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These findings elucidate the biological function of Fzd6 as a receptor that triggers Wnt/β-catenin signaling and the cellular mechanisms modulated by nanotopography during osteoblast differentiation. © 2020 Wiley Periodicals, Inc.We investigated the regulation of Cl- secretion by adrenoceptors in polarized 16HBE14o- human bronchial epithelial cells. Treatment with the nonselective β adrenoceptor agonist isoprenaline stimulated an increase in short-circuit current (ISC ), which was inhibited by the β adrenoceptor blocker propranolol. Treatment with procaterol, an agonist specific for the β2 adrenoceptor subtype, stimulated a similar increase in ISC , which was inhibited by the β2 adrenoceptor antagonist ICI 118551. Inhibitors of cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated Cl- channel (CaCC), but not K+ channel blockers, were able to inhibit the increase in ISC . "Trimultaneous" recording of ISC and intracellular cyclic adenosine monophosphate (cAMP) and Ca2+ levels in 16HBE14o- epithelia confirmed that the ISC induced by isoprenaline or procaterol involved both cAMP and Ca2+ signaling. Our results demonstrate that β2 adrenoceptors regulate Cl- secretion in the human airway epithelium by activating apical CFTRs and CaCCs via cAMP-dependent and intracellular Ca2+ -dependent mechanisms, respectively. © 2020 Wiley Periodicals, Inc.Asymmetric dimethylarginine (ADMA), an endogenous inhibitor and uncoupler of nitric oxide synthase, has gained attention as a risk factor for cardiac disease, metabolic syndrome, and cerebrovascular disease. In this study, we investigated the role of systemic ADMA overburden in cerebromicrovascular pathology associated with cognitive dysfunction using APPSwDI transgenic mice expressing human β-amyloid precursor protein Swedish (Tg-SwDI), a model of cerebrovascular β-amyloidosis. To induce systemic overburden of ADMA, Tg-SwDI mice were treated with a daily dose of exogenous ADMA. ADMA treatment resulted in elevated ADMA levels in the blood and brain of Tg-SwDI mice. NMS873 ADMA treatment induced the brain nitrosative stress and inflammation as well as enhanced the brain Aβ deposition and cognitive impairment in Tg-SwDI mice. However, ADMA treatment had no such effects on wild type mice. ADMA treatment also exacerbated brain microvascular pathology in Tg-SwDI mice as observed by increased blood-brain barrier dysfunction, loss of tight junction proteins, increased endothelial stress fibers, and decreased microvessel density in the brain. In addition, similar observations were made in cultured human brain microvessel endothelial cells, where ADMA in the presence of VEGF-induced endothelial cell signaling for F-actin stress fiber inducing endothelial barrier dysfunction. Overall, these data document the potential role of ADMA in the cognitive pathology under conditions of cerebrovascular β-amyloidosis. © 2020 Federation of American Societies for Experimental Biology.BACKGROUND AND OBJECTIVE Nasal symptoms of allergic rhinitis can be reduced with allergen-specific subcutaneous immunotherapy (SCIT). However, the mechanisms underlying the effectiveness of SCIT for Japanese cedar pollinosis are not well understood. We studied changes in the numbers of metachromatic cells, eosinophils and neutrophils in nasal swabs following SCIT for Japanese cedar pollinosis. METHODS Subjects were either untreated or given SCIT for 0.5 to 13 years duration. For the 2019 seasons, nasal swabs were taken in the pollinosis preseason (immunotherapy n = 36; untreated control, n = 62) and in the pollinosis season (immunotherapy n = 45; untreated control n = 46) and the numbers of mast cells, eosinophils and neutrophils assessed by microscopy. RESULTS There were significant improvements in symptom severities following SCIT in comparison to untreated subjects (P  less then  .0003, the Mann-Whitney U test) in preseason, and (P  less then  .00001) in season. Metachromatic cell counts from nasal swabs of SCIT subjects in preseason and in the season were lower than those of untreated subjects (P = .0029 and P = .031, respectively). Eosinophil numbers in nasal swabs of subjects given SCIT were lower than in untreated subjects (P = .0031) in season, but not in preseason. There were no significant differences in degrees of neutrophilia between untreated and SCIT subjects in preseason and in season. CONCLUSION One mechanism underlying the effectiveness of SCIT for Japanese cedar pollinosis involves a reduction in the number of metachromatic cells in nasal swabs in the preseason and an inhibition of increases in the number of metachromatic cells and eosinophils in season. © 2020 John Wiley & Sons Ltd.Small nucleolar RNA host gene 6 (SNHG6) has been recognized as an oncogene in numerous cancers and overexpression of SNHG6 was found to promote colorectal cancer (CRC). Hence, we performed a meta-analysis to examine the clinical importance of the long noncoding RNA (lncRNA) SNHG6. Moreover, comprehensive identification of RNA-binding proteins-mass spectrometry (ChIRP-MS) was conducted to explore the carcinogenic mechanism of lncRNA SNHG6 in CRC. Fourteen studies conducted on 1,139 patients were included in this meta-analysis. We also constructed the protein-protein interactive (PPI) network in string based on the ChIRP-MS results and cytoscape was used to identify core modules in the PPI network, which were then analyzed using the bioinformatics websites, cancer single-cell state atlas (CancerSEA) and Gprofilter. The clinical outcomes of the meta-analysis indicated that higher expression of SNHG6 was related with a poorer survival outcome (overall survival hazard ratio (HR) = 1.92; 95% confidence interval [Cl] 1.48, 2.49; p  less then  .0001; disease-free survival HR = 1.84; 95% Cl 1.02, 3.34; p = .044), higher tumor stage (odds ratio [OR] = 3.35; 95% Cl 2.57, 4.37; p  less then  .0001), distant metastasis (OR = 1.83; 95% Cl 1.11, 2.99; p = .017) and lymph node metastasis (OR = 1.33; 95% Cl 0.93, 1.89; p = .119). The ChIRP-MS results showed that core Module 1 of the PPI was significant in ribosomes and core Module 2 was mainly related to spliceosomes and messenger RNA processing. In conclusion, a higher expression of SNHG6 was found to be associated with a poorer survival outcome, high tumor stage, and distant metastasis in various solid tumors. SNHG6 was also found to be able to affect the processes of transcription and translation to promote CRC. © 2020 Wiley Periodicals, Inc.Large B-cell lymphoma with IRF4 rearrangement, and Burkitt-like lymphoma with 11q aberration are two provisional lymphoma entities in the 2017 revision of the WHO classification of lymphoid neoplasms. Despite being more frequent in young patients, knowledge regarding their true incidence and clinical features in unselected cohorts of paediatric and adolescent patients is limited. We screened for both entities among paediatric patients ( less then 18 years of age) in the German NHL-BFM (Non-Hodgkin lymphoma Berlin-Frankfurt-Münster) group. Among follicular lymphomas and diffuse large B-cell lymphomas (DLBCL), 7/34 cases (21%) showed an IRF4 break-apart pattern by fluorescence in situ hybridisation (FISH) and are associated with stages I and II disease (P = 0·043). Among lymphomas morphologically resembling Burkitt lymphoma, DLBCL and high-grade B-cell lymphoma, unclassifiable, 13/102 cases (13%) lacked a MYC break-apart pattern but were positive for 11q proximal gain and telomeric loss by FISH. MYC-negative Burkitt-like lymphomas with the typical 11q gain-loss pattern by FISH were older (P = 0·004), showed less male predominance (P = 0·003), lower stage (P = 0·040), lower serum LDH level (P = 0·01) and less abdominal involvement (P = 0·008) compared to high grade B-cell lymphomas without 11q gain-loss pattern. Both entities showed excellent outcome with overall survival of 100% when managed according to NHL-BFM strategies and may provide candidates for future therapy de-escalation in clinical trials. © 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.OBJECTIVE Early onset epileptic encephalopathy with suppression-burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage-dependent potassium channel subunit, leading to so-called KCNQ2-related epileptic encephalopathy (KCNQ2-REE). To study the pathophysiology of KCNQ2-REE in detail and to provide a relevant preclinical model, we generated and described a knock-in mouse model carrying the recurrent p.(Thr274Met) variant. METHODS We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre-deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomdevastating and currently intractable disease. © 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.BACKGROUND AND AIMS Tools to detect type 1 diabetes (T1D) individuals at overt cardiovascular disease (CVD) risk are scarce. We aimed to assess the usefulness of the score 'Steno Type 1 Risk Engine' (Steno-Risk) to identify T1D patients with advanced carotid atherosclerosis. MATERIAL AND METHODS T1D patients without CVD with at least one of the following were included ≥40 years, diabetic nephropathy, or diabetes duration ≥10 years with ≥1 CVD risk factor. Intima-media thickness (IMT) and plaque presence (IMT ≥1.5 mm) were assessed by standardized B-mode ultrasonography. Steno-Risk was used to estimate 10-year risk ( less then 10% low; 10%-20% moderate; ≥20% high risk). Associations between Steno-Risk and preclinical atherosclerosis were assessed after adjusting for other CVD risk factors. RESULTS We evaluated 302 patients (55% men, age 47.8 ± 9.8 years, T1D duration 26.3 ± 9.3 years). The prevalence of carotid plaque and ≥2 plaques were 36.4% and 19.2%, respectively; without sex differences. Age (57.4 ± 7.4 vs 37.1 ± 6.2 years), T1D duration (31.3 ± 10.4 vs 21.5 ± 7.1 years), hypertension (52.3% vs 6.3%), nephropathy (25.6% vs 5.1%) and retinopathy (53.5% vs 32.9%) were higher in high-risk (n = 86) vs low-risk participants (n = 79; P  less then  .001 for all). Preclinical atherosclerosis (IMT and plaque) increased in parallel with Steno-Risk (P  less then  .001). In logistic regression analysis, both age ≥40 years and Steno-Risk ≥20% were associated with the presence of plaque (OR 4.22 [1.57-11.36] and 3.79 [1.61-6.80]; respectively), but only high Steno-Risk remained independently associated with ≥2 plaques (OR 3.31 [1.61-6.80]). CONCLUSION Steno-Risk is independently associated with preclinical atherosclerosis. Further studies are needed to ascertain its usefulness in this high-risk population. © 2020 John Wiley & Sons Ltd.