Biology subjects

Coelho, D. M.

Publications and source records attributed to Coelho, D. M..

4 recordsLinked to original sources

bioRxiv2026

SlytheRINs: using graph parameters and residue interaction networks to analyze protein dynamics and structural ensembles

Establishing the relationship between protein structure and functional behavior remains a significant challenge. The recognition that proteins are inherently dynamic, with functions often dependent on conformational changes, is increasingly accepted. Among computational approaches for elucidating protein properties, Residue Interaction Network (RIN) analysis has emerged as a powerful tool. However, conventional RIN analysis is constrained by its reliance on single, static protein structures, which fail to capture the flexibility inherent in dynamic protein folding transitions. To address these limitations, SlytheRINs is introduced as an interactive tool designed for comparative analysis of protein conformations via RINs. SlytheRINs enables dynamic ensemble analysis by decomposing interaction network data across multiple conformations of a single protein and providing detailed residue-interaction mapping across conformational changes via graph parameters in comparative plots. Applying these principles, the conformational variations of the wild-type and a pathogenic variant (G188R) of the human Glucose-6-Phosphatase (G6PC1) catalytic subunit were compared to identify fluctuations in both chemical interactions and graph features associated with conformational changes induced by the residue modification. The analyses identified key shifts in dynamic residue interactions in the protein variant that compromise substrate binding and the catalytic site, thereby elucidating the impact on G6PC1s dynamic behavior and the resulting activity loss. AvailabilityThe source code for SlytheRINs is available on GitHub (https://github.com/evomol-lab/SlytheRINs), while the web tool and documentation are available at https://slytherins.streamlit.app.

bioinformatics↗

bioRxiv2025

Maturation of the glymphatic system confers innate resistance of the brain to Zika virus infection

The maturation of the glymphatic system initiates fluid dynamics in the central nervous system (CNS). Here, we demonstrate that the initiating glymphatic function results in a steep reduction in the susceptibility of the CNS to Zika virus (ZIKV) infection. In mice, ZIKV injection before glymphatic system maturation leads to widespread infection, vascular deformation, and disruption of Aqp4+ astrocytic networks. After the glymphatic system formation, the same challenge fails to cause disease or persistent infection. Pharmacological inhibition of vasopressin receptor 1a, which reduces perivascular fluid dynamics, reopens the window of susceptibility to ZIKV-related disease. These findings reveal the glymphatic system as an innate protective barrier that limits viral spread in the brain parenchyma and suggest a possible explanation for why late-gestation human fetuses and newborns are less susceptible to ZIKV. Moreover, these data indicate that children with ZIKV-caused malformations can have continuous brain inflammation due to a defective glymphatic system.

neuroscience↗

bioRxiv2020

Differential expression levels of Sox9 in early neocortical radial glial cells regulate the decision between stem cell maintenance and differentiation

Radial glial progenitor cells (RGCs) in the dorsal forebrain directly or indirectly produce excitatory projection neurons and macroglia of the neocortex. Recent evidence shows that the pool of RGCs is more heterogeneous than originally thought and that progenitor subpopulations can generate particular neuronal cell types. Using single cell RNA sequencing, we have studied gene expression patterns of two subtypes of RGCs that differ in their neurogenic behavior. One progenitor type rapidly produces postmitotic neurons, whereas the second progenitor remains relatively quiescence before generating neurons. We have identified candidate genes that are differentially expressed between these RGCs progenitor subtypes, including the transcription factor Sox9. Using in utero electroporation, we demonstrate that elevated Sox9 expression in progenitors prevents RGC division and leads to the generation of upper-layer cortical neurons from these progenitors at later ages. Our data thus reveal molecular differences between cortical progenitors with different neurogenic behavior and indicates that Sox9 is critical for the maintenance of RGCs to regulate the generation of upper layer neurons. SIGNIFICANCE STATEMENTThe existence of heterogeneity in the pool of RGCs and its relationship with the generation of cellular diversity in the cerebral cortex has been an interesting topic of debate for many years. Here we describe the existence of a subpopulation of RGCs with reduced neurogenic behavior at early embryonic ages presenting a particular molecular signature. This molecular signature consists of differential expression of some genes including the transcription factor Sox9, found to be a specific master regulator of this subpopulation of progenitor cells. Functional experiments perturbing Sox9 expressions levels reveal its instructive role in the regulation of the neurogenic behavior of RGCs and its relationship with the generation of upper layer projection neurons at later ages.

neuroscience↗

bioRxiv2018

Evidence of Muller glia conversion into retina ganglion cells using Neurogenin2

Macular Degeneration, Glaucoma, and Retinitis Pigmentosa are all leading causes of irreversible visual impairment in the elderly, affecting hundreds of millions of patients. Muller glia cells (MGC), the main type of glia found in the vertebrate retina, can resume proliferation in the adult injured retina and contribute to tissue repair. Also, MGC can be genetically reprogrammed through the expression of the transcription factor (TF) Achaete-scute homolog 1 (ASCL1) into induced neurons (iNs), displaying key hallmarks of photoreceptors, bipolar and amacrine cells, which may contribute to regenerate the damaged retina. Here, we show that the TF neurogenin 2 (NEUROG2) is also sufficient to lineage-reprogram MGC into iNs. The efficiency of MGC lineage conversion by NEUROG2 is similar to that observed after expression of ASCL1. However, reprogramming efficiency is affected by previous exposure to EGF and FGF2 during the expansion of MGC population. Transduction of either Neurog2 or Ascl1 led to the upregulation of key retina neuronal genes in MGC-derived iNs, but only NEUROG2 induced a consistent increase in the expression of putative retinal ganglion cell (RGC) genes. In vivo electroporation of Neurog2 in the neonatal retina also induced a shift in the generation of retinal cell subtypes, favoring the differentiation RGCs at the expense of MGCs. Altogether, our data indicate that Neurog2 induces lineage conversion of MGCs into RGC-like iNs.

neuroscience↗