First observation of MeV gamma-ray universe with bijective imaging spectroscopy using the Electron-Tracking Compton Telescope aboard SMILE-2+

MeV gamma-rays provide a unique window for the direct measurement of line emissions from radioisotopes, but observations have made little significant progress after COMPTEL/{\it CGRO}. To observe celestial objects in this band, we are developing an electron-tracking Compton camera (ETCC), which realizes both bijective imaging spectroscopy and efficient background reduction gleaned from the recoil electron track information. The energy spectrum of the observation target can then be obtained by a simple ON-OFF method using a correctly defined point spread function on the celestial sphere. The performance of celestial object observations was validated on the second balloon SMILE-2+ installed with an ETCC having a gaseous electron tracker with a volume of 30$\times$30$\times$30 cm$^3$. Gamma-rays from the Crab nebula were detected with a significance of 4.0$\sigma$ in the energy range 0.15--2.1 MeV with a live time of 5.1 h, as expected before launching. Additionally, the light curve clarified an enhancement of gamma-ray events generated in the Galactic center region, indicating that a significant proportion of the final remaining events are cosmic gamma rays. Independently, the observed intensity and time variation were consistent with the pre-launch estimates except in the Galactic center region. The estimates were based on the total background of extragalactic diffuse, atmospheric, and instrumental gamma-rays after accounting for the variations in the atmospheric depth and rigidity during the level flight. The Crab results and light curve strongly support our understanding of both the detection sensitivity and the background in real observations. This work promises significant advances in MeV gamma-ray astronomy

Epithelial Cell Mitochondrial Dysfunction and PINK1 Are Induced by Transforming Growth Factor- Beta1 in Pulmonary Fibrosis

Background: Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis. Methods: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis. Results: Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis. Conclusion: TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis

Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD

The Impact of Autophagy on Cell Death Modalities

Autophagy represents a homeostatic cellular mechanism for the turnover of organelles and proteins, through a lysosome-dependent degradation pathway. During starvation, autophagy facilitates cell survival through the recycling of metabolic precursors. Additionally, autophagy can modulate other vital processes such as programmed cell death (e.g., apoptosis), inflammation, and adaptive immune mechanisms and thereby influence disease pathogenesis. Selective pathways can target distinct cargoes (e.g., mitochondria and proteins) for autophagic degradation. At present, the causal relationship between autophagy and various forms of regulated or nonregulated cell death remains unclear. Autophagy can occur in association with necrosis-like cell death triggered by caspase inhibition. Autophagy and apoptosis have been shown to be coincident or antagonistic, depending on experimental context, and share cross-talk between signal transduction elements. Autophagy may modulate the outcome of other regulated forms of cell death such as necroptosis. Recent advances suggest that autophagy can dampen inflammatory responses, including inflammasome-dependent caspase-1 activation and maturation of proinflammatory cytokines. Autophagy may also act as regulator of caspase-1 dependent cell death (pyroptosis). Strategies aimed at modulating autophagy may lead to therapeutic interventions for diseases in which apoptosis or other forms of regulated cell death may play a cardinal role

Serum free IgE guided dose reduction of omalizumab: a case report

Abstract Background Omalizumab is a human IgG1 antibody against IgE used as a therapy for sever asthmatic patients with asthma. According to the guidelines of the Global Initiative for Asthma, omalizumab is an add-on drug at treatment step 5 that is used for severe asthma patients who are allergic to perennial allergens. The effects of omalizumab for severe asthma therapy have been validated in multiple clinical studies. However, the long-term effects of omalizumab on IgE production and possibility of resetting of administration dose of omalizumab remain unknown. Case Presentation The serum total and free IgE levels were measured over time in a 63-year-old female patient with allergic asthma who was administered 375 mg omalizumab biweekly for 36 months. Her symptoms did not worsen and clinical course remained favorable after reducing the dose to 375 mg per month. The serum free IgE levels temporarily increased following a dose reduction of omalizumab. The serum free IgE trough level temporarily increased at 4 weeks after capable to reduce the dosage; however, thereafter, the serum free IgE level decreased to desired levels (below 30 ng/mL). Conclusions The present case shows the possibility of reducing the dose following the long-term use of omalizumab. Considering the high medical cost of omalizumab, the dose reduction may be a viable option. It may be useful to measure the serum free IgE level to appropriately identify patients in whom the dose can be reduced, and to carefully monitor the clinical course