Biology subjects

De Cecco, M.

Publications and source records attributed to De Cecco, M..

3 recordsLinked to original sources

bioRxiv2022

Analysis of somatic mutations in senescent cells using single-cell whole-genome sequencing

SO_SCPLOWUMMARYC_SCPLOWSomatic mutations accumulate in multiple organs and tissues during aging and are a known cause of cancer. Here we tested whether mutations accumulate during replicative senescence. Cellular senescence is also a possible cause of functional decline in aging, yet also acts as an anti-cancer mechanism in vivo. Using single-cell whole-genome sequencing, we compared mutation burdens between early passage and deeply senescent human fibroblasts. The results showed that single-nucleotide variations and small insertions and deletions increased in senescent cells by about two-fold, but have the same spectrum as early passage cells, while it has been known that particular mutational signatures are found in tumor cells. In contrast, aneuploidies were observed in half the senescent cells, but largely absent in early passage cells. Thus, the patterns of mutations among senescent, normal-aged and tumor cells differ significantly.

genomics↗

bioRxiv2020

Basal ganglia high-frequency activity is co-modulated with the phase of motor cortical beta and shifted between the subthalamic nucleus and the internal pallidum during sustained motor control

Beta oscillations are readily observed in motor cortex and the basal ganglia, but to which extent they are functionally relevant is unclear. To understand how activity transfer between different nodes of the cortico-basal ganglia network is affected by cortical beta oscillations in different behavioural conditions, we recorded local field potentials and electroencephalography (EEG) activity in a low-force motor control task and during rest in Parkinsons patients undergoing deep brain stimulation (DBS) surgery. The patients received DBS of either the subthalamic nucleus (STN) or the internal globus pallidus (GPi), which allowed us to investigate if STN and GPi broad-band high-frequency activity (HFA; >150 Hz) is co-modulated with the phase of motor cortical beta activity. We found significant modulation patterns in the STN and the GPi, which were inverted while patients performed the task, showing that GPi activity fluctuations likely are crafted by other inputs than the direct excitatory STN afferents. We also found that consistent STN modulation disappeared during rest, showing disengagement in this condition, while GPi modulation was maintained, again evidencing that beta-band activity fluctuations in the GPi can be relatively independent of those in the STN. The difference between HFA modulation patterns in the task and rest recordings suggests a potential functional role of beta phase-locked HFA modulation in controlling sustained contractions. Examination of HFA co-modulation patterns at different sites of the cortico-basal ganglia-thalamo-cortical network under different behavioural conditions may provide a tool with which to define the impact of beta synchronization on network communication.

neuroscience↗

bioRxiv2018

Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice

Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6 deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA which triggers massive type I interferon response via activation of cGAS. Remarkably, nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number and type I interferons were elevated in the wild type aged mice. As sterile inflammation is a hallmark of aging we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.\n\nHighlightsO_LISIRT6 KO mice accumulate L1 cDNA triggering type I interferon response via cGAS pathway\nC_LIO_LIWild type aged mice accumulate L1 cDNA and display type I interferon response\nC_LIO_LIReverse transcriptase inhibitors rescue type I interferon response and DNA damage\nC_LIO_LIReverse transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice\nC_LI

molecular biology↗