全文获取类型
收费全文 | 3098篇 |
免费 | 195篇 |
国内免费 | 7篇 |
出版年
2022年 | 6篇 |
2021年 | 37篇 |
2020年 | 19篇 |
2019年 | 23篇 |
2018年 | 38篇 |
2017年 | 26篇 |
2016年 | 55篇 |
2015年 | 102篇 |
2014年 | 107篇 |
2013年 | 188篇 |
2012年 | 180篇 |
2011年 | 166篇 |
2010年 | 102篇 |
2009年 | 99篇 |
2008年 | 178篇 |
2007年 | 208篇 |
2006年 | 175篇 |
2005年 | 190篇 |
2004年 | 197篇 |
2003年 | 158篇 |
2002年 | 176篇 |
2001年 | 76篇 |
2000年 | 90篇 |
1999年 | 70篇 |
1998年 | 47篇 |
1997年 | 42篇 |
1996年 | 28篇 |
1995年 | 29篇 |
1994年 | 23篇 |
1993年 | 23篇 |
1992年 | 47篇 |
1991年 | 37篇 |
1990年 | 40篇 |
1989年 | 31篇 |
1988年 | 28篇 |
1987年 | 31篇 |
1986年 | 32篇 |
1985年 | 26篇 |
1984年 | 20篇 |
1983年 | 13篇 |
1982年 | 13篇 |
1981年 | 21篇 |
1980年 | 14篇 |
1979年 | 20篇 |
1978年 | 15篇 |
1977年 | 18篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1974年 | 4篇 |
1972年 | 6篇 |
排序方式: 共有3300条查询结果,搜索用时 203 毫秒
51.
Akihiko Kojima Satoshi Takita Tatsunobu Sumiya Koji Ochiai Kazuhiko Iwase Tetsuya Kishi Akira Ohinata Yuichi Yageta Tokutaro Yasue Yasushi Kohno 《Bioorganic & medicinal chemistry letters》2013,23(19):5311-5316
We previously identified KCA-1490 [(?)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model. 相似文献
52.
Ryosuke Tateishi Shuichiro Shiina Masaaki Akahane Jiro Sato Yuji Kondo Ryota Masuzaki Hayato Nakagawa Yoshinari Asaoka Tadashi Goto Kuni Otomo Masao Omata Haruhiko Yoshida Kazuhiko Koike 《PloS one》2013,8(4)
Background
In the treatment of hepatocellular carcinoma (HCC), hepatic resection has the advantage over radiofrequency ablation (RFA) in terms of systematic removal of a hepatic segment.Methods
We enrolled 303 consecutive patients of a single naïve HCC that had been treated by RFA at The University of Tokyo Hospital from 1999 to 2004. Recurrence was categorized as either intra- or extra-subsegmental as according to the Couinaud''s segment of the original nodule. To assess the relationship between the subsegments of the original and recurrent nodules, we calculated the kappa coefficient. We assessed the risk factors for intra- and extra-subsegmental recurrence independently using univariate and multivariate Cox proportional hazard regression. We also assessed the impact of the mode of recurrence on the survival outcome.Results
During the follow-up period, 201 patients in our cohort showed tumor recurrence distributed in a total of 340 subsegments. Recurrence was categorized as exclusively intra-subsegmental, exclusively extra-subsegmental, and simultaneously intra- and extra-subsegmental in 40 (20%), 110 (55%), and 51 (25%) patients, respectively. The kappa coefficient was measured at 0.135 (95% CI, 0.079–0.190; P<0.001). Multivariate analysis revealed that of the tumor size, AFP value and platelet count were all risk factors for both intra- and extra-subsegmental recurrence. Of the patients in whom recurrent HCC was found to be exclusively intra-subsegmental, extra-subsegmental, and simultaneously intra- and extra-subsegmental, 37 (92.5%), 99 (90.8%) and 42 (82.3%), respectively, were treated using RFA. The survival outcomes after recurrence were similar between patients with an exclusively intra- or extra-subsegmental recurrence.Conclusions
The effectiveness of systematic subsegmentectomy may be limited in the patients with both HCC and chronic liver disease who frequently undergo multi-focal tumor recurrence. 相似文献53.
54.
Hitomi Ueno Hajime Okita Shingo Akimoto Kenichiro Kobayashi Kazuhiko Nakabayashi Kenichiro Hata Junichiro Fujimoto Jun-ichi Hata Masahiro Fukuzawa Nobutaka Kiyokawa 《PloS one》2013,8(4)
A number of specific, distinct neoplastic entities occur in the pediatric kidney, including Wilms’ tumor, clear cell sarcoma of the kidney (CCSK), congenital mesoblastic nephroma (CMN), rhabdoid tumor of the kidney (RTK), and the Ewing’s sarcoma family of tumors (ESFT). By employing DNA methylation profiling using Illumina Infinium HumanMethylation27, we analyzed the epigenetic characteristics of the sarcomas including CCSK, RTK, and ESFT in comparison with those of the non-neoplastic kidney (NK), and these tumors exhibited distinct DNA methylation profiles in a tumor-type-specific manner. CCSK is the most frequently hypermethylated, but least frequently hypomethylated, at CpG sites among these sarcomas, and exhibited 490 hypermethylated and 46 hypomethylated CpG sites in compared with NK. We further validated the results by MassARRAY, and revealed that a combination of four genes was sufficient for the DNA methylation profile-based differentiation of these tumors by clustering analysis. Furthermore, THBS1 CpG sites were found to be specifically hypermethylated in CCSK and, thus, the DNA methylation status of these THBS1 sites alone was sufficient for the distinction of CCSK from other pediatric renal tumors, including Wilms’ tumor and CMN. Moreover, combined bisulfite restriction analysis could be applied for the detection of hypermethylation of a THBS1 CpG site. Besides the biological significance in the pathogenesis, the DNA methylation profile should be useful for the differential diagnosis of pediatric renal tumors. 相似文献
55.
Yasuhiro Ogawa Makoto Tanaka Miho Tanabe Toshihiro Suzuki Tadayasu Togawa Tomoko Fukushige Takuro Kanekura Hitoshi Sakuraba Kazuhiko Oishi 《PloS one》2013,8(1)
Sandhoff disease (SD) is a glycosphingolipid storage disease that arises from mutations in the Hexb gene and the resultant deficiency in β-hexosaminidase activity. This deficiency results in aberrant lysosomal accumulation of the ganglioside GM2 and related glycolipids, and progressive deterioration of the central nervous system. Dysfunctional glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem cell-based therapies. Here, we report the generation of disease-specific iPSCs from a mouse model of SD. These mouse model-derived iPSCs (SD-iPSCs) exhibited pluripotent stem cell properties and significant accumulation of GM2 ganglioside. In lineage-directed differentiation studies using the stromal cell-derived inducing activity method, SD-iPSCs showed an impaired ability to differentiate into early stage neural precursors. Moreover, fewer neurons differentiated from neural precursors in SD-iPSCs than in the case of the wild type. Recovery of the Hexb gene in SD-iPSCs improved this impairment of neuronal differentiation. These results provide new insights as to understanding the complex pathogenic mechanisms of SD. 相似文献
56.
Takeshi Shimamoto Nobutake Yamamichi Shinya Kodashima Yu Takahashi Mitsuhiro Fujishiro Masashi Oka Toru Mitsushima Kazuhiko Koike 《PloS one》2013,8(6)
Probably due to caffeine-induced gastric acid secretion, negative effects of coffee upon various upper-gastrointestinal diseases have been precariously accepted, despite the inadequate epidemiological evidence. Our aim is to evaluate the effect of coffee consumption on four major acid-related diseases: gastric ulcer (GU), duodenal ulcer (DU), reflux esophagitis (RE), and non-erosive reflux disease (NERD) based on the large-scale multivariate analysis. Of the 9,517 healthy adults, GU, DU, and RE were diagnosed by endoscopy, and NERD was diagnosed by the symptoms of heartburn and regurgitation without esophageal erosion. Associations between coffee consumption and the four disorders were evaluated, together with age, gender, body mass index (BMI), Helicobacter pylori (HP) infection status, pepsinogen I/II ratio, smoking, and alcohol. We further performed meta-analysis using the random effects model to redefine the relationship between coffee intake and peptic ulcer disease. The eligible 8,013 study subjects comprised of 5,451 coffee drinkers and 2,562 non-coffee drinkers. By univariate analysis, age, BMI, pepsinogen I/II ratio, smoking, and alcohol showed significant associations with coffee consumption. By multiple logistic regression analysis, positively correlated factors with significance were HP infection, current smoking, BMI, and pepsinogen I/II ratio for GU; HP infection, pepsinogen I/II ratio, and current smoking for DU; HP non-infection, male, BMI, pepsinogen I/II ratio, smoking, age, and alcohol for RE; younger age, smoking, and female for NERD. The meta-analyses could detect any association of coffee consumption with neither GU nor DU. In conclusion, there are no significant relationship between coffee consumption and the four major acid-related upper gastrointestinal disorders. 相似文献
57.
58.
Kosuke Murakami Chie Kurihara Tomoichiro Oka Takashi Shimoike Yoshiki Fujii Reiko Takai-Todaka YoungBin Park Takaji Wakita Tsukasa Matsuda Ryota Hokari Soichiro Miura Kazuhiko Katayama 《PloS one》2013,8(6)
Human noroviruses (NoVs) are a major cause of non-bacterial gastroenteritis. Although histo-blood group antigens (HBGAs) have been implicated in the initial binding of NoV, the mechanism of that binding before internalization is not clear. To determine the involvement of NoVs and HBGAs in cell binding, we examined the localization of NoV virus-like particles (VLPs) and HBGAs in a human intestinal cell line and the human ileum biopsy specimens by immunofluorescence microscopy. The localizations of Ueno 7k VLPs (genogroup II.6) and each HBGA (type H1-, H2- and Leb-HBGAs) on the human intestinal cell line, Caco-2, were examined by confocal laser-scanning microscopy. To explore any interactions of NoVs and HBGAs in vivo, fresh biopsy specimens from human ileum were directly incubated with NoV VLPs and examined by immunofluorescence microscopy. We found that VLP binding depended on the state of cell differentiation, but not on the presence of HBGAs. In differentiated Caco-2 cells, we detected no type H1 HBGAs, but VLPs bound to the cells anyway. We incubated fresh biopsies of human ileum directly with VLPs, a model that better replicates the in vivo environment. VLPs mainly bound epithelial cells and goblet cells. Although the incubations were performed at 4°C to hinder internalization, VLPs were still detected inside cells. Our results suggest that VLPs utilize molecule(s) other than HBGAs during binding and internalization into cells. 相似文献
59.
Yuji Shimizu Mio Nakazato Takaharu Sekita Koichiro Kadota Kazuhiko Arima Hironori Yamasaki Hisashi Goto Satoshi Shirahama Noboru Takamura Kiyoshi Aoyagi Takahiro Maeda 《Journal of physiological anthropology》2013,32(1):19
Background
Previous studies have reported an inverse association between height and risk of cardiovascular disease. However, evidence is limited for the association between risk of atherosclerosis and height. Further, although the association between atherosclerosis and body mass index (BMI) is reportedly positive, there have been no reports of studies on associations between height and atherosclerosis in relation to BMI.Methods
We conducted a cross-sectional study of Japanese men aged 30 to 89 years undergoing general health check-ups.Results
Of the 1,337 men, 312 were diagnosed with carotid atherosclerosis (carotid intima-media thickness (CIMT) ≥ 1.1 mm), but no significant association was found between height and carotid atherosclerosis for the entire study group. Stratification by BMI status of those analytical findings disclosed a significant inverse association between height and carotid atherosclerosis among overweight (BMI ≥ 25 kg/m2) but not among non-overweight (BMI < 25 kg/m2) men. The classical cardiovascular risk factors-adjusted odds ratio (OR) and 95% confidence interval (CI) of carotid atherosclerosis for an increment of one SD (standard deviation) in height (6.70 cm) were 0.71 (0.54 to 0.94) for overweight (BMI ≥ 25 kg/m2) and 1.05 (0.87 to 1.27) for non-overweight (BMI < 25 kg/m2) men.Conclusion
Independent from classical cardiovascular risk factors, height was found to be inversely associated with carotid atherosclerosis for overweight but not for non-overweight men. 相似文献60.
Yasuhito Hamaguchi Manabu Fujimoto Takashi Matsushita Kenzo Kaji Kazuhiro Komura Minoru Hasegawa Masanari Kodera Eiji Muroi Keita Fujikawa Mariko Seishima Hidehiro Yamada Ryo Yamada Shinichi Sato Kazuhiko Takehara Masataka Kuwana 《PloS one》2013,8(4)