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Biology subjects

Ghetti, S.

Publications and source records attributed to Ghetti, S..

10 recordsLinked to original sources

The development of navigation and attentional abilities shapes how children explore naturalistic environments

Exploration is fundamental to how children learn about the world. To explore a new environment comprehensively, a child must navigate without getting lost while simultaneously attending to salient information along the way. Both abilities improve across childhood, yet most studies examine them in isolation, often in constrained spaces with limited sensory complexity. Here, we asked 7- to 14-year-old children (N=42) and young adults (18-22; N=42) to freely explore a large furniture store in immersive virtual reality, which contained many objects and attention-capturing multisensory events. Surprisingly, despite traveling comparable distances, children explored less - they covered less spatial area and examined fewer unique objects than adults. Fine-grained analyses of their behaviors showed that the reduction in exploration was due to children spending more time backtracking and children taking longer to adapt to salient multisensory objects, which were uncorrelated across individuals after controlling for age and independently predicted exploration. However, only backtracking duration predicted success in a subsequent search task, demonstrating a link between navigational success during exploration and the quality of learned spatial representations for later use. Together, the results demonstrate that children explore less comprehensively than adults in large-scale spaces because they are susceptible to getting lost and perseverating on salient events nested within a large environment, but that these behaviors change with age. This suggests that while children are widely considered to be curious explorers within local environments, their ability to do so within larger environments is shaped by the maturation of cognitive systems that integrate experiences over complex contexts.

animal behavior and cognition↗

Self-guided search in immersive VR reveals active hierarchical planning

Despite the ubiquitous nature of visual search in our daily lives, our knowledge of the underlying mechanisms is almost entirely derived from studies using simple, synthetic stimuli briefly flashed on a computer monitor. In real life, however, visual search occurs in three-dimensional environments over much longer timescales and involves the dynamic coordination of attention, memory, and action planning, generating novel predictions that cannot be tested with traditional approaches. Here, we examined how self-guided visual search unfolds under naturalistic conditions that extend over space and time. We asked participants (N=80) to find specific objects (e.g., a green lamp, an orange shelf) in an immersive, visually rich virtual reality environment using range-limited teleportation (2 m steps). Consistent with our hypotheses, we found that self-guided search engaged a hierarchical information-seeking policy characterized at each stage by recurring plan-and-execute cycles paired with subgoal-specific attentional priorities. Subgoal priorities progressed from wayfinding to identification of clusters of target-similar objects, and then to specific target features. These search priorities progressively narrowed the search space through coordinated eye, head, and body movements that recurred throughout the task. We conclude that naturalistic search is hierarchical, built from sequential subgoals with shifting attentional priorities that single-level tasks cannot capture. Moreover, immersive VR with eye-head-body tracking dissociates motor planning from execution moments and reveals how looking content shifts with each task subgoal while the person moves through space, something desktop tasks cannot capture.

animal behavior and cognition↗

Molecular basis of cooperative assembly of the Ndc80-Ska kinetochore complex on microtubules

Successful chromosome segregation depends on robust kinetochore-microtubule attachments. The outer kinetochore load-bearers Ndc80 and Ska complexes functionally cooperate, but the molecular basis of their interaction remains elusive. Here, we combine cryo-EM and functional investigations of Ndc80:Ska on microtubules. Ndc80 forms longitudinal arrays along single protofilaments using two modules. The HEC1 N-terminal tail stabilizes interactions between microtubule-binding heads regulated by Aurora B. The HEC1 loop, away from microtubules, organizes Ndc80 coiled-coils into stacks matching the periodicity of tubulin subunits. SkaC binds to a previously unknown interface of Ndc80 as well as to microtubules, simultaneously stapling tubulin dimers longitudinally and neighboring protofilaments laterally. Our work demonstrates how several weak interactions of a small number of individual complexes are harnessed to generate a robust and regulated kinetochore coupler.

molecular biology↗

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↗

Interplay of kinetochores and catalysts drives rapid assembly of the mitotic checkpoint complex

The spindle assembly checkpoint (SAC) makes mitotic exit contingent on completion of sister chromatid biorientation, but how this coordination is achieved in practice remains poorly understood. Kinetochores, megadalton chromosome attachment sites to spindle microtubules, contribute to SAC signaling. However, it is unclear whether kinetochores are mere docking sites for SAC proteins, or further contribute to co-orientation of SAC catalysts, including MAD1:MAD2 and BUB1:BUB3, to facilitate SAC signaling. Here, we combined biochemical reconstitutions of kinetochores and the SAC to address this question in vitro. We engineered recombinant kinetochore particles that recruit most SAC components and activate SAC signaling after induction with Rapamycin, and challenged them with a battery of impairing mutants. At approximately physiological concentrations of SAC catalysts, kinetochores were crucially required for rapid assembly of the mitotic checkpoint complex (MCC), the SAC effector. Our observations depict kinetochores as a cradle that catalyzes rapid MCC assembly by concentrating and co-orienting distinct SAC catalysts.

biochemistry↗

Condensin II activation by M18BP1

Condensin complexes promote the drastic spatial rearrangement of the genome upon mitotic entry. Condensin II initiates chromosome condensation in early mitosis. To prevent chromosome condensation during interphase, condensin II is inhibited by MCPH1, but the mechanism is unknown. Through genetic and proteomic approaches, we identify M18BP1, a protein previously associated with centromere identity, as a factor required for condensin II localization to chromatin. M18BP1 directly binds condensin IIs CAP-G2 subunit and competes with MCPH1 for binding. Upon mitotic entry, CDK1 mediated phosphorylation may promote a switch from MCPH1 to M18BP1 binding to activate condensin II. Our results identify a fundamental and evolutionarily conserved mechanism of condensin II activation.

cell biology↗

Spatiospectral image processing workflow considerations for advanced MR spectroscopy of the brain

Magnetic resonance spectroscopy (MRS) is one of the few non-invasive imaging modalities capable of making neurochemical and metabolic measurements in vivo. Traditionally, the clinical utility of MRS has been narrow. The most common use has been the "single-voxel spectroscopy" variant to discern the presence of a lactate peak in the spectra in one location in the brain, typically to evaluate for ischemia in neonates. Thus, the reduction of rich spectral data to a binary variable has not classically necessitated much signal processing. However, scanners have become more powerful and MRS sequences more advanced, increasing data complexity and adding 2 to 3 spatial dimensions in addition to the spectral one. The result is a spatially- and spectrally-variant MRS image ripe for image processing innovation. Despite this potential, the logistics for robustly accessing and manipulating MRS data across different scanners, data formats, and software standards remain unclear. Thus, as research into MRS advances, there is a clear need to better characterize its image processing considerations to facilitate innovation from scientists and engineers. Building on established neuroimaging standards, we describe a framework for manipulating these images that generalizes to the voxel, spectral, and metabolite level across space and multiple imaging sites while integrating with LCModel, a widely used quantitative MRS peak-fitting platform. In doing so, we provide examples to demonstrate the advantages of such a workflow in relation to recent publications and with new data. Overall, we hope our characterizations will lower the barrier of entry to MRS processing for neuroimaging researchers.

bioengineering↗

The mitotic surveillance pathway requires PLK1-dependent 53BP1 displacement from kinetochores

53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactor USP28, it is part of the mitotic surveillance pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. 53BP1 dynamically associates with kinetochores, being recruited during prophase, and then undergoing a time-dependent loss of affinity. However, the relevance of this behaviour remains unclear. Here, we identify CENP-F as an interaction partner and kinetochore receptor for 53BP1. By engineering human cells with a CENP-F point mutation, we demonstrate that preventing 53BP1 kinetochore localization does not reduce MSP proficiency. Strikingly, however, preventing the loss of 53BP1 from the kinetochore by inhibiting Polo-like kinase 1 (PLK1) restrains MSP activity, a phenomenon that is abrogated in the CENP-F mutant condition. Taken together, we demonstrate that kinetochore-loaded 53BP1 represents an MSP functionally inhibited state and that PLK1-dependent re-localization of 53BP1 represents an important layer of MSP regulation.

cell biology↗

Changes in anterior and posterior hippocampus differentially predict item-space, item-time, and item-item memory improvement

Relational memory requires the hippocampus, but whether distinct hippocampal mechanisms along the anterior-posterior axis are required for different types of relations is debated. We investigated the contribution of structural changes in hippocampal head, body, and tail subregions to the capacity to remember item-space, item-time, and item-item relations. Memory for each relation and volumes of hippocampal subregions were assessed longitudinally in 171 participants across 3 time points (Mage at T1= 9.45 years; Mage at T2= 10.86 years, Mage at T3=12.12 years; comprising 393 behavioral assessments and 362 structural scans). Among older children, volumetric growth in: (a) head and body predicted improvements in item-time memory, (b) head predicted improvements in item-item memory; and (c) right tail predicted improvements in item-space memory. The present research establishes that volumetric changes in hippocampal subregions differentially predict changes in different aspects of relational memory, underscoring a division of labor along the hippocampal anterior-posterior axis.

neuroscience↗

The more you know: Investigating why adults get a bigger memory boost from semantic congruency than children

Humans possess the capacity to employ prior knowledge in the service of our ability to remember; thus, memory is oftentimes superior for information that is semantically congruent with our prior knowledge. This congruency benefit grows during development, but little is understood about neurodevelopmental differences that underlie this growth. Here, we sought to explore the brain mechanisms underlying these phenomena. To this end, we examined the neural substrates of semantically congruent vs. incongruent item-context associations in 116 children and 25 young adults who performed encoding and retrieval tasks during functional MRI data collection. Participants encoded item-context pairs by judging whether an item belonged in a scene. Episodic memory was then tested with a source memory task. Consistent with prior work, source memory accuracy improved with age, and was greater for congruent than incongruent pairs; further, this congruency benefit was greater in adults than children. Age-related differences were observed across univariate, functional connectivity, and multivariate analyses, particularly in lateral prefrontal cortex (PFC). In sum, our results revealed two general age differences. First, left ventrolateral/rostrolateral PFC exhibited age-related increases in univariate activity, as well as greater functional connectivity with temporal regions during the processing of congruency. Second, right rostrolateral PFC activation was associated with successfully encoded congruent associations in adults, but not children. Finally, multivariate analyses provided evidence for stronger veridical memory in adults than children in right ventrolateral PFC. These effects in right lateral PFC were significantly correlated with memory performance, implicating them in the process of remembering congruent associations. These results connect brain regions associated with top-down control in the congruency benefit and age-related improvements therein.

neuroscience↗