Lake Ontario Coastal Initiative Action Agenda

The mission of the Lake Ontario Coastal Initiative (LOCI), encompassing all New York State North Coast stakeholders from the Niagara River to the St. Lawrence River, is to enlist and retain broad public commitment for remediation, restoration, protection, conservation and sustainable use of the coastal region. This mission will be accomplished by securing funds and resources to achieve scientific understanding, educate citizens, and implement locally supported priorities, programs and projects as identified through this Initiative

Probabilistic functional tractography of the human cortex revisited

In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model-based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo-functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human.Peer reviewe

Phosphomimetic Mutation of the N-Terminal Lid of MDM2 Enhances the Polyubiquitination of p53 through Stimulation of E2-Ubiquitin Thioester Hydrolysis

Mouse double minute 2 (MDM2) has a phosphorylation site within a lid motif at Ser17 whose phosphomimeticmutation to Asp17 stimulates MDM2-mediated polyubiquitination of p53. MDM2 lid deletion, but not Asp17mutation, induced a blue shift in the λmax of intrinsic fluorescence derived from residues in the central domainincluding Trp235, Trp303, Trp323, and Trp329. This indicates that the Asp17 mutation does not alter theconformation of MDM2 surrounding the tryptophan residues. In addition, Phe235 mutation enhanced MDM2binding to p53 but did not stimulate its ubiquitination function, thus uncoupling increases in p53 binding from its E3ubiquitin ligase function. However, the Asp17mutation inMDM2 stimulated its discharge of the UBCH5a-ubiquitinthioester adduct (UBCH5a is a ubiquitin-conjugating enzyme E2D 1 UBC4/5 homolog yeast). This stimulation ofubiquitin discharge fromE2 was independent of the p53 substrate. There are now four known effects of the Asp17mutation on MDM2: (i) it alters the conformation of the isolated N-terminus as defined by NMR; (ii) it inducesincreased thermostability of the isolated N-terminal domain; (iii) it stimulates the allosteric interaction ofMDM2 withthe DNA-binding domain of p53; and (iv) it stimulates a novel protein–protein interaction with the E2-ubiquitincomplex in the absence of substrate p53 that, in turn, increases hydrolysis of theE2-ubiquitin thioester bond. Thesedata also suggest a new strategy to disrupt MDM2 function by targeting the E2-ubiquitin discharge reaction