全文获取类型
收费全文 | 1192篇 |
免费 | 52篇 |
国内免费 | 2篇 |
专业分类
1246篇 |
出版年
2024年 | 2篇 |
2023年 | 3篇 |
2022年 | 7篇 |
2021年 | 21篇 |
2020年 | 8篇 |
2019年 | 17篇 |
2018年 | 11篇 |
2017年 | 19篇 |
2016年 | 21篇 |
2015年 | 38篇 |
2014年 | 40篇 |
2013年 | 78篇 |
2012年 | 69篇 |
2011年 | 81篇 |
2010年 | 43篇 |
2009年 | 34篇 |
2008年 | 72篇 |
2007年 | 65篇 |
2006年 | 80篇 |
2005年 | 64篇 |
2004年 | 80篇 |
2003年 | 90篇 |
2002年 | 79篇 |
2001年 | 15篇 |
2000年 | 15篇 |
1999年 | 10篇 |
1998年 | 20篇 |
1997年 | 15篇 |
1996年 | 19篇 |
1995年 | 19篇 |
1994年 | 9篇 |
1993年 | 9篇 |
1992年 | 11篇 |
1991年 | 5篇 |
1990年 | 7篇 |
1989年 | 9篇 |
1988年 | 11篇 |
1987年 | 6篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 8篇 |
1981年 | 4篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1974年 | 3篇 |
1959年 | 1篇 |
排序方式: 共有1246条查询结果,搜索用时 0 毫秒
991.
Marumoto Y Terai S Urata Y Matsumoto T Mizunaga Y Yamamoto N Jin H Fujisawa K Murata T Shinoda K Nishina H Sakaida I 《Biochemical and biophysical research communications》2008,367(3):546-552
We have previously shown that infusion of bone marrow cells (BMC) improves CCl4-induced cirrhosis. However, it is unclear why the injected BMC are resistant to CCl4 damage and subsequently improve the local microenvironment in damaged liver. To analyze the cellular phenomena involved in this process, we studied the damaged liver using electron microscopy. We found that CCl4 caused rough endoplasmic reticula to swell in hepatocytes. To analyze the gene expression patterns associated with this process, we conducted PCR-selected suppressive subtractive hybridization. We found that expression levels of HSP84, HSP40, and XBP1 differed markedly between control liver and liver infused with BMC. Immunohistochemical staining revealed that expression levels of HSP84 and HSP40 were markedly higher in the early phase of differentiation immediately after BMC infusion, but decreased over time. XBP1 expression remained high during the late phase, and GRP78 expression increased with XBP1 activation. We also found that GFP-positive BMC expressed XBP1 and GRP78. XBP1 and GRP78 are associated with ER stress. Thus, continuous high XBP1 and GRP78 expression might be essential for the survival and proliferation of BMC in a CCl4-induced persistent liver damage environment. 相似文献
992.
Issei Saeki Takahiro Yamasaki Norikazu Tanabe Takuya Iwamoto Toshihiko Matsumoto Yohei Urata Isao Hidaka Tsuyoshi Ishikawa Taro Takami Naoki Yamamoto Koichi Uchida Shuji Terai Isao Sakaida 《PloS one》2015,10(5)
MethodsWe retrospectively analyzed 90 advanced HCC patients with elevated baseline alpha-fetoprotein (AFP) and/or des-gamma-carboxy prothrombin (DCP) levels and analyzed various parameters for their possible use as predictors of response and survival. AFP and DCP responses were assessed after half a course of HAIC (2 weeks); a positive-response was defined as a reduction of ≥ 20% from baseline.ResultsMultivariate analysis identified DCP response (odds ratio 16.03, p < 0.001) as an independent predictor of treatment response. In multivariate analysis, Child-Pugh class A (hazard ratio [HR] 1.99, p = 0.018), AFP response (HR 2.17, p = 0.007), and DCP response (HR 1.90, p = 0.030) were independent prognostic predictors. We developed an Assessment for Continuous Treatment with HAIC (ACTH) score, including the above 3 factors, which ranged from 0 to 3. Patients stratified into two groups according to this score showed significantly different prognoses (≤1 vs. ≥2 points: median survival time, 15.1 vs. 8.7 months; p = 0.003).ConclusionsThe ACTH score may be useful in the therapeutic assessment of HCC patients receiving HAIC. 相似文献
993.
Takahito Miyake Hisashi Shirakawa Ayaka Kusano Shinya Sakimoto Masakazu Konno Takayuki Nakagawa Yasuo Mori Shuji Kaneko 《Biochemical and biophysical research communications》2014
Microglia are immune cells that maintain brain homeostasis at a resting state by surveying the environment and engulfing debris. However, in some pathological conditions, microglia can produce neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO) that lead to neuronal degeneration. Inflammation-induced calcium (Ca2+) signaling is thought to underlie this abnormal activation of microglia, but the mechanisms are still obscure. We previously showed that combined application of lipopolysaccharide and interferon γ (LPS/IFNγ) induced-production of NO in microglia from wild-type (WT) mice is significantly reduced in microglia from transient receptor potential melastatin 2 (TRPM2)-knockout (KO) mice. Here, we found that LPS/IFNγ produced a late-onset Ca2+ signaling in WT microglia, which was abolished by application of the NADPH oxidase inhibitor diphenylene iodonium (DPI) and ML-171. In addition, pharmacological blockade or gene deletion of TRPM2 channel in microglia did not show this Ca2+ signaling. Furthermore, pharmacological manipulation and Western blotting revealed that Ca2+ mobilization, the proline-rich tyrosine kinase 2 (Pyk2), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) contributed to TRPM2-mediated LPS/IFNγ-induced activation, while the extracellular signal-regulated protein kinase (ERK) did not. These results suggest that LPS/IFNγ activates TRPM2-mediated Ca2+ signaling, which in turn increases downstream p38 MAPK and JNK signaling and results in increased NO production in microglia. 相似文献
994.
Kikuchi R Sobue S Murakami M Ito H Kimura A Iwasaki T Shibayama S Takagi A Kojima T Suzuki M Banno Y Nozawa Y Murate T 《FEBS letters》2007,581(9):1800-1804
1α,25-Dihydroxyvitamin D3 (VitD3) increases protein and gene expression of phospholipase D1 (PLD1), but not PLD2, in HaCaT human keratinocytes. We show that VitD3 increases PLD1 gene expression through a vitamin D responsive element (VDRE) on the 5′ PLD1 promoter (−260 bp to −246 bp from exon 1). Similar results were obtained by transfecting VitD3 receptor (VDR) into HEK293 cells, which are originally VitD3-unresponsive. Electrophoresis mobility shift assays (EMSA) and chromatin immunoprecipitation (CHIP) assays showed that the complex of VitD3, VDR and retinoid X receptor α (RXRα) binds to the VDRE and increases PLD1 gene expression in HaCaT cells. 相似文献
995.
Haramoto Y Takahashi S Asashima M 《Biochemical and biophysical research communications》2006,346(2):470-478
The transforming growth factor-beta (TGF-beta) superfamily member, Xenopus nodal-related 3 (Xnr3), induces neural tissues through inhibition of bone morphogenetic proteins (BMPs). We recently identified an inhibitory mechanism in which the pro-region of Xenopus tropicalis nodal-related 3 (Xtnr3) physically interacts with BMP ligands. Here, we show that disulfide-linked heterodimerization does not contribute to BMP inhibition by Xtnr3 and that the Xtnr3 mature region, overexpression of which can induce the same phenotype as full-length Xtnr3, does not inhibit BMP signaling. Furthermore, we find that the BMP-inhibitory domains of Xtnr3 are separately located in the N- and C-terminal regions of the pro-region. These results indicate the pro-region of Nodal-related 3 is both necessary and sufficient for its BMP inhibition. 相似文献
996.
Nobuhiro Hiraishi Shuji Kanmura Kouhei Oda Shiho Arima Kotaro Kumagai Seiichi Mawatari Shiroh Tanoue Fumisato Sasaki Shinichi Hashimoto Akio Ido 《Biochemistry and Biophysics Reports》2019
Colorectal cancer is a multi-factorial disease involving genetic, environmental and lifestyle risk factors. In recent years, many changes in the bacterial composition of the intestinal microflora have been reported in colorectal cancer, suggesting the involvement of the intestinal microflora in the development and progression of colorectal cancer. Along with these reports, research on lactic acid bacteria that have a beneficial effect on the human body for the purpose of improving the intestinal environment and treating intestinal diseases has advanced. Among these studies, biogenics (defined as a component derived from lactic acid bacteria that acts directly on diseases regardless of the state of intestinal microflora) is a recent concept derived from the work on probiotics. Based on this concept, it is important to evaluate the effectiveness of various components derived from lactic acid bacteria in the treatment to diseases from and apply them in prevention and treatment. In this study, we investigated the antitumor effect of an extract obtained from Lactobacillus plantarum strain 06CC2 on colorectal cancer cells. In in vitro experiments, the extract derived from Lactobacillus plantarum 06CC2 significantly suppressed the proliferation of Caco2 colorectal cancer cells in comparison to control and non-cancer cells. Furthermore, we found that endoplasmic reticulum stress and the JNK/p38 MAPK signaling system are involved in the induction of apoptosis. These findings indicate the direct antitumor effect of the Lactobacillus plantarum 06CC2 extract on Caco2 colorectal cancer cells, and that this extract may have potential application as a biogenics. 相似文献
997.
Masami Iida Akira Endo Shuji Fujita Masaaki Numata Kazuo Suzuki Shigeki Nunomura Tomoya Ogawa 《Glycoconjugate journal》1996,13(2):203-211
The first total synthesis of glycononaosyl ceramide with a sialyl dimeric Lex sequence 1 is described. Regio- and stereo-selective glycosylations of sialyl donors 6,7,8 with the suitably protected Lex trisaccharide acceptors 9,10 were performed to give the expected tetrasaccharides 15 and 21, which were converted into the corresponding donors 20 and 22. Boron trifluoride etherate-promoted glycosylation of 20 with pentasaccharide acceptor 11 afforded regioselectively the expected nonasaccharide 23. After replacing benzyl groups of 23 by acetyl groups, the anomeric acetate was transformed into the -trichloroacetimidate 27. The crucial coupling between 27 and (2S, 3R, 4E-3-O-benzoyl-2-N-tetracosanoylsphingenine 3 was executed to afford completely protected -glycoside 28. Finally, selective cleavage of the methyl ester and N,O-deprotection of 28 gave the target ganglioside 1.Dedicated to Professor Sen-itiroh Hakomori on the occasion of his 65th birthday. 相似文献
998.
Kotaro Kumagai Kazuaki Tabu Fumisato Sasaki Yoichiro Takami Yuko Morinaga Seiichi Mawatari Shinichi Hashimoto Shiroh Tanoue Shuji Kanmura Tsutomu Tamai Akihiro Moriuchi Hirofumi Uto Hirohito Tsubouchi Akio Ido 《PloS one》2015,10(11)
Background and aims
Glycoprotein nonmetastatic melanoma B (Gpnmb), a transmembrane glycoprotein that is expressed in macrophages, negatively regulates inflammation. We have reported that Gpnmb is strongly expressed in the livers of rats fed a choline-deficient, L-amino acid-defined (CDAA) diet. However, the role of macrophage-expressed Gpnmb in liver injury is still unknown. This study aimed to clarify the characteristics of infiltrating macrophages that express Gpnmb, and the involvement of Gpnmb in the repair process in response to liver injury.Methods
C57BL/6J, DBA/2J [DBA] and DBA/2J-Gpnmb+ [DBA-g+] mice were treated with a single intraperitoneal injection of carbon tetrachloride (CCl4) at a dose of 1.0 mL/kg body weight. Mice were sacrificed at predetermined time points, followed by measurement of serum alanine aminotransferase (ALT) levels and histological examination. Expression of Gpnmb, pro-/anti-inflammatory cytokines, and profibrotic/antifibrotic factors were examined by quantitative RT-PCR and/or Western blotting. Immunohistochemistry, fluorescent immunostaining and flow cytometry were used to determine the expression of Gpnmb, CD68, CD11b and α-SMA, phagocytic activity, and the presence of apoptotic bodies. We used quantitative RT-PCR and ELISA to examine TGF-β and MMP-13 expression and the concentrations and supernatants of isolated infiltrating hepatic macrophages transfected with siGpnmb.Results
In C57BL/6J mice, serum ALT levels increased at two days after CCl4 injection and decreased at four days. Gpnmb expression in the liver was stimulated four days after CCl4 injection. Histological examination and flow cytometry showed that Gpnmb-positive cells were almost positive for CD68-positive macrophages, contained engulfed apoptotic bodies and exhibited enhanced phagocytic activity. Isolated infiltrating hepatic macrophages transfected with siGpnmb showed high MMP-13 secretion. There was no significant difference in the magnitude of CCl4-induced liver injury between DBA-g+ and DBA mice. However, hepatic MMP-13 expression, as well as α-SMA expression and collagen production, increased significantly in DBA-g+ compared with DBA mice.Conclusions
Gpnmb-positive macrophages infiltrate the liver during the recovery phase of CCl4–induced acute liver injury and contribute to the balance between fibrosis and fibrolysis in the repair process following acute liver injury. 相似文献999.
Trehalose is a disaccharide of glucose found in diverse organisms and is suggested to act as a stress protectant against heat, cold, desiccation, anoxia, and oxidation. Here, we demonstrate that treatment of Caenorhabditis elegans with trehalose starting from the young‐adult stage extended the mean life span by over 30% without any side effects. Surprisingly, trehalose treatment starting even from the old‐adult stage shortly thereafter retarded the age‐associated decline in survivorship and extended the remaining life span by 60%. Demographic analyses of age‐specific mortality rates revealed that trehalose extended the life span by lowering age‐independent vulnerability. Moreover, trehalose increased the reproductive span and retarded the age‐associated decrease in pharyngeal‐pumping rate and the accumulation of lipofuscin autofluorescence. Trehalose also enhanced thermotolerance and reduced polyglutamine aggregation. These results suggest that trehalose suppressed aging by counteracting internal or external stresses that disrupt protein homeostasis. On the other hand, the life span‐extending effect of trehalose was abolished in long‐lived insulin/IGF‐1‐like receptor (daf‐2) mutants. RNA interference‐mediated inactivation of the trehalose‐biosynthesis genes trehalose‐6‐phosphate synthase‐1 (tps‐1) and tps‐2, which are known to be up‐regulated in daf‐2 mutants, decreased the daf‐2 life span. These findings indicate that a reduction in insulin/IGF‐1‐like signaling extends life span, at least in part, through the aging‐suppressor function of trehalose. Trehalose may be a lead compound for potential nutraceutical intervention of the aging process. 相似文献
1000.
Junko Tomizuka Shuji Tachibanaki Satoru Kawamura 《The Journal of biological chemistry》2015,290(15):9399-9411
Visual pigment in photoreceptors is activated by light. Activated visual pigment (R*) is believed to be inactivated by phosphorylation of R* with subsequent binding of arrestin. There are two types of photoreceptors, rods and cones, in the vertebrate retina, and they express different subtypes of arrestin, rod and cone type. To understand the difference in the function between rod- and cone-type arrestin, we first identified the subtype of arrestins expressed in rods and cones in carp retina. We found that two rod-type arrestins, rArr1 and rArr2, are co-expressed in a rod and that a cone-type arrestin, cArr1, is expressed in blue- and UV-sensitive cones; the other cone-type arrestin, cArr2, is expressed in red- and green-sensitive cones. We quantified each arrestin subtype and estimated its concentration in the outer segment of a rod or a cone in the dark; they were ∼0.25 mm (rArr1 plus rArr2) in a rod and 0.6–0.8 mm (cArr1 or cArr2) in a cone. The effect of each arrestin was examined. In contrast to previous studies, both rod and cone arrestins suppressed the activation of transducin in the absence of visual pigment phosphorylation, and all of the arrestins examined (rArr1, rArr2, and cArr2) bound transiently to most probably nonphosphorylated R*. One rod arrestin, rArr2, bound firmly to phosphorylated pigment, and the other two, rArr1 and cArr2, once bound to phosphorylated R* but dissociated from it during incubation. Our results suggested a novel mechanism of arrestin effect on the suppression of the R* activity in both rods and cones. 相似文献