Genetics of Parkinson’s Disease: state-of-the-art and role in clinical settings

Introduction. Advances in sequencing technologies have enabled extensive genetic testing on an individual basis. Genome-wide association studies (GWAS) have provided insight into the pathophysiology of PD. Additionally, direct-to-consumer genetic testing has enabled the identification of genetic diseases and risk factors without genetic counselling. As genetics increasingly permeates clinical practice, this paper aims to summarise the most important information on genetics in PD forclinical practitioners. State-of-the-art. LRRK2 mutations may be found in c.1% of all PD patients with an indistinguishable phenotype from sporadic PD. LRRK2-PD is more prevalent in patients with a positive family history (5-6%) and among certain populations (e.g. up to 41% in North Africans and Ashkenazi Jews). Other familial forms include PRKN (patients with early onset, EOPD), VPS35 (Western European ancestry), PINK1 (EOPD), DJ-1 (EOPD), and SNCA. GBA mutations are found in a large number of PD patients and are associated with faster progression and a poorer prognosis. GWAS have identified 90 genetic risk variants for developing PD and several genetic modifiers for the age at onset, disease progression, and response to treatment. Clinical implications. Multigene panels using next-generation sequencing (NGS) are the first choice for genetic testing in clinical settings. Whole exome sequencing is increasingly being used, particularly as the second-tier testing in patients with negative results of multigene panels. NGS may not detect accurately copy number variants (CNV), meaning that additional analysis is warranted. In a case of a variant of unknown significance (VUS), we suggest firstly searching the up-to-date literature. Segregation studies and in silico predictions may shed more light on the character of the VUS; however, functional studies remain the gold standard. Several interventional clinical trials are active for carriers of LRRK2 and/or GBA mutations. Future directions. Application of artificial intelligence and machine learning will enable high-throughput analysis of largesets of multimodal data. We speculate that, in the future, the treatment landscape for PD will be similar to that in oncological conditions, in which the presence of certain gene mutations or gene overexpression determines the prognosis and treatment decision-making

Unexpected Crossover in the kinetics of mutarotation in the supercooled region : the role of H-bonds

Intra- and intermolecular studies on the molten L-sorbose have been carried out at variable temperature conditions to determine the crosover temperature (Tc). In addition, isothermal time-dependent FTIR and Raman measurements were performed to probe the pace of mutarotation and activation energy of this reaction in the studied saccharide, which varied from 53–62 kJ/mol up to 177–192 kJ/mol below and above Tc, respectively. To explain the change in activation barrier for the mutarotation a complementary analysis using difference FTIR spectra collected around Tc = 365 K in the hydroxyl region has been done. It was found that the alteration of kinetic parameters and molecular dynamics around Tc are strictly related to the variation in the strength of H-bonds which above Tc are significantly weaken, increasing the freedom of rotation of functional groups and movement of individual molecules. That phenomenon most likely affects the proton transfer, underlying molecular mechanism of mutarotation, which may lead to the significant increase in activation barrier. The new insight into a molecular aspect of the mutarotation around Tc has created an opportunity to better understanding the relationship between physics of condensed matter and the potential role of H-bonds dynamics on the progress of the chemical reaction in highly viscous systems

Leveraging Case Study Research: A Mechanism to Measure Teaching Effectiveness

This article shares findings from a descriptive, multiple case study assessing graduate outcomes 2.5 years after the completion of a teacher education program. Case study was used as an alternative to value-added measures to holistically examine complex attributes of effective teaching. Mixed methods data collection included graduate and supervisor surveys, self and supervisor evaluation of skills and dispositions, interviews, and classroom observations. Results indicated participants effectively applied the knowledge, skills, and dispositions the program was designed to achieve in the areas of Learner and Learning, Content, Instructional Practice, and Professional Responsibility. Three major recommendations emerged: 1) the necessity to develop established proficiency levels for new teachers related to diverse learners, 2) the need for shared responsibility of outcomes and targeted induction support, and 3) support for supervisor evaluation as a viable mechanism for education program accountability of teaching effectiveness of graduates

Potential use of glucocorticosteroids in CSF1R mutation carriers – current evidence and future directions

We recently found that glucocorticosteroids (GCs) have protective effects in CSF1R mutation carriers against developing symptomatic CSF1R-related leukoencephalopathy. Our findings were subsequently confirmed in a mouse model study. We have received many questions from patients, their families, patient organisations, and healthcare practitioners about the optimal type of GCs, the dose, the route of administration, and application timing. This paper attempts to answer the most urgent of these questions based on our previous studies and personal observations. Despite the promising observations, more research on larger patient groups is needed to elucidate the beneficial actions of GCs in CSF1R mutation carriers

Microstructural and magnetic characterization of Ni0.5Zn0.5Fe2O4 ferrite nanoparticles

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Simulation studies of annihilation-photon's polarisation via Compton scattering with the J-PET tomograph

J-PET is the first positron-emission tomograph (PET) constructed from plastic scintillators. It was optimized for the detection of photons from electron-positron annihilation. Such photons, having an energy of 511 keV, interact with electrons in plastic scintillators predominantly via the Compton effect. Compton scattering is at most probable at an angle orthogonal to the electric field vector of the interacting photon. Thus registration of multiple photon scatterings with J-PET enables to determine the polarization of the annihilation photons. In this contribution we present estimates on the physical limitation in the accuracy of the polarization determination of $511$~keV photons with the J-PET detector.Comment: Submitted to Hyperfine Interaction

Feasibility studies of the polarization of photons beyond the optical wavelength regime with the J-PET detector

J-PET is a detector optimized for registration of photons from the electron-positron annihilation via plastic scintillators where photons interact predominantly via Compton scattering. Registration of both primary and scattered photons enables to determinate the linear polarization of the primary photon on the event by event basis with a certain probability. Here we present quantitative results on the feasibility of such polarization measurements of photons from the decay of positronium with the J-PET and explore the physical limitations for the resolution of the polarization determination of 511 keV photons via Compton scattering. For scattering angles of about 82 deg (where the best contrast for polarization measurement is theoretically predicted) we find that the single event resolution for the determination of the polarization is about 40 deg (predominantly due to properties of the Compton effect). However, for samples larger than ten thousand events the J-PET is capable of determining relative average polarization of these photons with the precision of about few degrees. The obtained results open new perspectives for studies of various physics phenomena such as quantum entanglement and tests of discrete symmetries in decays of positronium and extend the energy range of polarization measurements by five orders of magnitude beyond the optical wavelength regime.Comment: 10 pages, 14 figures, submitted to EPJ

Three-dimensional image reconstruction in J-PET using Filtered Back Projection method

We present a method and preliminary results of the image reconstruction in the Jagiellonian PET tomograph. Using GATE (Geant4 Application for Tomographic Emission), interactions of the 511 keV photons with a cylindrical detector were generated. Pairs of such photons, flying back-to-back, originate from e+e- annihilations inside a 1-mm spherical source. Spatial and temporal coordinates of hits were smeared using experimental resolutions of the detector. We incorporated the algorithm of the 3D Filtered Back Projection, implemented in the STIR and TomoPy software packages, which differ in approximation methods. Consistent results for the Point Spread Functions of ~5/7,mm and ~9/20, mm were obtained, using STIR, for transverse and longitudinal directions, respectively, with no time of flight information included.Comment: Presented at the 2nd Jagiellonian Symposium on Fundamental and Applied Subatomic Physics, Krak\'ow, Poland, June 4-9, 2017. To be published in Acta Phys. Pol.

A feasibility study of ortho-positronium decays measurement with the J-PET scanner based on plastic scintillators

We present a study of the application of the Jagiellonian Positron Emission Tomograph (J-PET) for the registration of gamma quanta from decays of ortho-positronium (o-Ps). The J-PET is the first positron emission tomography scanner based on organic scintillators in contrast to all current PET scanners based on inorganic crystals. Monte Carlo simulations show that the J-PET as an axially symmetric and high acceptance scanner can be used as a multi-purpose detector well suited to pursue research including e.g. tests of discrete symmetries in decays of ortho-positronium in addition to the medical imaging. The gamma quanta originating from o-Ps decay interact in the plastic scintillators predominantly via the Compton effect, making the direct measurement of their energy impossible. Nevertheless, it is shown in this paper that the J-PET scanner will enable studies of the o-Ps$\to3\gamma$ decays with angular and energy resolution equal to $\sigma(\theta) \approx 0.4^{\circ}$ and $\sigma(E) \approx 4.1$ keV, respectively. An order of magnitude shorter decay time of signals from plastic scintillators with respect to the inorganic crystals results not only in better timing properties crucial for the reduction of physical and instrumental background, but also suppresses significantly the pileups, thus enabling compensation of the lower efficiency of the plastic scintillators by performing measurements with higher positron source activities