ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells

<p>Abstract</p> <p>Background</p> <p>Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4⁺T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The <it>HTLV-1 bZIP factor </it>(<it>HBZ</it>) gene, which is encoded by the minus strand of the viral genome, is expressed as an antisense transcript in all ATL cases. By using yeast two-hybrid screening, we identified activating transcription factor 3 (ATF3) as an HBZ-interacting protein. ATF3 has been reported to be expressed in ATL cells, but its biological significance is not known.</p> <p>Results</p> <p>Immunoprecipitation analysis confirmed that ATF3 interacts with HBZ. Expression of ATF3 was upregulated in ATL cell lines and fresh ATL cases. Reporter assay revealed that ATF3 could interfere with the HTLV-1 Tax's transactivation of the 5' proviral long terminal repeat (LTR), doing so by affecting the ATF/CRE site, as well as HBZ. Suppressing ATF3 expression inhibited proliferation and strongly reduced the viability of ATL cells. As mechanisms of growth-promoting activity of ATF3, comparative expression profiling of ATF3 knockdown cells identified candidate genes that are critical for the cell cycle and cell death, including cell division cycle 2 (CDC2) and cyclin E2. ATF3 also enhanced p53 transcriptional activity, but this activity was suppressed by HBZ.</p> <p>Conclusions</p> <p>Thus, ATF3 expression has positive and negative effects on the proliferation and survival of ATL cells. HBZ impedes its negative effects, leaving ATF3 to promote proliferation of ATL cells via mechanisms including upregulation of CDC2 and cyclin E2. Both HBZ and ATF3 suppress Tax expression, which enables infected cells to escape the host immune system.</p

ベタヒスチンが一側内耳破壊後のラットの前庭代償に与える影響

Background: Vestibular compensation (VC) after unilateral labyrinthectomy (UL) consists of the initial and late processes. These processes can be evaluated based on the decline in the frequency of spontaneous nystagmus (SN) and the number of MK801-induced Fos-positive neurons in the contralateral medial vestibular nucleus (contra-MVe) in rats. Histamine H3 receptors (H3R) are reported to be involved in the development of VC. Objective: We examined the effects of betahistine, an H3R antagonist, on the initial and late processes of VC in UL rats. Methods: Betahistine dihydrochloride was continuously administered to the UL rats at doses of 100 and 200 mg/kg/day using an osmotic minipump. MK801 (1.0 mg/kg) was intraperitoneally administered on days 7, 10, 12, and 14 after UL, while Fos-positive neurons were immunohistochemically stained in the contra-MVe. Results: The SN disappeared after 42 h, and continuous infusion of betahistine did not change the decline in the frequency of SN. The number of MK801-induced Fos-positive neurons in contra-MVe significantly decreased on days 7, 10, and 12 after UL in a dose-dependent manner in the betahistine-treated rats, more so than in the saline-treated rats. Conclusion: These findings suggest that betahistine facilitated the late, but not the initial, process of VC in UL rats

テレワーカーの地域分布に関する実証研究

本論文では、テレワーカーを対象とした調査のデータ分析を通じて、テレワークと空間的拘束の関係についての考察を試みた。筆者らは2021年11月にオンライン・アンケートによる独自調査を実施した。その結果のひとつとして、就業者におけるテレワーカー率が首都圏に向かうにしたがって増加していることが判明した。テレワーカーの１日の居場所についての統計では一定割合の雇用者が出勤しており、反面、昼間に自宅で仕事をしているテレワーカーについてはパソコンなどを使用したデスクワークが中心となっている。標準地域コードを用いたテレワークの実態解析では、テレワーカー率が衛生都市に居住し政令指定都市に通勤する就業者で最も高く、その理由のひとつとして通勤時間の長さが挙げられることを示した

Multiomics Investigation Revealing the Characteristics of HIV-1-Infected Cells In Vivo

For eradication of HIV-1 infection, it is important to elucidate the detailed features and heterogeneity of HIV-1-infected cells in vivo. To reveal multiple characteristics of HIV-1-producing cells in vivo, we use a hematopoietic-stem-cell-transplanted humanized mouse model infected with GFP-encoding replication-competent HIV-1. We perform multiomics experiments using recently developed technology to identify the features of HIV-1-infected cells. Genome-wide HIV-1 integration-site analysis reveals that productive HIV-1 infection tends to occur in cells with viral integration into transcriptionally active genomic regions. Bulk transcriptome analysis reveals that a high level of viral mRNA is transcribed in HIV-1-infected cells. Moreover, single-cell transcriptome analysis shows the heterogeneity of HIV-1-infected cells, including CXCL13high cells and a subpopulation with low expression of interferon-stimulated genes, which can contribute to efficient viral spread in vivo. Our findings describe multiple characteristics of HIV-1-producing cells in vivo, which could provide clues for the development of an HIV-1 cure

Identification of 45 New Neutron-Rich Isotopes Produced by In-Flight Fission of a 238U Beam at 345 MeV/nucleon

A search for new isotopes using in-flight fission of a 345 MeV/nucleon 238U beam has been carried out at the RI Beam Factory at the RIKEN Nishina Center. Fission fragments were analyzed and identified by using the superconducting in-flight separator BigRIPS. We observed 45 new neutron-rich isotopes: 71Mn, 73,74Fe, 76Co, 79Ni, 81,82Cu, 84,85Zn, 87Ga, 90Ge, 95Se, 98Br, 101Kr, 103Rb, 106,107Sr, 108,109Y, 111,112Zr, 114,115Nb, 115,116,117Mo, 119,120Tc, 121,122,123,124Ru, 123,124,125,126Rh, 127,128Pd, 133Cd, 138Sn, 140Sb, 143Te, 145I, 148Xe, and 152Ba

HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo

Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (Treg). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for Treg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ Treg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased Treg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ Treg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of Treg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases

<症例>受傷後4年を経過して発症した外傷性右横隔膜ヘルニアの1例 : 本邦鈍的外傷性横隔膜ヘルニアの統計的観察

We describe our experience with a patient in whom a traumatic right diaphragmatic hernia developed 4 years after sustaining injury and review cases of delayed diaphragmatic injury reported in Japan. The patient was a 28-year-old man who sustained a severe contusion of the right epigastric region and fractured a right rib in a traffic accident in September 1992. In August 1996, the patient presented with shortness of breath on effort or after meals. A chest roentgenogram revealed intestinal gas in the right side of the thoracic cavity. A right diaphragmatic hernia was diagnosed on the basis of a gastrointestinal series, and the patient was operated on. The hernial orifice extended anteriorly from the central tendon in an 11:00 direction and measured 11×6 cm. The small intestine, right side of the colon, and liver were herniated. A total of 297 cases of blunt traumatic diaphragmatic hernia were reported in Japan between 1981 and 1996, including 47 cases (left side, 32 cases; right side, 15 cases) of delayed diaphragmatic hernia, defined as occurring one month or more after injury. Diaphragmatic hernia should be considered as a possible diagnosis in patients with abnormal shadows in the thoracic region who have recently sustained injury or who have a past history of injury.受傷後4年を経過して発症した外傷性右横隔膜へルニアの1例と本邦の鈍的外傷性横隔膜へルニアの報告例の統計的観察について検討した. 【症例】28歳, 男性. 1992年9月交通事故により右肋骨骨折を伴う右上腹部の鈍的外傷を受けた. 1996年8月労作時や食後の息切れが出現した. 胸部X-P 写真およひ消化管造影検査で右横隔膜ヘルニアと診断し手術を施行した. 破裂部位は右横隔膜の腱中心の前方11時方向で, 筋線維方向に 11×6cm の破裂部位を認めた. 脱出臓器は小腸, 右結腸および肝右葉であった. また, 1981年から1996年までに本邦で鈍的外傷による横隔膜へルニアの報告例は297例であった. そのうち受傷後1ヶ月以降に発症した遅発性横隔膜ヘルニアは47例 （右32例, 左15例）であった. 受傷直後はもとより外傷の既往があり, 胸部異常陰影のある患者には本疾患を念頭におくことが大切である

Dose-rate Effect of High-LET Ion Beams on Human Tumor Cells

It is known that radiobiological effectiveness decrease with decrease of the dose-rate for gamma-rays or neutrons. Radiosensitivity as cell survival changes with the dose-rate between 0.2 Gy/hr and 60 Gy/hr (HP Leenhouts et al, J. Radiol. Prot. 10; 95-102, 1990) in mouse CHO cells. There are little reports concerning the dose-arte effects by exposure of ion-beams. Astronauts may receive very low-dose-rate ion-beam radiations. RBE is an important factor to estimate the risk of biological effects by ion-beams, however the RBE is usually estimated from the data at high-dose-rate. Thus, we studied the dose-rate effect on radiosensitivity for heavy ion-beams on cell survival.A human salivary grand tumor cells (HSG) cultured in Eagle\u27s MEM medium in 5% CO2 conteining air at 37 Co was used. A 290 MeV/u carbon-ion beams having 70keV/um of the LET were used at HIMAC facility in the National Institute of Radiological Sciences, Chiba, Japan. Exponentially growing cells cultured in flasks (NUNC 170920) were irradiated with different doses up to about 4.5 Gy that corresponds the cell survival reduce to be less than 1 %, with different dose-rate between 0.5 and 600 Gy/hr. Irradiated cells were sub-cultured just after the exposure, incubated for 13 days, and then colonies consists more than 50 cells were counted as survived cells. The data were plotted on a usual semi logarithmic chart, and compare the survival curves with different dose-rate. All the data from different lower dose-rate exposure plotted on a curve produced by high-dose-rate (10 Gy/min) experiments. It is also found that there are no significant changes in survival parameters by the dose-rate. The survival curve parameters, such as alpha, beta, and D0 were 0.86 Gy-1, 0.10 Gy-2, and 0.78 Gy at 10 Gy/min experiments, and the values varied among 0.69-1.11 Gy-1, 0.05-0.15 Gy-2, and 0.74-0.83 Gy, respectively. In conclusion, the dose-rate effect on cell survival could not observe in the dose-rates tested (611-0.49 Gy/hr) on the cells used (HSG). Alternation of the dose-rate may not affect at the estimation of RBE.36th COSPAR Scientific Assembl