Immunopharmacological properties of Oren-gedoku-to (a Kampo medicine, Huang-Lian-Jie-Du-Tang) on contact hypersensitivity reaction in mice

We investigated the effects of Oren-gedoku-to (Huang-Lian-Jie-Du-Tang), a Kampo medicine, on DNFB-induced contact hypersensitivity (CHS) response in mice in order to further clarify the immunopharmacological properties of this formulation. 1) Administration of Oren-gedoku-to decreased the magnitude of ear swelling in the CHS response and shortened the affected period. The inhibitory effect on ear swelling was observed even when Oren-gedoku-to was given orally with different timing schedules. 2) The expressions of mRNAs for CD8, IFN-7 and TNF-α in the ear of Oren-gedoku-to-treated mice were markedly decreased 24 h after the challenge. 3) The number of skin-draining regional lymph node cells (LNCs), CD4^+ T cells and CD8^+ T cells was decreased without affecting the ratio of CD8^+/CD4^+ T cells. 4) Oren-gedoku-to resulted in a marked impairment of the hapten-specific development of LNCs. These results suggest that the suppressive effect of Oren-gedoku-to on ear swelling was partly caused by the suppression of lymphocyte proliferation. 接触過敏反応(CHS)に対する黄連解毒湯の抑制効果について検討した。1g/kgの黄連解毒湯を感作日より連続投与することで,DNFB塗布による耳介の腫脹は軽減し,その持続時間も短縮した。また,黄連解毒湯の投与期間を変更(感作後0-2日間あるいは4-6日間の投与)しても抑制効果が認められた。耳介局所では,黄連解毒湯の連続投与により,CD8,IFN-γおよびTNF-αのmRNA発現は減弱した。所属リンパ節では,全リンパ節細胞,CD8^+T細胞,CD4^+T細胞の数が減少したが,CD8/CD4比に変化はみられなかった。さらに,リンパ節細胞のハプテン特異的な増殖能は抑制された。以上の結果より,黄連解毒湯のCHSの抑制効果にハプテン特異的リンパ球の増殖抑制が関与していると考えられた

Caenorhabditis elegans ortholog of the p24/p22 subunit, DNC-3, is essential for the formation of the dynactin complex by bridging DNC-1/p150Glued and DNC-2/dynamitin

Dynactin is a multisubunit protein complex required for the activity of cytoplasmic dynein. In Caenorhabditis elegans, although 10 of the 11 dynactin subunits were identified based on the sequence similarities to their orthologs, the p24/p22 subunit has not been detected in the genome. Here, we demonstrate that DNC-3 (W10G11.20) is the functional counterpart of the p24/p22 subunit in C. elegans. RNAi phenotypes and subcellular localization of DNC-3 in early C. elegans embryos were nearly identical to those of the known dynactin components. All other dynactin subunits were co-immunoprecipitated with DNC-3, indicating that DNC-3 is a core component of dynactin. Furthermore, the overall secondary structure of DNC-3 resembles to those of the mammalian and yeast p24/p22. We found that DNC-3 is required for the localization of the DNC-1/p150Glued and DNC-2/dynamitin, the two components of the projection arm of dynactin, to the nuclear envelope of meiotic nuclei in the adult gonad. Moreover, DNC-3 physically interacted with DNC-1 and DNC-2 and significantly enhanced the binding ability between DNC-1 and DNC-2 in vitro. These results suggest that DNC-3 is essential for the formation of the projection arm subcomplex of dynactin

A Proteomic Approach for the Diagnosis of ‘Oketsu’ (blood stasis), a Pathophysiologic Concept of Japanese Traditional (Kampo) Medicine

‘Oketsu’ is a pathophysiologic concept in Japanese traditional (Kampo) medicine, primarily denoting blood stasis/stagnant syndrome. Here we have explored plasma protein biomarkers and/or diagnostic algorithms for ‘Oketsu’. Sixteen rheumatoid arthritis (RA) patients were treated with keishibukuryogan (KBG), a representative Kampo medicine for improving ‘Oketsu’. Plasma samples were diagnosed as either having an ‘Oketsu’ (n = 19) or ‘non-Oketsu’ (n = 29) state according to Terasawa's ‘Oketsu’ scoring system. Protein profiles were obtained by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) and hierarchical clustering and decision tree analyses were performed. KBG treatment for 4 or 12 weeks decreased the ‘Oketsu’ scores significantly. SELDI protein profiles gave 266 protein peaks, whose expression was significantly different between the ‘Oketsu’ and ‘non-Oketsu’ states. Hierarchical clustering gave three major clusters (I, II, III). The majority (68.4%) of ‘Oketsu’ samples were clustered into one cluster as the principal component of cluster I. The remaining ‘Oketsu’ profiles constituted a minor component of cluster II and were all derived from patients cured of the ‘Oketsu’ state at 12 weeks. Construction of the decision tree addressed the possibility of developing a diagnostic algorithm for ‘Oketsu’. A reduction in measurement/pre-processing conditions (from 55 to 16) gave a similar outcome in the clustering and decision tree analyses. The present study suggests that the pathophysiologic concept of Kampo medicine ‘Oketsu’ has a physical basis in terms of the profile of blood proteins. It may be possible to establish a set of objective criteria for diagnosing ‘Oketsu’ using a combination of proteomic and bioinformatics-based classification methods

Liquid biopsy for patients with IBD-associated neoplasia

Background It is often difficult to diagnose inflammatory bowel disease (IBD)-associated neoplasia endoscopically due to background inflammation. In addition, due to the absence of sensitive tumor biomarkers, countermeasures against IBD-associated neoplasia are crucial. The purpose of this study is to develop a new diagnostic method through the application of liquid biopsy. Methods Ten patients with IBD-associated cancers and high-grade dysplasia (HGD) with preserved tumor tissue and blood were included. Tumor and non-tumor tissues were analyzed for 48 cancer-related genes using next-generation sequencing. Simultaneously, circulating tumor DNA (ctDNA) was analyzed for mutations in the target genes using digital PCR. Results Out of 10 patients, seven had IBD-related cancer and three had IBD-related HGD. Two patients had carcinoma in situ; moreover, three had stageII and two had stage III. To avoid false positives, the mutation rate cutoff was set at 5% based on the control results; seven of 10 (70%) tumor tissue samples were mutation-positive. Mutation frequencies for each gene were as follows: TP53 (20.9%; R136H), TP53 (25.0%; C110W), TP53 (8.5%; H140Q), TP53 (31.1%; R150W), TP53 (12.8%; R141H), KRAS (40.0%; G12V), and PIK3CA (34.1%; R 88Q). The same mutations were detected in the blood of these seven patients. However, no mutations were detected in the blood of the remaining three patients with no tumor tissue mutations. The concordance rate between tumor tissue DNA and blood ctDNA was 100%. Conclusion Blood liquid biopsy has the potential to be a new method for non-invasive diagnosis of IBD-associated neoplasia

Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA

Background and Aim Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. Methods Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. Results Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were −124bp G > A and 10 were −146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des‐gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P Conclusions TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC

Novel Anti-Obesity Properties of Palmaria mollis in Zebrafish and Mouse Models

(1) Background: The red seaweed Palmaria mollis (PM), which has a bacon-like taste, is increasingly being included in Western diets. In this study, we evaluate anti-obesity effects of PM using diet-induced obese (DIO) zebrafish and mice models. (2) Methods: We fed PM-containing feed to DIO-zebrafish and mice, and evaluated the anti-obesity effects We also analyzed gene expression changes in their liver and visceral adipose tissues (VAT). (3) Results: PM ameliorated several anti-obesity traits in both animals, including dyslipidaemia, hepatic steatosis, and visceral adiposity. In liver tissues of DIO-zebrafish and mice, PM upregulated gene expressions involved in peroxisome proliferator-activated receptor alpha (PPARA) pathways, and downregulated peroxisome proliferator-activated receptor gamma (PPARG) pathways, suggesting that the lipid-lowering effect of PM might be caused by activation of beta-oxidation and inhibition of lipogenesis. In VAT, PM downregulated genes involved in early and late adipocyte differentiation in zebrafish, but not in mice. (4) Conclusions: We have demonstrated that PM can prevent hepatic steatosis and visceral adiposity for the first time. Dietary supplementation of PM as a functional food may be suitable for obesity prevention and reduction in the prevalence of obesity-related diseases

GEOTAIL observation of the SGR1806-20 Giant Flare: The first 600 ms

On December 27, 2004, plasma particle detectors on the GEOTAIL spacecraft detected an extremely strong signal of hard X-ray photons from the giant flare of SGR1806-20, a magnetar candidate. While practically all gamma-ray detectors on any satellites were saturated during the first ~500 ms interval after the onset, one of the particle detectors on GEOTAIL was not saturated and provided unique measurements of the hard X-ray intensity and the profile for the first 600 ms interval with 5.48 ms time resolution. After ~50 ms from the initial rapid onset, the peak photon flux (integrated above ~50 keV) reached the order of 10^7 photons sec^{-1} cm^{-2}. Assuming a blackbody spectrum with kT=175 keV, we estimate the peak energy flux to be 21 erg sec^{-1} cm^{-2} and the fluence (for 0-600 ms) to be 2.4 erg cm^{-2}. The implied energy release comparable to the magnetic energy stored in a magnetar (~10^{47} erg) suggests an extremely efficient energy release mechanism.Comment: 6 pages, 2 color figures, submitted to Natur

Hyper Suprime-Cam Year 3 Results: Cosmology from Cosmic Shear Two-point Correlation Functions

We perform a blinded cosmology analysis with cosmic shear two-point correlation functions (2PCFs) measured from more than 25 million galaxies in the Hyper Suprime-Cam three-year shear catalog in four tomographic redshift bins ranging from 0.3 to 1.5. After conservative masking and galaxy selection, the survey covers 416 deg$^2$ of the northern sky with an effective galaxy number density of 15 arcmin$^{-2}$ over the four redshift bins. The 2PCFs adopted for cosmology analysis are measured in the angular range: $7.1 < \theta/{\rm arcmin} < 56.6$ for $\xi_+$ and $31.2 <\theta/{\rm arcmin} < 248$ for $\xi_-$, with a total signal-to-noise ratio of 26.6. We apply a conservative, wide, flat prior on the photometric redshift errors on the last two tomographic bins, and the relative magnitudes of the cosmic shear amplitude across four redshift bins allow us to calibrate the photometric redshift errors. With this flat prior on redshift errors, we find $\Omega_{\rm m}=0.256_{-0.044}^{+0.056}$ and $S_8\equiv \sigma_8 \sqrt{\Omega_{\rm m}/0.3}=0.769_{-0.034}^{+0.031}$ (both 68\% CI) for a flat $\Lambda$ cold dark matter cosmology. We find, after unblinding, that our constraint on $S_8$ is consistent with the Fourier space cosmic shear and the 3$\times$2pt analyses on the same HSC dataset. We carefully study the potential systematics from astrophysical and systematic model uncertainties in our fiducial analysis using synthetic data, and report no biases (including projection bias in the posterior space) greater than $0.5\sigma$ in the estimation of $S_8$. Our analysis hints that the mean redshifts of the two highest tomographic bins are higher than initially estimated. In addition, a number of consistency tests are conducted to assess the robustness of our analysis. Comparing our result with Planck-2018 cosmic microwave background observations, we find a ~$2\sigma$ tension for the $\Lambda$CDM model.Comment: 38 pages, 32 figures, 4 tables (PRD in press.

Hitomi X-Ray Studies of Giant Radio Pulses from the Crab Pulsar

To search for giant X-ray pulses correlated with the giant radio pulses (GRPs) from the Crab pulsar, we performed a simultaneous observation of the Crab pulsar with the X-ray satellite Hitomi in the 2300 keV band and the Kashima NICT radio telescope in the 1.41.7 GHz band with a net exposure of about 2 ks on 2016 March 25, just before the loss of the Hitomi mission. The timing performance of the Hitomi instruments was confirmed to meet the timing requirement and about 1000 and 100 GRPs were simultaneously observed at the main pulse and inter-pulse phases, respectively, and we found no apparent correlation between the giant radio pulses and the X-ray emission in either the main pulse or inter-pulse phase. All variations are within the 2 fluctuations of the X-ray fluxes at the pulse peaks, and the 3 upper limits of variations of main pulse or inter-pulse GRPs are 22% or 80% of the peak flux in a 0.20 phase width, respectively, in the 2300 keV band. The values for main pulse or inter-pulse GRPs become 25% or 110%, respectively, when the phase width is restricted to the 0.03 phase. Among the upper limits from the Hitomi satellite, those in the 4.510 keV and 70300 keV bands are obtained for the first time, and those in other bands are consistent with previous reports. Numerically, the upper limits of the main pulse and inter-pulse GRPs in the 0.20 phase width are about (2.4 and 9.3) 10(exp 11) erg cm(exp 2), respectively. No significant variability in pulse profiles implies that the GRPs originated from a local place within the magnetosphere. Although the number of photon-emitting particles should temporarily increase to account for the brightening of the radio emission, the results do not statistically rule out variations correlated with the GRPs, because the possible X-ray enhancement may appear due to a >0.02% brightening of the pulse-peak flux under such conditions

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation