Interaction of synchronized dynamics in cortical and subcortical circuits in Parkinson’s disease

poster abstractParkinson’s disease pathophysiology is marked by increased oscillatory and synchronous activity in the beta frequency band in cortical and basal ganglia circuits. This study explores the functional connections between synchronized dynamics of cortical areas and dynamics of subcortical areas in Parkinson’s disease. We simultaneously recorded neuronal units (spikes) and local field potentials (LFP) from subthalamic nucleus (STN), and electroencephalograms (EEGs) from the scalp in parkinsonian patients and analyzed the correlation between the time-courses of the spike-LFP synchronization and inter-electrode EEG synchronization. We found the (noninvasively obtained) time-course of the synchrony strength between EEG electrodes and the (invasively obtained) time-course of the synchrony between spiking unit and LFP in STN to be weakly, but significantly correlated with each other. This correlation is largest for the bilateral motor EEG synchronization followed by bilateral frontal EEG synchronization. Our observations suggest that there may be multiple functional modes by which the cortical and basal ganglia circuits interact with each other in Parkinson’s disease: not only synchronization may be observed between some areas in cortex and the basal ganglia, but also synchronization within cortex and within basal ganglia may be related, suggesting potentially more global way of functional interaction. More coherent dynamics in one brain region may modulate or activate the dynamics of another brain region in a more powerful way causing correlations between changes in synchrony strength in both regions

Cortex – basal ganglia synchronization in Parkinson’s disease

poster abstractIncreased synchrony in the beta band in cortico-basal ganglia circuits is well described in patients with PD. Less is known, however, about how these abnormal firing patterns are correlated across these brain regions. In this study we investigated how this intra-operative data recorded from STN correlates with scalp recorded EEG. Intraoperative single unit recordings and LFPs were obtained from STN and scalp EEG recordings were collected from four electrodes positioned over prefrontal and motor areas. We computed the STN spike-LFP (Local Filed Potential) phase synchrony over short temporal windows as it fluctuates in time. We also computed the EEG phase synchrony index time series for all 6 pairs of EEG electrodes. Next we explored cross-correlation between the two synchrony level time-series of the spike-LFP vs. EEG pairs. EEG synchrony was found to be correlated with spike-LFP synchrony. Correlation between surface EEG and STN was strongest for ipsilateral EEG and STN recordings. Spike-LFP synchronization is believed to characterize the input-output characteristics of STN dynamics and to be strongly relevant to the expression of motor symptoms. Our results indicate that non-invasive and relatively simple EEG recordings retain some information about synchronous dynamics in the subcortical regions, which can be access only in an invasive manner during functional neurosurgical procedures

Z→bbˉZ\to b\bar b in U(1)RU(1)_R Symmetric Supersymmetry

We compute the one-loop corrections to the $Z \to b\bar{b}$ vertex in the $U(1)_R$ symmetric minimal supersymmetric extension of the standard model. We find that the predicted value of $R_b$ is consistent with experiment if the mass of the lighter top squark is no more than 180 GeV. Furthermore, other data combines to place a lower bound of 88 GeV on the mass of the light top squark. A top squark in this mass range should be accessible to searches by experiments at FNAL and LEP.Comment: Corrected typos; added footnotes and a reference. 19 pages, LaTeX, includes 8 figures, full postscript version at http://smyrd.bu.edu/htfigs/htfigs.htm

Brane Decay of a (4+n)-Dimensional Rotating Black Hole. II: spin-1 particles

The present works complements and expands a previous one, focused on the emission of scalar fields by a (4+n)-dimensional rotating black hole on the brane, by studying the emission of gauge fields on the brane from a similar black hole. A comprehensive analysis of the particle, energy and angular momentum emission rates is undertaken, for arbitrary angular momentum of the black hole and dimensionality of spacetime. Our analysis reveals the existence of a number of distinct features associated with the emission of spin-1 fields from a rotating black hole on the brane, such as the behaviour and magnitude of the different emission rates, the angular distribution of particles and energy, the relative enhancement compared to the scalar fields, and the magnitude of the superradiance effect. Apart from their theoretical interest, these features can comprise clear signatures of the emission of Hawking radiation from a brane-world black hole during its spin-down phase upon successful detection of this effect during an experiment.Comment: 35 pages, 19 figures, Latex fil

Genome-Wide Significant Risk Loci for Mood Disorders in the Old Order Amish Founder Population

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with \u3e2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1. Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies

Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

SummaryAlzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Aβ42 levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Aβ40 levels while concomitantly elevating levels of Aβ38 and Aβ37. Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Aβ42; chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs)

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin