Biology subjects

Falco, A.

Publications and source records attributed to Falco, A..

6 recordsLinked to original sources

bioRxiv2025

Three-Dimensional-Mapping of Smooth Muscle Morphogenesis in the Vertebrate Gastrointestinal Tract

Gastrointestinal (GI) motility depends on smooth muscle contractions to propel contents through the digestive tract. GI muscle is organized into two perpendicular layers: the inner circular smooth muscle (CSM) and the outer longitudinal smooth muscle (LSM) layers. This organization is important for proper motility. Despite several investigations, GI smooth muscle development remains poorly understood due to several limitations. Previous studies mainly relied on SMA detection in tissue sections and focused on a single organ or developmental stage. They often overlooked key smooth muscle markers such as CALPONIN and {gamma}SMA and largely neglected the LSM layer. In this study, we combined confocal imaging of whole-mount three-dimensional-cleared embryonic chick guts with heatmap analysis to generate the first spatial atlas of smooth muscle development. We characterize the expression patterns of SMA, {gamma}SMA, and CALPONIN1, thereby mapping the dynamics of the formation and differentiation of CSM and LSM layers along the antero-posterior axis. This study provides a framework for future investigations into the regulatory mechanisms governing smooth muscle patterning and maturation along the GI tract.

developmental biology↗

bioRxiv2025

Electrophysiological and network dynamics disruption of hippocampal CA1 neurons after NMDAr blockade by MK-801

The N-methyl-D-aspartate receptor (NMDAr) hypofunction hypothesis suggests that excitatory-inhibitory (E-I) imbalance underlies cognitive deficits associated with neuropsychiatric disorders, such as schizophrenia (SCZ). In this study, we investigated the impact of NMDAr blockade on pyramidal neurons and interneurons in the CA1 region of the hippocampus using in vivo electrophysiological recordings during both spontaneous and exploratory behaviors. Through the administration of MK-801, an NMDAr antagonist, we assessed changes in spike train dynamics, network synchrony, and neuronal modulation by oscillatory activity, with particular emphasis on theta, gamma, and sharp-wave ripple (SWR) oscillations. We found that NMDAr blockade significantly disrupted the E-I balance, leading to altered spike train properties, reduced bursting propensity, and impaired neuronal synchronization. These changes were accompanied by decreased modulation of pyramidal neurons and interneurons by theta and gamma oscillations, as well as diminished recruitment of pyramidal neurons during SWR events. Additionally, the correlation between firing rates and movement speed was reduced, reflecting deficits in spatial coding and memory processing. Moreover, MK-801 administration disrupted place cell stability and spatial information processing. These effects likely contribute to functional disconnection between the hippocampus and other brain regions, such as the prefrontal cortex, and may underlie SCZ-associated cognitive impairments. Our findings provide valuable insights into the cellular and network-level mechanisms affected by NMDAr dysfunction, highlighting the role of oscillatory activity and spike timing in cognitive deficits. This work advances our understanding of how NMDAr hypofunction impacts hippocampal circuits and identifies potential targets for therapeutic interventions aimed at restoring cognitive function in neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway

ObjectiveClinical research has identified stomach dysmotility as a common feature of obesity. However, the specific mechanisms driving gastric emptying dysfunction in patients with obesity remain largely unknown. In this study, we investigated potential mechanisms by focusing on the homeostasis of gastric smooth muscle, using tissue samples from both patient and mice, as well as human cell culture system. DesignTissue samples were collected from patients who underwent sleeve gastrectomy for obesity, as well as from control subjects with standard weight who were undergoing treatment for gastric or esophageal carcinoma. Stomach tissues were harvested from mice after 12 weeks on a High-Fat Diet (HFD). Differentiated human gastric smooth muscle cells (SMCs) were treated with lipids, siRNA-peptide-based nanoparticles and/or pharmaceutical compounds. All experimental conditions were analyzed for their effects on SMC differentiation using stage-specific smooth muscle markers. Additionally, lipidomic and RNA sequencing analyses were performed on human gastric SMC cultures. The findings were assessed in patients with obesity to evaluate their clinical relevance. ResultsThe smooth muscle layers in gastric tissue from both patients with obesity and mice fed on a HFD exhibited altered differentiation status. Treatment of differentiated human gastric SMCs with lipids phenocopies these alterations and is associated with increased expression of PDK4 and ANGPTL4. Inhibition of PDK4 or ANGPTL4 upregulation prevents these lipid-induced modifications. Mechanistically, lipid treatment activates PPARD, which regulates PDK4 and ANGPTL4 upregulation, leading to SMC dedifferentiation. Notably, PDK4 and ANGPTL4 levels correlate with immaturity and alteration of gastric smooth muscle in patients with obesity. ConclusionObesity triggers a phenotypic change in gastric SMCs, driven by the activation of the PPARD/PDK4/ANGPTL4 pathway. These mechanistic insights offer potential biomarkers for diagnosing stomach dysmotility in patients with obesity.

physiology↗

bioRxiv2022

Progression Analysis of Disease with Survival (PAD-S) by SurvMap identifies different prognostic subgroups of breast cancer in a large combined set of transcriptomics and methylation studies

Progression analysis of disease (PAD) is a methodology that incorporates the output of Disease-Specific Genomic Analyses (DSGA) to an unsupervised classification scheme based on Topological Data Analysis (TDA). PAD makes use of data derived from healthy individuals to split individual diseased samples into healthy and disease components. Then, the shape characteristics of the disease component are extracted trough the generation of a combinatioral graph by means of the Mapper algorithm. In this paper we introduce a new filtering function for the Mapper algorithm that naturally integrates information on genes linked to disease-free or overall survival. We propose a new PAD-extended methodology termed Progression Analysis of Disease with Survival (PAD-S) and implement it in an R package called SurvMap which allows users to carry out all the steps involved in PAD-S, as well as in traditional PAD analyses. We tested PAD-S methodology using SurvMap on a large combined transcriptomics breast cancer dataset demonstrating its capacity to identify sets of samples displaying highly significant differences in terms of disease free survival (p = 8 x 10-14) and idiosyncratic biological features. PAD-S and SurvMap were also able to identify sets of samples with significantly different relapse-free survivals and molecular profiles inside breast cancer intrinsic subgroups (luminal A, luminal B, Her2, and basal). Finally, to illustrate that PAD-S and SurvMap are general-purpose analysis tools that can be applied to different types of omics data, we also carried out analyses in a breast cancer methylation dataset derived from The Cancer Genome Atlas (TCGA) identifying groups of patients with significant differences in terms of overall survival and methylation profiles.

bioinformatics↗

bioRxiv2022

High-Resolution Ultrasound and Speckle Tracking: a non-invasive approach to assess in vivo gastrointestinal motility during development

Gastrointestinal motor activity has been extensively studied in adults, conversely only few studies have investigated fetal motor skills. When the gastrointestinal tract starts to contract during the embryonic period and how this function evolves during development are not known. Here, we adapted a non-invasive high-resolution echography technique combined with speckle tracking analysis to examine the gastrointestinal tract motor activity dynamics during chick embryo development. We provided the first recordings of fetal gastrointestinal motility in living embryos. We found that although gastrointestinal contractions appear very early during development, they become synchronized only at the end of the fetal period. To validate this approach, we used various pharmacological inhibitors and BAPX1 gene overexpression in vivo. We found that the enteric nervous system determinates the onset of the synchronized contractions in the stomach. Moreover, alteration of smooth muscle fiber organization led to an impairment of this functional activity. Altogether, our findings show that non-invasive high-resolution echography and speckle tracking analysis allow visualizing and quantifying gastrointestinal motility during development and highlight the progressive acquisition of functional and coordinated gastrointestinal motility before birth.

developmental biology↗

bioRxiv2018

25-HYDROXYL-CHOLESTEROL BINDS AND ENHANCE ANTI-VIRAL EFFECTS OF ZEBRAFISH MONOMERIC C-REACTIVE PROTEINS

C-reactive proteins (CRP) are among the faster acute-phase inflammation-responses coded by one gene in humans (hcrp) and seven genes (crp1-7) in zebrafish (Danio rerio). In this study, preferential 25-hydroxycholesterol (25HOCh) binding to zebrafish CRP1-7 compared to other lipids were predicted by in silico docking and confirmed by solid-phase binding-assays. In addition, 25HOCh enhanced methyl-betacyclodextrin-sensitive (Cholesterol-dependent) CRP1-7 anti-viral effects in a fine-tunned isoform-dependent manner. In silico and structural studies suggested that the crosstalk between the anti-viral enhancements of both 25HOCh and CRP1-7 were dependent on protein monomers rather than oligomers but differred among isoforms. The presence of oxidized cholesterols in human atherosclerotic plaques amplifies the importance that similar interactions may have for vascular and/or neurodegenerative diseases during viral infections. In this context, the zebrafish model offers a genetic tool to further investigate how the expression and functions of different CRP isoforms and/or transcript variants may be controlled.

immunology↗