Enhanced expression of interferon-inducible protein 10 associated with Th1 profiles of chemokine receptor in autoimmune pulmonary inflammation of MRL/lpr mice

MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop systemic lupus erythematosus (SLE)-like disease. The natural history of the pulmonary involvement and the underlying mechanism of leukocyte infiltration into the lungs of MRL/lpr mice and SLE patients remains elusive. We aimed to investigate the expression profiles of chemokines and chemokine receptors in the lung of the SLE-prone mouse. We examined the correlation between lung inflammation and expression of IP-10 (interferon-γ-inducible protein 10), a CXC chemokine, and TARC (thymus- and activation-regulated chemokine), a CC chemokine, in MRL/lpr mice, MRL/Mp-+/+ (MRL/+) mice, and C57BL/6 (B6) control mice. The extent of cell infiltration in the lung was assessed histopathologically. Reverse transcriptase PCR showed up-regulation of IP-10 mRNA expression in the lungs (P < 0.05) of MRL/lpr mice, in comparison with MRL/+ or B6 mice. The increase paralleled increased expression of a specific IP-10 receptor, CXCR3, and correlated with the degree of infiltration of mononuclear lymphocytes. In contrast, lung expression of TARC and its specific receptor, CCR4, were suppressed in MRL/lpr mice. Immunohistology showed that macrophage-like cells were the likely source of IP-10. Flow cytometric analyses revealed that the CXCR3-expressing cells were mainly infiltrating CD4 T cells and macrophages, which correlated with the degree of mononuclear lymphocyte infiltration. Recent data suggest that Th1 cells and Th1-derived cytokines play an important role in the development of SLE-like disease in MRL/lpr mice. Our results suggest that IP-10 expression in the lung is involved, through CXCR3, in the pathogenesis of pulmonary inflammation associated with migration of Th1 cells

RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy

Cutaneous malignant melanoma is one of the most serious skin cancers and is highly invasive and markedly resistant to conventional therapy. Melanomagenesis is initially triggered by environmental agents including ultraviolet (UV), which induces genetic/epigenetic alterations in the chromosomes of melanocytes. In human melanomas, the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways are two major signaling pathways and are constitutively activated through genetic alterations. Mutations of RAF, RAS, and PTEN contribute to antiapoptosis, abnormal proliferation, angiogenesis, and invasion for melanoma development and progression. To find better approaches to therapies for patients, understanding these MAPK and AKT signaling mechanisms of melanoma development and progression is important. Here, we review MAPK and AKT signaling networks associated with melanoma development and progression

CO Multi-line Imaging of Nearby Galaxies (COMING). IX. 12^{12}CO(JJ=2-1)/12^{12}CO(JJ=1-0) line ratio on kiloparsec scales

While molecular gas mass is usually derived from $^{12}$CO($J$=1-0) - the most fundamental line to explore molecular gas - it is often derived from $^{12}$CO($J$=2-1) assuming a constant $^{12}$CO($J$=2-1)/$^{12}$CO($J$=1-0) line ratio ($R_{2/1}$). We present variations of $R_{2/1}$ and effects of the assumption that $R_{2/1}$ is a constant in 24 nearby galaxies using $^{12}$CO data obtained with the Nobeyama 45-m radio telescope and IRAM 30-m telescope. The median of $R_{2/1}$ for all galaxies is 0.61, and the weighted mean of $R_{2/1}$ by $^{12}$CO($J$=1-0) integrated-intensity is 0.66 with a standard deviation of 0.19. The radial variation of $R_{2/1}$ shows that it is high (~0.8) in the inner ~1 kpc while its median in disks is nearly constant at 0.60 when all galaxies are compiled. In the case that the constant $R_{2/1}$ of 0.7 is adopted, we found that the total molecular gas mass derived from $^{12}$CO($J$=2-1) is underestimated/overestimated by ~20%, and at most by 35%. The scatter of a molecular gas surface density within each galaxy becomes larger by ~30%, and at most by 120%. Indices of the spatially resolved Kennicutt-Schmidt relation by $^{12}$CO($J$=2-1) are underestimated by 10-20%, at most 39% in 17 out of 24 galaxies. $R_{2/1}$ has good positive correlations with star-formation rate and infrared color, and a negative correlation with molecular gas depletion time. There is a clear tendency of increasing $R_{2/1}$ with increasing kinetic temperature ($T_{\rm kin}$). Further, we found that not only $T_{\rm kin}$ but also pressure of molecular gas is important to understand variations of $R_{2/1}$. Special considerations should be made when discussing molecular gas mass and molecular gas properties inferred from $^{12}$CO($J$=2-1) instead of $^{12}$CO($J$=1-0).Comment: 29 pages, 18 figures, 5 tables. Accepted for publication in PASJ. The original resolution version is available here (https://astro3.sci.hokudai.ac.jp/~radio/coming/publications/COMING_IX_org_res.pdf

Molecular Network Associated with MITF in Skin Melanoma Development and Progression

Various environmental and genetic factors affect the development and progression of skin cancers including melanoma. Melanoma development is initially triggered by environmental factors including ultraviolet (UV) light, and then genetic/epigenetic alterations occur in skin melanocytes. These first triggers alter the conditions of numerous genes and proteins, and they induce and/or reduce gene expression and activate and/or repress protein stability and activity, resulting in melanoma progression. Microphthalmia-associated transcription factor (MITF) is a master regulator gene of melanocyte development and differentiation and is also associated with melanoma development and progression. To find better approaches to molecular-based therapies for patients, understanding MITF function in skin melanoma development and progression is important. Here, we review the molecular networks associated with MITF in skin melanoma development and progression

Alteration of FHR pattern and cerebral metabolic rate of glucose of the fetus measured by positron emission tomography during progress of acidemia. The significance of overshoot acceleration in FHR

Peer Reviewe

CO Multi-line Imaging of Nearby Galaxies (COMING). III. Dynamical effect on molecular gas density and star formation in the barred spiral galaxy NGC 4303

We present the results of $^{12}$CO($J$=1-0) and $^{13}$CO($J$=1-0) simultaneous mappings toward the nearby barred spiral galaxy NGC 4303 as a part of the CO Multi-line Imaging of Nearby Galaxies (COMING) project. Barred spiral galaxies often show lower star-formation efficiency (SFE) in their bar region compared to the spiral arms. In this paper, we examine the relation between the SFEs and the volume densities of molecular gas $n(\rm{H}_2)$ in the eight different regions within the galactic disk with CO data combined with archival far-ultraviolet and 24 $\mu$m data. We confirmed that SFE in the bar region is lower by 39% than that in the spiral arms. Moreover, velocity-alignment stacking analysis was performed for the spectra in the individual regions. The integrated intensity ratios of $^{12}$CO to $^{13}$CO ($R_{12/13}$) range from 10 to 17 as the results of stacking. Fixing a kinetic temperature of molecular gas, $n(\rm{H}_2)$ was derived from $R_{12/13}$ via non-local thermodynamic equilibrium (non-LTE) analysis. The density $n(\rm{H}_2)$ in the bar is lower by 31-37% than that in the arms and there is a rather tight positive correlation between SFEs and $n(\rm{H}_2)$, with a correlation coefficient of $\sim 0.8$. Furthermore, we found a dependence of $n(\rm{H}_2)$ on the velocity dispersion of inter-molecular clouds ($\Delta V/ \sin i$). Specifically, $n(\rm{H}_2)$ increases as $\Delta V/ \sin i$ increases when $\Delta V/ \sin i < 100$ km s$^{-1}$. On the other hand, $n(\rm{H}_2)$ decreases as $\Delta V/ \sin i$ increases when $\Delta V/ \sin i > 100$ km s$^{-1}$. These relations indicate that the variations of SFE could be caused by the volume densities of molecular gas, and the volume densities could be governed by the dynamical influence such as cloud-cloud collisions, shear and enhanced inner-cloud turbulence.Comment: 15 pages, 8 figures, accepted for publication in PAS

CO Multi-line Imaging of Nearby Galaxies (COMING) IV. Overview of the Project

Observations of the molecular gas in galaxies are vital to understanding the evolution and star-forming histories of galaxies. However, galaxies with molecular gas maps of their whole discs having sufficient resolution to distinguish galactic structures are severely lacking. Millimeter wavelength studies at a high angular resolution across multiple lines and transitions are particularly needed, severely limiting our ability to infer the universal properties of molecular gas in galaxies. Hence, we conducted a legacy project with the 45 m telescope of the Nobeyama Radio Observatory, called the CO Multi-line Imaging of Nearby Galaxies (COMING), which simultaneously observed 147 galaxies with high far-infrared flux in $^{12}$CO, $^{13}$CO, and C$^{18}$O $J=1-0$ lines. The total molecular gas mass was derived using the standard CO-to-H$_2$ conversion factor and found to be positively correlated with the total stellar mass derived from the WISE $3.4 \mu$m band data. The fraction of the total molecular gas mass to the total stellar mass in galaxies does not depend on their Hubble types nor the existence of a galactic bar, although when galaxies in individual morphological types are investigated separately, the fraction seems to decrease with the total stellar mass in early-type galaxies and vice versa in late-type galaxies. No differences in the distribution of the total molecular gas mass, stellar mass, and the total molecular gas to stellar mass ratio was observed between barred and non-barred galaxies, which is likely the result of our sample selection criteria, in that we prioritized observing FIR bright (and thus molecular gas-rich) galaxies.Comment: Accepted for publication in PASJ; 47 pages, 5 tables, 29 figures. On-line supplementary images are available at this URL (https://astro3.sci.hokudai.ac.jp/~radio/coming/publications/). CO data is available at the Japanese Virtual Observatory (JVO) website (https://jvo.nao.ac.jp/portal/nobeyama/coming.do) and the project website (https://astro3.sci.hokudai.ac.jp/~radio/coming/data/

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049