D'Andrea, A. | bioRxiv Science

bioRxiv2023

Intrinsic motor network connectivity predicts corticospinal excitability

State-dependent non-invasive brain stimulation (NIBS) informed by electroencephalography (EEG) has contributed to the understanding of NIBS inter-subject and inter-session variability. While these approaches focused on local EEG characteristics, it is acknowledged that the brain exhibits an intrinsic long-range dynamic organization in networks. This proof-of-concept study explores whether EEG connectivity of the primary motor cortex (M1) in the pre-stimulation period aligns with the motor network (MN) and how MN state affects responses to transcranial magnetic stimulation (TMS) of M1. One thousand suprathreshold TMS pulses were delivered to left M1 in 8 subjects at rest, with simultaneous EEG. Motor evoked potentials (MEPs) were measured from the right hand. Source-space functional connectivity of left M1 to the whole-brain was assessed using the imaginary part of the Phase Locking Value at the frequency of the sensorimotor {micro}-rhythm in a 1-second window before the pulse. Group-level connectivity revealed functional links between left M1, left supplementary motor area, and right M1. Also, pulses delivered at high MN connectivity states result in a greater MEP amplitude compared to low connectivity states. At single-subject level, this relation is more expressed in subjects that feature an overall high cortico-spinal excitability. In conclusion, this study paves the way for MN connectivity based NIBS. HighlightsO_LIEEG pre-stimulus connectivity of left M1 largely corresponds to the motor network C_LIO_LIStronger motor network (MN) connectivity corresponds to greater MEP amplitudes C_LIO_LILinear regression models based on MN connectivity predicts MEP amplitude C_LI

neuroscience↗

bioRxiv2018

WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers

Summary paragraphSynthetic lethality, an interaction whereby the co-occurrence of two or more genetic events lead to cell death but one event alone does not, can be exploited to develop novel cancer therapeutics1. DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired DNA repair pathway, which can lead these cells to become dependent on specific repair proteins2. The success of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors in homologous recombination-deficient cancers highlights the potential of this approach in clinical oncology3,4. Hypothesizing that other DNA repair defects would give rise to alternative synthetic lethal relationships, we asked if there are specific dependencies in cancers with microsatellite instability (MSI), which results from impaired DNA mismatch repair (MMR). Here we analyzed data from large-scale CRISPR/Cas9 knockout and RNA interference (RNAi) silencing screens and found that the RecQ DNA helicase WRN was selectively essential in MSI cell lines, yet dispensable in microsatellite stable (MSS) cell lines. WRN depletion induced double-strand DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models specifically required the helicase activity, but not the exonuclease activity of WRN. These findings expose WRN as a synthetic lethal vulnerability and promising drug target in MSI cancers.

cancer biology↗