The Sarin-like Organophosphorus Agent bis(isopropyl methyl)phosphonate Induces Apoptotic Cell Death and COX-2 Expression in SK-N-SH Cells

Organophosphorus compounds, such as sarin, are highly toxic nerve agents that inhibit acetylcholinesterase (AChE), but not cholinesterase, via multiple mechanisms. Recent studies have shown that organophosphorus compounds increase cyclooxygenase-2 (COX-2) expression and induce neurotoxicity. In this study, we examined the toxicity of the sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate (BIMP) and the effects of BIMP on COX-2 expression in SK-N-SH human neuroblastoma cells. Exposure to BIMP changed cell morphology and induced caspase-dependent apoptotic cell death accompanied by cleavage of caspase 3, caspase 9, and poly (ADP-ribose) polymerase (PARP). It also increased COX-2 expression, while pretreatment with a COX inhibitor, ibuprofen, decreased BIMP-dependent cell death and COX-2 expression in SK-N-SH cells. Thus, our findings suggest that BIMP induces apoptotic cell death and upregulates COX-2 expression

Autopsy Findings Involving Murderous Intent: Comparison between Positive and Negative Murderous Intent Cases in Japan

The presence or absence of murderous intent is an important fact during criminal trials. To verify autopsy findings that were considered as evidence of murderous intent, we compared autopsy findings in homicide cases committed with and without murderous intent (n = 12 and n = 11, respectively). Although the number of wounds may only be limited to one or two, stab wounds on the trunk of the body from a sharp instrument can be a significant evidence of murderous intent. Bruise or petechial haemorrhage at the back or limbs caused by blunt instruments or without any weapons do not indicate the presence of murderous intent. Although results in this study should be carefully interpreted in other jurisdictions, statistical analysis comparing cases with and without murderous intents might be a valuable methodology to understand autopsy findings involving murderous intent in Japan

Euglena gracilis-derived β-glucan paramylon entrains the peripheral circadian clocks in mice

Paramylon, a β-1,3-glucan storage polysaccharide derived from Euglena gracilis, has various health benefits, such as anti-obesity effects and modulation of immune function. However, whether paramylon intake affects the circadian clock remains unknown. In this study, we examined the effect of paramylon intake on the circadian clock. The results showed that the paramylon intake regulated peripheral clocks in mice. Furthermore, cecal pH and short-chain fatty acid concentrations after paramylon intake were measured. The correlation between changes in the expression of clock-related genes and alterations in the intestinal environment was confirmed. In addition, peripheral clock entrainment by paramylon intake was not observed in antibiotic-treated mice whose gut microbiota was weakened. These findings suggest that the regulation of the circadian clock by paramylon intake was mediated by changes in gut microbiota. In addition, the entraining effect of paramylon intake was also confirmed in mice bred under conditions mimicking social jetlag, which implies that paramylon intake may contribute to recovery from social jetlag. Thus, the appropriate consumption of paramylon may have a beneficial effect on health from a chrono-nutritional perspective

Dust from Comet 209P/LINEAR during its 2014 Return: Parent Body of a New Meteor Shower, the May Camelopardalids

We report a new observation of the Jupiter-family comet 209P/LINEAR during its 2014 return. The comet is recognized as a dust source of a new meteor shower, the May Camelopardalids. 209P/LINEAR was apparently inactive at a heliocentric distance rh = 1.6 au and showed weak activity at rh < 1.4 au. We found an active region of <0.001% of the entire nuclear surface during the comet's dormant phase. An edge-on image suggests that particles up to 1 cm in size (with an uncertainty of factor 3-5) were ejected following a differential power-law size distribution with index q=-3.25+-0.10. We derived a mass loss rate of 2-10 kg/s during the active phase and a total mass of ~5x10^7 kg during the 2014 return. The ejection terminal velocity of millimeter- to centimeter-sized particles was 1-4 m/s, which is comparable to the escape velocity from the nucleus (1.4 m/s). These results imply that such large meteoric particles marginally escaped from the highly dormant comet nucleus via the gas drag force only within a few months of the perihelion passage.Comment: 18 pages, 4 figures, accepted on 2014 December 11 for publication in the Astrophysical Journal Letter

Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth

Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3−/−) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3−/−, in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3−/−, compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3−/−. These results demonstrate significance of host stromal PGE2-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors

Towards HCP-Style macaque connectomes: 24-Channel 3T multi-array coil, MRI sequences and preprocessing

© 2020 The Author(s) Macaque monkeys are an important animal model where invasive investigations can lead to a better understanding of the cortical organization of primates including humans. However, the tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the smaller macaque brain, high spatial, temporal, and angular resolutions combined with high signal-to-noise ratio are required to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. This coil enables adaptation of the Human Connectome Project (HCP) image acquisition protocols to the in-vivo macaque brain. In addition, we adapted HCP preprocessing methods to the macaque brain, including spatial minimal preprocessing of structural, functional MRI (fMRI), and diffusion MRI (dMRI). The coil provides the necessary high signal-to-noise ratio and high efficiency in data acquisition, allowing four- and five-fold accelerations for dMRI and fMRI. Automated FreeSurfer segmentation of cortex, reconstruction of cortical surface, removal of artefacts and nuisance signals in fMRI, and distortion correction of dMRI all performed well, and the overall quality of basic neurobiological measures was comparable with those for the HCP. Analyses of functional connectivity in fMRI revealed high sensitivity as compared with those from publicly shared datasets. Tractography-based connectivity estimates correlated with tracer connectivity similarly to that achieved using ex-vivo dMRI. The resulting HCP-style in vivo macaque MRI data show considerable promise for analyzing cortical architecture and functional and structural connectivity using advanced methods that have previously only been available in studies of the human brain

Roles of Protease-Activated Receptor-2 in Atherogenesis

Background: The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X (FXa), are expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. Methods: We generated apolipoprotein E-deficient (ApoE-/-) mice lacking systemic PAR-2 expression (PAR-2-/-ApoE-/-). ApoE-/- mice which lack or express PAR-2 only in bone-marrow (BM) cells were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a western-type diet (WTD) by histological analyses, quantitative RT-PCR, and western blotting. In vitro experiments using BM-derived macrophages were performed to confirm pro-inflammatory roles of PAR-2. The association between plasma FXa level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention. Results: PAR-2-/-ApoE-/- mice showed reduced atherosclerotic lesions in the aortic arch (P<0.05) along with features of stabilized atherosclerotic plaques such as less lipid deposition (P<0.05), collagen loss (P<0.01), macrophage accumulation (P<0.05), and inflammatory molecule expression (P<0.05) compared with ApoE-/- mice. Systemic PAR2 deletion in ApoE-/- mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in ApoE-/- mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that FXa or a specific peptide agonist of PAR-2 significantly increased expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2-deficient mice. Activation of NF-κB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma FXa level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score (P<0.05) and plaque volume (P<0.01). Conclusions: PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE-/- mice. This signaling pathway may also participate in atherogenesis in humans

肥満によって遊離する脂肪細胞由来のDNA断片が脂肪組織の炎症とインスリン抵抗性を引き起こす

Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance