Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1

BACKGROUND We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown. METHODS A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer. RESULTS Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53. CONCLUSION Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity

Alcoholism and recovery: A case study of a former professional footballer

What little we know about alcoholism amongst professional footballers comes largely from the media (often tabloid newspapers) and published autobiographies and biographies of high profile stars. The coverage often focuses on deviant behaviour when drunk, such as driving under the influence, marital infidelity, violence, and breaking team rules. There is little or no published research which seeks to understand better what it is like to suffer from alcoholism from the perspective of the player-addicts themselves. In this paper I present a case study of British footballer who had a brief professional career and is in recovery from alcoholism. His subjective experience of alcoholism provides valuable insights into the underlying triggers and/or causes of the illness; its destructive nature; the link between the individual’s addiction and his social circumstances (including football); and his recovery

Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis

BACKGROUND: The GOLD classification of COPD severity introduces a stage 0 (at risk) comprising individuals with productive cough and normal lung function. The aims of this study were to investigate total mortality risks in GOLD stages 0–4 with special focus on stage 0, and furthermore to assess the influence of symptoms of chronic bronchitis on mortality risks in GOLD stages 1–4. METHOD: Between 1974 and 1992, a total of 22 044 middle-aged individuals participated in a health screening, which included a spirometry as well as recording of respiratory symptoms and smoking habits. Individuals with comorbidity at baseline (diabetes, stroke, cancer, angina pectoris, or heart infarction) were excluded from the analyses. Hazard ratios (HR 95% CI) of total mortality were analyzed in GOLD stages 0–4 with individuals with normal lung function and without symptoms of chronic bronchitis as a reference group. HR:s in smoking individuals with symptoms of chronic bronchitis within the stages 1–4 were calculated with individuals with the same GOLD stage but without symptoms of chronic bronchitis as reference. RESULTS: The number of deaths was 3674 for men and 832 for women based on 352 324 and 150 050 person-years respectively. The proportion of smokers among men was 50% and among women 40%. Self reported comorbidity was present in 4.6% of the men and 6.6% of the women. Among smoking men, Stage 0 was associated with an increased mortality risk, HR; 1.65 (1.32–2.08), of similar magnitude as in stage 2, HR; 1.41 (1.31–1.70). The hazard ratio in stage 0 was significantly higher than in stage 1 HR; 1.13 (0.98–1.29). Among male smokers with stage 1; HR: 2.04 (1.34–3.11), and among female smokers with stage 2 disease; HR: 3.16 (1.38–7.23), increased HR:s were found in individuals with symptoms of chronic bronchitis as compared to those without symptoms of chronic bronchitis. CONCLUSION: Symptoms fulfilling the definition of chronic bronchitis were associated with an increased mortality risk among male smokers with normal pulmonary function (stage 0) and also with an increased risk of death among smoking individuals with mild to moderate COPD (stage 1 and 2)

Measuring the effectiveness of in-hospital and on-base Prevent Alcohol and Risk-related Trauma in Youth (P.A.R.T.Y.) programs on reducing alcohol related harms in naval trainees: P.A.R.T.Y. Defence study protocol

Abstract Background Reducing alcohol related harms in Australian Defence Force (ADF) trainees has been identified as a priority, but there are few evidence-based prevention programs available for the military setting. The study aims to test whether the P.A.R.T.Y. program delivered in-hospital or on-base, can reduce harmful alcohol consumption among ADF trainees. Methods/design The study is a 3-arm randomized controlled trial, involving 953 Royal Australian Navy trainees from a single base. Trainees, aged 18 to 30 years, will be randomly assigned to the study arms: i. in-hospital P.A.R.T.Y.; ii. On-base P.A.R.T.Y.; and iii. Control group. All groups will receive the routine ADF annual alcohol awareness training. The primary outcome is the proportion of participants reporting an Alcohol Use Disorders Identification Test (AUDIT) score of 8 or above at 12 months’ post-intervention. The secondary outcome is the number of alcohol related incidents reported to the Royal Australian Navy (RAN) in the 12 months’ post-intervention. Discussion This is the first trial of the use of the P.A.R.T.Y. program in the military. If the proposed intervention proves efficacious, it may be a useful program in the early education of RAN trainees. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614001332617 , date of registration: 18/12/2014 ‘retrospectively registered’

Developing Single-Molecule TPM Experiments for Direct Observation of Successful RecA-Mediated Strand Exchange Reaction

RecA recombinases play a central role in homologous recombination. Once assembled on single-stranded (ss) DNA, RecA nucleoprotein filaments mediate the pairing of homologous DNA sequences and strand exchange processes. We have designed two experiments based on tethered particle motion (TPM) to investigate the fates of the invading and the outgoing strands during E. coli RecA-mediated pairing and strand exchange at the single-molecule level in the absence of force. TPM experiments measure the tethered bead Brownian motion indicative of the DNA tether length change resulting from RecA binding and dissociation. Experiments with beads labeled on either the invading strand or the outgoing strand showed that DNA pairing and strand exchange occurs successfully in the presence of either ATP or its non-hydrolyzable analog, ATPγS. The strand exchange rates and efficiencies are similar under both ATP and ATPγS conditions. In addition, the Brownian motion time-courses suggest that the strand exchange process progresses uni-directionally in the 5′-to-3′ fashion, using a synapse segment with a wide and continuous size distribution

Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study

Objectives To derive and validate risk prediction algorithms to estimate the risk of covid-19 related mortality and hospital admission in UK adults after one or two doses of covid-19 vaccination.Design Prospective, population based cohort study using the QResearch database linked to data on covid-19 vaccination, SARS-CoV-2 results, hospital admissions, systemic anticancer treatment, radiotherapy, and the national death and cancer registries.Settings Adults aged 19-100 years with one or two doses of covid-19 vaccination between 8 December 2020 and 15 June 2021.Main outcome measures Primary outcome was covid-19 related death. Secondary outcome was covid-19 related hospital admission. Outcomes were assessed from 14 days after each vaccination dose. Models were fitted in the derivation cohort to derive risk equations using a range of predictor variables. Performance was evaluated in a separate validation cohort of general practices.Results Of 6 952 440 vaccinated patients in the derivation cohort, 5 150 310 (74.1%) had two vaccine doses. Of 2031 covid-19 deaths and 1929 covid-19 hospital admissions, 81 deaths (4.0%) and 71 admissions (3.7%) occurred 14 days or more after the second vaccine dose. The risk algorithms included age, sex, ethnic origin, deprivation, body mass index, a range of comorbidities, and SARS-CoV-2 infection rate. Incidence of covid-19 mortality increased with age and deprivation, male sex, and Indian and Pakistani ethnic origin. Cause specific hazard ratios were highest for patients with Down’s syndrome (12.7-fold increase), kidney transplantation (8.1-fold), sickle cell disease (7.7-fold), care home residency (4.1-fold), chemotherapy (4.3-fold), HIV/AIDS (3.3-fold), liver cirrhosis (3.0-fold), neurological conditions (2.6-fold), recent bone marrow transplantation or a solid organ transplantation ever (2.5-fold), dementia (2.2-fold), and Parkinson’s disease (2.2-fold). Other conditions with increased risk (ranging from 1.2-fold to 2.0-fold increases) included chronic kidney disease, blood cancer, epilepsy, chronic obstructive pulmonary disease, coronary heart disease, stroke, atrial fibrillation, heart failure, thromboembolism, peripheral vascular disease, and type 2 diabetes. A similar pattern of associations was seen for covid-19 related hospital admissions. No evidence indicated that associations differed after the second dose, although absolute risks were reduced. The risk algorithm explained 74.1% (95% confidence interval 71.1% to 77.0%) of the variation in time to covid-19 death in the validation cohort. Discrimination was high, with a D statistic of 3.46 (95% confidence interval 3.19 to 3.73) and C statistic of 92.5. Performance was similar after each vaccine dose. In the top 5% of patients with the highest predicted covid-19 mortality risk, sensitivity for identifying covid-19 deaths within 70 days was 78.7%.Conclusion This population based risk algorithm performed well showing high levels of discrimination for identifying those patients at highest risk of covid-19 related death and hospital admission after vaccination

Effects of alcohol preload on attentional bias towards cocaine-related cues

Background Drug and alcohol users have an ‘attentional bias’ for substance-related cues, which is likely to reflect the incentive-motivational properties of those cues. Furthermore, administration of an alcohol preload increases attentional bias for alcohol and tobacco-related cues in heavy drinkers and tobacco smokers, respectively. The present study investigated attentional bias for cocaine cues in cocaine users and non-users following administration of either alcohol or placebo. Method Thirty-two regular cocaine users and 40 non-users took part. Participants were administered alcohol or placebo, and administration was double blind. After drink administration, a Visual Probe task and Modified Stroop task were used to assess attentional bias. Subjective craving and alcohol outcome expectancies were also measured. Results There was a significant interaction between group and drink type on the visual probe task indicating that cocaine users who had received alcohol had increased attentional bias for cocaine pictures compared to non-users and cocaine users who received placebo. The cocaine Stroop revealed no differences between cocaine users and non-users, and no effects of alcohol in either group. Conclusions Alcohol preload in regular cocaine users increases attentional bias for cocaine cues. However, cocaine users who received placebo did not show attentional bias for cocaine stimuli. Future research should investigate the effects of alcohol preload on attentional bias in cocaine-dependent individuals

Slepian functions and their use in signal estimation and spectral analysis

It is a well-known fact that mathematical functions that are timelimited (or spacelimited) cannot be simultaneously bandlimited (in frequency). Yet the finite precision of measurement and computation unavoidably bandlimits our observation and modeling scientific data, and we often only have access to, or are only interested in, a study area that is temporally or spatially bounded. In the geosciences we may be interested in spectrally modeling a time series defined only on a certain interval, or we may want to characterize a specific geographical area observed using an effectively bandlimited measurement device. It is clear that analyzing and representing scientific data of this kind will be facilitated if a basis of functions can be found that are "spatiospectrally" concentrated, i.e. "localized" in both domains at the same time. Here, we give a theoretical overview of one particular approach to this "concentration" problem, as originally proposed for time series by Slepian and coworkers, in the 1960s. We show how this framework leads to practical algorithms and statistically performant methods for the analysis of signals and their power spectra in one and two dimensions, and on the surface of a sphere.Comment: Submitted to the Handbook of Geomathematics, edited by Willi Freeden, Zuhair M. Nashed and Thomas Sonar, and to be published by Springer Verla