全文获取类型
收费全文 | 7795篇 |
免费 | 472篇 |
国内免费 | 2篇 |
出版年
2023年 | 13篇 |
2022年 | 36篇 |
2021年 | 104篇 |
2020年 | 67篇 |
2019年 | 76篇 |
2018年 | 126篇 |
2017年 | 91篇 |
2016年 | 172篇 |
2015年 | 233篇 |
2014年 | 299篇 |
2013年 | 532篇 |
2012年 | 495篇 |
2011年 | 479篇 |
2010年 | 315篇 |
2009年 | 339篇 |
2008年 | 534篇 |
2007年 | 482篇 |
2006年 | 481篇 |
2005年 | 503篇 |
2004年 | 523篇 |
2003年 | 458篇 |
2002年 | 405篇 |
2001年 | 128篇 |
2000年 | 110篇 |
1999年 | 116篇 |
1998年 | 96篇 |
1997年 | 78篇 |
1996年 | 55篇 |
1995年 | 73篇 |
1994年 | 62篇 |
1993年 | 55篇 |
1992年 | 74篇 |
1991年 | 64篇 |
1990年 | 59篇 |
1989年 | 65篇 |
1988年 | 52篇 |
1987年 | 47篇 |
1986年 | 34篇 |
1985年 | 43篇 |
1984年 | 36篇 |
1983年 | 27篇 |
1982年 | 28篇 |
1981年 | 32篇 |
1980年 | 21篇 |
1979年 | 24篇 |
1978年 | 17篇 |
1977年 | 22篇 |
1976年 | 17篇 |
1974年 | 15篇 |
1969年 | 13篇 |
排序方式: 共有8269条查询结果,搜索用时 31 毫秒
991.
Shigekiyo Matsumoto Chihiro Shingu Hironori Koga Satoshi Hagiwara Hideo Iwasaka Takayuki Noguchi Isao Yokoi 《Neurochemical research》2010,35(7):1010-1016
Electron spin resonance (ESR)-silent ascorbate solutions generate a detectable, likely concentration-dependent signal of ascorbyl
free radicals (AFR) immediately upon addition of a molar excess of dimethyl sulfoxide (DMSO). We aimed to perform quantitative
ESR analysis of AFR in real time after addition of DMSO (AFR/DMSO) to evaluate ascorbate concentrations in fresh hippocampus
or plasma following systemic administration of kainate in mice. Use of a special tissue-type quartz cell allowed immediate
detection of AFR/DMSO ESR spectra in fresh tissues from mice. AFR/DMSO content was increased significantly in fresh hippocampus
or plasma obtained during kainate-induced seizures of mice, reaching maximum levels at 90 min after intraperitoneal administration
of 50 mg/kg kainic acid. This suggests that oxidative injury of the hippocampus resulted from the accumulation of large amounts
of ascorbic acid in the brain after kainic acid administration. AFR/DMSO content measured on an ESR spectrometer can be used
for real-time evaluation of ascorbate content in fresh tissue. Due to the simplicity, good performance, low cost and real-time
monitoring of ascorbate, this method may be applied to clinical research and treatment in the future. 相似文献
992.
Takaaki Kobayashi Mizuki Watanabe Akira Yoshida Shizuo Yamada Mika Ito Hiroshi Abe Yoshihiro Ito Mituhiro Arisawa Satoshi Shuto 《Bioorganic & medicinal chemistry》2010,18(3):1076-1082
On the basis of the previous results on a histamine H4 receptor agonist 4-methylhistamine and a cyclopropane-based conformationally restricted analog CEIC (3) with potent H3/H4 receptor antagonistic effect, 4-methylhistamine analogs 4 and 5 of CEIC were designed and synthesized. Compound 4 showed strong affinity (Ki = 38.7 nM) for the H3 receptor, which was more potent than a well-known H3 antagonist thioperamide. Stable tautomer and conformation of 3 and 4, which can affect the pharmacological activity, were analyzed by ab initio calculations. 相似文献
993.
Yoshihisa Nakada Thomas D. Aicher Yvan Le Huerou Timothy Turner Scott A. Pratt Stephen S. Gonzales Steve A. Boyd Hiroshi Miki Toshihiro Yamamoto Hiroshi Yamaguchi Koki Kato Shuji Kitamura 《Bioorganic & medicinal chemistry》2010,18(7):2785-2795
A series of diacylethylenediamine derivatives were synthesized and evaluated for their inhibitory activity against DGAT-1 and pharmacokinetic profile to discover new small molecule DGAT-1 inhibitors. Among the compounds, N-[2-({[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)ethyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 3x showed potent inhibitory activity and excellent PK profile. Oral administration of 3x to mice with dietary-induced obesity resulted in reduced body weight gain and white adipose tissue weight. 相似文献
994.
995.
996.
Yutaka Amako Kyoko Tsukiyama-Kohara Asao Katsume Yuichi Hirata Satoshi Sekiguchi Yoshimi Tobita Yukiko Hayashi Tsunekazu Hishima Nobuaki Funata Hiromichi Yonekawa Michinori Kohara 《Journal of virology》2010,84(1):303-311
The lack of a small-animal model has hampered the analysis of hepatitis C virus (HCV) pathogenesis. The tupaia (Tupaia belangeri), a tree shrew, has shown susceptibility to HCV infection and has been considered a possible candidate for a small experimental model of HCV infection. However, a longitudinal analysis of HCV-infected tupaias has yet to be described. Here, we provide an analysis of HCV pathogenesis during the course of infection in tupaias over a 3-year period. The animals were inoculated with hepatitis C patient serum HCR6 or viral particles reconstituted from full-length cDNA. In either case, inoculation caused mild hepatitis and intermittent viremia during the acute phase of infection. Histological analysis of infected livers revealed that HCV caused chronic hepatitis that worsened in a time-dependent manner. Liver steatosis, cirrhotic nodules, and accompanying tumorigenesis were also detected. To examine whether infectious virus particles were produced in tupaia livers, naive animals were inoculated with sera from HCV-infected tupaias, which had been confirmed positive for HCV RNA. As a result, the recipient animals also displayed mild hepatitis and intermittent viremia. Quasispecies were also observed in the NS5A region, signaling phylogenic lineage from the original inoculating sequence. Taken together, these data suggest that the tupaia is a practical animal model for experimental studies of HCV infection.Hepatitis C virus (HCV) is a small enveloped virus that causes chronic hepatitis worldwide (32). HCV belongs to the genus Hepacivirus of the family Flaviviridae. Its genome comprises 9.6 kb of single-stranded RNA of positive polarity flanked by highly conserved untranslated regions at both the 5′ and 3′ ends (4, 27, 29). The 5′ untranslated region harbors an internal ribosomal entry site (29) that initiates translation of a single open reading frame encoding a large polyprotein comprising about 3,010 amino acids (35). The encoded polyprotein is co- and posttranslationally processed into 10 individual viral proteins (15).In most cases of human infection, HCV is highly potent and establishes lifelong persistent infection, which progressively leads to chronic hepatitis, liver steatosis, cirrhosis, and hepatocellular carcinoma (9, 16, 21). The most effective therapy for treatment of HCV infection is administration of pegylated interferon combined with ribavirin. However, the combination therapy is an arduous regimen for patients; furthermore, HCV genotype 1b does not respond efficiently (19). The prevailing scientific opinion is that a more viable option than interferon treatment is needed.The chimpanzee is the only validated animal model for in vivo studies of HCV infection, and it is capable of reproducing most aspects of human infection (5, 18, 23, 28, 35, 36). The chimpanzee is also the only validated animal for testing the authenticity and infectivity of cloned viral sequences (8, 14, 35, 36). However, chimpanzees are relatively rare and expensive experimental subjects. Cross-species transmission from infected chimpanzees to other nonhuman primates has been tested but has proven unsuccessful for all species evaluated (1).The tupaia (Tupaia belangeri), a tree shrew, is a small nonprimate mammal indigenous to certain areas of Southeast Asia (6). It is susceptible to infection with a wide range of human-pathogenic viruses, including hepatitis B viruses (13, 20, 31), and appears to be permissive for HCV infection (33, 34). In an initial report, approximately one-third of inoculated animals exhibited acute, transient infection, although none developed the high-titer sustained viremia characteristic of infection in humans and chimpanzees (33). The short duration of follow-up precluded any observation of liver pathology. In addition to the putative in vivo model, cultured primary hepatocytes from tupaias can be infected with HCV, leading to de novo synthesis of HCV RNA (37). These reports strongly support tupaias as a valid model for experimental studies of HCV infection. However, longitudinal analyses evaluating the clinical development and pathology of HCV-infected tupaias have yet to be examined. In the present study, we describe the clinical development and pathology of HCV-infected tupaias over an approximately 3-year time course. 相似文献
997.
998.
Junya Nojima Kazuhiro Kanomata Yumi Takada Toru Fukuda Shoichiro Kokabu Satoshi Ohte Takatora Takada Tohru Tsukui Takamasa S. Yamamoto Hiroki Sasanuma Katsumi Yoneyama Naoto Ueno Yasushi Okazaki Ryutaro Kamijo Tetsuya Yoda Takenobu Katagiri 《The Journal of biological chemistry》2010,285(20):15577-15586
999.
Nao Hiramoto-Yamaki Shingo Takeuchi Shuhei Ueda Kohei Harada Satoshi Fujimoto Manabu Negishi Hironori Katoh 《The Journal of cell biology》2010,190(3):461-477
EphA2, a member of the Eph receptor family, is frequently overexpressed in a variety of human cancers, including breast cancers, and promotes cancer cell motility and invasion independently of its ligand ephrin stimulation. In this study, we identify Ephexin4 as a guanine nucleotide exchange factor (GEF) for RhoG that interacts with EphA2 in breast cancer cells, and knockdown and rescue experiments show that Ephexin4 acts downstream of EphA2 to promote ligand-independent breast cancer cell migration and invasion toward epidermal growth factor through activation of RhoG. The activation of RhoG recruits its effector ELMO2 and a Rac GEF Dock4 to form a complex with EphA2 at the tips of cortactin-rich protrusions in migrating breast cancer cells. In addition, the Dock4-mediated Rac activation is required for breast cancer cell migration. Our findings reveal a novel link between EphA2 and Rac activation that contributes to the cell motility and invasiveness of breast cancer cells. 相似文献
1000.
Day TA Palle K Barkley LR Kakusho N Zou Y Tateishi S Verreault A Masai H Vaziri C 《The Journal of cell biology》2010,191(5):953-966
The E3 ubiquitin ligase Rad18 guides DNA Polymerase eta (Polη) to sites of replication fork stalling and mono-ubiquitinates proliferating cell nuclear antigen (PCNA) to facilitate binding of Y family trans-lesion synthesis (TLS) DNA polymerases during TLS. However, it is unclear exactly how Rad18 is regulated in response to DNA damage and how Rad18 activity is coordinated with progression through different phases of the cell cycle. Here we identify Rad18 as a novel substrate of the essential protein kinase Cdc7 (also termed Dbf4/Drf1-dependent Cdc7 kinase [DDK]). A serine cluster in the Polη-binding motif of Rad 18 is phosphorylated by DDK. Efficient association of Rad18 with Polη is dependent on DDK and is necessary for redistribution of Polη to sites of replication fork stalling. This is the first demonstration of Rad18 regulation by direct phosphorylation and provides a novel mechanism for integration of S phase progression with postreplication DNA repair to maintain genome stability. 相似文献