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103. Erratum: Silencing by small RNAs is linked to endosomal trafficking

Author

Lee, Young Sik, primary, Pressman, Sigal, additional, Andress, Arlise P., additional, Kim, Kevin, additional, White, Jamie L., additional, Cassidy, Justin J., additional, Li, Xin, additional, Lubell, Kim, additional, Lim, Do Hwan, additional, Cho, Ik Sang, additional, Nakahara, Kenji, additional, Preall, Jonathan B., additional, Bellare, Priya, additional, Sontheimer, Erik J., additional, and Carthew, Richard W., additional

Published
2009
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104. Silencing by small RNAs is linked to endosomal trafficking

Author

Lee, Young Sik, primary, Pressman, Sigal, additional, Andress, Arlise P., additional, Kim, Kevin, additional, White, Jamie L., additional, Cassidy, Justin J., additional, Li, Xin, additional, Lubell, Kim, additional, Lim, Do Hwan, additional, Cho, Ik Sang, additional, Nakahara, Kenji, additional, Preall, Jonathan B., additional, Bellare, Priya, additional, Sontheimer, Erik J., additional, and Carthew, Richard W., additional

Published
2009
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109. A phase II multicenter trial of concurrent chemoradiotherapy with weekly nedaplatin in advanced uterine cervical carcinoma: Tohoku Gynecologic Cancer Unit Study

Author

Mizunuma, Hideki, primary, Tase, Toru, additional, Sato, Akira, additional, Tanaka, Toshinobu, additional, Sugiyama, Toru, additional, Kurachi, Hirohisa, additional, Okamura, Kunihiro, additional, Yaegashi, Nobuo, additional, Yamada, Hidekazu, additional, Sato, Hirokazu, additional, Shoji, Tadahiro, additional, Nakahara, Kenji, additional, Takano, Tadao, additional, and Yokoyama, Yoshihito, additional

Published
2008
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125. Endometriosis and Oocyte Quality

Author

Saito, Hidekazu, primary, Seino, Tomofumi, additional, Kaneko, Tomoko, additional, Nakahara, Kenji, additional, Toya, Mayumi, additional, and Kurachi, Hirohisa, additional

Published
2002
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145. CLONING AND SEQUENCING OF ENDOCHITINASE GENES FROM GLIOCLADIUM VIRENS AND TRICHODERMA SPECIES.

Author

Nakahara, Kenji, Yoshida, Kouji, Ito, Tsutae, Suzaki, Kouichi, and Kudo, Akira

Subjects
*NUCLEOTIDE sequence, *GLIOCLADIUM, *NUCLEIC acid analysis, *TRICHODERMA, *PLANT diseases
Abstract

Nucleotide sequences containing the genetic determinants of the endochitinase of Gliocladium virences as weal as those of Trichoderma harzianum, T. hamatum. T. viride and T. pseudokoningii were determined. The ORFs of 1287 or 1293 nucleotides were interrupted by throe introns. The deduced amino acid sequences of endochitinase of G. virens were highly homologous to those of Trichoderma species (82-97% identity), although the culture filtrates from G, virens showed a much stronger inhibitory effect on growth of Helicobasidium mompa than those from Trichoderma species. Phylogenic analysis showed that these sequences could be divided into three clusters regardless of genus or species. [ABSTRACT FROM AUTHOR]

Published
2001
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146. Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

Author

Unoh, Yuto, Uehara, Shota, Nakahara, Kenji, Nobori, Haruaki, Yamatsu, Yukiko, Yamamoto, Shiho, Maruyama, Yuki, Taoda, Yoshiyuki, Kasamatsu, Koji, Suto, Takahiro, Kouki, Kensuke, Nakahashi, Atsufumi, Kawashima, Sho, Sanaki, Takao, Toba, Shinsuke, Uemura, Kentaro, Mizutare, Tohru, Ando, Shigeru, Sasaki, Michihito, Orba, Yasuko, Sawa, Hirofumi, Sato, Akihiko, Sato, Takafumi, Kato, Teruhisa, and Tachibana, Yuki

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622exhibited antiviral activity in vitroagainst current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivofor once-daily oral dosing. Furthermore, S-217622dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.

Published
2022
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147. Balancing potency and basicity by incorporating fluoropyridine moieties: Discovery of a 1-amino-3,4-dihydro-2,6-naphthyridine BACE1 inhibitor that affords robust and sustained central Aβ reduction.

Author

Nakahara, Kenji, Mitsuoka, Yasunori, Kasuya, Satoshi, Yamamoto, Takahiko, Yamamoto, Shiho, Ito, Hisanori, Kido, Yasuto, and Kusakabe, Ken-ichi

Subjects
*AMYLOID beta-protein precursor, *BASICITY, *MOIETIES (Chemistry), *ALZHEIMER'S disease
Abstract

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been pursued as a prime target for the treatment of Alzheimer's disease (AD). In this report, we describe the discovery of BACE1 inhibitors with a 1-amino-3,4-dihydro-2,6-naphthyridine scaffold. Leveraging known inhibitors 2a and 2b , we designed the naphthyridine-based compounds by removing a structurally labile moiety and incorporating pyridine rings, which showed increased biochemical and cellular potency, along with reduced basicity on the amidine moiety. Introduction of a fluorine atom on the pyridine culminated in compound 11 which had improved cellular activity as well as further reduced basicity and demonstrated a robust and sustained cerebrospinal fluid (CSF) Aβ reduction in dog. The crystal structure of compound 11 bound to BACE1 confirmed van der Waals interactions between the fluorine on the pyridine and Tyr71 in the flap. [Display omitted] • A 1-amino-3,4-dihydro-2,6-naphthyridine BACE1 inhibitor offering robust and sustained CSF Aβ reduction was identified. • Incorporation of fluoropyridines reduced basicity with increased biochemical and cellular potency, which led to significant central activity. • X-ray analysis confirmed the key interactions of the fluoropyridine moiety with BACE1. [ABSTRACT FROM AUTHOR]

Published
2021
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148. On the Tz'u Poetry of Liu Yung

Author

Nakahara, Kenji

Abstract

The tz'u poet Liu Yung, who flourished in the early years of the Northern Sung, is noted for the popular nature of his work. This reputation, it would appear, stems from his erotic poetry, which is the subject of this article. In examining Liu Yung's erotic poetry, comparison has been made with the erotic poetry in tz'u form of T'ang and Five Dynasties times and that by Liu Yung's contemporaries such as Chang Hsien, Yen Shu, and Ou-yang Hsiu. The erotic poetry examined, it was found, could be divided into two categories. The first is the so-called kuei-yuan poetry, the poetry of the woman wronged or neglected. The second is the poetry which concentrates upon a description of the woman herself. An examination of the poetry of the first category reveals that most poets of the T'ang, Five Dynasties, and early Sung tended to convey a sense of the sadness or resentment of the woman neglected by her lover indirectly through a description of her appearance, the articles which surround her, or the setting in which she is seen. Liu Yung's poems of this type, however, are quite different, for he allows the woman to express her feelings by describing them directly in her own words. Poems in the second category by Liu Yung's predecessors and contemporaries, it was found, tended to be devoted entirely to a description of the beauty and attractiveness of the woman portrayed. Those by Liu Yung, however, give voice to the speaker's own love for the woman he beholds. Liu Yung's erotic poems, as may be seen, thus give frank and open expression to the feelings of love and passion in the heart of the speaker or the person depicted, and because of this directness deserve, at least in the writer's opinion, to be evaluated very highly. On the other hand, Liu Yung does not employ a compressed mode of expression, as do many other poets, and his works therefore lack the suggestiveness that generally results from such a mode of expression. It is probable that he wrote in this manner because of the nature of the melodies to which his poems were fitted. The fact that the melodies to which the tz'u poems of this period were sung are now entirely lost is particularly regrettable in the case of Liu Yung, hindering as it does a proper appreciation of his work.

Published
1975

150. RNA silencing-related genes contribute to tolerance of infection with potato virus X and Y in a susceptible tomato plant.

Author

Kwon, Joon, Kasai, Atsushi, Maoka, Tetsuo, Masuta, Chikara, Sano, Teruo, and Nakahara, Kenji S.

Subjects
POTATO virus X, POTATO virus Y, VIRUS diseases, RNA polymerases, RNA interference, DOUBLE-stranded RNA, NICOTIANA benthamiana, REVERSE transcriptase
Abstract

Background: In plants, the RNA silencing system functions as an antiviral defense mechanism following its induction with virus-derived double-stranded RNAs. This occurs through the action of RNA silencing components, including Dicer-like (DCL) nucleases, Argonaute (AGO) proteins, and RNA-dependent RNA polymerases (RDR). Plants encode multiple AGOs, DCLs, and RDRs. The functions of these components have been mainly examined in Arabidopsis thaliana and Nicotiana benthamiana. In this study, we investigated the roles of DCL2, DCL4, AGO2, AGO3 and RDR6 in tomato responses to viral infection. For this purpose, we used transgenic tomato plants (Solanum lycopersicum cv. Moneymaker), in which the expression of these genes were suppressed by double-stranded RNA-mediated RNA silencing. Methods: We previously created multiple DCL (i.e., DCL2 and DCL4) (hpDCL2.4) and RDR6 (hpRDR6) knockdown transgenic tomato plants and here additionally did multiple AGO (i.e., AGO2 and AGO3) knockdown plants (hpAGO2.3), in which double-stranded RNAs cognate to these genes were expressed to induce RNA silencing to them. Potato virus X (PVX) and Y (PVY) were inoculated onto these transgenic tomato plants, and the reactions of these plants to the viruses were investigated. In addition to observation of symptoms, viral coat protein and genomic RNA were detected by western and northern blotting and reverse transcription-polymerase chain reaction (RT-PCR). Host mRNA levels were investigated by quantitative RT-PCR. Results: Following inoculation with PVX, hpDCL2.4 plants developed a more severe systemic mosaic with leaf curling compared with the other inoculated plants. Systemic necrosis was also observed in hpAGO2.3 plants. Despite the difference in the severity of symptoms, the accumulation of PVX coat protein (CP) and genomic RNA in the uninoculated upper leaves was not obviously different among hpDCL2.4, hpRDR6, and hpAGO2.3 plants and the empty vector-transformed plants. Moneymaker tomato plants were asymptomatic after infection with PVY. However, hpDCL2.4 plants inoculated with PVY developed symptoms, including leaf curling. Consistently, PVY CP was detected in the uninoculated symptomatic upper leaves of hpDCL2.4 plants through western blotting. Of note, PVY CP was rarely detected in other asymptomatic transgenic or wild-type plants. However, PVY was detected in the uninoculated upper leaves of all the inoculated plants using reverse transcription-polymerase chain reactions. These findings indicated that PVY systemically infected asymptomatic Moneymaker tomato plants at a low level (i.e., no detection of CP via western blotting). Conclusion: Our results indicate that the tomato cultivar Moneymaker is susceptible to PVX and shows mild mosaic symptoms, whereas it is tolerant and asymptomatic to systemic PVY infection with a low virus titer. In contrast, in hpDCL2.4 plants, PVX-induced symptoms became more severe and PVY infection caused symptoms. These results indicate that DCL2, DCL4, or both contribute to tolerance to infection with PVX and PVY. PVY CP and genomic RNA accumulated to a greater extent in DCL2.4-knockdown plants. Hence, the contribution of these DCLs to tolerance to infection with PVY is at least partly attributed to their roles in anti-viral RNA silencing, which controls the multiplication of PVY in tomato plants. The necrotic symptoms observed in the PVX-infected hpAGO2.3 plants suggest that AGO2, AGO3 or both are also distinctly involved in tolerance to infection with PVX. [ABSTRACT FROM AUTHOR]

Published
2020
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