The short isoform of ErbB3-binding protein 1 (Ebp1), p42, is considered to be a potent tumor suppressor in a number of human cancers, although the mechanism by which it exerts this tumor-suppressive ...activity is unclear. Here, we report that p42 interacts with the cSH2 domain of the p85 subunit of phosphathidyl inositol 3-kinase (PI3K), leading to inhibition of its lipid kinase activity. Importantly, we found that p42 induces protein degradation of the p85 subunit and further identified HSP70/CHIP complex as a novel E3 ligase for p85 that is responsible for p85 ubiquitination and degradation. In this process, p42 couples p85 to the HSP70/CHIP-mediated ubiquitin-proteasomal system (UPS), thereby promoting a reduction of p85 levels both in vitro and in vivo. Thus, the tumor-suppressing effects of p42 in cancer cells are driven by negative regulation of the p85 subunit of PI3K.
Background. Vitamin D, an important modulator of the immune system, has been shown to protect mucosal barrier homeostasis. This study investigates the effects of vitamin D deficiency on ...infection-induced changes in intestinal epithelial barrier function in vitro and on Citrobacter rodentium–induced colitis in mice. Methods. Polarized epithelial Caco2-bbe cells were grown in medium with or without vitamin D and challenged with enterohemorrhagic Escherichia coli O157:H7. Barrier function and tight junction protein expression were assessed. Weaned C57BL/6 mice were fed either a vitamin D-sufficient or vitamin D-deficient diet and then infected with C. rodentium. Disease severity was assessed by histological analysis, intestinal permeability assay, measurement of inflammatory cytokine levels, and microbiome analysis. Results. 1,25(OH)₂D₃ altered E. coli O157:H7-induced reductions in transepithelial electrical resistance (P<.01), decreased permeability (P<.05), and preserved barrier integrity. Vitamin D-deficient mice challenged with C. rodentium demonstrated increased colonic hyperplasia and epithelial barrier dysfunction (P<.0001 and P<.05, respectively). Vitamin D deficiency resulted in an altered composition of the fecal microbiome both in the absence and presence of C. rodentium infection. Conclusions. This study demonstrates that vitamin D is an important mediator of intestinal epithelial defenses against infectious agents. Vitamin D deficiency predisposes to more-severe intestinal injury in an infectious model of colitis.
Rationale
Flexible behavior optimization relies on cognitive control which includes the ability to suppress automatic responses interfering with relevant goals. Extensive evidence suggests that the ...anterior cingulate cortex (ACC) is the central node in a predominantly frontal cortical network subserving executive tasks. Neuroimaging studies indicate that the ACC is sensitive to acute intoxication during conflict, but such evidence is limited to tasks using manual responses with arbitrary response contingencies.
Objectives
The present study was designed to examine whether alcohol's effects on top–down cognitive control would generalize to the oculomotor system during inhibition of hardwired saccadic responses.
Methods
Healthy social drinkers (
N
= 22) underwent functional magnetic resonance imaging (fMRI) scanning and eye movement tracking during alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. They performed visually guided prosaccades (PS) towards a target and volitional antisaccades (AS) away from it. To mitigate possible vasoactive effects of alcohol on the BOLD (blood oxygenation level-dependent) signal, resting perfusion was quantified with arterial spin labeling (ASL) and used as a covariate in the BOLD analysis.
Results
Saccadic conflict was subserved by a distributed frontoparietal network. However, alcohol intoxication selectively attenuated activity only in the ACC to volitional AS and erroneous responses.
Conclusions
This study provides converging evidence for the selective ACC vulnerability to alcohol intoxication during conflict across different response modalities and executive tasks, confirming its supramodal, high-level role in cognitive control. Alcohol intoxication may impair top–down regulative functions by attenuating the ACC activity, resulting in behavioral disinhibition and decreased self-control.
This study aims to explore the nature of GP-counsellor interaction during discussions of patients' mental health issues in primary care services. An ethnographic discourse analysis of audio-recorded ...GP-counsellor conversations and the participating counsellor's reflective accounts. Two participating GPs and one counsellor were recruited from a private medical clinic in Hong Kong. The GPs and the counsellor mainly discussed their patients' issues in terms of medication management, the counsellor's case conceptualization, the case management, knowledge transfer and acknowledging the partnership. During case discussions, both the GPs and the counsellor used a range of interactional strategies to clarify a patient's condition and treatment plans for mutual understanding. The GPs and the counsellor co-construct an insider discourse that covers a greater diversity of topics, including both medical and non-medical concerns. The research findings have implications for theory and practice, including the potential of ethnographic discourse analysis in understanding the features of participants' behavior and evaluating the effectiveness of communication in a particular setting, as well as the importance of exploring professionalized discourse during GP-counsellor communication in developing training programs aimed at enhancing staff awareness of effective IPC communication.
ABSTRACT The BESS-Polar Collaboration measured the energy spectra of cosmic-ray protons and helium during two long-duration balloon flights over Antarctica in 2004 December and 2007 December at ...substantially different levels of solar modulation. Proton and helium spectra probe the origin and propagation history of cosmic rays in the galaxy, and are essential to calculations of the expected spectra of cosmic-ray antiprotons, positrons, and electrons from interactions of primary cosmic-ray nuclei with the interstellar gas, and to calculations of atmospheric muons and neutrinos. We report absolute spectra at the top of the atmosphere for cosmic-ray protons in the kinetic energy range 0.2-160 GeV and helium nuclei in the range 0.15-80 GeV/nucleon. The corresponding magnetic-rigidity ranges are 0.6-160 GV for protons and 1.1-160 GV for helium. These spectra are compared to measurements from previous BESS flights and from ATIC-2, PAMELA, and AMS-02. We also report the ratio of the proton and helium fluxes from 1.1 to 160 GV and compare this to the ratios from PAMELA and AMS-02.
Carbon nanotubes (CNT) have received considerable interest in many industries, but composite coatings of CNTs have not yet been sufficiently developed for use in biomedical implants. This ...investigation elucidates the wear and corrosion behavior of electroplated Ni/CNT composite coatings on Ti–6Al–4V alloy in Hanks’ solution. Experimental results indicate that the CNTs in an electroplated Ni/CNT composite coating increase its hardness to 98.5% higher than that of a pure Ni coating. Additionally, an Ni/CNT composite coating can form stable and dense passive film, which significantly improves wear and corrosion in Hanks′ solution.
► In this work, Ni–CNTs composite coatings were successfully deposited on a Ti–6Al–4V alloy substrate by electrodeposition. ► The CNTs were uniformly dispersed in the nickel matrix, causing particle dispersion to strengthen the composite coatings. ► The hardness of the Ni–CNTs composite coatings increased when the CNTs concentration in the electrolyte increased. ► Incorporating CNTs in Ni coating that was electroplated on Ti–6Al–4V alloy yielded in a stable and dense passive film by increasing pitting potential. This effect significantly improved wear and corrosion resistance in Hanks’ solution.
GEROS-ISS stands for GNSS REflectometry, radio occultation, and scatterometry onboard the International Space Station (ISS). It is a scientific experiment, successfully proposed to the European Space ...Agency in 2011. The experiment as the name indicates will be conducted on the ISS. The main focus of GEROS-ISS is the dedicated use of signals from the currently available Global Navigation Satellite Systems (GNSS) in L-band for remote sensing of the Earth with a focus to study climate change. Prime mission objectives are the determination of the altimetric sea surface height of the oceans and of the ocean surface mean square slope, which is related to sea roughness and wind speed. These geophysical parameters are derived using reflected GNSS signals (GNSS reflectometry, GNSS-R). Secondary mission goals include atmosphere/ionosphere sounding using refracted GNSS signals (radio occultation, GNSS-RO) and remote sensing of land surfaces using GNSS-R. The GEROS-ISS mission objectives and its design, the current status, and ongoing activities are reviewed and selected scientific and technical results of the GEROS-ISS preparation phase are described.
The embryoid body test (EBT) is a developmental toxicity test method that measures the size of embryoid bodies (EBs) and the viability of mouse embryonic stem cells (mESCs) and fibroblasts (3T3 ...cells). The previous pre-validation study confirmed the high accuracy (above 80%) of EBT using 26 coded test chemicals. This second-phase validation study assessed the inter-laboratory reproducibility (5 chemicals in common) and predictive capacity (10 chemicals in each laboratory) test using the coded test chemicals at three laboratories. For the prediction model, the accuracy is increased when more data is accumulated. Therefore, we updated the prediction model and analyzed the results of the second year with the newly created-prediction model. Statistical analysis of the inter-laboratory reproducibility test results indicated that accuracy, sensitivity, and specificity were 87%, 78%, and 100%, respectively. The results of the statistical analysis of the predictive capacity test showed an accuracy of 80%, sensitivity of 78%, and specificity of 81%. In conclusion, the EBT can accurately classify various embryotoxicants within a short period and with relatively little effort. Therefore, EBT can be used as a good way to test developmental toxicity.
Multiple studies have shown conflicting results on the correlation between the EGFR T790M quantitative level and survival outcomes in osimertinib-treated patients. We sought to validate such ...correlations using data from an osimertinib early access programme (EAP) providing access for metastatic non-small cell lung cancer patients with limited treatment options.
This observational, multicentre, retrospective analysis included EAP participants who received osimertinib until disease progression, intolerable toxicities or death. Digital droplet polymerase chain reaction-based quantitative plasma genotyping was carried out upon disease progression and data were analysed to explore the relationships between T790M mutant allele fraction (MAF), T790M copy number, MAF ratio and post-osimertinib overall survival. Real-world treatment outcomes and safety were also evaluated.
Data from 156 EAP participants were analysed (median follow-up 37.7 months). The median age was 62 years, 62.2% were women, 79.5% were never-smokers, 60.9% had Eastern Cooperative Oncology Group performance status 0/1. In patients with available plasma data (n = 114), T790M MAF (%) showed no significant relationships with overall survival (hazard ratio 1.02; 95% confidence interval 0.99–1.04) or time to treatment discontinuation (TTD) (hazard ratio 1.01; 95% confidence interval 0.98–1.04). Absolute T790M copy number and T790M to activating EGFR mutation MAF ratio also showed no prognostic value. The investigator-assessed response rate was 42.3% and the disease control rate was 85.5%. The median TTD was 15.8 (95% confidence interval 12.5–18.5) months and the median overall survival was 22.3 (95% confidence interval 18.6–26.1) months.
T790M MAF did not correlate with TTD or overall survival in this EAP cohort but limitations should not be overlooked. Observed survival outcomes and the toxicity profile were consistent with data from other real-world series.
•Quantitative measurements of EGFR T790M have been suggested to correlate with osimertinib treatment outcomes but findings are conflicting.•No correlation with duration of post-osimertinib survival or time on treatment was found for various T790M quantitative measurements.•Pre-treatment plasma T790M quantitative measurements showed no prognostic role in this cohort, but survival and toxicities observed were consistent with other real-world series.•Very low plasma T790M MAF should not exclude patients from consideration for osimertinib treatment.
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