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Application-specific integrated circuits of DIE8 (ATLAS, CERN), NINO (ALICE, CERN), and PADI (CBM, GSI) amplifiers−discriminators have been designed specifically for applications with resistive ...plate chambers, a new type of multichannel detectors. The main development trends formed during the creation of new, large-scale experiments at the Large Hadron Collider (LHC) are shown. The main characteristics of the integrated circuits, the motivation for setting the design task, problems, and application features are compared.
The time over threshold (TOT) method that uses a pulse sine shaper, which is based on the mathematical function of the raised cosine (FRC), is described. The FRC has an important property for the TOT ...method—the formation of a smooth pulse with the variability of both the smoothing coefficient and the response time. In this case, the shape of the FRC pulse is independent of the input pulse action within a given time range. Thus, on the basis of the FRC, it was possible to create a pulse sine shaper with a preset time response, which provided an unambiguous dependence of the TOT-pulse duration on the input charge, and to improve the accuracy characteristics due to optimal spectral filtering in the FRC. A pulse sine shaper based on the FRC was successfully used in the reading systems of the HADES (GSI, Darmstadt, Germany) and BM&N (JINR, Dubna) experiments. The total number of reading channels was more than 5000; the method has an error of ~0.3%.
Mutations in the glucocerebrosidase gene (GBA) encoding the lysosomal enzyme glucocerebrosidase (GCase) cause Gaucher disease (GD) and are the most commonly known genetic risk factor for Parkinson ...disease (PD). Ambroxol is one of the most effective pharmacological chaperones of GCase. Fourteen GD patients, six PD patients with mutations in the GBA gene (GBA-PD), and thirty controls were enrolled. GCase activity and hexosylsphingosine (HexSph) concentration were measured in dried blood and macrophage spots using liquid chromatography coupled with tandem mass spectrometry. The effect of ambroxol on GCase translocation to lysosomes was assessed using confocal microscopy. The results showed that ambroxol treatment significantly increased GCase activity in cultured macrophages derived from patient blood monocytic cell (PBMC) of GD (by 3.3-fold) and GBA-PD patients (by 3.5-fold) compared to untreated cells (p < 0.0001 and p < 0.0001, respectively) four days after cultivation. Ambroxol treatment significantly reduced HexSph concentration in GD (by 2.1-fold) and GBA-PD patients (by 1.6-fold) (p < 0.0001 and p < 0.0001, respectively). GD macrophage treatment resulted in increased GCase level and increased enzyme colocalization with the lysosomal marker LAMP2. The possible binding modes of ambroxol to mutant GCase carrying N370S amino acid substitution at pH 4.7 were examined using molecular docking and molecular dynamics simulations. The ambroxol position characterized by minimal binding free energy was observed in close vicinity to the residue, at position 370. Taken together, these data showed that PBMC-derived macrophages could be used for assessing ambroxol therapy response for GD patients and also for GBA-PD patients.
•Ambroxol increases GCase activity in cultured macrophages of GD and GBA-PD patients.•Ambroxol reduces HexSph level in cultured macrophages of GD and GBA-PD patients.•Ambroxol increases GCase translocation to lysosomes in GD macrophages.•Ambroxol increases GCase level in cultured macrophages of GD patients.•Ambroxol acts as GCase concurrent inhibitor and allosteric pharmacological chaperone.
•TT variant of rs8475 of SCARB2 increased twice risk of sporadic Parkinson’s disease•rs6812193 and rs8475 of SCARB2 are not genetic modifier of age at onset of PD•rs6812193 and rs8475 of SCARB2 do ...not influence on SCARB2 expression•SCARB2 expression could be modified with GBA mutations
Lysosomal integral membrane protein-2 (LIMP-2), encoded by the SCARB2 gene, is the specific lysosomal receptor for glucocerebrosidase enzyme. Association between rs6812193 and rs68250047 of SCARB2 with PD has been shown in genetic studies, including large genome-wide association studies. The aim of the current study was to determine whether rs6812193 and rs8475 are associated with PD in Russia. rs6812193 and rs8475 were genotyped in a total of 604 PD patients (65 PD patients with positive (fPD) and 539 PD patients with negative family history (sPD)) and 413 controls and also in 17 patients with PD associated with GBA mutations (PD-GBA) and 18 asymptomatic GBA mutation carriers (GBA-Carriers). SCARB2 expression was measured by real-time PCR in CD45+ blood cells in part of individuals in the studied groups. No linkage disequilibrium was shown between rs6812193 and rs8475 in Russian population. Increased PD risk for TT variant of rs8475 (OR = 2.02; p < 0.001) was found in sPD patients but not in fPD. rs6812193 and rs8475 were not associated with age at onset (AAO) of PD. SCARB2 expression level was decreased in GBA-PD patients and GBA-Carriers compared to PD patients (padjusted = 0.02, padjusted = 0.003, respectively) and GBA-Carriers compared to controls (padjusted = 0.013) with no significant difference in PD patients and controls. SCARB2 expression was not modified with rs6812193 and rs8475.
In conclusion, rs8475 was associated with PD status. rs6812193 and rs8475 are not genetic modifier of AAO of PD and do not influence on SCARB2 mRNA level in CD45+ blood cells in studied groups. SCARB2 expression could be modified with GBA mutations and is independent of PD status.
Plasma cytokine concentration in patients with Parkinson’s disease and mutation in
GBA
gene, in patients with sporadic Parkinson’s disease, and in healthy volunteers were measured by ELISA and ...multiplex analysis. In patients with Parkinson’s disease and mutation in
GBA
gene, elevated plasma concentrations of IL-1β and TNFα were revealed by ELISA in comparison with both controls and patients with sporadic form of Parkinson’s disease. Multiplex analysis revealed enhanced secretion of IL-1β, IL-2, IFNγ and reduced plasma levels of monocyte chemoattractant protein-1 (MCP-1) in patients with Parkinson’s disease and mutation in
GBA
gene (in comparison with other groups) and increased plasma levels of IL-13 (only in comparison with the healthy volunteers). Our results support the hypothesis that the concentrations of inflammatory mediators are increased in patients with Parkinson’s disease and mutation in
GBA
gene.
The present paper deals with permeability of the low-temperature phase of a fullerite using molecular dynamics methods. A discrete model of the material based on “atom−atom” interactions between ...penetrating components and nodes of the fullerene crystal structure is considered. For the purpose of saving calculation time, when collecting statistical data on passage of molecules and atoms through the porous material under consideration, we found a centrally symmetric distribution of the fullerene action energy and constructed a model of the material based on “smoothed” fullerene particles. The calculations determined permeability of a fullerite membrane containing up to ten planar lattices of the crystal structure. The selectivity factor of the considered membrane, with respect to other components of natural gas is also determined.
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•A model of the permeability of molecules through a fullerite crystal is presented.•Potential of interaction between a molecule and a fullerene particle is taken into account.•The discrete model of a low-temperature fullerite is presented.
High-rate glass MRPC for fixed target experiments at Nuclotron Kuzmin, N.A.; Ladygin, E.A.; Ladygin, V.P. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2019, Letnik:
916
Journal Article
Recenzirano
Odprti dostop
A Multi-gap Resistive Plate Chamber (MRPC) equipped with heaters to improve the counting rate capability was designed for the BM@N experiment in Dubna. The measurements were performed using a muon ...beam at IHEP U-70 accelerator in Protvino. The MRPC at 40°C tolerates counting rate up to 6 kHz/cm2 with time resolution ∼65 ps and efficiency ∼95% which complies with the conditions of the experiment.
Parkinsons disease (PD) is a multifactorial neurodegenerative disease. To date, genome-wide association studies have identified more than 70 loci associated with the risk of PD. Variants in the GBA ...gene encoding glucocerebrosidase are quite often found in PD patients in all populations across the world, which justifies intensive investigation of this gene. A number of biochemical features have been identified in patients with GBA-associated Parkinsons disease (GBA-PD). In particular, these include decreased activity of glucocerebrosidase and accumulation of the glucosylceramide substrate. These features were the basis for putting forward a hypothesis about treatment of GBA-PD using new strategies aimed at restoring glucocerebrosidase activity and reducing the substrate concentration. This paper discusses the molecular and genetic mechanisms of GBA-PD pathogenesis and potential approaches to the treatment of this form of the disease.
Beam test of FARICH prototype with digital photon counter Barnyakov, A.Yu; Barnyakov, M.Yu; Bobrovnikov, V.S. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2013, Letnik:
732
Journal Article
Recenzirano
In June 2012 we tested a Focusing Aerogel RICH detector prototype based on Digital Photon Counters (DPC) by Philips at the CERN PS T10 beam line with a particle momentum up to 6GeV/c. The prototype ...comprises a 20×20cm2 photon detector with 48×48 DPC pixels. In order to reduce the dark count rate, the photon detector was cooled to −40°C in addition to disabling individual DPC's microcells. A four layer focusing aerogel radiator with 200mm focal distance was studied. We obtained a Cherenkov angle resolution of 3.61±0.04mrad. The mean number of photoelectrons in a ring is 12. Directly measured π/K separation at 6GeV/c momentum is 3.5σ, μ/π separation is 5.3σ at 1GeV/c. A comparison with a Monte Carlo simulation is presented as well.
•Focusing Aerogel RICH prototype with Digital Photon Counters by Philips was built.•The prototype was tested at the CERN PS T10 beam line.•We observed Cherenkov rings with 12 photoelectrons in average.•Timing resolution of DPCs is 48ps for single photons.•Cherenkov angle resolution is 3.64±0.04mrad per ring.
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