Impact of Partial Volume Correction on [18F]GE-180 PET Quantification in Subcortical Brain Regions of Patients with Corticobasal Syndrome.

Corticobasal syndrome (CBS) is a rare neurodegenerative condition characterized by four-repeat tau aggregation in the cortical and subcortical brain regions and accompanied by severe atrophy. The aim of this study was to evaluate partial volume effect correction (PVEC) in patients with CBS compared to a control cohort imaged with the 18-kDa translocator protein (TSPO) positron emission tomography (PET) tracer [18F]GE-180. Eighteen patients with CBS and 12 age- and sex-matched healthy controls underwent [18F]GE-180 PET. The cortical and subcortical regions were delineated by deep nuclei parcellation (DNP) of a 3D-T1 MRI. Region-specific subcortical volumes and standardized uptake values and ratios (SUV and SUVr) were extracted before and after region-based voxel-wise PVEC. Regional volumes were compared between patients with CBS and controls. The % group differences and effect sizes (CBS vs. controls) of uncorrected and PVE-corrected SUVr data were compared. Single-region positivity in patients with CBS was assessed by a >2 SD threshold vs. controls and compared between uncorrected and PVE-corrected data. Smaller regional volumes were detected in patients with CBS compared to controls in the right ventral striatum (p = 0.041), the left putamen (p = 0.005), the right putamen (p = 0.038) and the left pallidum (p = 0.015). After applying PVEC, the % group differences were distinctly higher, but the effect sizes of TSPO uptake were only slightly stronger due to the higher variance after PVEC. The single-region positivity of TSPO PET increased in patients with CBS after PVEC (100 vs. 83 regions). PVEC in the cortical and subcortical regions is valuable for TSPO imaging of patients with CBS, leading to the improved detection of elevated [18F]GE-180 uptake, although the effect sizes in the comparison against the controls did not improve strongly

In Vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies

Background: Neuroinflammation has received growing interest as a therapeutic target in neurodegenerative disorders, including 4-repeat tauopathies. Objectives: The aim of this cross-sectional study was to investigate 18 kDa translocator protein positron emission tomography (PET) as a biomarker for microglial activation in the 4-repeat tauopathies corticobasal degeneration and progressive supranuclear palsy. Methods Specific binding of the 18 kDa translocator protein tracer F-18-GE-180 was determined by serial PET during pharmacological depletion of microglia in a 4-repeat tau mouse model. The 18 kDa translocator protein PET was performed in 30 patients with corticobasal syndrome (68 +/- 9 years, 16 women) and 14 patients with progressive supranuclear palsy (69 +/- 9 years, 8 women), and 13 control subjects (70 +/- 7 years, 7 women). Group comparisons and associations with parameters of disease progression were assessed by region-based and voxel-wise analyses. Results Tracer binding was significantly reduced after pharmacological depletion of microglia in 4-repeat tau mice. Elevated 18 kDa translocator protein labeling was observed in the subcortical brain areas of patients with corticobasal syndrome and progressive supranuclear palsy when compared with controls and was most pronounced in the globus pallidus internus, whereas only patients with corticobasal syndrome showed additionally elevated tracer binding in motor and supplemental motor areas. The 18 kDa translocator protein labeling was not correlated with parameters of disease progression in corticobasal syndrome and progressive supranuclear palsy but allowed sensitive detection in patients with 4-repeat tauopathies by a multiregion classifier. Conclusions: Our data indicate that F-18-GE-180 PET detects microglial activation in the brain of patients with 4-repeat tauopathy, fitting to predilection sites of the phenotype. The 18 kDa translocator protein PET has a potential for monitoring neuroinflammation in 4-repeat tauopathies. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Odorant-Dependent Generation of Nitric Oxide in Mammalian Olfactory Sensory Neurons

The gaseous signalling molecule nitric oxide (NO) is involved in various physiological processes including regulation of blood pressure, immunocytotoxicity and neurotransmission. In the mammalian olfactory bulb (OB), NO plays a role in the formation of olfactory memory evoked by pheromones as well as conventional odorants. While NO generated by the neuronal isoform of NO synthase (nNOS) regulates neurogenesis in the olfactory epithelium, NO has not been implicated in olfactory signal transduction. We now show the expression and function of the endothelial isoform of NO synthase (eNOS) in mature olfactory sensory neurons (OSNs) of adult mice. Using NO-sensitive micro electrodes, we show that stimulation liberates NO from isolated wild-type OSNs, but not from OSNs of eNOS deficient mice. Integrated electrophysiological recordings (electro-olfactograms or EOGs) from the olfactory epithelium of these mice show that NO plays a significant role in modulating adaptation. Evidence for the presence of eNOS in mature mammalian OSNs and its involvement in odorant adaptation implicates NO as an important new element involved in olfactory signal transduction. As a diffusible messenger, NO could also have additional functions related to cross adaptation, regeneration, and maintenance of MOE homeostasis

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies.

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases

The Stimulatory Gαs Protein Is Involved in Olfactory Signal Transduction in Drosophila

Seven-transmembrane receptors typically mediate olfactory signal transduction by coupling to G-proteins. Although insect odorant receptors have seven transmembrane domains like G-protein coupled receptors, they have an inverted membrane topology, constituting a key difference between the olfactory systems of insects and other animals. While heteromeric insect ORs form ligand-activated non-selective cation channels in recombinant expression systems, the evidence for an involvement of cyclic nucleotides and G-proteins in odor reception is inconsistent. We addressed this question in vivo by analyzing the role of G-proteins in olfactory signaling using electrophysiological recordings. We found that Gαs plays a crucial role for odorant induced signal transduction in OR83b expressing olfactory sensory neurons, but not in neurons expressing CO2 responsive proteins GR21a/GR63a. Moreover, signaling of Drosophila ORs involved Gαs also in a heterologous expression system. In agreement with these observations was the finding that elevated levels of cAMP result in increased firing rates, demonstrating the existence of a cAMP dependent excitatory signaling pathway in the sensory neurons. Together, we provide evidence that Gαs plays a role in the OR mediated signaling cascade in Drosophila

GEO-6 assessment for the pan-European region

Through this assessment, the authors and the United Nations Environment Programme (UNEP) secretariat are providing an objective evaluation and analysis of the pan-European environment designed to support environmental decision-making at multiple scales. In this assessment, the judgement of experts is applied to existing knowledge to provide scientifically credible answers to policy-relevant questions. These questions include, but are not limited to the following:• What is happening to the environment in the pan-European region and why?• What are the consequences for the environment and the human population in the pan-European region?• What is being done and how effective is it?• What are the prospects for the environment in the future?• What actions could be taken to achieve a more sustainable future?<br/

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI