MDM2 is a novel E3 ligase for HIV-1 Vif

The human immunodeficiency virus type 1 (HIV-1) Vif plays a crucial role in the viral life cycle by antagonizing a host restriction factor APOBEC3G (A3G). Vif interacts with A3G and induces its polyubiquitination and subsequent degradation via the formation of active ubiquitin ligase (E3) complex with Cullin5-ElonginB/C. Although Vif itself is also ubiquitinated and degraded rapidly in infected cells, precise roles and mechanisms of Vif ubiquitination are largely unknown. Here we report that MDM2, known as an E3 ligase for p53, is a novel E3 ligase for Vif and induces polyubiquitination and degradation of Vif. We also show the mechanisms by which MDM2 only targets Vif, but not A3G that binds to Vif. MDM2 reduces cellular Vif levels and reversely increases A3G levels, because the interaction between MDM2 and Vif precludes A3G from binding to Vif. Furthermore, we demonstrate that MDM2 negatively regulates HIV-1 replication in non-permissive target cells through Vif degradation. These data suggest that MDM2 is a regulator of HIV-1 replication and might be a novel therapeutic target for anti-HIV-1 drug

Subaru High-z Exploration of Low-Luminosity Quasars (SHELLQs). IX. Identification of Two Red Quasars at z > 5.6

We present the first discovery of dust-reddened quasars (red quasars) in the high-z universe (z >5.6). This is a result from the Subaru High-z Exploration of Low-Luminosity Quasars (SHELLQs) project, which is based on the sensitive multi-band optical imaging data produced by the Hyper Suprime-Cam (HSC) Subaru Strategic Program survey. We identified four red quasar candidates from the spectroscopically confirmed 93 high-z quasars in the SHELLQs sample, based on detections in the Wide-field Infrared Survey Explorer (WISE) data at 3.4 and 4.6 um (rest-frame ~5000-6500 A). The amount of dust reddening was estimated with spectral energy distribution (SED) fits over optical and mid-infrared wavelengths. Two of the four candidates were found to be red quasars with dust reddening of E(B-V) > 0.1. The remaining SHELLQs quasars without individual WISE detections are significantly fainter in the WISE bands and bluer than the red quasars, although we did detect them in the W1 band in a stacked image. We also conducted the same SED fits for high-z optically-luminous quasars, but no red quasar was found. This demonstrates the power of Subaru HSC to discover high-z red quasars, which are fainter than the limiting magnitudes of past surveys in the rest-frame ultraviolet, due to dust extinction.Comment: Accepted for publication in PAS

Prevention of lethal hepatic injury in Long-Evans Cinnamon (LEC) rats by D-galactosamine hydrochloride

Repeated injections of D-galactosamine hydrochloride (GalN) increase the survival rate of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson’s disease. The aim of the present study was to investigate the mechanism of GalN for prevention of spontaneous lethal hepatic injury in LEC rats. MaleLEC rats were given a single subcutaneous injection of 300mg/kg of GalN or vehicle (0.9%NaCl) at 14weeks, and killed at 28 weeks of age. Next, 6-week-old male LEC rats were given weekly subcutaneous injections of 300 mg/kg of GalN or vehicle for 3 or 12 weeks, and their hepatic 8-hydroxydeoxy-2’-guanosine (8-OHdG), glutathione peroxidase (GPX), and catalase activities were measured. None of GalN-treated rats died of hepatic injury (0/12), whereas the mortality rate of control rats given 0.9% NaCl was 17% (2/12). GalN administration for 12 weeks decreased the hepatic 8-OHdG, and GalN administration for either 3 or 12weeks increased the glutathione peroxidase activity. GalN administration increased the serum level of alanine aminotransferase, and accelerated megalocytic degeneration of the hepatocytes. GalN treatment is effective in preventing lethal hepatitis in LEC rats and decrease of oxidative DNA damage by GalN plays an important role in increase of the survival rate

E3 Ubiquitin Ligase Synoviolin Is Involved in Liver Fibrogenesis

Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis.The expression and localization of synoviolin in the liver were analyzed in CCl(4)-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno(+/-) mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno(+/-) mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno(-/-) mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno(-/-) MEF cells.In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno(+/-) mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno(+/-) mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno(-/-) MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum.Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis

Discovery of the First Low-Luminosity Quasar at z > 7

We report the discovery of a quasar at z = 7.07, which was selected from the deep multi-band imaging data collected by the Hyper Suprime-Cam (HSC) Subaru Strategic Program survey. This quasar, HSC J124353.93+010038.5, has an order of magnitude lower luminosity than do the other known quasars at z > 7. The rest-frame ultraviolet absolute magnitude is M1450 = -24.13 +/- 0.08 mag and the bolometric luminosity is Lbol = (1.4 +/- 0.1) x 10^{46} erg/s. Its spectrum in the optical to near-infrared shows strong emission lines, and shows evidence for a fast gas outflow, as the C IV line is blueshifted and there is indication of broad absorption lines. The Mg II-based black hole mass is Mbh = (3.3 +/- 2.0) x 10^8 Msun, thus indicating a moderate mass accretion rate with an Eddington ratio 0.34 +/- 0.20. It is the first z > 7 quasar with sub-Eddington accretion, besides being the third most distant quasar, known to date. The luminosity and black hole mass are comparable to, or even lower than, those measured for the majority of low-z quasars discovered by the Sloan Digital Sky Survey, and thus this quasar likely represents a z > 7 counterpart to quasars commonly observed in the low-z universe.Comment: Accepted for publication in ApJ Letter

Huge splenic epidermoid cyst with elevation of serum CA19-9 level

A 30-year-old female was referred to our hospital for further examination of liver dysfunction. A huge, soft mass was noted in her left upper quadrant on physical examination. Abdominal ultrasonography and computed tomography revealed a huge cystic tumor of 20 cm in the hilus of the spleen. Serum CA19-9 was 491 U/ml, and splenectomy was performed under suspicion of a malignant cystic tumor. The inner surface of the cyst was lined by squamous epithelial cells that were immunohistochemically positive for CA19-9. Serum CA19-9 level was normalized after the surgery. Our case of a very rare, huge epidermoid cyst of the spleen suggests that measurement of the serum CA19-9 level is useful for evaluating therapeutic efficacy of a splenic epidermoid cyst

Subaru High-z Exploration of Low-luminosity Quasars (SHELLQs). XIII. Large-scale Feedback and Star Formation in a Low-luminosity Quasar at z = 7.07 on the Local Black Hole to Host Mass Relation

We present Atacama Large Millimeter/submillimeter Array [C II] 158 μm line and underlying far-infrared (FIR) continuum emission observations (0 70 × 0 56 resolution) toward HSC J124353.93+010038.5 (J1243+0100) at z = 7.07, the only low-luminosity (M1450 > −25 mag) quasar currently known at z > 7. The FIR continuum is bright (1.52 mJy) and resolved with a total luminosity of LFIR = 3.5 × 1012 Le. The spatially extended component is responsible for ∼40% of the emission. The area-integrated [C II] spectrum shows a broad wing (FWHM = 997 km s−1 , L[C II] = 1.2 × 109 Le), as well as a bright core (FWHM = 235 km s−1 , L[C II] = 1.9 × 109 Le). This wing is the first detection of a galactic-scale quasar-driven outflow (atomic outflow rate >447 Me yr−1 ) at z > 7. The estimated large mass-loading factor of the total outflow (e.g., 9 relative to the [C II]-based star formation rate) suggests that this outflow will soon quench the star formation of the host. The core gas dynamics are governed by rotation, with a rotation curve suggestive of a compact bulge (∼3.3 × 1010 Me), although it is not yet spatially resolved. Finally, we found that J1243+0100 has a black hole mass–to–dynamical mass (and –to–bulge mass) ratio of ∼0.4% (∼1%), consistent with the local value within the uncertainties. Our results therefore suggest that the black hole–host coevolution relation is already in place at z ∼ 7 for this object

Anti-podoplanin antibody against MPM

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat–human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ- 8, and NZ-12, a novel rat–human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a+) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56+) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56+) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56+) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM