Peccei-Quinn Inflation at the Pole and Axion Kinetic Misalignment

We propose a minimal extension of the Standard Model with the Peccei-Quinn (PQ) scalar field and explain the relic density of the QCD axion through the kinetic misalignment with a relatively small axion decay constant. To this purpose, we consider a slow-roll inflation from the radial component of the PQ field with the PQ conserving potential near the pole of its kinetic term and investigate the post-inflationary dynamics of the PQ field for reheating. The angular mode of the PQ field, identified with the QCD axion, receives a nonzero velocity during inflation due to the PQ violating potential, evolving with an approximately conserved Noether PQ charge. We determine the reheating temperature from the perturbative decays and scattering processes of the inflaton and obtain dark radiation from the axions produced from the inflaton scattering at a testable level in the future Cosmic Microwave Background experiments. We show the correlation between the reheating temperature, the initial velocity of the axion and the axion decay constant, realizing the axion kinetic misalignment for the correct relic density.Comment: 25 pagesm 3 figure

Recurrent acute portal vein thrombosis in liver cirrhosis treated by rivaroxaban

Cirrhosis can occur with the development of portal vein thrombosis (PVT). PVT may aggravate portal hypertension, and it can lead to hepatic decompensation. The international guideline recommends for anticoagulation treatment to be maintained for at least 3 months in all patients with acute PVT. Low-molecular-weight-heparin and changing to warfarin is the usual anticoagulation treatment. However, warfarin therapy is problematic due to a narrow therapeutic window and the requirement for frequent dose adjustment, which has prompted the development of novel oral anticoagulants for overcoming these problems. We report a 63-year-old female who experienced complete resolution of recurrent acute PVT in liver cirrhosis after treatment with rivaroxaban

Efficacy and safety of daclatasvir and asunaprevir for hepatitis C virus genotype 1b infection

Background/Aims: The treatment strategy for hepatitis C virus (HCV) has been changing rapidly since the introduction of direct-acting antivirals such as daclatasvir (DCV) and asunaprevir (ASV). We evaluated the efficacy and safety of DCV and ASV for HCV in real-life practice. Methods: Patients were treated with 60 mg of DCV once daily plus 200 mg of ASV twice daily for 24 weeks, and followed for 12 weeks. The primary endpoint was a sustained virological response at 12 weeks after treatment (SVR12) and safety. Results: This retrospective study included eight patients with chronic HCV genotype 1b infection. All of the enrolled patients were diagnosed with liver cirrhosis, and their mean age was 65.75 years. One patient was a nonresponder and two patients relapsed with previous pegylated interferon (PegIFN) and ribavirin (RBV) treatment. None of the patient showed NS5A mutation. An SVR12 was achieved in 88% of cases by the DCV and ASV combination therapy. The serum transaminase level and the aspartate-aminotransferase-to-platelet ratio were improved after the treatment. DCV and ASV were well tolerated in most of the patients, with treatment discontinuation due to adverse events (elevated liver enzyme and decompensation) occurring in two patients. Conclusion: In this study, combination of DCV and ASV treatment achieved a high sustained virological response with few adverse events even in those with cirrhosis, advanced age, and nonresponse/relapse to previous interferon-based therapy. Close monitoring of safety issues may be necessary when treating chronic HCV patients receiving DCV and ASV, especially in older patient and those with cirrhosis

Hepatocyte-Derived Lipotoxic Extracellular Vesicle Sphingosine 1-Phosphate Induces Macrophage Chemotaxis

Background: The pathophysiology of non-alcoholic steatohepatitis involves hepatocyte lipotoxicity due to excess saturated free fatty acids and concomitant proinflammatory macrophage effector responses. These include the infiltration of macrophages into hepatic cords in response to incompletely understood stimuli. Stressed hepatocytes release an increased number of extracellular vesicles (EVs), which are known to participate in intercellular signaling and coordination of the behavior of immune cell populations via their cargo. We hypothesized that hepatocyte-derived lipotoxic EVs that are enriched in sphingosine 1-phosphate (S1P) are effectors of macrophage infiltration in the hepatic microenvironment.Methods: Lipotoxic EVs were isolated from palmitate treated immortalized mouse hepatocytes and characterized by nanoparticle tracking analysis. Lipotoxic EV sphingolipids were quantified using tandem mass spectrometry. Wildtype and S1P1 receptor knockout bone marrow-derived macrophages were exposed to lipotoxic EV gradients in a microfluidic gradient generator. Macrophage migration toward EV gradients was captured by time-lapse microscopy and analyzed to determine directional migration. Fluorescence-activated cell sorting along with quantitative PCR and immunohistochemistry were utilized to characterize the cell surface expression of S1P1 receptor on intrahepatic leukocytes and hepatic expression of S1P1 receptor, respectively.Results: Palmitate treatment induced the release of EVs. These EVs were enriched in S1P. Palmitate-induced S1P enriched EVs were chemoattractive to macrophages. EV S1P enrichment depended on the activity of sphingosine kinases 1 and 2, such that, pharmacological inhibition of sphingosine kinases 1 and 2 resulted in a significant reduction in EV S1P cargo without affecting the number of EVs released. When exposed to EVs derived from cells treated with palmitate in the presence of a pharmacologic inhibitor of sphingosine kinases 1 and 2, macrophages displayed diminished chemotactic behavior. To determine receptor-ligand specificity, we tested the migration responses of macrophages genetically deleted in the S1P1 receptor toward lipotoxic EVs. S1P1 receptor knockout macrophages displayed a marked reduction in their chemotactic responses toward lipotoxic palmitate-induced EVs.Conclusions:Palmitate-induced lipotoxic EVs are enriched in S1P through sphingosine kinases 1 and 2. S1P-enriched EVs activate persistent and directional macrophage chemotaxis mediated by the S1P1 receptor, a potential signaling axis for macrophage infiltration during hepatic lipotoxicity, and a potential therapeutic target for non-alcoholic steatohepatitis

Comparison and analysis of the prevalence of hepatitis C virus infection by region in the Republic of Korea during 2005-2012

Background/AimsThis study compared the prevalence of hepatitis C virus (HCV) infection in the Republic of Korea and estimated the high-risk regions and towns.MethodsNational Health Insurance Service data for 8 years from 2005 to 2012 were used. The subjects of the study had visited medical facilities and been diagnosed with or received treatment for acute or chronic HCV as a primary or secondary disease according to ICD-10 codes of B17.1 or B18.2, respectively. Any patient who received treatment for the same disease multiple times during 1 year was counted as one patient in that year. To correct for the effect of the age structure of the population by year and region, the age-adjusted prevalence was calculated using the direct method based on the registered population in 2010.ResultsThe overall prevalence of HCV infection among Korean adults (>20 years old) increased from 0.14% in 2005 to 0.18% in 2012. The sex-, age-, and region-adjusted prevalence in 2012 was 0.18%. The prevalence was highest in Busan, Jeonnam, and Gyeongnam, and there were towns with noticeably higher prevalences within these regions: Jindo (0.97%) in Jeonnam, Namhae (0.90%) in Gyeongnam, and Seo-gu (0.86%) in Busan.ConclusionsThe prevalence of HCV infection differs by regions as well as towns in the Republic of Korea, and is highest in Busan, Jeonnam, and Gyeongnam. The reasons for the high prevalence in these specific regions should be identified, since this could help prevent HCV infections in the future. In addition, active surveillance and treatment policies should be introduced to stop any further spread of infection in these high-prevalence regions

Enhanced ferroelectric switching speed of Si-doped HfO2 thin film tailored by oxygen deficiency

Investigations concerning oxygen deficiency will increase our understanding of those factors that govern the overall material properties. Various studies have examined the relationship between oxygen deficiency and the phase transformation from a nonpolar phase to a polar phase in HfO2 thin films. However, there are few reports on the effects of oxygen deficiencies on the switching dynamics of the ferroelectric phase itself. Herein, we report the oxygen- deficiency induced enhancement of ferroelectric switching properties of Si-doped HfO2 thin films. By controlling the annealing conditions, we controlled the oxygen deficiency concentration in the ferroelectric orthorhombic HfO2 phase. Rapid high-temperature (800 degrees C) annealing of the HfO2 film accelerated the characteristic switching speed compared to low-temperature (600 degrees C) annealing. Scanning transmission electron microscopy and electron energy-loss spectroscopy (EELS) revealed that thermal annealing increased oxygen deficiencies, and first-principles calculations demonstrated a reduction of the energy barrier of the polarization flip with increased oxygen deficiency. A Monte Carlo simulation for the variation in the energy barrier of the polarization flipping confirmed the increase of characteristic switching speed

The structure of human EXD2 reveals a chimeric 3' to 5' exonuclease domain that discriminates substrates via metal coordination.

EXD2 (3'-5' exonuclease domain-containing protein 2) is an essential protein with a conserved DEDDy superfamily 3'-5' exonuclease domain. Recent research suggests that EXD2 has two potential functions: as a component of the DNA double-strand break repair machinery and as a ribonuclease for the regulation of mitochondrial translation. Herein, electron microscope imaging analysis and proximity labeling revealed that EXD2 is anchored to the mitochondrial outer membrane through a conserved N-terminal transmembrane domain, while the C-terminal region is cytosolic. Crystal structures of the exonuclease domain in complex with Mn2+/Mg2+ revealed a domain-swapped dimer in which the central α5-α7 helices are mutually crossed over, resulting in chimeric active sites. Additionally, the C-terminal segments absent in other DnaQ family exonucleases enclose the central chimeric active sites. Combined structural and biochemical analyses demonstrated that the unusual dimeric organization stabilizes the active site, facilitates discrimination between DNA and RNA substrates based on divalent cation coordination and generates a positively charged groove that binds substrates.Cell Logistics Research Center [2016R1A5A1007318]; Basic Research Program, National Research Foundation of Korea [NRF-2019R1A2C3008463]; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [HI18C1395]; Institute for Basic Science [IBS-R022-D1]. Funding for open access charge: Cell Logistics Research Center, National Research Foundation of Korea [2016R1A5A1007318]

Efficacy and safety of sofosbuvir plus ribavirin for Korean patients with hepatitis C virus genotype 2 infection: A retrospective multi-institutional study

Background/Aims Sofosbuvir plus ribavirin is a standard treatment for patients infected with chronic hepatitis C virus (HCV) genotype 2 in Korea. The purpose of this study was to examine the efficacy and safety of this treatment in Korean patients with chronic HCV genotype 2 infection. Methods We retrospectively analyzed clinical data of patients treated with sofosbuvir plus ribavirin for chronic HCV genotype 2 from May 2016 to December 2017 at eight hospitals located in the Daejeon-Chungcheong area. Results A total of 172 patients were treated with sofosbuvir plus ribavirin. Of them, 163 patients completed the treatment, and 162 patients were tested for sustained virologic response 12 weeks after treatment discontinuation (SVR12). Mean age was 59.6±12.3 years (27–96), and 105 (64.4%) patients were female. Of the total patients, 49 (30.1%) were diagnosed with cirrhosis, and 31 of them were treated for 16 weeks. Sofosbuvir plus ribavirin was the first-line treatment for 144 (88.3%) patients. Eleven (6.7%) patients were intolerant to previous interferon-based treatment. Eight (5.0%) patients relapsed after interferon-based treatment. HCV RNA non-detection rate at 4, 8, and 12 weeks was 97.5%, 99.1%, and 99.3%, respectively, and SVR12 was 98.8% (161/163). During treatment, 18 (11.0%) patients had to reduce their administrated dose of ribavirin because of anemia. One patient stopped the treatment because of severe anemia. Other adverse events, including dizziness, indigestion, and headache, were found in 26 (16.0%) patients. Conclusions A 12-16 week treatment with sofosbuvir plus ribavirin is remarkably effective and well tolerated in Korean patients with chronic HCV genotype 2 infection