Biology subjects

Pellegrini, V.

Publications and source records attributed to Pellegrini, V..

3 recordsLinked to original sources

bioRxiv2025

Arousal-related mediation of perceptual belief updating across auditory domains

Belief updating refers to the integration of prior beliefs with incoming evidence and guides decision-making under uncertainty. In response to surprising events, this process is thought to be modulated by the locus-coeruleus-noradrenaline (LC-NA) arousal system, observable via pupil dilations (PDs). Pertinent literature has mostly focused on conscious, high-level decision-making and estimation processes, while assuming that the same principles apply to low-level sensory perceptual decision-making and generalize across tasks, domains and modalities. To address some of these assumptions, we devised a novel perceptual discrimination paradigm, investigating behavior and PDs across auditory domains. Participants were presented with auditory sequences of randomized length at a rapid pace, changing intermittently between two latent states: acceleration vs. deceleration (temporal group, N = 25) and clockwise vs. counterclockwise movement (spatial group, N = 22). Under high uncertainty, participants continuously inferred latent states to report the final state per sequence. To extract per-stimulus estimates of PDs during sequences, we fitted a deconvolution-based general linear model to the continuous pupil traces with a free amplitude parameter reflecting ongoing PDs. A Bayesian observer model was fitted to participants responses and used to estimate information gain and surprisal for every stimulus. Participants performance and PDs showed strong sensitivity to the occurrence of change-points. Both computational variables significantly predicted PDs in both domains, with information gain outperforming surprisal in a model comparison. Further model comparison revealed significant preference for models excluding possible domain-specific effects over models including them, pointing towards a constant effect over domains. We conclude that behavior and associated PDs observed in our purely perceptual auditory task align with Bayesian principles of belief updating. The observed lack of domain specificity supports the assumed generalizability of belief updating.

neuroscience↗

bioRxiv2024

B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements

The B cell receptor (BCR) is essential for mature B cell lymphomas, serving as therapeutic target. Here, we show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. HGBCL-DH-BCL2 with undetectable IGH (IGHUND) differ from IGH-expressing counterparts for germinal center-zone gene programs, MYC expression and T cell infiltration. While IGH+ HGBCL-DH-BCL2 prefer IGM/IG-Kappa expression, IGHUND counterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGHUND HGBCL-DH-BCL2 preserve IGHV gene integrity, overcoming antigen-driven selection. IGH silencing precedes onset and shapes evolution of HGBCL-DH-BCL2 from Follicular Lymphoma (FL) or FL/HGBCL-DH-BCL2 common precursor. In FL/HGBCL-DH-BCL2 pairs and HGBCL-DH-BCL2 models, BCR silencing promoted RAG1/2-dependent IG light chain editing, causing t(8;22)(q24;q11)/IGL::MYC. IGH silencing protected HGBCL-DH-BCL2 models from killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, HGBCL-DH-BCL2 primarily originate from BCR-silenced isotype-switched t(14;18)/IGH::BCL2-positive (pre)FL cells acquiring IGL::MYC translocations during IG light chain revision, with clinical implications. SignificanceThese findings link BCR silencing in isotype-switched t(14;18)+ Follicular Lymphoma cells (or their precursors) to RAG1/2 re-expression, promoting IGL::MYC translocations responsible for transformation into high-grade B cell lymphomas (HGBCL). Predominant silencing of the BCR complex in HGBCL with MYC and BCL2 rearrangements protects tumor cells from CD79B-directed Polatuzumab-Vedotin killing.

cancer biology↗

bioRxiv2024

Drug-repurposing screen identifies thiostrepton as a novel regulator of the tumor suppressor DAB2IP

The tumor suppressor DAB2IP, a RasGAP and cytoplasmic adaptor protein, modulates signal transduction in response to several extracellular stimuli, negatively regulating multiple oncogenic pathways. Accordingly, the loss of DAB2IP in tumor cells fosters metastasis and enhances chemo- and radio-resistance. DAB2IP is rarely mutated in cancer but is frequently downregulated or inactivated by multiple mechanisms. Solid experimental evidence show that DAB2IP reactivation can reduce cancer aggressiveness in tumors driven by multiple different oncogenic mutations, making this protein an interesting target for anti-cancer therapy. Based on these premises, we screened a library of FDA-approved drugs to search for molecules that can increase DAB2IP protein levels. We exploited CRISPR/Cas9 gene editing to generate two prostate cancer cell models in which endogenous DAB2IP is fused to HiBiT, a peptide tag that enables luminescence-based detection of protein levels in a sensitive and quantitative manner. Using this approach, we identified drugs able to increase DAB2IP levels. We focus our attention on thiostrepton, a natural cyclic oligopeptide antibiotic that has been reported to inhibit survival of various cancer cell lines. Functional experiments revealed that the cancer inhibitory effect of thiostrepton is reduced in the absence of DAB2IP, suggesting that the observed upregulation contributes to its action. These findings encourage the further development of thiostrepton for the treatment of solid cancers, and unveil a novel molecular mechanism underlying its anti-tumoral action.

cancer biology↗