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PubblicazioneFoxg1 promotes neuron allocation to engrams and facilitates fear memorization(SISSA, 2026-04-20)In addition to orchestrate telencephalic development, the transcription factor Foxg1 is involved in mutual positive feedback with neuronal activity. Based on that, we hypothesized an involvement of it in learning and engram dynamics. We observed that its sparse and mild neuronal upregulation improved learning abilities as evaluated by a CFC assay. This effect was specifically pronounced upon early memory retrieval and disappeared when Foxg1-GOF neurons were silenced by a Gi DREADD effector. A prevailing positive relationship was detectable between Foxg1 expression level and the probability of a neuron getting recruited into training and recall engrams, in structures involved in both short- and long-term memory formation. Moreover, Foxg1 upregulation elicited a generalized shrinkage of engrams and increased the fraction of late recall engram cells already active at the time of training. Together, these findings establish Foxg1 as a key effector linking neuronal excitability to engram allocation and memory recall.
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PubblicazioneUnzipping of knotted DNA via nanopore translocation( 2025)DNA unzipping by nanopore translocation has implications in diverse contexts, from polymer physics to single-molecule manipulation to DNA-enzyme interactions in biological systems. Here we use molecular dynamics simulations and a coarse-grained model of DNA to address the nanopore unzipping of DNA filaments that are knotted. This previously unaddressed problem is motivated by the fact that DNA knots inevitably occur in isolated equilibrated filaments and in vivo. We study how different types of tight knots in the DNA segment just outside the pore impact unzipping at different driving forces. We establish three main results. First, knots do not significantly affect the unzipping process at low forces. However, knotted DNAs unzip more slowly and heterogeneously than unknotted ones at high forces. Finally, we observe that the microscopic origin of the hindrance typically involves two concurrent causes: the topological friction of the DNA chain sliding along its knotted contour and the additional friction originating from the entanglement with the newly unzipped DNA. The results reveal a previously unsuspected complexity of the interplay of DNA topology and unzipping, which should be relevant for interpreting nanopore-based single-molecule unzipping experiments and improving the modeling of DNA transactions in vivo.
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PubblicazioneMapping cryptic phosphorylation sites in the human proteome( 2025)Advances in computational and experimental methods have revealed the existence of transient, non-native protein folding intermediates that could play roles in disparate biological processes, from regulation of protein expression to disease-relevant misfolding mechanisms. Here, we tested the possibility that specific post-translational modifications may involve residues exposed during the folding process by assessing the solvent accessibility of 87,138 post-translationally modified amino acids in the human proteome. Unexpectedly, we found that one-third of phosphorylated proteins present at least one phosphosite completely buried within the protein’s inner core. Computational and experimental analyses suggest that these cryptic phosphosites may become exposed during the folding process, where their modification could destabilize native structures and trigger protein degradation. Phylogenetic investigation also reveals that cryptic phosphosites are more conserved than surface-exposed phosphorylated residues. Finally, cross-referencing with cancer mutation databases suggests that phosphomimetic mutations in cryptic phosphosites can increase tumor fitness by inactivating specific onco-suppressors. These findings define a novel role for co-translational phosphorylation in shaping protein folding and expression, laying the groundwork for exploring the implications of cryptic phosphorylation in health and disease.
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PubblicazioneFeedback from retinal ganglion cells to the inner retina( 2021)Retinal ganglion cells (RGCs) are thought to be strictly postsynaptic within the retina. They carry visual signals from the eye to the brain, but do not make chemical synapses onto other retinal neurons. Nevertheless, they form gap junctions with other RGCs and amacrine cells, providing possibilities for RGC signals to feed back into the inner retina. Here we identified such feedback circuitry in the salamander and mouse retinas. First, using biologically inspired circuit models, we found mutual inhibition among RGCs of the same type. We then experimentally determined that this effect is mediated by gap junctions with amacrine cells. Finally, we found that this negative feedback lowers RGC visual response gain without affecting feature selectivity. The principal neurons of the retina therefore participate in a recurrent circuit much as those in other brain areas, not being a mere collector of retinal signals, but are actively involved in visual computations.
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PubblicazioneHierarchical modeling of gravitational-wave populations for disentangling environmental and modified-gravity effects( 2026)The upcoming Laser Interferometer Space Antenna will detect up to thousands of extreme-massratio inspirals (EMRIs). These sources will spend 105 cycles in band and are therefore sensitive to tiny changes in the general-relativistic dynamics, potentially induced by astrophysical environments or modifications of general relativity (GR). Previous studies have shown that these effects can be highly degenerate for a single source. However, it may be possible to distinguish between them at the population level, because environmental effects should impact only a fraction of the sources, while modifications of GR would affect all. We therefore introduce a population-based hierarchical framework to disentangle the two hypotheses. Using simulated EMRI populations, we perform tests of the null vacuum-GR hypothesis and two alternative beyond-vacuum-GR hypotheses, namely, migration torques (environmental effects) and time-varying G (modified gravity). We find that with as few as X20 detected sources our framework can statistically distinguish between these three hypotheses and even indicate if both environmental and modified gravity effects are simultaneously present in the population. Our framework can be applied to other models of beyond-vacuum-GR effects available in the literature.