Biology subjects

Mangoni, M.

Publications and source records attributed to Mangoni, M..

6 recordsLinked to original sources

bioRxiv2026

Dynamic consensus pocket detection across molecular dynamics ensembles reveals persistent and transient druggable sites

The traditional "one drug, one target" paradigm assumes that drugs interact with a single specific binding site. Modern pharmacology has proven this definition overly simplistic and, instead, recognizes that drugs operate within complex biological systems and often interact with multiple targets. In this context, proteins cannot be viewed as possessing a single functional binding site, but rather as dynamic entities capable of accommodating ligands at multiple regions, including transient and cryptic pockets. Here, we review and repurpose representative pocket detection tools across geometry-based, energy-based, and machine/deep learning approaches, originally designed to work on static conformations, to evaluate their agreement on molecular dynamics-derived conformational ensembles. Using GLUT1 protein as a dynamic transporter model and Aldose reductase as a cryptic-pocket reference system, we combine inter-tool concordance, HDBSCAN-based spatial clustering, volumetric IoU analysis, and temporal persistence scoring. Our results show that different algorithmic classes capture complementary aspects of pocket dynamics, with energy-based methods showing stronger sensitivity to transient cryptic regions and geometry-based approaches depending more strongly on pre-formed cavities. This work proposes a consensus-oriented framework for identifying conserved and transient druggable pockets in dynamic protein systems.

bioinformatics↗

bioRxiv2025

nAPOGEE: A machine-learning platform for clinically actionable pathogenicity assessment of all mitochondrial noncoding variants

Mitochondrial noncoding variants, particularly those in tRNA and rRNA genes, pose significant challenges for clinical interpretation due to heteroplasmy, broad phenotypic heterogeneity where symptoms can overlap with other conditions, and the limited availability of well-established genotype-phenotype correlations. Despite their central role in mitochondrial translation, these variants have remained largely unexplored by the existing variant-effect predictors. Here, we present nAPOGEE, a novel machine-learning framework specifically designed to assess the pathogenicity of all possible single-nucleotide variants in human mitochondrial noncoding RNAs. nAPOGEE integrates two specialized predictors: tAPOGEE, which outperforms existing tools for tRNAs, and rAPOGEE, the first dedicated classifier for mitochondrial rRNA variants. Using curated training datasets, phylogenetic conservation metrics, secondary structure modeling, RNA-specific embeddings, and thermodynamic features, nAPOGEE provides biologically interpretable predictions and posterior probabilities aligned with the ACMG/AMP guidelines. Applied to both curated variant sets and population-scale data, nAPOGEE revealed consistent spatial correlation of the predicted pathogenicity, reflecting underlying structural and evolutionary constraints. This study addresses a longstanding gap in mitochondrial genomics and offers a clinically applicable tool for variant prioritization, reclassification, and research into mitochondrial disease mechanisms.

bioinformatics↗

bioRxiv2025

NetMD: Unsupervised Synchronization of Molecular Dynamics Trajectories via Graph Embedding and Time Warping

Molecular dynamics (MD) simulations yield detailed atomistic views of biomolecular processes, yet comparing independent trajectories is hindered by stochastic divergence. Here, we introduce NetMD, a computational approach that synchronizes and analyzes MD trajectories by combining graph-based representations with dynamic time warping. Frames are transformed into residue-contact graphs, entropy-filtered to retain variable interactions, and embedded as low-dimensional vectors. NetMD then uses time-warping barycenter averaging to align these vector trajectories, yielding a consensus "average" trajectory while pruning the outlier simulations. Applied to diverse systems, such as transporters, demethylases, and protein complexes, NetMD revealed shared multiphase dynamics and pinpointed mutation- or ligand-specific deviations. Thus, this method enables an unsupervised, time-resolved comparison of MD ensembles across conditions. It is robust, broadly applicable, and available as an open-source software, offering a powerful tool for uncovering common patterns and critical divergences in biomolecular dynamics.

bioinformatics↗

bioRxiv2024

T-type calcium channels participate in intrinsic and synaptic activity of PKCγ neurons of the dorsal horn of the spinal cord during chronic pain

ABSTRACTThe disinhibition of the excitatory PKC{gamma} interneurons plays a central role during mechanical allodynia in the dorsal horn of the spinal cord, routing harmless information to nociceptive pathways. The T-type calcium channel Cav3.2, necessary for mechanical and cold allodynia, is found in most PKC{gamma} neurons of the spinal cord. In this study, the role of Cav3.2 in PKC{gamma} neurons was studied after its pharmacological inhibition and its conditional deletion (KO) in Cav3.2GFP-Flox KI x PKC{gamma}-CreERT2 x Ai14 mice in normal conditions and in the spared-nerve-injury (SNI) model of neuropathic pain. Conditional deletion of Cav3.2 increased the hind-paw basal mechanical sensitivity before surgery, and decreased mechanical pain 7 days, but not 28 days, after surgery. At the cellular level, Cav3.2 participated in the low-threshold currents of PKC{gamma} neurons and the T-type calcium current of PKC{gamma} neurons was decreased in KO mice as compared to wild-type (WT). This loss did not convert into proportional alterations in subthreshold properties including "rebound" potentials, suggesting the involvement of other T-type channels. Action potential kinetics and firing properties seemed similar in WT and KO mice too, but rebound potentials were diminished in the SNI model in WT but not in KO mice. In addition, the modulations of firing properties induced by T-type channel pharmacological blocker Z944 observed in WT mice were absent in KO mice and after SNI. Furthermore, the pairing of action potentials was modified after SNI in WT mice, and not in KO mice. At the synaptic level, excitatory currents were lowered 7- and 28-days after surgery, while inhibitory currents were lowered only at 28 days. These changes were not found in Cav3.2-ablated neurons. Miniature currents analysis indicated that Cav3.2 was involved in both excitatory and inhibitory synaptic transmissions at the level of PKC{gamma} neurons. Surprisingly, Z944 did not mimic the effects of Cav3.2 ablation in PKC{gamma} neurons, suggesting distinct and eventually opposite roles of other T-type calcium channels. Altogether, our results show that Cav3.2 is not mandatory for firing of PKC{gamma} neurons of the dorsal horn of the spinal cord, but that it participates to the SNI-induced changes in their intrinsic and synaptic activity, including changes in their excitatory and inhibitory controls. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/627933v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1a297daorg.highwire.dtl.DTLVardef@19f7a76org.highwire.dtl.DTLVardef@120f688org.highwire.dtl.DTLVardef@119658e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Investigating mitochondrial gene expression patterns in Drosophila melanogaster using network analysis to understand aging mechanisms

The process of aging is a complex phenomenon that involves a progressive decline in physiological functions required for survival and fertility. To better understand the mechanisms underlying this process, the scientific community has utilized several tools. Among them, mitochondrial DNA has emerged as a crucial factor in biological aging, given that mitochondrial dysfunction is thought to significantly contribute to this phenomenon. Additionally, Drosophila melanogaster has proven to be a valuable model organism for studying aging due to its low cost, capacity to generate large populations, and ease of genetic manipulation and tissue dissection. Moreover, graph theory has been employed to understand the dynamic changes in gene expression patterns associated with aging and to investigate the interactions between aging and aging-related diseases. In this study, we have integrated these approaches to examine the patterns of gene co-expression in Drosophila melanogaster at various stages of development. By applying graph-theory techniques, we have identified modules of co-expressing genes, highlighting those that contain a significantly high number of mitochondrial genes. We found important mitochondrial genes involved in aging and age-related diseases in Drosophila melanogaster, including UQCR-C1, ND-B17.2, ND-20, and Pdhb. Our findings shed light on the role of mitochondrial genes in the aging process and demonstrate the utility of Drosophila melanogaster as a model organism and graph theory in aging research.

bioinformatics↗

bioRxiv2018

Bradycardic mice undergo effective heart rate improvement after specific homing to the sino-atrial node and differentiation of adult muscle derived stem cells.

Current treatments for heart automaticity disorders still lack a safe and efficient source of stem cells to restore normal biological pacemaking. Since adult Muscle-Derived Stem Cells (MDSC) show multi-lineage differentiation in vitro including into spontaneously beating cardiomyocytes, we questioned whether they could effectively differentiate into cardiac pacemakers, a specific population of cardiomyocytes producing electrical impulses in the sino-atrial node (SAN) of adult heart. We show here that beating cardiomyocytes, differentiated from MDSC in vitro, exhibit typical characteristics of cardiac pacemakers: expression of markers of the SAN lineage Hcn4, Tbx3 and Islet1, as well as spontaneous calcium transients and hyperpolarization-activated "funny" current and L-type Cav1.3 channels. Pacemaker-like myocytes differentiated in vitro from Cav1.3-deficient mouse stem cells produced slower rate of spontaneous Ca2+ transients, consistent with the reduced activity of native pacemakers in mutant mice. In vivo, undifferentiated wild type MDSC migrated and homed with increased engraftment to the SAN of bradycardic mutant Cav1.3-/- within 2-3 days after systemic I.P. injection. The increased homing of MDSCs corresponded to increased levels of the chemokine SDF1 and its receptor CXCR4 in mutant SAN tissue and was ensued by differentiation of MDSCs into Cav1.3-expressing pacemaker-like myocytes within 10 days and a significant improvement of the heart rate maintained for up to 40 days. Optical mapping and immunofluorescence analyses performed after 40 days on SAN tissue from transplanted wild type and mutant mice showed MDSCs integrated as pacemaking cells both electrically and functionally within recipient mouse SAN. These findings identify MDSCs as directly transplantable stem cells that efficiently home, differentiate and improve heart rhythm in mouse models of congenital bradycardia.

cell biology↗