Activation of p53 as a causal step for atherosclerosis induced by polycyclic aromatic hydrocarbons

AbstractThis study was performed to prove our hypothesis that the metabolite(s) of polycyclic aromatic hydrocarbons (PAHs) caused the activation or phosphorylation of p53 via DNA damage to suppress the liver X receptor (LXR)-mediated signal transductions as a probably more direct mechanism. We found that LXR-mediated trans-activation was inhibited by 3-methylchoranthrene (MC) and doxorubicin (Dox) in HepG2 cells carrying wild-type p53, but not in Hep3B cells possessing mutant p53. The exogenous expression of wild-type p53 suppressed the LXR-mediated trans-activation in Hep3B cells. The expression of mRNA for ATP binding cassette A1 was suppressed by MC and Dox in HepG2 cells. The protein expression of retinoid X receptor (RXR), a partner of LXR to form a heterodimer, was suppressed by MC and Dox in HepG2 cells

Estimating the dopant distribution in Ca-doped alpha-SiAlON: statistical HAADF-STEM analysis and large-scale atomic modeling

We investigated the dopant distribution in Ca-doped alpha-SiAlON by using high-angle annular dark-field scanning transmission electron microscopy and a multi-slice image simulation. Our results showed that the electron wave propagated by hopping to adjacent Si(Al) and N(O) columns. The image intensities of the Ca columns had wider dispersions than other columns. To estimate the Ca distribution in the bulk material, we performed a Monte Carlo atomic simulation of the alpha-SiAlON with Ca dopants. A model including a short-range Coulomb-like repulsive force between adjacent Ca atoms reproduced the dispersion of the intensity distribution of the Ca column in the experimental image

Study of laser frequency stability from the observed vertical wind velocity by the Na lidar at Troms*

The Tenth Symposium on Polar Science/Ordinary sessions: [OS] Space and upper atmospheric sciences, Wed. 4 Dec. /Entrance Hall (1st floor) at National Institute of Polar Research (NIPR

The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus.

Because a rank-ordered recruitment of motor units occurs during isometric contraction of jaw-closing muscles, jaw-closing motoneurons (MNs) may be recruited in a manner dependent on their soma sizes or input resistances (IRs). In the dorsolateral part of the trigeminal motor nucleus (dl-TMN) in rats, MNs abundantly express TWIK (two-pore domain weak inwardly rectifying K channel)-related acid-sensitive-K(+) channel (TASK)-1 and TASK3 channels, which determine the IR and resting membrane potential. Here we examined how TASK channels are involved in IR-dependent activation/recruitment of MNs in the rat dl-TMN by using multiple methods. The real-time PCR study revealed that single large MNs (>35 μm) expressed TASK1 and TASK3 mRNAs more abundantly compared with single small MNs (15-20 μm). The immunohistochemistry revealed that TASK1 and TASK3 channels were complementarily distributed in somata and dendrites of MNs, respectively. The density of TASK1 channels seemed to increase with a decrease in soma diameter while there were inverse relationships between the soma size of MNs and IR, resting membrane potential, or spike threshold. Dual whole-cell recordings obtained from smaller and larger MNs revealed that the recruitment of MNs depends on their IRs in response to repetitive stimulation of the presumed Ia afferents. 8-Bromoguanosine-cGMP decreased IRs in small MNs, while it hardly changed those in large MNs, and subsequently decreased the difference in spike-onset latency between the smaller and larger MNs, causing a synchronous activation of MNs. These results suggest that TASK channels play critical roles in rank-ordered recruitment of MNs in the dl-TMN

A case of severe eosinophilic asthma and refractory rheumatoid arthritis well controlled by combination of IL-5Rα antibody and TNFα inhibitor

Letter to the Edito

A statistical study of convective and dynamic instabilities in the polar upper mesosphere above Tromsø

We have studied the convective (or static) and dynamic instabilities between 80 and 100 km above Tromsø (69.6° N, 19.2° E) using temperature and wind data of 6 min and 1 km resolutions primarily almost over a solar cycle obtained with the sodium lidar at Tromsø. First, we have calculated Brunt–Väisälä frequency (N) for 339 nights obtained from October 2010 to December 2019, and the Richardson number (Ri) for 210 nights obtained between October 2012 to December 2019. Second, using those values (N and Ri), we have calculated probabilities of the convective instability (N2<0) and the dynamic instability (0≤Ri<0.25) that can be used for proxies for evaluating the atmospheric stability. The probability of the convective instability varies from about 1% to 24% with a mean value of 9%, and that of the dynamic instability varies from 4 to 20% with a mean value of 10%. Third, we have compared these probabilities with the F10.7 index and local K-index. The probability of the convective instability shows a dependence (its correlation coefcient of 0.45) of the geomagnetic activity (local K-index) between 94 and 100 km, suggesting an auroral infuence on the atmospheric stability. The probability of the dynamic instability shows a solar cycle dependence (its correlation coefcient being 0.54). The probability of the dynamic instability shows the dependence of the 12 h wave amplitude (meridional and zonal wind components) (C.C.=0.52). The averaged potential energy of gravity waves shows decrease with height between 81 and 89 km, suggesting that dissipation of gravity waves plays an important role (at least partly) in causing the convective instability below 89 km. The probability of the convective instability at Tromsø appears to be higher than that at middle/low latitudes, while the probability of the dynamic instability is similar to that at middle/low latitudes

Study on the reusability of fluorescent nuclear track detectors using optical bleaching

Fluorescent nuclear track detectors (FNTDs) based on Al${_2}$O${_3}$:C,Mg crystals are luminescent detectors that can be used for dosimetry and detection of charged particles and neutrons. These detectors can be utilised for imaging applications where a reasonably high track density, approximately of the order of 1 $\times$ $10^4$ tracks in an area of 100 $\times$ 100 $\mu$m$^2$, is required. To investigate the reusability of FNTDs for imaging applications, we present an approach to perform optical bleaching under the required track density conditions. The reusability was assessed through seven irradiation-bleaching cycles. For the irradiation, the studied FNTD was exposed to alpha-particles from an $^{241}$Am radioactive source. The optical bleaching was performed by means of ultraviolet laser light with a wavelength of 355 nm. Three dedicated regions on a single FNTD with different accumulated track densities and bleaching conditions were investigated. After every irradiation-bleaching cycle, signal-to-noise ratio was calculated to evaluate FNTD performance. It is concluded that FNTDs can be reused at least seven times for applications where accumulation of a high track density is required

A case of a pulmonary artery sling misdiagnosed as refractory asthma for 20 years

We report the case of a 25-year-old woman with a pulmonary artery sling who was misdiagnosed as having childhood-onset refractory asthma for approximately 20 years. The use of computed tomography may be useful for diagnosing this rare condition

A multicenter randomized controlled trial to evaluate the efficacy and safety of nelfinavir in patients with mild COVID-19

Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms