Biology subjects

Saraiva, L. R.

Publications and source records attributed to Saraiva, L. R..

11 recordsLinked to original sources

bioRxiv2025

A sensory map of the gastrointestinal tract

The gut, like the skin, exhibits a spatially organized sensory system with distinct regions specialized for detecting and responding to diverse signals including immune, microbial, and nutrient stimuli. This study employed spatial transcriptomics to characterize the molecular landscape of gut sensory cells along the gastrointestinal tract, revealing regional differences in gene expression profiles associated with various sensory modalities. We found that genes related to hormone and neurotransmission expression varied along the gut length at different resolutions, suggesting a division of labor where hormones mediate broader effects and neurotransmission enables rabid, localized signaling. Immune-related genes also exhibit spatial patterns, with increased expression towards the colon, consistent with the higher microbial density in this region. Furthermore, nutrient sensing is spatially regulated, with differential expression of receptors for fats, sugars, proteins, vitamins, and minerals along the gut. This spatial map of gut sensory cell gene expression provides a foundation for deciphering the complex code underlying gut-brain communication.

neuroscience↗

bioRxiv2024

Predicted mechanistic impacts of human protein missense variants

Genome sequencing efforts have led to the discovery of tens of millions of protein missense variants found in the human population with the majority of these having no annotated role and some likely contributing to trait variation and disease. Sequence-based artificial intelligence approaches have become highly accurate at predicting variants that are detrimental to the function of proteins but they do not inform on mechanisms of disruption. Here we combined sequence and structure-based methods to perform proteome-wide prediction of deleterious variants with information on their impact on protein stability, protein-protein interactions and small-molecule binding pockets. AlphaFold2 structures were used to predict approximately 100,000 small-molecule binding pockets and stability changes for over 200 million variants. To inform on protein-protein interfaces we used AlphaFold2 to predict structures for nearly 500,000 protein complexes. We illustrate the value of mechanism-aware variant effect predictions to study the relation between protein stability and abundance and the structural properties of interfaces underlying trans protein quantitative trait loci (pQTLs). We characterised the distribution of mechanistic impacts of protein variants found in patients and experimentally studied example disease linked variants in FGFR1.

bioinformatics↗

bioRxiv2023

Distinct adrenal gland macrophages regulate corticosteroid production

The adrenal glands are hormone secreting glands that sit on top of the kidneys. Adrenal glands produce glucocorticoids, mineralocorticoids, and catecholamines, and are therefore critical regulators of the stress response, the immune response, metabolism, and blood pressure. Despite being identified for more that 30 years, our understanding of adrenal macrophages remains incomplete. In numerous other tissues, macrophages carry out a plethora of physiological and homeostatic roles in addition to their classical immune functions. The aim of this study was to characterise the macrophage compartment of the adrenal gland and assess its contribution to adrenal function. Using an in vivo approach, we herein describe two morphologically and spatially distinct subsets of adrenal macrophages - dendritic-like macrophages that are present throughout the gland in young and old mice, and "foamy" lipid-laden macrophages that accumulate in the murine adrenal cortex in an age and diet-dependent manner. Furthermore, we present data showing that these foamy-like macrophages accumulate cholesterol and thereby regulate adrenal hormonal output, at steady state and in the context of obesity. We hereby provide novel insights into the physiological roles of macrophages in the adrenal gland and the mechanisms by which adrenal hormone production is regulated.

immunology↗

bioRxiv2023

Short-term consumption of ultra-processed semi-synthetic diets impairs the sense of smell and brain metabolism in mice

The prevalence of highly-palatable, ultra-processed food in our modern diet has exacerbated obesity rates and contributed to a global health crisis. While accumulating evidence suggests that chronic consumption of ultra-processed semi-synthetic food is detrimental to sensory and neural physiology, it is unclear whether its short-term intake has adverse effects. Here, we assessed how short-term consumption (<2 months) of three ultra-processed diets (one grain-based diet, and two semi-synthetic) influence olfaction and brain metabolism in mice. Our results demonstrate that short-term consumption of semi-synthetic diets, regardless of macronutrient composition, adversely affect odor-guided behaviors, physiological responses to odorants, transcriptional profiles in the olfactory mucosa and brain regions, and brain glucose metabolism and mitochondrial respiration. These findings reveal that even short periods of ultra-processed semi-synthetic food consumption are sufficient to cause early olfactory and brain abnormalities, which has the potential to alter food choices and influence the risk of developing metabolic disease.

neuroscience↗

bioRxiv2021

The anatomical logic of smell

The sense of smell helps us navigate the environment, but its molecular architecture and underlying logic remain unknown. The spatial location of odorant receptor genes (Olfrs) in the nose is widely thought to be independent of the structural diversity of the odorants they detect. Using spatial transcriptomics, we created a genome-wide 3D atlas of the mouse olfactory mucosa (OM). Topographic maps of genes differentially expressed in space reveal that both Olfrs and non-Olfrs are distributed in a continuous and overlapping fashion over five broad zones in the OM. The spatial locations of Olfrs correlate with the mucus solubility of the odorants they recognize, providing direct evidence for the chromatographic theory of olfaction. This resource resolved the molecular architecture of the mouse OM, and will inform future studies on mechanisms underlying Olfr gene choice, axonal pathfinding, patterning of the nervous system, and basic logic for the peripheral representation of smell.

neuroscience↗

bioRxiv2021

Odor Blocking Of Stress

Scents have been employed for millennia to allay fear and stress, but whether they do so is poorly understood. In response to fear and stress, hypothalamic corticotropin releasing hormone neurons (CRHNs) induce increases in blood stress hormones. Here, we find that certain structurally and perceptually dissimilar odorants can block mouse stress hormone responses to three potent stressors: physical restraint, predator odor, and male-male social confrontation. Both odorants activate GABAergic inhibitory neurons presynaptic to CRHNs in the hypothalamic ventromedial nucleus (VMH). Stimulation of those neurons inhibits restraint-induced activation of CRHNs and stress hormone increase, mimicking a blocking odorant. Conversely, their silencing prevents odorant blocking of both responses. Notably, we also observed odor blocking of stressor activation in neurons presynaptic to CRHNs in the bed nucleus of the stria terminalis (BNST). Together, these findings indicate that selected odorants can indeed block stress responses, and that odor blocking can occur via two routes: a direct route in which blocking odor signals directly inhibit CRHNs and an indirect route in which they inhibit stressor activation of neurons presynaptic to CRHNs and prevent them from transmitting stress signals to CRHNs.

neuroscience↗

bioRxiv2020

Deconstructing the mouse olfactory percept through an olfactory ethological atlas

Odor perception in non-humans is poorly understood. Here, we generated the most comprehensive murine olfactory ethological atlas to date, consisting of behavioral responses to a diverse panel of 73 odorants, including 12 at multiple concentrations. These data revealed that the mouse behavior is incredibly diverse, and changes in response to odor identity and intensity. Using only behavioral responses, ~30% of the 73 odorants could be identified with high accuracy (>96%) by a trained classifier. Mouse behavior occupied a low-dimensional space, consistent with analyses of human olfactory perception. While mouse olfactory behavior is difficult to predict from the corresponding human olfactory percept, three fundamental properties are shared: odor valence is the primary axis of olfactory perception; the physicochemical properties of odorants can predict the olfactory percept; and odorant concentration quantitatively and qualitatively impacts olfactory perception. These results provide a template for future comparative studies of olfactory percepts among species.

neuroscience↗

bioRxiv2020

Multi-organ transcriptomic profiling reveals differential regulation of the immune system among the brain-liver-fats organ network of short-term fasted mice

Different fasting regimens are known to promote health, mitigate chronic immunological disorders, and improve age-related pathophysiological parameters in animals and humans. Indeed, several clinical trials are currently ongoing using fasting as a potential therapy for a wide range of conditions. Fasting alters metabolism by acting as a reset for energy homeostasis. However, the molecular mechanisms underlying the beneficial effects of short-term fasting (STF) are still not well understood, particularly at the systems or multi-organ level. Here, we investigated the dynamic gene expression patterns associated with six periods of STF in nine different mouse organs. We cataloged the transcriptional dynamics within and between organs during STF and discovered differential temporal effects of STF among organs. Using gene ontology enrichment analysis, we identified an organ network sharing 37 common biological pathways perturbed by STF. This network incorporates the brain, liver, interscapular brown adipose tissue, and posterior-subcutaneous white adipose tissue, hence we named it the brain-liver-fats organ network. Using Reactome pathways analysis, we identified the immune system, dominated by T cell regulation processes, as a central and prominent target of systemic modulations during STF in this organ network. The changes we identified in specific immune components point to the priming of adaptive immunity and parallel the fine-tuning of innate immune signaling. Our study provides a comprehensive multi-organ transcriptomic profiling of mice subjected to multiple periods of STF, and adds new insights into the molecular modulators involved in the systemic immuno-transcriptomic changes that occur during short-term energy loss.

systems biology↗

bioRxiv2019

A transcriptomic atlas of mammalian olfactory mucosae reveals an evolutionary influence on food odor detection in humans

The mammalian olfactory system displays species-specific adaptations to different ecological niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) sub-types across 95 million years of mammalian evolution, we applied RNA-sequencing of whole olfactory mucosa samples from mouse, rat, dog, marmoset, macaque and human. We find that OSN subtypes representative of all known mouse chemosensory receptor gene families are present in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory receptors (ORs) are distributed across a large dynamic range and that homologous subtypes can be either highly abundant across all species or species/order-specific. Interestingly, highly abundant mouse and human OSN subtypes detect odorants with similar sensory profiles, and sense ecologically relevant odorants, such as mouse semiochemicals or human key food odorants. Taken together, our results allow for a better understanding of the evolution of mammalian olfaction in mammals and provide insights into the possible functions of highly abundant OSN subtypes in mouse and human.

neuroscience↗

bioRxiv2018

Interspecific variation of olfactory preferences in flies, mice, and humans

Aiming to unravel interspecific differences in olfactory preferences, we performed comparative studies of odor valence in flies, mice, and humans. Our analysis revealed that odor preferences of flies correlate positively with the ones of mice and negatively with the ones of humans, but found no evidence supporting the hypothesis that humans and mice prefer the same odors. We further find that odorants eliciting the highest and lowest preferences are often advertising critical biological sources (e.g., food or oviposition sites), suggesting that evolutionary pressures reflecting the ecological needs of each species shape olfactory preferences.

neuroscience↗

bioRxiv2017

Heterogeneity of hypothalamic Pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing

Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterised simply as direct targets for leptin, recent data suggest a more complex architecture. Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons. Of 163 neurons, 118 expressed high levels of Pomc with little/no Agrp expression and were considered \"canonical\" POMC neurons (P+). The other 45/163 expressed low levels of Pomc and high levels of Agrp (A+P+). Unbiased clustering analysis of P+ neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P+ neurons expressed the leptin receptor (Lepr) compared with 58% (26/45) of A+P+ neurons. In contrast, the insulin receptor (Insr) was expressed at similar frequency on P+ and A+P+ neurons (64% and 55%, respectively). These data reveal arcuate POMC neurons to be a highly heterogeneous population.

neuroscience↗