non-replicating adenovirus vaccine ChAdOx1-S, the mRNA vaccine BNT162b2 and the inactivated SARS-CoV-2 vaccine BBIBP-CorV, increasing cross-reactive antibody responses. Our study indicates that the adjuvanted Gamma RBD vaccine is highly immunogenic and a broad-spectrum vaccine candidate to combat SARS-CoV-2 variants including Omicron.

immunology↗

bioRxiv2018

The amplitude in periodic neural state trajectories underlies the tempo of rhythmic tapping

Our motor commands can be exquisitely timed according to the demands of the environment, and the ability to generate rhythms of different tempos is a hallmark of musical cognition. Yet, the neuronal basis behind rhythmic tapping remains elusive. Here we found that the activity of hundreds of primate MPC neurons show a strong periodic pattern that becomes evident when their activity is projected into a lower dimensional state space. We show that different tempos are encoded by circular trajectories that travelled at a constant speed but with different radii, and that this neuronal code is highly resilient to the number of participating neurons. Crucially, the changes in the amplitude of the oscillatory dynamics in neuronal state space are a signature of beat-based timing, regardless of whether it is guided by an external metronome or is internally controlled and is not the result of repetitive motor commands. Furthermore, the increase in amplitude and variability of the neural trajectories accounted for the scalar property of interval timing. In addition, we found that the interval-dependent increments in the radius of periodic neural trajectories are the result of larger number of neurons engaged in the production of longer intervals. Our results support the notion that beat-based timing during rhythmic behaviors is encoded in the radial curvature of periodic MPC neural population trajectories.

neuroscience↗

bioRxiv2018

A dual sRNA in Staphylococcus aureus induces a metabolic switch responding to glucose consumption

Pathogenic bacteria must rapidly adapt to ever-changing environmental signals or nutrient availability resulting in metabolism remodeling. The carbon catabolite repression represents a global regulatory system, allowing the bacteria to express genes involved in carbon utilization and metabolization of the preferred carbon source. In Staphylococcus aureus, regulation of catabolite repressing genes is mediated by the carbon catabolite protein A (CcpA). Here, we have identified a CcpA-dependent small non-coding RNA, RsaI that is inhibited by high glucose concentrations. RsaI represses the translation of mRNAs encoding a major permease of glucose uptake, the FN3K enzyme that protects proteins against damages caused by high glucose concentrations, and IcaR, the transcriptional repressor of exopolysaccharide production. Besides, RsaI regulates the activities of other sRNAs responding to the uptake of glucose-6 phosphate or NO. Finally, RsaI inhibits the expression of several enzymes involved in carbon catabolism pathway, and activates genes involved in energy production, fermentation and NO detoxification when the glucose concentration decreases. This multifunctional RNA provides a signature for a metabolic switch when glucose is scarce and growth is arrested.

microbiology↗