Following the launch of Rare Isotope Science Project in December 2011, a heavy ion accelerator complex in South Korea, named RAON, has since been designed. It includes a muon facility for muon spin ...rotation, relaxation, and resonance. The facility will be provided with 600 MeV and 100 kW (one-fourth of the maximum power) proton beam. In this study, the graphite target in RAON was designed to have a rotating disk shape and was cooled by radiative heat transfer. This cool-down process has the following advantages: a low-temperature gradient in the target and the absence of a liquid coolant cooling system. Monte Carlo simulations and ANSYS calculations were performed to optimize the target system in a thermally stable condition when the 100 kW proton beam collided with the target. A comparison between the simulation and experimental data was also included in the design process to obtain reliable results. The final design of the target system will be completed within 2020, and its manufacturing is in progress. The manufactured target system will be installed at the RAON in the Sindong area near Daejeon-city in 2021 to carry out verification experiments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Increasing evidence suggests that olfactory dysfunction is an endophenotype of schizophrenia, and thus the olfactory system can be studied both in relation to this sensory dysfunction and also as a ...means of examining pathophysiologic mechanisms of schizophrenia. In this study, we examined human olfactory neuroepithelial (ON) biopsy tissues and their in vitro culture cells for ligand-induced guanine nucleotide-binding protein (G protein) activation and downstream signaling. We assessed the binding of a nonhydrolyzable GTP analogue (35)SGTPγS binding to specific G protein subtypes in response to odorants, dopamine, or serotonin in ON cell membranes from matched schizophrenia-control subjects. In response to odorant mixtures, we found decreased (35)SGTPγS binding to Gαs/olf in schizophrenia patients. These changes were not mediated by mRNA expression of key molecules of G protein coupling, including adenylate cyclase III (ACIII), protein kinase A (PKA), protein kinase Cγ (PKCγ), or Gαs or Gαolf in ON cells or ON biopsy tissues. In contrast, dopamine (DA)- and serotonin (5HT)-induced S(35)-GTPγS binding to Gαs/olf and Gαq/11 were significantly increased in schizophrenia cases, while these parameters were strikingly reduced by in vitro treatment with antipsychotics. Patients with schizophrenia exhibit increases in electrolfactogram (EOG) recordings, suggesting enhanced odorant-induced activation. Our results of decreased odorant-induced G protein activation may point further downstream for underlying mechanisms for increased EOG measures. Increased G protein activation in response to DA and 5HT may suggest increased postreceptor DA or 5HT signaling as an additional mechanism of dopaminergic or serotonergic dysregulation in schizophrenia.
Abstract The reconstruction method was proposed more than a decade ago to boost the signal of baryonic acoustic oscillations measured in galaxy redshift surveys, which is one of key probes for dark ...energy. After moving the observed overdensities in galaxy surveys back to their initial position, the reconstructed density field is closer to a linear Gaussian field, with higher-order information moved back into the power spectrum. We find that by jointly analysing power spectra measured from the pre- and post-reconstructed galaxy samples, higher-order information beyond the 2-point power spectrum can be efficiently extracted, which generally yields an information gain upon the analysis using the pre- or post-reconstructed galaxy sample alone. This opens a window to easily use higher-order information when constraining cosmological models.
Background
Patients with severe long‐chain fatty acid oxidation disorders (LC‐FAODs) experience serious morbidity and mortality despite traditional dietary management including medium‐chain ...triglyceride (MCT)–supplemented, low‐fat diets. Triheptanoin is a triglyceride oil that is broken down to acetyl–coenzyme A (CoA) and propionyl‐CoA, which replenishes deficient tricarboxylic acid cycle intermediates. We report the complex medical and nutrition management of triheptanoin therapy initiated emergently for 3 patients with LC‐FAOD.
Methods
Triheptanoin (Ultragenyx Pharmaceutical, Inc, Novato, CA, USA) was administered to 3 patients with LC‐FAOD on a compassionate‐use basis. Triheptanoin was mixed with non–MCT‐containing low‐fat formula. Patients were closely followed with regular cardiac and laboratory monitoring.
Results
Cardiac ejection fraction normalized after triheptanoin initiation. Patients experienced fewer hospitalizations related to metabolic crises while on triheptanoin. Patient 1 has tolerated oral administration without difficulty since birth. Patients 2 and 3 experienced increased diarrhea. Recurrent breakdown of the silicone gastrostomy tube occurred in patient 3, whereas the polyurethane nasogastric tube for patient 2 remained intact. Patient 3 experiences recurrent episodes of elevated creatine kinase levels and muscle weakness associated with illness. Patient 3 had chronically elevated C10‐acylcarnitines while on MCT supplementation, which normalized after initiation of triheptanoin and discontinuation of MCT oil.
Conclusions
Triheptanoin can ameliorate acute cardiomyopathy and increase survival in patients with severe LC‐FAOD. Substituting triheptanoin for traditional MCT‐based treatment improves clinical outcomes. MCT oil might be less effective in carnitine‐acylcarnitine translocase deficiency patients compared with other FAODs and needs further investigation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
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Sulfur mustard (SM) and its analog nitrogen mustard (NM) are potent bifunctional alkylating agents that induce skin blisters. They crosslink proteins and DNA and alter cell adhesion of ...basement membrane molecules. Dermal toxicity of the mustard agents includes separation of the epidermis and dermis, a strong inflammatory response, and prolonged wound healing. Matricellular proteins (MPs) including SPARC and hevin (aka SPARC‐like 1) are secreted proteins that are incorporated into the provisional matrix upon injury. MPs act as temporally dynamic signaling molecules to modulate cell‐matrix interactions during healing. Hevin can be cleaved by proteinase ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4). This cleavage produces a SPARC‐like fragment (SLF) which is essential to tissue development and wound healing. The expression and removal of MPs is controlled in normal healing, but may persist in chronic skin wounds. The temporal and spatial expression of MPs may play a role in the delayed repair of mustard injury. SPARC, hevin, ADAMTS4, and the basement membrane zone (BMZ) marker, laminin 332 (LM332), were examined over the course of 10 days after exposure of mouse dorsal skin to 5 μmoles NM. In unexposed controls, immunofluorescence (IF) analysis of LM332 showed continuous staining across the BMZ, with minimal staining of SPARC, and hevin. At 1 day post NM‐exposure, H & E staining showed characteristic dermal‐epidermal separations, while IF showed a spotty discontinuous pattern for LM332. Strong staining of SPARC appeared throughout the BMZ. Hevin staining was less intense than SPARC at this time point. Hevin became more apparent in the hyperplastic epidermis at 3 days post‐NM. By days 7–10, hevin stained throughout the hyperplastic epidermis. WB analysis confirmed the sequential deposition of SPARC and hevin in NM injured skin. SPARC showed a 43 kDa band at 1 day, and hevin showed both full length (130 kDa) and fragments (75, 66, and 43 kDa) at 1–10 days post NM exposure. In addition, activated forms of ADAMTS4 were observed in NM exposed skin samples with bands at 75, 60, and 50 kDa by WB. Dual IF staining showed ADAMTS4 co‐localized with hevin in the BMZ and in the basal keratinocytes. This suggests hevin may be processed by ADAMTS4 to produce SLF for wound repair in our injury model. Overall, we observed sequential expression of SPARC and hevin in the BMZ of NM induced skin wounds. This may play a role in modulating the delayed wound healing of vesicant induced injury.
Support or Funding Information
ES005022, T32ES007148, and NIAMS U54AR055073
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Arecoline, the main areca alkaloid in betel quid (BQ), is reported to have cytotoxic, genotoxic, and mutagenic effects in various cells. It shows strong correlation to the incidence of oral submucous ...fibrosis, leukoplakia, and oral cancer. To clarify the role of arecoline in BQ-induced carcinogenesis, primary human gingival keratinocyes (GK) and human KB epithelial cells were used for studying the molecular mechanisms of arecoline-mediated cell cycle deregulation for comparison. After 24
h of exposure, arecoline (0.2–0.8
mM) inhibited KB cell growth in a dose- and time-dependent manner with a reduction in cell number by 27–37 and 37–58%, respectively, as determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and sulforhodamine B (SRB) assays. Incubation of KB cells with arecoline (0.1–0.4
mM) caused late-S and G2/M phases’ cell cycle arrest. Western blot analysis revealed that arecoline induced cyclin Bl, Wee 1, and phosphorylated cdc2 protein levels whereas it declined p21 protein expression in KB cancer cells. Nevertheless, arecoline induced p21, but decreased cdc2 and cyclin B1 protein levels in GK. We demonstrated that higher concentrations of arecoline (0.2–1.2
mM) induced both cell necrosis and apoptosis as detected by DNA fragmentation and Annexin V–PI staining after long-term (48
h) treatment. Our results suggest that differential regulation of S and/or G2/M cell cycle-related proteins in the GK and KB cells play a crucial role in different stages of BQ-mediated carcinogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
ZnO nanorods (NRs) were grown on graphene oxide (GO) with hydrothermal method and their structural, optical, and electrical properties were compared with those of ZnO NRs grown on quartz without GO. ...The enhancement of the crystallinity and the reduction of the oxygen vacancies of ZnO NRs on GO (ZnO/GO) were observed. TEM/EDS observation demonstrated the increase of oxygen concentration in ZnO NR by growing on GO due to the diffusion from the GO during solution synthesis process. From the conductivity measurement of a ZnO NR, however, the conductivity of ZnO NR on GO turned out to be much lower than that of ZnO NR on quartz. This confirms that diffused oxygen from GO fills the oxygen vacancies inside ZnO NRs, and that it leads to a decrease of the conductivity that is caused by the reduction of the charge-carrier concentration in ZnO NRs. These findings offer insightful information to apply high-performance ZnO/GO hybrid devices via process optimization.
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IJS, KILJ, NUK, PNG, UL, UM
Since its discovery, lithium has been shown to act upon various neurotransmitter systems at multiple levels of signaling in the brain. Lithium, affecting each neurotransmitter system within complex ...interactive neuronal networks, is suggested to restore the balance among aberrant signaling pathways in critical regions of the brain. Recent molecular studies have revealed the action of lithium on signal transduction mechanisms, such as phosphoinositide hydrolysis, adenylyl cyclase, G protein, glycogen synthase kinase-3beta, protein kinase C, and its substrate myristoylated alanine-rich C kinase substrate. Such effects are thought to trigger long-term changes in neuronal signaling patterns that account for the prophylactic properties of lithium in the treatment of bipolar disorder. Through its effects on glycogen synthase kinase-3beta and protein kinase C, lithium may alter the level of phosphorylation of cytoskeletal proteins, which leads to neuroplastic changes associated with mood stabilization. Chronic lithium regulates transcriptional factors, which in turn may modulate the expression of a variety of genes that compensate for aberrant signaling associated with the pathophysiology of bipolar disorder. Future studies on long-term neuroplastic changes caused by lithium in the brain will set the stage for new drug-discovery opportunities.
Background We sought to determine whether a 600-mg loading dose of clopidogrel reduces myocardial infarct size compared with a 300-mg dose using contrast-enhanced magnetic resonance imaging in ...patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods In 198 patients undergoing primary PCI for STEMI, contrast-enhanced magnetic resonance imaging was performed a median of 7 days after the index event. Infarct size was measured on delayed-enhancement imaging, and area at risk (AAR) was quantified on T2-weighted images. Results Baseline characteristics were not significantly different between the 600-mg clopidogrel loading group (n = 117) and the 300-mg group (n = 81). The median infarct size was significantly smaller in the 600-mg group than in the 300-mg group (17.3% 8.9%-26.2% vs 21.7% 12.9%-30.0%, P = .03). Myocardial salvage index (AAR − infarct size × 100/AAR) was greater in the 600-mg group than in the 300-mg group (47.7 33.7-60.9 vs 32.0 23.6-51.5, P < .01). Patients in the 600-mg group also had a significantly lower extent of microvascular obstruction and smaller number of segments with >75% of infarct transmurality than did those in the 300-mg group. After propensity score matching, the 600-mg group had smaller infarct size and greater myocardial salvage index compared with the 300-mg group. In multivariate analysis, the use of a 600-mg clopidogrel loading dose significantly reduced the risk of a large infarct (odds ratio 0.53, 95% CI 0.29-0.98, P = .04). Conclusions In patients undergoing primary PCI for STEMI, a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage compared with a 300-mg loading dose.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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