Miracle-dz/UniFAR-FTUs huggingface dataset:
Nobiletin, a Polymethoxylated Flavone, Inhibits Glioma Cell Growth and Migration via Arresting Cell Cycle and Suppressing MAPK and Akt Pathways

Nobiletin, a bioactive polymethoxylated flavone (5,6,7,8,3',4'‐hexamethoxyflavone), is abundant in citrus fruit peel. Although nobiletin exhibits antitumor activity against various cancer cells, the effect of nobiletin on glioma cells remains unclear. The aim of this study was to determine the effects of nobiletin on the human U87 and Hs683 glioma cell lines. Treating glioma cells with nobiletin (20–100 µm) reduced cell viability and arrested the cell cycle in the G0/G1 phase, as detected using a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and propidium iodide (PI) staining, respectively; however, nobiletin did not induce cell apoptosis according to PI‐annexin V double staining. Data from western blotting showed that nobiletin significantly attenuated the expression of cyclin D1, cyclin‐dependent kinase 2, cyclin‐dependent kinase 4, and E2 promoter‐binding factor 1 (E2F1) and the phosphorylation of Akt/protein kinase B and mitogen‐activated protein kinases, including p38, extracellular signal‐regulated kinase, and c‐Jun N‐terminal kinase. Our data also showed that nobiletin inhibited glioma cell migration, as detected by both functional wound healing and transwell migration assays. Altogether, the present results suggest that nobiletin inhibits mitogen‐activated protein kinase and Akt/protein kinase B pathways and downregulates positive regulators of the cell cycle, leading to subsequent suppression of glioma cell proliferation and migration. Our findings evidence that nobiletin may have potential for treating glioblastoma multiforme. Copyright © 2015 John Wiley & Sons, Ltd.
Concurrent adversities and deliberate self-harm among indigenous Sami and majority Norwegian adolescents: the Norwegian Arctic Adolescent Health Study

Abstract Background: Few studies have investigated proximal relationships between deliberate self-harm (DSH) and concurrent adversities. Objective: We aimed to investigate these relationships in a community population of 4881 indigenous Sami and majority Norwegian adolescents, 15 to 16 years old, and related to ethnicity and gender. Methods: Youth with and without self-reports of DSH last year were compared on 12 concurrent adversities, on scales measuring family and peer functioning, and on sociodemographic conditions. Results: DSH last year was reported by 22.3% of the adolescents, and by more girls (28.8%) than boys (15.9%). All 12 concurrent adversities were related strongly to DSH last year. Deliberate self-harmers reported twice as many concurrent adversities as non-DSHs, and a large effect size (Cohen’s d = 0.80) indicated a strong multiple additive relationship, but among DSHs no ethnic or gender differences were found. Multivariately, among Sami youth sexual abuse [odds ratio (OR), 8.4] was strongly related to DSH, whereas among majority Norwegians sexual abuse (OR, 3.9) and violence (OR, 4.5) were identified as the strongest predictors. Similarly, among boys violence from adults (OR, 8.8) was associated most strongly with DSH, whereas among girls sexual abuse (OR, 4.3) was the most robust predictor. DSHs reported more conflicts with parents, less family support and involvement, and more peer problems than non-DSHs, and DHS girls had more difficulties in these relationships than DHS boys. Only small ethnic differences were found. Conclusion: Adolescent DSHs reported twice as many concurrent adversities as non-DSHs, sexual abuse and violence were strongly related to DSH. Ethnic and gender differences in risk factors were found. Clinicians should inquire about traumatic experiences such as sexual and physical abuses, and should have a family, peer, and gender perspective in their work.
Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Significance Stromal interaction molecule (STIM) 1 is an essential activator of the ORAI1 calcium (Ca2+) channel that mediates Ca2+ entry into many cell types. Patients with mutations in STIM1 or ORAI1 genes suffer from a severe immunodeficiency syndrome. Here, we studied a disease-causing mutant of STIM1 that is incapable of activating ORAI1 channels, thereby uncovering key molecular mechanisms of STIM1 function. The autosomal recessive R429C mutation interferes with the structural integrity of a protein–protein interaction domain in STIM1 and impairs the ability of STIM1 to multimerize and bind to ORAI1. Drugs targeting this domain may provide a means to selectively modulate STIM1–ORAI1 interaction and Ca2+ entry as a novel approach to treat autoimmune diseases and other disorders associated with abnormal ORAI1-mediated Ca2+ entry. Store-operated Ca2+ entry (SOCE) is a universal Ca2+ influx pathway that is important for the function of many cell types. SOCE occurs upon depletion of endoplasmic reticulum (ER) Ca2+ stores and relies on a complex molecular interplay between the plasma membrane (PM) Ca2+ channel ORAI1 and the ER Ca2+ sensor stromal interaction molecule (STIM) 1. Patients with null mutations in ORAI1 or STIM1 genes present with severe combined immunodeficiency (SCID)-like disease. Here, we describe the molecular mechanisms by which a loss-of-function STIM1 mutation (R429C) in human patients abolishes SOCE. R429 is located in the third coiled-coil (CC3) domain of the cytoplasmic C terminus of STIM1. Mutation of R429 destabilizes the CC3 structure and alters the conformation of the STIM1 C terminus, thereby releasing a polybasic domain that promotes STIM1 recruitment to ER–PM junctions. However, the mutation also impairs cytoplasmic STIM1 oligomerization and abolishes STIM1–ORAI1 interactions. Thus, despite its constitutive localization at ER–PM junctions, mutant STIM1 fails to activate SOCE. Our results demonstrate multifunctional roles of the CC3 domain in regulating intra- and intermolecular STIM1 interactions that control (i) transition of STIM1 from a quiescent to an active conformational state, (ii) cytoplasmic STIM1 oligomerization, and (iii) STIM1–ORAI1 binding required for ORAI1 activation.
A Novel Function of Monomeric Amyloid β-Protein Serving as an Antioxidant Molecule against Metal-Induced Oxidative Damage

Aggregated and oligomeric amyloid β-protein (Aβ) is known to exhibit neurotoxicity. However, the action of Aβ monomers on neurons is not fully understood. We have studied aggregation state-dependent actions of Aβ and found an oligomer-specific effect of Aβ on lipid metabolism in neurons (Michikawa et al., 2001). Here, we show a novel function of monomeric Aβ1–40, which is the major species found in physiological fluid, as a natural antioxidant molecule that prevents neuronal death caused by transition metal-induced oxidative damage. Monomeric Aβ1–40, which is demonstrated by SDS-PAGE after treatment with glutaraldehyde, protects neurons cultured in a medium containing 1.5 μm Fe(II) without antioxidant molecules. Metal ion chelators such as EDTA, CDTA (trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid), and DTPA (diethylenetriamine-N,N,N′,N",N"-penta-acetic acid, an iron-binding protein, transferrin, and antioxidant scavengers such as catalase, glutathione, and vitamin E also inhibit neuronal death under the same conditions. Monomeric Aβ1–40 inhibits neuronal death caused by Cu(II), Fe(II), and Fe(III) but does not protect neurons against H2O2-induced damage. Monomeric Aβ1–40 inhibits the reduction of Fe(III) induced by vitamin C and the generation of superoxides and prevents lipid peroxidation induced by Fe(II). Aβ1–42 remaining as a monomer also exhibits antioxidant and neuroprotective effects. In contrast, oligomeric and aggregated Aβ1–40 and Aβ1–42 lose their neuroprotective activity. These results indicate that monomeric Aβ protects neurons by quenching metal-inducible oxygen radical generation and thereby inhibiting neurotoxicity. Because aggregated Aβ is known to be an oxygen radical generator, our results provide a novel concept that the aggregation-dependent biological effects of Aβ are dualistic, being either an oxygen radical generator or its inhibitor.
The PKC, HOG and Ca2+ signalling pathways co‐ordinately regulate chitin synthesis in Candida albicans

Chitin is an essential component of the fungal cell wall and its synthesis is under tight spatial and temporal regulation. The fungal human pathogen Candida albicans has a four member chitin synthase gene family comprising of CHS1 (class II), CHS2 (class I), CHS3 (class IV) and CHS8 (class I). LacZ reporters were fused to each CHS promoter to examine the transcriptional regulation of chitin synthesis. Each CHS promoter had a unique regulatory profile and responded to the addition of cell wall damaging agents, to mutations in specific CHS genes and exogenous Ca2+. The regulation of both CHS gene expression and chitin synthesis was co‐ordinated by the PKC, HOG MAP kinase and Ca2+/calcineurin signalling pathways. Activation of these pathways also resulted in increased chitin synthase activity in vitro and elevated cell wall chitin content. Combinations of treatments that activated multiple pathways resulted in synergistic increases in CHS expression and in cell wall chitin content. Therefore, at least three pathways co‐ordinately regulate chitin synthesis and activation of chitin synthesis operates at both transcriptional and post‐transcriptional levels.
Markers of systemic bacterial exposure in periodontal disease and cardiovascular disease risk: a systematic review and meta-analysis.

BACKGROUND Recent meta-analyses reported a weak association between periodontal disease (PD) on clinical examination and cardiovascular disease (CVD). Systemic bacterial exposure from periodontitis, which correlates poorly with the clinical examination, has been proposed as the more biologically pertinent risk factor. The purpose of this study was to review and analyze the association between PD with elevated systemic bacterial exposure and CVD. METHODS We searched in the PubMed, Cochrane Controlled Trials Register, EMBASE, and SCOPUS databases for all literature examining PD and CVD. From 10 selected publications, we extracted 12 cohort (N = 5) and cross-sectional (N = 7) studies and included 11 of these in a meta-analysis. With stratified analyses, this resulted in 14 analyses of coronary heart disease (CHD; N = 7), stroke (N = 4), and carotid intima-medial thickening (CIMT; N = 3) as a measure of early atherosclerosis. Systemic bacterial exposure was measured by periodontal bacterial burden (N = 1), periodontitis-specific serology (N = 12), or C-reactive protein (N = 1). RESULTS Periodontal disease with elevated markers of systemic bacterial exposure was associated strongly with CHD compared to subjects without PD, with a summary odds ratio of 1.75 (95% confidence interval (CI): 1.32 to 2.34; P <0.001). This group was not associated with CVD events or with stroke but was associated with a significant increase in mean CIMT (0.03 mm; 95% CI: 0.02 to 0.04). CONCLUSION Periodontal disease with elevated bacterial exposure is associated with CHD events and early atherogenesis (CIMT), suggesting that the level of systemic bacterial exposure from periodontitis is the biologically pertinent exposure with regard to atherosclerotic risk.
Observations in experimental magnesium depletion.

Studies of experimental magnesium depletion have been reported in the past (1-8). This report describes a re-evaluation of this problem in which some of the previous observations have been confirmed and extended. In particular these studies were concerned with the interrelationships between magnesium deficiency and the metabolism of potassium, calcium, and phosphorus. In addition, the pathologic alterations of the kidneys were examined. These latter observations will be alluded to here, although they have been reported in an abstract (9), and will be the subject of a more detailed discussion in another publication.
Encoding of Naturalistic Stimuli by Local Field Potential Spectra in Networks of Excitatory and Inhibitory Neurons

Recordings of local field potentials (LFPs) reveal that the sensory cortex displays rhythmic activity and fluctuations over a wide range of frequencies and amplitudes. Yet, the role of this kind of activity in encoding sensory information remains largely unknown. To understand the rules of translation between the structure of sensory stimuli and the fluctuations of cortical responses, we simulated a sparsely connected network of excitatory and inhibitory neurons modeling a local cortical population, and we determined how the LFPs generated by the network encode information about input stimuli. We first considered simple static and periodic stimuli and then naturalistic input stimuli based on electrophysiological recordings from the thalamus of anesthetized monkeys watching natural movie scenes. We found that the simulated network produced stimulus-related LFP changes that were in striking agreement with the LFPs obtained from the primary visual cortex. Moreover, our results demonstrate that the network encoded static input spike rates into gamma-range oscillations generated by inhibitory–excitatory neural interactions and encoded slow dynamic features of the input into slow LFP fluctuations mediated by stimulus–neural interactions. The model cortical network processed dynamic stimuli with naturalistic temporal structure by using low and high response frequencies as independent communication channels, again in agreement with recent reports from visual cortex responses to naturalistic movies. One potential function of this frequency decomposition into independent information channels operated by the cortical network may be that of enhancing the capacity of the cortical column to encode our complex sensory environment.
Linear regression analysis: part 14 of a series on evaluation of scientific publications.

BACKGROUND Regression analysis is an important statistical method for the analysis of medical data. It enables the identification and characterization of relationships among multiple factors. It also enables the identification of prognostically relevant risk factors and the calculation of risk scores for individual prognostication. METHODS This article is based on selected textbooks of statistics, a selective review of the literature, and our own experience. RESULTS After a brief introduction of the uni- and multivariable regression models, illustrative examples are given to explain what the important considerations are before a regression analysis is performed, and how the results should be interpreted. The reader should then be able to judge whether the method has been used correctly and interpret the results appropriately. CONCLUSION The performance and interpretation of linear regression analysis are subject to a variety of pitfalls, which are discussed here in detail. The reader is made aware of common errors of interpretation through practical examples. Both the opportunities for applying linear regression analysis and its limitations are presented.
Clinical experience as evidence in evidence-based practice.

BACKGROUND This paper's starting point is the recognition (descriptive not normative) that, for the vast majority of day-to-day clinical decision-making situations, the 'evidence' for decision-making is experiential knowledge. Moreover, reliance on this knowledge base means that nurses must use cognitive shortcuts or heuristics for handling information when making decisions. These heuristics encourage systematic biases in decision-makers and deviations from the normative rules of 'good' decision-making. AIMS The aim of the paper is to explore three common heuristics and the biases that arise when handling complex information in clinical decision-making (overconfidence, hindsight and base rate neglect) and, in response to these biases, to illustrate some simple techniques for reducing the negative influence of heuristics. DISCUSSION Nurses face a limited range of types of uncertainty in their clinical decisions and draw primarily on experiential knowledge to handle these uncertainties. This paper argues that experiential knowledge is a necessary but not sufficient basis for clinical decision-making. It illustrates how overconfidence in one's knowledge base, being correct 'after the event' or with the benefit of hindsight, and ignoring the base rates associated with events, conditions or health states, can impact on professional judgements and decisions. The paper illustrates some simple strategies for minimizing the impact of heuristics on the real-life clinical decisions of nurses. CONCLUSION The paper concludes that more research knowledge of the impact of heuristics and techniques to combat them in nursing decisions is needed.
Daily smoking and lower back pain in adult Canadians: the Canadian Community Health Survey

Background: Lower back pain (LBP) is one of the primary causes of disability in the Canadian community. However, only a limited number of studies have addressed the association between daily smoking and LBP in Canada. Of the studies that have explored this association, many had small sample sizes and failed to control for confounders. Objective: The primary objective of the study was to determine if daily smoking is associated with an increased risk of having LBP. The secondary objectives were to assess the risk for LBP among occasional smokers and to determine the prevalence of LBP in relation to different covariates. Data and study design: Using the Canadian Community Health Survey (cycle 3.1) data, 73,507 Canadians between the ages of 20 and 59 years were identified. LBP status, smoking level, sex, age, body mass index (BMI), level of activity and level of education were assessed in these subjects. Methods: Stratified analysis and logistic regression analysis were used to detect effect modifications and to adjust for covariates. Population weight and design were taken into consideration. Results: The prevalence of LBP was 23.3% among daily smokers and 15.7% among non-smokers. Age and sex were found to be effect modifiers. The association between LBP and daily smoking was statistically significant in all ages and genders; this association was stronger for younger age groups. The adjusted odds ratio for male daily smokers aged 20 to 29 was 1.87 (95% CI = 1.62, 2.17); findings were similar for women. Occasional smoking slightly increased the odds of having back pain. Conclusion: Young Canadian daily smokers are at higher risk for LBP. This study also suggests a positive correlation between smoking dose and the risk of LBP. These findings indicate that smoking behavioral modification may have an impact on reducing back pain especially among young adults.
Radio-frequency ablation of hepatic metastases: postprocedural assessment with a US microbubble contrast agent--early experience.

PURPOSE To evaluate contrast agent-enhanced ultrasonography (US) in the detection of untreated tumor after radio-frequency (RF) ablation of hepatic metastases. MATERIALS AND METHODS Twenty patients with solitary colorectal liver metastases underwent percutaneous RF tumor ablation. Pre- and postablation imaging was performed with nonenhanced and enhanced color and power Doppler US and contrast-enhanced helical computed tomography (CT). Initial follow-up CT and US were performed 24 hours after ablation. The findings at US and CT were compared. RESULTS Nonenhanced US demonstrated intratumoral signal in 15 of 20 metastases before ablation. This signal increased after contrast agent administration. Contrast-enhanced US performed 24 hours after ablation demonstrated residual foci of enhancement in three tumors, whereas no US signals were seen in any tumor on nonenhanced scans. CT demonstrated small (< 3-mm) persistent foci of residual enhancement in these three tumors and in three additional lesions that were not seen at US (US sensitivity, 50%; specificity, 100%; diagnostic agreement with CT, 85%). All six patients with evidence of residual tumor underwent repeat RF ablation. CONCLUSION Contrast-enhanced US may depict residual tumor after RF application and thereby enable additional directed therapy. The potential reduction in treatment sessions and/or ancillary imaging procedures might increase the ease and practicality of percutaneous ablation of focal hepatic metastases.
Ulcerative Colitis and Crohn’s Disease Are Associated with Decreased Serum Selenium Concentrations and Increased Cardiovascular Risk

The incidence of inflammatory bowel disease (IBD) and associated oxidative stress is increasing. The antioxidant mineral selenium (Se) was measured in serum samples from 106 IBD patients (53 with ulcerative colitis (UC) and 53 with Crohn’s disease (CD)) and from 30 healthy controls. Serum Se concentrations were significantly lower in UC and CD patients than in healthy controls (p < 0.001) and significantly lower in CD patients than in UC patients (p = 0.006). Se concentrations in patients were significantly influenced by sex, body mass index (BMI), the inflammatory biomarker α-1-antitrypsin, surgery, medical treatment, the severity, extent, and form of the disease and the length of time since onset (p < 0.05). Se concentrations in IBD patients were positively and linearly correlated with nutritional (protein, albumin, prealbumin, cholinesterase and total cholesterol) and iron status-related (hemoglobin, Fe and hematocrit) parameters (p < 0.05). A greater impairment of serum Se and cardiovascular status was observed in CD than in UC patients. An adequate nutritional Se status is important in IBD patients to minimize the cardiovascular risk associated with increased inflammation biomarkers, especially in undernourished CD patients, and is also related to an improved nutritional and body iron status.
Histamine selectively enhances human immunoglobulin E (IgE) and IgG4 production induced by anti-CD58 monoclonal antibody

We studied the effects of histamine on human immunoglobulin (IgE) and IgG4 production. Histamine selectively enhanced IgE and IgG4 production in purified surface IgE and IgG4 negative (sIgE-sIgG4-) B cells from normal donors stimulated with interleukin (IL)-4 plus anti-CD58 or IL- 13 plus anti-CD58 monoclonal antibody (mAb) without affecting production of IgG1, IgG2, IgG3, IgM, IgA1, or IgA2. In cultures with IL- 4 plus anti-CD58 mAb, histamine-induced enhancement of IgE and IgG4 production was specifically blocked by thioperamide (H3 receptor antagonist), and was inhibited by anti-IL-10 antibody (Ab). In contrast, in cultures with IL-13 plus anti-CD58 mAb, histamine-induced enhancement was blocked by dimaprit (H1 receptor antagonist), and was inhibited by anti-IL-6 mAb. Histamine also enhanced IgE and IgG4 production by in vivo-generated sIgE+ and sIgG4+ B cells, respectively, from atopic patients; enhancement was blocked by dimaprit and thioperamide, and was inhibited by anti-IL-6 mAb and anti-IL-10 Ab. In sIgE-sIgG4- B cells, IL-4 plus anti-CD58 mAb induced IL-10 production and IL-10 receptor expression, whereas IL-13 plus anti-CD58 mAb induced IL-6 production and IL-6 receptor expression. Histamine increased IL-10 and IL-6 production without affecting IL-10 and IL-6 receptor expression, in cultures with IL-4 plus anti-CD58 mAb and with IL-13 plus anti-CD58 mAb, respectively, which was blocked by thioperamide and dimaprit, respectively. In contrast, sIgE+ and sIgG4+ B cells spontaneously produced both IL-6 and IL-10 and constitutively expressed IL-6 and IL-10 receptors, and histamine increased IL-6 and IL-10 production without affecting IL-6 or IL-10 receptor expression, which was blocked by thioperamide and dimaprit. These results indicate that histamine enhanced IgE and IgG4 production by increasing endogenous IL- 6 and IL-10 production via H1 and H3 receptors, respectively.