The Effect of Auditory Stimuli on the Quantitative Electroencephalogram in Patients with Parkinson's Disease

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder worldwide with increasing incidence and prevalence. It mainly affects the motor system due to a loss of dopaminergic neurons in the substantia nigra and leads to cardinal symptoms including brady-/akinesia, tremor, muscle stiffness and postural instability. After clinical diagnosis, treatment is primarily based on L- dopa, dopamine agonists and MAO-B inhibitors. Even with therapy, PD continues to progress and remains uncurable. In recent years, music therapy has been established as a complementary therapy due to a variety of positive effects, mainly on the motor system. However, it is still insufficiently explained what exactly renders music therapy so effective. Possible explanations range from an increased dopamine release to a better functional connectivity of different brain areas. The aim of this methodologically innovative study was to find underlying mechanisms for the effectiveness of music therapy based on EEG analysis. The analysis of the EEG was chosen due to its good temporal resolution, fast availability and relatively low costs. The research questions were first, whether it is generally possible to distinguish patients with PD from Healthy Controls (HC) based on their EEG. Second, whether auditory stimuli show an effect on the EEG. Third, which features precisely a differentiation of both groups in the EEG is based on. And fourth, which characteristics render an auditory stimulus effective. The study was conducted in collaboration between the University of British Columbia (UBC) in Vancouver and the Philipps-Universität Marburg. In 2017 and 2018, 12 patients with PD and 4 age- matched HC were tested at the UBC campus. A total of 5 EEGs (conditions) were recorded from each subject at rest and under auditory stimulation. The three stimuli differed in complexity (Rain vs Spring Walk) and modulation (rhythmic and non-rhythmic). For a more precise interpretation of the results, natural sounds were used as stimuli instead of music. Due to the amount of data, a custom-made pattern recognition algorithm (Support Vector Machine) was used, distinguishing both groups through a hyperplane within a high-dimensional feature space. Redundant data was removed in advance by calculating the mutual information quotient to include only relevant data in the final analysis. It could be shown that, first, the differentiation of both groups on the basis of the EEG is generally possible, in this case even with a convincing classification accuracy of up to 90 %. Second, the auditory stimuli mainly had an effect on the EEG samples of HC and made the classification more complex: the EEG samples of the HC approached those of the PD patients within the feature space, rendering a common hyperplane for all conditions ineffective. Based on shared features but with a separate hyperplane in each condition classification accuracy of 80-90 % and thus very good discrimination of both groups could be achieved again even under the influence of auditory stimuli. 68 Third, the by far most important features to distinguish both groups were related to the delta frequency band (0.5-4 Hz) including band power, indices of the delta band, and harmonic parameters. The increased importance of delta in PD matches existing literature, most likely due to cognitive decline. This study enhances existing literature on delta by the harmonic parameters, mainly the center frequency and the spectral value thereof. In addition, the delta frequency band is often linked to relaxation and sleep. Thus, the convergence of the EEG samples is most likely explained by stimulus- induced relaxation. Another important feature seems to be the phase lag index. It is also mentioned in the literature as an indicator of mild cognitive impairment and decreases under the influence of the stimuli. A link between the PLI and functional connectivity, as mentioned in the literature, cannot be shown in this study. Fourth, the convergence of the HC samples towards the PD samples was particularly evident in the rain conditions with misclassifications of up to 80 %. This was the case in both the rhythmic and non- rhythmic variants. Given the importance of rhythm as often shown in literature on music therapy it appears that the intended modulation was not perceived as rhythmic by the subjects. The convergence of samples was less evident in the spring walk condition, where higher frequency bands were relevant too. Auditory stimuli thus seem to need a basic complexity to show an effect on the EEG. Approaches to further research arise. For example, if the delta band is expected to be important, greater epoch lengths than in this study (3 seconds) could be analyzed to avoid false interpretations due to epochs being too short to capture very slow oscillations. In addition, a general slowing of the EEG is probably not specific for PD. For a more specific analysis, the inclusion of participants with mild cognitive impairment (PD-MCI as well as MCI not caused by PD) would be useful. Testing more complex stimuli such as music, an inclusion of motor functions in the analysis or even a measurement of dopamine levels would also remain of interest. Looking at the study design, a more balanced patient population might be beneficial. In order to show an effect of music therapy in the EEG, a convergence of PD samples towards HC samples would have been desirable. Due to the relaxation, the opposite was the case. The chosen methodology, however, seems very appropriate. The classification of both groups was possible on a convincingly high level and recommends this approach for further research, due to its variability beyond neurology and even medicine

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Field assisted sintering of fine-grained Li7−3xLa3Zr2AlxO12 solid electrolyte and the influence of the microstructure on the electrochemical performance

The synthesis and processing of fine-grained Li7−3xLa3Zr2AlxO12 (x = 0.15, 0.17, 0.20) solid electrolyte (LLZO) is performed for the first time using a combination of nebulized spray pyrolysis (NSP) and field assisted sintering technique (FAST). Using FAST, the grain growth is suppressed and highly dense ceramics with 93% of the theoretical density are obtained. A tetragonal lattice distortion is observed after the sintering process. Although this structural modification has been reported to have lower Li-ion mobility compared to the cubic modification, the total conductivity of the sample at room temperature is found to be 0.33 mS cm−1, i.e. comparable to phase-pure cubic LLZO. The activation energy of 0.38 eV is also comparable to the literature values. Galvanostatic cycling of a symmetrical cell Li|LLZO|Li shows a good cycling stability over 100 h. The interfacial resistance in contact with Li-metal is determined using alternating current impedance spectroscopy to be 76 Ω cm2 and 69 Ω cm2 before and after cycling at different current densities, respectively

3rd Conference on Isogeometric Analysis and Applications

This proceedings volume gathers a selection of outstanding research papers presented at the third Conference on Isogeometric Analysis and Applications, held in Delft, The Netherlands, in April 2018. This conference series, previously held in Linz, Austria, in 2012 and Annweiler am Trifels, Germany, in 2014, has created an international forum for interaction between scientists and practitioners working in this rapidly developing field. Isogeometric analysis is a groundbreaking computational approach that aims to bridge the gap between numerical analysis and computational geometry modeling by integrating the finite element method and related numerical simulation techniques into the computer-aided design workflow, and vice versa. The methodology has matured over the last decade both in terms of our theoretical understanding, its mathematical foundation and the robustness and efficiency of its practical implementations. This development has enabled scientists and practitioners to tackle challenging new applications at the frontiers of research in science and engineering and attracted early adopters for this his novel computer-aided design and engineering technology in industry. The IGAA 2018 conference brought together experts on isogeometric analysis theory and application, share their insights into challenging industrial applications and to discuss the latest developments as well as the directions of future research and development that are required to make isogeometric analysis an established mainstream technology

Quantifying the effects of urban stormwater management - towards a novel approach for integrated planning

ABSTRACT Integrated planning of stormwater management requires a quantitative description of positive and negative effects of possible measures. We suggest quantifying these effects with generic performance indicators within eight categories: building physics and services, landscape quality, urban climate, biodiversity, groundwater, surface water, direct costs and indirect environmental costs. First results indicate that the defined performance indicators allow an objective pre-selection of measures based on their ability to reach local stormwater management goals. The final selection of measures should be based on an evaluation for a specific city quarter (to reduce indicator uncertainty) and reviewed by local stake holders

Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease

Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions

B CELL-SPECIFIC CONDITIONAL EXPRESSION OF MYD88P.L252P LEADS TO THE DEVELOPMENT OF DIFFUSE LARGE B CELL LYMPHOMA IN MICE

The adaptor protein MYD88 is critical to relay activation of Toll-like receptor signaling to NF-{kappa}B activation.MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B cell malignancies, including diffuse large B cell lymphoma (DLBCL). 29% of activated B cell (ABC)-type DLBCL, which is characterized by constitutive activation of the NF-{kappa}B pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model, in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P)(the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These animals develop a lympho-proliferative disease, and occasional transformation into clonal lymphomas. The clonal disease displays morphological and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression ofBCL2 Cross-validation experiments in human DLBCL samples revealed that bothMYD88andCD79Bmutations are substantially enriched in ABC-DLBCL, compared to germinal center B cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occur with MYD88 mutations, further validating our approach. Lastly,in silicoexperiments revealed that particularly MYD88-mutant ABC-DLBCL cells display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL, which could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL

Modification of kidney barrier function by the urokinase receptor

9 páginas, 5 figuras, 1 tabla -- PAGS nros. 55-63Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of v3 integrin. Mice lacking uPAR (Plaur- /- ) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active 3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate v3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of v3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeabilityThis work was supported by US National Institutes of Health (NIH) grants DK073495 (to J.R.), DK057683, DK062472 and the George M. O'Brien Kidney Center DK064236 (to P.M.). C.W. is the Halpin Scholar of the American Society of Nephrology. C.C.M. was supported by a scholarship of the German Academic Exchange Service. M.M.A. was supported by NIH training grant T32DK007540. Gene expression studies of uPAR in human disease were performed in the framework of the European renal cDNA bank. We thank all members of the European Renal cDNA Bank and their patients for their support (for participating centers at the time of the study, see ref. 26). Part of the electron microscopy work was performed in the Microscopy Core facility of the Massachusetts General Hospital Program in Membrane Biology and was supported by an NIH Program Project grant (DK38452)Peer reviewe