Quantitative features of EEG and STN-LFP of Parkinson’s patients with motor symptoms

Parkinson's disease motor symptoms are associated with excessive beta oscillations in the subthalamic nucleus (STN). However, multi-modal signals recorded during and after implantation of deep brain stimulation (DBS) electrode can provide many other, more fine-grained features. Various studies are currently searching for the features that can be useful in providing a meaningful relationship with various Parkinson’s symptoms. Finding them will allow for more precise diagnostics and treatment. Yet, studies correlating quantitative measures based on electroencephalogram (EEG) with motor symptoms have yielded no clear relationship [3], inviting further exploration. We use a large dataset to systematically investigate relationships between quantitative EEG, local field potential (LFP) in STN, and motor symptoms. The LFP and EEG data are measured in 30s blocks during surgery for the deep brain stimulation electrode placement on different electrode depths. We analyze the scale-free behavior of the EEG and LFP signals and their potential implications for Parkinson’s disease motor symptoms. We use Detrended Fluctuation Analysis (DFA) to quantify the scaling of the signal, with the DFA exponent quantifying this scaling analogously to the Hurst exponent. In our case, we are particularly interested in the dynamics of envelope amplitude modulation of cortical EEG [see Fig. 1A-D] and how it relates to the concurrently recorded signal in STN. Previous studies have shown that cortical signals exhibit scale-free behavior in the alpha and beta bands [1]. We additionally demonstrate that the DFA exponent of the alpha band strongly correlates with the power of the alpha band [see Fig. 1E]. Furthermore, previous studies have shown a correlation between cortical long-range temporal correlations (LRTC) and imaginary coherence in STN [2]. We extend these results to the larger patients cohort and include an investigation of the relationship with symptoms. <br

A pre-catalytic non-covalent step governs DNA polymerase β fidelity

DNA polymerase beta (pol beta) selects the correct deoxyribonucleoside triphosphate for incorporation into the DNA polymer. Mistakes made by pol beta lead to mutations, some of which occur within specific sequence contexts to generate mutation hotspots. The adenomatous polyposis coli (APC) gene is mutated within specific sequence contexts in colorectal carcinomas but the underlying mechanism is not fully understood. In previous work, we demonstrated that a somatic colon cancer variant of pol beta, K289M, misincorporates deoxynucleotides at significantly increased frequencies over wild-type pol beta within a mutation hotspot that is present several times within the APC gene. Kinetic studies provide evidence that the rate-determining step of pol beta catalysis is phosphodiester bond formation and suggest that substrate selection is governed at this step. Remarkably, we show that, unlike WT, a pre-catalytic step in the K289M pol beta kinetic pathway becomes slower than phosphodiester bond formation with the APC DNA sequence but not with a different DNA substrate. Based on our studies, we propose that precatalytic conformational changes are of critical importance for DNA polymerase fidelity within specific DNA sequence contexts.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Probing DNA Base-Dependent Leaving Group Kinetic Effects on the DNA Polymerase Transition State

We examine the DNA polymerase β (pol β) transition state (TS) from a leaving group pre-steady-state kinetics perspective by measuring the rate of incorporation of dNTPs and corresponding novel β,γ-CXY-dNTP analogues, including individual β,γ-CHF and -CHCl diastereomers with defined stereochemistry at the bridging carbon, during the formation of right (R) and wrong (W) base pairs. Brønsted plots of log <i>k</i>_pol versus p<i>K</i>_a4 of the leaving group bisphosphonic acids are used to interrogate the effects of the base identity, the dNTP analogue leaving group basicity, and the precise configuration of the C-X atom in <i>R</i> and <i>S</i> stereoisomers on the rate-determining step (<i>k</i>_pol). The dNTP analogues provide a range of leaving group basicity and steric properties by virtue of monohalogen, dihalogen, or methyl substitution at the carbon atom bridging the β,γ-bisphosphonate that mimics the natural pyrophosphate leaving group in dNTPs. Brønsted plot relationships with negative slopes are revealed by the data, as was found for the dGTP and dTTP analogues, consistent with a bond-breaking component to the TS energy. However, greater multiplicity was shown in the linear free energy relationship, revealing an unexpected dependence on the nucleotide base for both A and C. Strong base-dependent perturbations that modulate TS relative to ground-state energies are likely to arise from electrostatic effects on catalysis in the pol active site. Deviations from a uniform linear Brønsted plot relationship are discussed in terms of insights gained from structural features of the prechemistry DNA polymerase active site