Biology subjects

Rodrigues, T.

Publications and source records attributed to Rodrigues, T..

9 recordsLinked to original sources

bioRxiv2026

CCR2 is a potential biomarker and therapeutic target in Group 3 medulloblastoma

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, classified into four molecular subgroups: WNT, SHH, Group 3, and Group 4. Among these, Group 3 MB displays the worst prognosis with highest rates of dissemination and the worst survival outcomes. While current therapies control the primary tumor, metastatic disease remains largely incurable underscoring the need for novel therapeutic options. The CCL2/CCR2 axis is a well establish metastases driver in systemic tumors through the promotion of angiogenesis and cell migration. Recently, this axis has been implicated in MB pathogenesis and dissemination, particularly in Group 3 tumors. Therefore, we hypothesize that CCR2 represents a therapeutically actionable driver in aggressive MB. Methods: The clinical relevance of CCR2 in MB was assessed using publicly available gene expression data from two independent datasets. CCR2 expression was further evaluated by immunohistochemistry on paired primary and recurrent/metastatic tumor samples to validate these findings. Functional studies using ONS76 and UW228 MB cells with CCR2 overexpression evaluated proliferation, migration and CCR2 downstream signaling. Orthotopic xenograft mouse models assessed CCR2 effect on tumor invasion, dissemination, and survival. An in-silico drug screening identified potential CCR2 antagonists that were tested in vitro and in vivo. Results: Gene expression data analysis across 1094 MB primary samples correlated high CCR2 expression with dissemination and reduced survival in Group 3 MB patients. In an independent MB patient cohort, CCR2 protein levels were increased in recurrent/metastatic tumors compared with paired primary tumors. CCR2 overexpression in vitro promoted cancer cell proliferation and migration. CCR2-driven MB mouse xenografts, exhibited an aggressive disease phenotype and decreased survival, resembling Group 3 tumors. CCR2 targeting with Cenicriviroc suppressed CCR2-mediated signaling and showed therapeutic efficacy against established MB tumors in vivo. Conclusions: CCR2 identifies aggressive Group 3 MB and represents a promising actionable target for therapy.

cancer biology↗

bioRxiv2026

Foveal vision in fast-flying birds hunting on the wing

Processing rapid motion while maintaining high spatial acuity is a fundamental evolutionary challenge for the vertebrate visual system. Here, we investigated the structural adaptations enabling aerial insectivores - swifts (Apus apus) and swallows (Hirundo rustica, Delichon urbicum) - to track and capture prey at high speeds. We show that these phylogenetically distinct species share highly specialized temporal foveae that provide sharp frontal vision. Strikingly, this avian specialization converges on primate foveal architecture, featuring cones with long axons and a unique cluster of large, orthotopic ganglion cells (soma area [≥] 200 {micro}m{superscript 2}) surrounding a deep foveal pit. By tracking their large axons, we mapped their neural representation within the optic nerve and tectum. Despite the low abundance of these foveal cells, their substantial tectal magnification reflects high processing demands. This cluster of putative motion-sensitive ganglion cells suggests that foveal neural circuitry links high-acuity vision to rapid temporal processing in these birds.

neuroscience↗

bioRxiv2025

New Histone H4 variant and H2B variant Exhibits Distinct Genomic Locations, Chromatin Affinities, and Dynamics Throughout Life Cycle and Cell Cycle of Trypanosoma cruzi

Histone variants play crucial roles in chromatin organization and transcriptional regulation in eukaryotes. Unusually, trypanosomatids display histone variants for all histones, although a functional homolog of histone H4 variant (H4.V) had not yet been described in Trypanosoma cruzi. In this study, we identified a H4.V in T. cruzi that is encoded by a single-copy gene located apart from the typical tandem arrays of canonical histone H4. Functional characterization using ChIP-seq assays revealed that H4.V is located at telomeric regions, demarcates convergent strand-switch regions (cSSRs), and determines new transcription termination sites at codirectional PTUs interrupted by tDNA loci. Throughout the cell cycle, H4.V transcript levels remain stable, while protein abundance increases in G2/M, as shown by immunofluorescence and image flow cytometry. In contrast, the histone H2B variant (H2B.V) transcripts peak at S-phase, and protein abundance accumulates progressively. H4.V is more abundant in the nuclei of metacyclic trypomastigotes but barely detectable in amastigotes and bloodstream trypomastigotes. In contrast, H2B.V shows a punctate nuclear pattern and is present in all life stages, with the highest levels also observed in metacyclics. During metacyclogenesis, both variants show a progressive increase in expression, particularly H4.V, suggesting a role in parasite differentiation. Ultimately, salt extraction experiments demonstrated differing chromatin binding affinities across life stages for both variants, with H4.V displaying a more permanent chromatin association than H2B.V, indicating that H4.V may be associated with a more compact chromatin state. Our data reveal H4.V as a novel histone variant in T. cruzi, characterized by unique genomic localization, expression profiles, and chromatin-binding dynamics in contrast to H2B.V, underscoring its potential function as an epigenetic marker in transcriptional regulation and adaptation to diverse host environments. Author summaryChromatin is composed of a group of proteins called histones that are involved in compacting DNA and thereby affecting many DNA-associated mechanisms, such as replication and transcription. Histone variants share distinct primary sequences from the canonical ones and display different roles and genomic locations. While variants of histone H3 and H2A are common in all eukaryotes, variants of H2B and H4 are unusual, except in trypanosomatids, a group of parasites that cause human and veterinary diseases. Among them, Trypanosoma cruzi, the causative agent of Chagas disease, exhibits variants for three core histones, but a variant of histone H4 (H4.V) had not been described. Here, we identify H4.V and demonstrate its preferential deposition at telomeres, convergent strand-switch regions (cSSRs), and codirectional polycistronic transcription units (PTUs) interrupted by tDNA loci, likely marking transcription termination sites. Both variants are enriched in the nuclei of metacyclic trypomastigotes; however, H4.V is barely detectable in amastigotes and bloodstream trypomastigotes, while H2B.V is consistently present in all forms. Additionally, each variant shows distinct chromatin-binding affinities across life stages, with H4.V potentially linked to a more compact chromatin state. Our findings reveal a novel histone variant with unique dynamics and epigenetic roles distinct from H2B.V in T. cruzi.

microbiology↗

bioRxiv2022

Increased neuron density in the midbrain of foveate birds results from profound change in tissue morphogenesis

The increase of brain neuron number in relation with brain size is currently considered to be the major evolutionary path to high cognitive power in amniotes. However, how changes in neuron density did contribute to the evolution of the information-processing capacity of the brain remains unanswered. High neuron densities are seen as the main reason why the fovea located at the optical center of the retina is responsible for sharp vision in birds and primates. The emergence of foveal vision is considered as a breakthrough innovation in visual system evolution. We found that neuron densities in the largest visual center of the midbrain - i.e., the optic tectum - are two to four times higher in modern birds with one or two foveae compared to birds deprived of this specialty. Interspecies comparisons enabled us to identify elements of a hitherto unknown developmental process set up by foveate birds for increasing neuron density in the upper layers of their optic tectum. The late progenitor cells that generate these neurons proliferate in a ventricular zone that can expand only radially. In this particular context, the number of cells in ontogenetic columns increases, thereby setting the conditions for higher cell densities in the upper layers once neurons did migrate. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/514341v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1861345org.highwire.dtl.DTLVardef@15b5557org.highwire.dtl.DTLVardef@13fec7borg.highwire.dtl.DTLVardef@1bea1bb_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe presence of a fovea is associated with increased neuron density in the optic tectum C_LIO_LIFovea number and deepness influence neuron density in the optic tectum C_LIO_LIIncreased neuron density in the upper layers of the optic tectum requires major developmental changes C_LIO_LIPostponed cell migration, prolonged cell proliferation, hindered tissue growth are necessary settings for achieving high neuron density C_LI

neuroscience↗

bioRxiv2022

Embryonic cortical layer 5 pyramidal neurons form an active, transient circuit motif perturbed by autism-associated mutations

Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that embryonic layer 5 pyramidal neurons, identified through single cell transcriptomics, display two phases of circuit assembly in vivo. At E14.5, a multi-layered circuit motif, composed of a single layer 5 cell type, forms. This motif is transient, switching to a second circuit motif, involving all three types, by E17.5. In vivo targeted single cell recordings and two-photon calcium imaging of embryonic layer 5 neurons reveal that, in both phases, neurons have active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses. Embryonic layer 5 neurons strongly express autism-associated genes, and perturbing these genes disrupts the switch between the two motifs. Hence, layer 5 pyramidal neurons form transient active pyramidal-to-pyramidal circuits, at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.

neuroscience↗

bioRxiv2022

Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.

immunology↗

bioRxiv2020

A transient decrease in mitochondrial activity is required to establish the ganglion cell fate in retina adapted for high acuity vision

Although the plan of the retina is well conserved in vertebrates, there are considerable variations in cell type diversity and number, as well as in the organization and properties of the tissue. The high ratios of retinal ganglion cells (RGCs) to cones in primate fovea and bird retinas favor neural circuits essential for high visual acuity and color vision. The role that cell metabolism could play in cell fate decision during embryonic development of the nervous system is still largely unknown. Here, we describe how subtle changes of mitochondrial activity along the pathway converting uncommitted progenitors into newborn RGCs increase the recruitment of RGC-fated progenitors. ATOH7, a proneural protein dedicated to the production of RGCs in vertebrates, activates transcription of the Hes5.3 gene in pre-committed progenitors. The HES5.3 protein, in turn, regulates a transient decrease in mitochondrial activity via the retinoic acid signaling pathway few hours before cell commitment. This metabolic shift lengthens the progression of the ultimate cell cycle and is a necessary step for upregulating Atoh7 and promoting RGC differentiation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/002998v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@60b51aorg.highwire.dtl.DTLVardef@111be27org.highwire.dtl.DTLVardef@1db19f8org.highwire.dtl.DTLVardef@1860da3_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

developmental biology↗

bioRxiv2019

Mutational burden of hepatoblastomas: a role for the CX3CL1/CX3CR1 chemokine signaling pathway

BackgroundHepatoblastoma is an embryonal liver tumor supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. CTNNB1 is the only recurrently mutated gene, and this relative paucity of somatic mutations poses a challenge to risk stratification and development of targeted therapies. MethodsIn this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. ResultsOur data disclosed a low mutational background with only three recurrently mutated genes: CTNNB1 and two novel candidates, CX3CL1 and CEP164. The major finding was a recurrent mutation (A235G) identified in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed up-regulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 pathway occurs in hepatoblastomas, with a predominance of these proteins in the cytoplasm of tumor cells. These proteins were not detected in the infiltrated lymphocytes of inflammatory regions of the tumors, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative tumor cells, but strongly positive infiltrated lymphocytes. Our data suggested that CX3CL1/CX3CR1 upregulation may be a common feature of hepatoblastomas, potentially related to chemotherapy response and progression. In addition, three mutational signatures were identified in hepatoblastomas, two of them with predominance of either the COSMIC signatures 1 and 6, found in all cancer types, or the COSMIC signature 29, related only with tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C>A mutations. ConclusionsOverall, we present here evidence that CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with hepatoblastoma tumorigenesis or progression, besides reporting a novel mutational signature specific to a hepatoblastoma subset.

cancer biology↗

bioRxiv2018

Neural circuit basis of aversive odour processing in Drosophila from sensory input to descending output.

Evolution has shaped nervous systems to produce stereotyped behavioural responses to ethologically relevant stimuli. For example when laying eggs, female Drosophila avoid geosmin, an odorant produced by toxic moulds. Here we identify second, third, and fourth order neurons required for this innate olfactory aversion. Connectomics data place these neurons in a complete synaptic circuit from sensory input to descending output. We find multiple levels of valence-specific convergence, including a novel form of axo-axonic input onto second order neurons conveying another danger signal, the pheromone of parasitoid wasps. However, we also observe extensive divergence: second order geosmin neurons connect with a diverse array of 80 third order cell types. We find a pattern of convergence of aversive odour channels at this level. Crossing one more synaptic layer, we identified descending neurons critical for egg-laying aversion. Our data suggest a transition from a labelled line organisation in the periphery to a highly distributed central brain representation that is then coupled to distinct descending pathways.

neuroscience↗