Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a ...possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1
; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca
/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1
; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
To investigate the anti-obesity effect of Rubi Fructus (RF) extract using brown adipose tissue (BAT) and primary brown preadipocytes in vivo and in vitro.
Male C57BL/6 J mice (n=5 per group) were fed ...a high-fat diet (HFD) for 10 weeks with or without RF. Brown preadipocytes from the interscapular BAT of mice (age, post-natal days 1-3) were cultured with differentiation media (DM) including isobutylmethylxanthine, dexamethasone, T3, indomethacin and insulin with or without RF.
In HFD-induced obese C57BL/6 J mice, long-term RF treatment significantly reduced weight gain as well as the weights of the white adipose tissue, liver and spleen. Serum levels of total cholesterol and low-density lipoprotein cholesterol were also reduced in the HFD group which received RF treatment. Furthermore, RF induced thermogenic-, adipogenic- and mitochondria-related gene expressions in BAT. In primary brown adipocytes, RF effectively stimulated the expressions of thermogenic- and mitochondria-related genes. In addition, to examine whether LIPIN1, a regulator of adipocyte differentiation, is regulated by RF, Lipin1 small interfering RNA (siRNA) and RF were pretreated in primary brown adipocytes. Pretreatment with Lipin1 siRNA and RF downregulated the DM-induced expression levels of thermogenic- and mitochondria-related genes. Moreover, RF markedly upregulated AMP-activated protein kinase. Our study shows that RF is capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes.
This study demonstrates that RF prevents the development of obesity in mice fed with a HFD and that it is also capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes, which suggests that RF has potential as a therapeutic application for the treatment or prevention of obesity.
Neutrino elastic scattering observation with NaI (NEON) is an experiment designed to detect neutrino-nucleus coherent scattering using reactor electron antineutrinos. NEON is based on an array of six ...NaI(Tl) crystals with a total mass of 13.3 kg, located at the tendon gallery that is 23.7 m away from a reactor core with a thermal power of 2.8 GW in the Hanbit nuclear power complex. The installation of the NEON detector was completed in December 2020, and since May 2021, the detector has acquired data at full reactor power. Based on the observed light yields of the NaI crystals of approximately 22, number of photoelectrons per unit keV electron-equivalent energy (keVee), and 6 counts/kg/keV/day background level at 2–6 keVee energy, coherent elastic neutrino-nucleus scattering (CE
ν
NS) observation sensitivity is evaluated as more than 3
σ
assuming 1-year reactor-on and 100 days reactor-off data, 0.2 keVee energy threshold, and 7 counts/keV/kg/day background in the signal region of 0.2
-
0.5 keVee. This paper describes the design of the NEON detector, including the shielding arrangement, configuration of NaI(Tl) crystals, and associated operating systems. The initial performance and associated sensitivity of the experiment are also presented.
The Korea Invisible Mass Search (KIMS) collaboration has developed low-background NaI(Tl) crystals that are suitable for the direct detection of WIMP dark matter. Building on experience accumulated ...during the KIMS-CsI programs, the KIMS-NaI experiment will consist of a 200 kg NaI(Tl) crystal array surrounded by layers of shielding structures and will be operated at the Yangyang underground laboratory. The goal is to provide an unambiguous test of the DAMA/LIBRA annual modulation signature. Measurements of six prototype crystals show progress in the reduction of internal contamination from radioisotopes. Based on our understanding of these measurements, we expect to achieve a background level in the final detector configuration that is less than 1 count/day/keV/kg for recoil energies around 2 keV. The annual modulation sensitivity for the KIMS-NaI experiment shows that an unambiguous 7
σ
test of the DAMA/LIBRA signature would be possible with a 600 kg year exposure with this system.
Background and purpose
We investigated changes in deep gray matter (DGM) volume and its relationship to cognition and clinical factors in a large cohort of patients with neuromyelitis optica spectrum ...disorder (NMOSD) and compared them with results from multiple sclerosis (MS).
Methods
Brain magnetic resonance imaging (3 Tesla) and clinical data from 91 patients with NMOSD, 52 patients with MS and 44 healthy controls (HCs) were prospectively evaluated. Differences in DGM volumes were compared among groups. The relationships between DGM atrophy and clinical variables were also analysed.
Results
Patients with NMOSD exhibited significantly reduced thalamic volumes compared with HCs (P = 0.029), although this atrophy was less severe than that seen in patients with MS (P < 0.001). DGM atrophy was restricted to the thalamus in NMOSD, but it was broadly distributed in MS. Patients with NMOSD with cognitive impairment (CI) exhibited more severe thalamic atrophy than those with cognitive preservation (P = 0.017) and HCs (P = 0.003), whereas patients with MS with CI revealed DGM atrophy across the entire structure, with the exception of the bilateral pallidum, left hippocampus and amygdala, relative to HCs. The Expanded Disability Status Scale score was correlated with thalamic atrophy in both NMOSD and MS. Patients with NMOSD with brain lesions demonstrated more severe thalamic atrophy than did those without brain lesions and HCs (P < 0.001).
Conclusions
The DGM atrophy was less severe and more selectively distributed in NMOSD than in MS. Thalamic atrophy was associated with clinical disability, including CI, in both NMOSD and MS.
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of ...111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.
Summary
Background
Asthma is a chronic inflammatory disease caused by complex interactions of genetic, epigenetic, and environmental factors. For this reason, new approaches are required to clarify ...the pathogenesis of asthma by systemic review.
Objective
We applied a 1H‐NMR metabolomics approach to investigate the altered metabolic pattern in sera from patients with asthma and sought to identify the mechanism underlying asthma and potential biomarkers.
Method
A global profile of sera from patients with asthma (n = 39) and controls (n = 26) was generated using 1H‐NMR spectroscopy coupled with multivariate statistical analysis. Endogenous metabolites in serum were rapidly measured using the target‐profiling procedure.
Results
Multivariate statistical analysis showed a clear distinction between patients with asthma and healthy subjects. Sera of asthma patients were characterized by increased levels of methionine, glutamine, and histidine and by decreased levels of formate, methanol, acetate, choline, O‐phosphocholine, arginine, and glucose. The metabolites detected in the sera of patients with asthma are involved in hypermethylation, response to hypoxia, and immune reaction. Furthermore, the levels of serum metabolites from patients with asthma correlated with asthma severity; in particular, lipid metabolism was altered in patients with lower forced expiratory volume in 1 s percentage (FEV1%) predicted values. In addition, potential biomarkers showed strong predictive power in ROC analysis, and the presence of asthma in external validation models was predicted with high accuracy (90.9% for asthma and 100% for control subjects).
Conclusion & Clinical Relevance
These data showed that 1H‐NMR‐based metabolite profiling of serum may be useful for the effective diagnosis of asthma and a further understanding of its pathogenesis.
Summary
Background
Asthma in the elderly (aged ≥ 65 years old) is a significant concern with high morbidity, but the pathophysiology remains unclear particularly in late‐onset asthma. Recent studies ...suggest staphylococcal enterotoxin IgE (SE‐IgE) sensitization to be a risk factor for asthma in general populations; however, the associations have not been examined in late‐onset elderly asthma.
Objective
We aimed to examine the associations of SE‐IgE sensitization with late‐onset asthma in the elderly, using a database of elderly asthma cohort study.
Methods
A total of 249 elderly patients with asthma and 98 controls were analysed. At baseline, patients were assessed for demographics, atopy, induced sputum profiles and comorbidities including chronic rhinosinusitis (CRS). Serum total IgE and SE‐IgE levels were measured. Asthma severity was assessed on the basis of asthma outcomes during a 12‐month follow‐up period.
Results
At baseline, serum SE‐IgE concentrations were significantly higher in patients with asthma than in controls median 0.16 (interquartile range 0.04–0.53) vs. 0.10 (0.01–0.19), P < 0.001. Elderly asthma patients with high SE‐IgE levels had specific characteristics of having more severe asthma, sputum eosinophilia and CRS, compared to those with lower SE‐IgE levels. In multivariate logistic regression analyses, the associations between serum SE‐IgE concentrations and severe asthma were significant, independently of covariables SE‐IgE‐high (≥ 0.35 kU/L) vs. negative (< 0.10 kU/L) group: odds ratio 7.47, 95% confidence interval 1.86–30.03, P = 0.005. Multiple correspondence analyses also showed that high serum SE‐IgE level had close relationships with severe asthma, CRS and sputum eosinophilia together.
Conclusions and Clinical Relevance
This is the first report on the significant associations of SE‐IgE sensitization with late‐onset asthma in the elderly, particularly severe eosinophilic asthma with CRS comorbidity. Our findings indicate a potential implication of SE in the high morbidity burden of elderly asthma and suggest clues to the pathogenesis of severe late‐onset eosinophilic asthma in the elderly.
The COSINE-100 dark matter search experiment is an array of NaI(Tl) crystal detectors located in the Yangyang Underground Laboratory (Y2L). To understand measured backgrounds in the NaI(Tl) crystals ...we have performed Monte Carlo simulations using the Geant4 toolkit and developed background models for each crystal that consider contributions from both internal and external sources, including cosmogenic nuclides. The background models are based on comparisons of measurement data with Monte Carlo simulations that are guided by a campaign of material assays and are used to evaluate backgrounds and identify their sources. The average background level for the six crystals (70 kg total mass) that are studied is 3.5 counts/day/keV/kg in the (2–6) keV energy interval. The dominant contributors in this energy region are found to be
210
Pb and
3
H.
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