Biology subjects

Giannini, M.

Publications and source records attributed to Giannini, M..

3 recordsLinked to original sources

bioRxiv2020

TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

TDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. Here, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, and R loop-dependent increased DSBs and Fanconi Anemia repair centers. Similar results were observed in a non-neuronal model of HeLa cells depleted of TDP-43. These results uncover a new role of TDP-43 in the control of co-transcriptional R-loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R-loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies.

molecular biology↗

bioRxiv2019

Neural Correlates of Task-related Refixation Behaviour

Information uptake during scene viewing under free viewing conditions is crucially determined by the scanning plan. This plan is determined both by top-down and bottom-up factors. To capture top-down factors affecting saccade planning, we compared EEG between first fixations and refixations on items varying in task-relevance. First fixations and refixations impose different working memory costs because first fixations involve encoding of new items whereas refixations involve rehearsal of existing items in working memory. These memory requirements also differ with the task-relevance of the item being encoded. Together, these two factors of task-relevance and memory processes related to refixation behavior would affect saccade planning. In a visual task involving search and memorization of multiple targets, we compared saccade-related potentials (SRPs) between first fixations and refixations for task-relevant (target) and task-irrelevant (distractor) items. We assessed the interval preceding a saccade away from the fixation of interest. Studying this presaccadic interval revealed how mechanisms related to saccade preparation are affected by task-relevance and refixation behavior. We found higher SRP amplitudes for first fixations than refixations over the occipital region for task-relevant items only. Our findings indicate that saccade planning is modulated by both task-relevance of an item and working memory load.

neuroscience↗

bioRxiv2019

Revising the scanning plan for continued visual exploration: the neurophysiology of refixation-related behavior

Eye tracking studies suggest that refixations, fixations to locations previously visited, serve to recover information lost or missed during earlier exploration of a visual scene. These studies have largely ignored the role of precursor fixations, previous fixations on locations the eyes return to later. We consider the possibility that preparations to return later are already made during precursor fixations. This would mark precursor fixations as a special category of fixations, i.e., distinct in neural activity from other fixation categories such as refixations and fixations to locations visited only once. To capture the neural signals associated with fixation categories, we analyzed EEG and eye movement recorded simultaneously in a free-viewing contour search task. We developed a methodological pipeline involving regression-based deconvolution modeling, allowing our analyses to account for overlapping EEG responses due to the saccade sequence and other oculomotor covariates. We found that precursor fixations were preceded by the largest saccades among the fixation categories. Independently of the effect of saccade length, EEG amplitude was enhanced in precursor fixations compared to the other fixation categories 200-400 ms after fixation onsets, most noticeably over the occipital areas. We concluded that precursor fixations play a pivotal role in visual perception, marking the continuous occurrence of transitions between exploratory and exploitative modes of eye movement in natural viewing behavior.

neuroscience↗