Biology subjects

Nardi, F.

Publications and source records attributed to Nardi, F..

4 recordsLinked to original sources

bioRxiv2026

Proximity-Informed Graph Learning Defines Spatial Protein Communities for Tumor-Associated Proximity Antigen Discovery

The spatial organization of membrane proteins is an underexplored dimension of cell-surface biology. Spatial proximity shapes cellular function and therapeutic targetability, yet efforts to identify tumor-associated antigens (TAAs) have largely focused on expression alone. Here, we developed an industrialized surface-protein proximity mapping workflow to interrogate TAAs within their membrane microenvironments. In the process, we generated 248 proximity maps across 12 receptor tyrosine kinases (RTKs) and 28 tumor cell systems. This proximity atlas enabled two advances: first, MetaMap, a correlation-based analytical framework that defines spatial protein communities and infers non-targeted proximal proteins from reproducible proximity signatures; and second, tumor-associated proximity antigens (TAPAs), a conceptual class of co-targets defined by disease-specific spatial proximity to TAAs rather than expression alone. Applying these proximity-derived relationships within a multimodal prioritization framework, we identified and validated an EGFRxCDCP1 TAA-TAPA pair that enhanced tumor cell killing across therapeutic modalities. By integrating spatial organization with multimodal data, this work expands the design space for precision-guided therapeutic strategies.

cancer biology↗

bioRxiv2024

An NAMPT Inhibitor Decreases NAMPT Capture by an Antibody Directed against the 5-Phosphoribosyl-1-Pyrophosphate-Binding Loop: A Rational for an NAMPT Occupancy Assay

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD) biosynthesis. NAMPT inhibitors (NAMPTi) have been shown to be NAMPT substrates. The resulting NAMPTi-phosphoribose (RP) adduct binds tightly to NAMPT and inhibits the enzyme. Using new NAMPTi, SAR154782, structural analyses performed in this study unveiled a close proximity of the SAR154782-RP complex to the 5-phosphoribosyl-1-pyrophosphate-binding (PRPP-binding) loop within the NAMPT catalytic site. The PRPP-binding loop of NAMPT is subject to conformational flexibility. Interestingly, the PRPP-binding loop domain is oriented to the outer side of the NAMPT dimer and can potentially serve as an antigen-binding site for antibodies. Here we report for the first time that the NAMPTi-RP adduct bound to NAMPT decreases NAMPT capture by an antibody directed against the c-terminal PRPP-binding loop in NAMPT. This finding was then used to explore cellular NAMPT occupancy. The NAMPTi-RP complex displays a sustained, cellular NAMPT occupancy that correlates with the inhibition of NAMPT activity. Moreover, a good correlation between NAMPT occupancy, NAD decrease, and NAMPTi efficacy was observed in-vivo in a NCI-H82 small cell lung cancer (SCLC) xenograft model. NAMPT-occupancy assay can be used in clinical settings to better define the optimal dose levels and dose regimen for effective NAMPT inhibition.

cancer biology↗

bioRxiv2024

Integrating Secondary Structure Information Enhances Phylogenetic Signal in Mitochondrial Protein Coding Genes

Secondary structures have long been held to carry significant phylogenetic information, but the difficulty in collating primary sequence and structural information has frequently hindered its full application in phylogenetic studies. Here, we focus on the implementation of secondary structure information (inner, outer and transmembrane regions) to improve partitioning in datasets of mitochondrial Protein-Coding Genes for phylogenetic analysis. A new pipeline called TRAMPO was developed to partition alignment sites accordingly. The inclusion of this structural information in phylogenetic analyses was shown to produce an improvement in the phylogenetic signal of mitochondrial protein coding genes. We speculate that the observed, distinctive, compositional bias towards thymines in second codon sites of transmembrane regions, as well as selection, may be among the possible driving forces. This effect is especially relevant in lineages older than 50 Ma, where the signal of second codon positions becomes more relevant as first and third codon sites begin experiencing saturation.

evolutionary biology↗

bioRxiv2024

Motor Learning Mechanisms are not modified by Feedback Manipulations in a Real-World Task

Error-based and reward-based mechanisms of motor learning co-occur in real-world scenarios but are traditionally isolated in laboratory tasks via feedback manipulations. This study examines the distinctiveness of these mechanisms by applying a lab-based feedback manipulation to a real-world task. Using Embodied Virtual Reality (EVR) of pool billiards - allowing for full proprioception via interaction with the physical pool table, cue stick, and balls - we introduced visual perturbations to a real-world task. 32 participants (12 F) underwent two sessions learning a visuomotor rotation, once with error and once with reward feedback. While naive participants corrected the entire rotation with error feedback, only partial correction was observed with reward feedback, highlighting the influence of the feedback regime on learning. However, the reward-dependent motor variability, lag-1 autocorrelation decay, and inter-trial variability decay - all indicators of reward-based and skill learning - were higher in the error feedback session, suggesting that the provided visual feedback did not exclusively engage specific learning mechanisms. Analysis of post-movement beta rebound (PMBR), a brain activity marker of learning mechanisms, revealed a decrease in PMBR with reward feedback but no consistent trend during error feedback sessions. These findings support the behavioural results, suggesting that while reward feedback was absent in error conditions, participants still engaged in reward-based learning. This study underscores the complexity of motor learning processes and highlights that visual feedback by itself can not elucidate the interplay between error-based and reward-based mechanisms in real-world contexts.

neuroscience↗