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101.
Koichiro Harada Hideki Kubo Yoshitaka Tomigahara Kazuhiko Nishioka Junya Takahashi Mio Momose Shinichi Inoue Atsuyuki Kojima 《Bioorganic & medicinal chemistry letters》2010,20(1):272-275
The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17β-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17β-HSD isoenzymes and nuclear receptors. 相似文献
102.
103.
Satoi Nagasawa Anna S. Sedukhina Yuko Nakagawa Ichiro Maeda Manabu Kubota Shigeko Ohnuma Koichiro Tsugawa Tomohiko Ohta Marta Roche-Molina Juan A. Bernal Ana J. Narváez Anand D. Jeyasekharan Ko Sato 《PloS one》2015,10(2)
LSD1, a lysine-specific histone demethylase, is overexpressed in several types of cancers and linked to poor outcomes. In breast cancer, the significance of LSD1 overexpression is not clear. We have performed an in silico analysis to assess the relationship of LSD1 expression to clinical outcome. We demonstrate that LSD1 overexpression is a poor prognostic factor in breast cancer, especially in basal-like breast cancer, a subtype of breast cancer with aggressive clinical features. This link is also observed in samples of triple negative breast cancer. Interestingly, we note that overexpression of LSD1 correlates with down-regulation of BRCA1 in triple negative breast cancer. This phenomenon is also observed in in vitro models of basal-like breast cancer, and is associated with an increased sensitivity to PARP inhibitors. We propose therefore that high expression levels of the demethylase LSD1 is a potential prognostic factor of poor outcome in basal-like breast cancer, and that PARP inhibition may be a therapeutic strategy of interest in this poor prognostic subtype with overexpression of LSD1. 相似文献
104.
Riki Okita Diana Wolf Koichiro Yasuda Ai Maeda Takuro Yukawa Shinsuke Saisho Katsuhiko Shimizu Yoshiyuki Yamaguchi Mikio Oka Eiichi Nakayama Andreas Lundqvist Rolf Kiessling Barbara Seliger Masao Nakata 《PloS one》2015,10(10)
IntroductionSeveral cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown.MethodsThis study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis.ResultsWe demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a.ConclusionIn keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells. 相似文献
105.
Toshio Watanabe Toshihisa Takeuchi Osamu Handa Yasuhisa Sakata Tetsuya Tanigawa Masatsugu Shiba Yuji Naito Kazuhide Higuchi Kazuma Fujimoto Toshikazu Yoshikawa Tetsuo Arakawa 《PloS one》2015,10(4)
Background
Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant.Aim
We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy.Methods
We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks.Results
The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated.Conclusions
High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.Trial Registration
UMIN Clinical Trials Registry UMIN000003463 相似文献106.
Yuji Shimizu Koichiro Kadota Jun Koyamatsu Hirotomo Yamanashi Mako Nagayoshi Miki Noda Takayuki Nishimura Jun Tayama Yasuhiro Nagata Takahiro Maeda 《Journal of physiological anthropology》2015,34(1)
Background
Activated mineralocorticoid receptors influence the association between daily salt intake and blood pressure. A relatively low mineralocorticoid receptor function is reported to be a risk for mental distress such as depression. Since mental distress is also a known risk for hypertension and cardiovascular disease, understanding of the association between estimated daily salt intake and mental distress contributing to hypertension is important for risk estimation for cardiovascular disease. However, no single study has reported this association.Methods
We conducted a cross-sectional study of 1014 Japanese men undergoing general health check-ups. Mental distress was diagnosed as a Kessler 6 scale score ≥5. We also classified mental distress by levels of hypertension. Estimated daily salt intake was calculated from a causal urine specimen.Results
Independent from classical cardiovascular risk factors and thyroid disease, we found a significant inverse association between estimated daily salt intake and mental distress. When we analyzed for mental distress and hypertension, we also found a significant association. With the reference group being the lowest tertiles of estimated daily salt intake, the multivariable odds ratios (ORs) of mental distress and mental distress with hypertension for the highest tertiles were 0.50 (0.29–0.88) and 0.46 (0.22–0.96).Conclusions
Lower estimated daily salt intake is a significant risk of mental distress for rural community-dwelling Japanese men. Since depression is reported to be associated with cardiovascular disease, risk estimation for the lower intake of salt on mental distress, especially for mental distress with hypertension, may become an important tool to prevent cardiovascular disease. 相似文献107.
The impact of masticatory ability as evaluated by salivary flow rates on obesity in japanese: The Toon health study
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108.
109.
Yasuhiro Moriwaki Kiyoko Takada Toshinori Nagasaki Natsuki Kubo Tomohiro Ishii Kazuaki Kose Taihei Kageyama Shoutaro Tsuji Koichiro Kawashima Hidemi Misawa 《PloS one》2015,10(10)
Background
SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown.Objectives
Our aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs).Results
SLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus), which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus.Conclusions
These results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus. 相似文献110.
Hiroyuki Imai Kiyoshi Kano Wataru Fujii Ken Takasawa Shoichi Wakitani Masato Hiyama Koichiro Nishino Ken Takeshi Kusakabe Yasuo Kiso 《PloS one》2015,10(6)
Polyploid amphibians and fishes occur naturally in nature, while polyploid mammals do not. For example, tetraploid mouse embryos normally develop into blastocysts, but exhibit abnormalities and die soon after implantation. Thus, polyploidization is thought to be harmful during early mammalian development. However, the mechanisms through which polyploidization disrupts development are still poorly understood. In this study, we aimed to elucidate how genome duplication affects early mammalian development. To this end, we established tetraploid embryonic stem cells (TESCs) produced from the inner cell masses of tetraploid blastocysts using electrofusion of two-cell embryos in mice and studied the developmental potential of TESCs. We demonstrated that TESCs possessed essential pluripotency and differentiation potency to form teratomas, which differentiated into the three germ layers, including diploid embryonic stem cells. TESCs also contributed to the inner cell masses in aggregated chimeric blastocysts, despite the observation that tetraploid embryos fail in normal development soon after implantation in mice. In TESCs, stability after several passages, colony morphology, and alkaline phosphatase activity were similar to those of diploid ESCs. TESCs also exhibited sufficient expression and localization of pluripotent markers and retained the normal epigenetic status of relevant reprogramming factors. TESCs proliferated at a slower rate than ESCs, indicating that the difference in genomic dosage was responsible for the different growth rates. Thus, our findings suggested that mouse ESCs maintained intrinsic pluripotency and differentiation potential despite tetraploidization, providing insights into our understanding of developmental elimination in polyploid mammals. 相似文献