This article presents the optimal design of a permanent magnet synchronous generator (PMSG). A finite element (FE) model is used to construct a metamodel, which afterward is utilized to define the ...objective function that models the PMSG. Kriging modeling is employed along with the design of experiments based on Latin hypercube sampling. The utilization of a surrogate model allows to speed up the optimization process while keeping the accuracy since they are developed from the FE analysis. On the other hand, it has been reported that the non-sorting genetic algorithm (NSGA) III is better than NSGA-II because it can solve multi- and many-objective optimization problems. This article demonstrates by numerical experiments that NSGA-III can be successfully used in the optimal design of PMSG with three objectives.
The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein ...contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein.
Opioids are well known for their robust analgesic effects. Chronic activation of mu opioid receptors (MOPs) is, however, accompanied by various unwanted effects such as analgesic tolerance. Among ...other mechanisms, interactions between MOPs and delta opioid receptors (DOPs) are thought to play an important role in morphine‐induced behavioral adaptations. Interestingly, certain conditions such as inflammation enhance the function of the DOP through a MOP‐dependent mechanism. Here, we investigated the role of DOPs during the development of morphine tolerance in an animal model of chronic inflammatory pain. Using behavioral approaches, we first established that repeated systemic morphine treatment induced morphine analgesic tolerance in rats coping with chronic inflammatory pain. We then observed that blockade of DOPs with subcutaneous naltrindole (NTI), a selective DOP antagonist, significantly attenuated the development of morphine tolerance in a dose‐dependent manner. We confirmed that this effect was DOP mediated by showing that an acute injection of NTI had no effect on morphine‐induced analgesia in naive animals. Previous pharmacological characterizations revealed the existence of DOP subtype 1 and DOP subtype 2. As opposed to NTI, 7‐benzylidenenaltrexone and naltriben were reported to be selective DOP subtype 1 and DOP subtype 2 antagonists, respectively. Interestingly, naltriben but not 7‐benzylidenenaltrexone was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that targeting of DOP subtype 2 with antagonists provides a valuable strategy to attenuate the analgesic tolerance that develops after repeated morphine administration in the setting of chronic inflammatory pain.
We investigated the role of DOP during the development of morphine‐tolerance in an animal model of chronic inflammatory pain. Interestingly, naltriben, (DOP2 selective antagonist) but not BNTX (DOP1 selective antagonist) was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that the blocking DOP2 provides a valuable strategy to attenuate morphine analgesic tolerance in the setting of chronic inflammatory pain.
To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all ...suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.
The calpain family is a group of cysteine proteases unique in their dependency on calcium to attain functionally active forms. Calpains are involved in a wide range of cellular calcium-regulated ...functions, including signal transduction, cell proliferation and differentiation, and apoptosis. Moreover, altered calpain activity has been observed in several human diseases. Specific calpain inhibitors hold promise for the treatment of neuromuscular and neurodegenerative diseases in which calpains have been shown to be upregulated (e.g. Parkinson's disease and Duchenne muscular dystrophy). Conversely, calpain activators could be a useful approach for those diseases where reduced calpain activity has been observed, such as type 2 diabetes or metabolic syndrome.
Uptake by the dopamine transporter (DAT) is the primary pathway for the clearance of extracellular dopamine (DA) and consequently for regulating the magnitude and duration of dopaminergic signaling. ...Amphetamine (AMPH) has been shown to decrease simultaneously DAT cell-surface expression and (3)HDA uptake. We have shown that insulin and its subsequent signaling through the phosphatidylinositol 3-kinase (PI3K)-dependent pathway oppose this effect of AMPH by promoting increased cell-surface expression. Here, we used human embryonic kidney 293 cells stably expressing the human DAT (hDAT cells) to investigate the downstream cellular components important for this effect of insulin. Akt is a protein kinase effector immediately downstream of PI3K. Both overexpression of a dominant-negative mutant of Akt (K179R) and the addition of 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine HCl (ML9), a pharmacological inhibitor of Akt, decreased cell-surface expression of DAT, suggesting a role of basal Akt signaling in the homoeostasis of DAT. Moreover, expression of a constitutively active Akt mutant reduced the ability of AMPH to decrease hDAT cell-surface expression as well as (3)HDA uptake. In contrast, overexpression of K179R blocked the ability of insulin to oppose AMPH-induced reduction of hDAT cell-surface expression and (3)HDA uptake, as did ML9. Our data demonstrate that hDAT cell-surface expression is regulated by the insulin signaling pathway and that Akt plays a key role in the hormonal modulation of AMPH-induced hDAT trafficking and in the regulation of basal hDAT cell-surface expression.
Large-scale physics experiments running at high interaction rates place a high demand on the data acquisition system (DAQ) responsible for transporting the data from the detector to the storage. The ...antiProton ANihilation at DArmstadt (PANDA) at the facility for anti-proton and ion research (FAIR) is one such experiment of the future that will not use fixed hardware triggers; instead, the event selection is based on real-time feature extraction, filtering, and high-level correlations. A firmware framework for such real-time data processing has been developed and tested with hardware setup for a PANDA Forward Tracker (FT) prototype. The solution is applicable for other detector subsystems based on the so-called Trigger Readout Board (TRB) data read-out system.
The CMS High-Granularity Calorimeter (HGCAL) imposes extremely challenging specifications for the front-end electronics: high dynamic range, low noise, high-precision time information and low power ...consumption, as well as the need to select and transmit trigger information with a high transverse and longitudinal granularity. HGCROC2 is the second prototype of the readout chip embedding almost all the final functionalities. It has 72 channels of the full analog chain: low noise and high gain preamplifier and shapers, a 10-bit 40 MHz SAR-ADC which provides the charge measurement over the linear range of the preamplifier, after the preamplifier saturation a discriminator and TDC provide the charge information from ToT (200 ns dynamic range and 50 ps binning), and a fast discriminator and TDC provide timing information to 25 ps accuracy. This paper reports on the performance in terms of noise, charge and timing, the DAQ and Trigger paths, as well as results from radiation qualification with total ionizing dose (TID) and heavy ions for single-event effects (SEE).
A new design of a detector plane of sub-millimetre thickness for an electromagnetic sampling calorimeter is presented. It is intended to be used in the luminometers LumiCal and BeamCal in future ...linear e
+
e
-
collider experiments. The detector planes were produced utilising novel connectivity scheme technologies. They were installed in a compact prototype of the calorimeter and tested at DESY with an electron beam of energy 1–5 GeV. The performance of a prototype of a compact LumiCal comprising eight detector planes was studied. The effective Molière radius at 5 GeV was determined to be (8.1 ± 0.1 (stat) ± 0.3 (syst)) mm, a value well reproduced by the Monte Carlo (MC) simulation (8.4 ± 0.1) mm. The dependence of the effective Molière radius on the electron energy in the range 1–5 GeV was also studied. Good agreement was obtained between data and MC simulation.
Three-dimensional (3D) printing, specifically digital light processing (DLP) technique, can be used to manufacture plastic scintillators of any shape. The purpose of this study was to determine the ...light output of DLP 3D-printed scintillators for dosimetry applications. Two types of plastic scintillators with dimensions 10 mm × 10 mm × 10 mm were fabricated using DLP 3D-printing at Hanyang University, South Korea. The light output of these DLP 3D-printed samples was measured and compared to that of a commercial plastic scintillator of the same dimensions, RP-408, produced by casting. The 3D-printed scintillators emitting violet and blue light had a lower relative light output by 49% and 43%, respectively, compared to the RP-408 reference scintillator. We also investigated three types of scintillator surface finishing methods: the original surface made by the 3D printer, a sanded surface, and a polished surface. Furthermore, three wrapping configurations were tested: bare scintillator, diffuse-type polytetrafluoroethylene tape, and specular-type enhanced specular reflector foil. Both reflector types, diffuse and specular, reflected blue light with comparable efficiency. Additionally, emission and transmission spectra of the samples were measured. Emission maxima were located at 430 nm for RP-408, and 438 and 475 nm for two 3D-printed samples. Transmittance at the wavelength of maximum emission was equal to 89% for RP-408, and 73% and 66% for the two DLP-printed samples. Although the light output of the 3D-printed scintillators was about 50% lower than that of the commercial plastic scintillator, due to characteristics of 3D-printed plastic scintillators, i.e. fast, low-cost production, and easy customization of the printed shape, they are promising as an active part of dosimeters for use in high intensity gamma radiation fields produced by medical linear accelerators with acceptable signal-to-noise ratio level.
•3D printing technique was used to manufacture plastic scintillators.•Light output of three types of blue-emitting plastic scintillators was measured.•Original, sanded and polished scintillator surface finishes were investigated.•Diffuse and specular reflectors have comparable light reflection efficiency.•3D-printed scintillators are sufficient for use in dosimetry in radiation therapy.
PDF
