全文获取类型
收费全文 | 1015篇 |
免费 | 45篇 |
国内免费 | 2篇 |
出版年
2022年 | 9篇 |
2021年 | 12篇 |
2020年 | 9篇 |
2019年 | 12篇 |
2018年 | 19篇 |
2017年 | 9篇 |
2016年 | 27篇 |
2015年 | 33篇 |
2014年 | 37篇 |
2013年 | 67篇 |
2012年 | 62篇 |
2011年 | 50篇 |
2010年 | 31篇 |
2009年 | 38篇 |
2008年 | 50篇 |
2007年 | 43篇 |
2006年 | 50篇 |
2005年 | 50篇 |
2004年 | 51篇 |
2003年 | 45篇 |
2002年 | 43篇 |
2001年 | 30篇 |
2000年 | 28篇 |
1999年 | 28篇 |
1998年 | 10篇 |
1997年 | 12篇 |
1996年 | 5篇 |
1995年 | 11篇 |
1994年 | 9篇 |
1993年 | 6篇 |
1992年 | 17篇 |
1991年 | 9篇 |
1990年 | 15篇 |
1989年 | 25篇 |
1988年 | 12篇 |
1987年 | 17篇 |
1986年 | 5篇 |
1985年 | 14篇 |
1984年 | 7篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1981年 | 6篇 |
1980年 | 4篇 |
1979年 | 8篇 |
1978年 | 4篇 |
1976年 | 4篇 |
1975年 | 8篇 |
1965年 | 1篇 |
1963年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有1062条查询结果,搜索用时 818 毫秒
141.
Hideaki Fujii Satomi Imaide Shigeto Hirayama Toru Nemoto Hiroaki Gouda Shuichi Hirono Hiroshi Nagase 《Bioorganic & medicinal chemistry letters》2012,22(24):7711-7714
To clarify the essential structures of an opioid κ receptor selective agonist, nalfurafine, for binding to the κ receptor, we designed and synthesized the decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position. The introduction of a hydroxy group to the derivatives increased the affinity and selectivity to the κ receptor regardless of the configuration at the 3-position. However, their affinities were lower than those of nalfurafine with the phenolic hydroxy group. The results suggested that the acidity of the hydroxy group would play an important role in the interaction with the opioid receptor. The low affinities of the 3-keto derivatives indicated that the 3-hydroxy group may participate in the hydrogen bonding with the receptor site not as a hydrogen acceptor but as a hydrogen donor. This is the first experimental evidence for a role as a hydrogen donor for the 3-hydroxy group in morphinans. Furthermore, the κ selectivities in these derivatives with the 6α-amide side chain were affected by the the 3-hydroxy group. The obtained structure–activity relationship information is expected to be useful for the design of more selective ligands for the κ receptor. 相似文献
142.
A new sesquiterpene glycoside, (?)-epi-α-bisabolol 6-deoxy-β-d-gulopyranodide (1), has been isolated from the glandular trichome exudate of Brillantaisia owariensis (Acanthaceae). The structure of compound 1 was determined by spectroscopic analysis as well as acidic hydrolysis of 1 leading to (?)-epi-α-bisabolol (2) and 6-deoxy-d-gulose (3). This is the first study to analyze secondary metabolites from glandular trichome exudates of plants belonging to the Acanthaceae family. 6-Deoxygulopyranoside is the first example of an epi-α-bisabolol glycoside of plant origin. 相似文献
143.
Furuta T Murao LA Lan NT Huy NT Huong VT Thuy TT Tham VD Nga CT Ha TT Ohmoto Y Kikuchi M Morita K Yasunami M Hirayama K Watanabe N 《PLoS neglected tropical diseases》2012,6(2):e1505
Background
Recent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase) and -related cytokines (IL-4, -9, and -17) between patients with differing severity of Dengue fever and healthy controls.Methodology/Principal Findings
The study was performed at Children''s Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF), Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS), as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9.Conclusions
As mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity. 相似文献144.
Yasuyuki Fujii Hidenori OhtakeNaoya Ono Toshifumi HaraTakanobu Sakurai Syuya TakahashiTetsuo Takayama Yoshiki FukasawaFumiyasu Shiozawa Narutoshi TsukaharaTakehiro Hirayama Yasuyuki IgarashiRyo Goitsuka 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2012,1821(4):600-606
Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking via type-1 S1P receptor (S1P1) and participates in many pathological conditions. We developed a novel type S1P1-selective antagonist, TASP0251078, which is structurally unrelated to S1P. This competitive antagonist inhibited binding of S1P to S1P1 resulting in reduced signaling downstream of S1P1, including GTPγS-binding and cAMP formation. TASP0251078 also inhibited S1P-induced cellular responses such as chemotaxis and receptor-internalization. Furthermore, when administered in vivo, TASP0251078 induced lymphopenia in blood, which is different from previously reported effects of other S1P1-antagonists. In a mouse contact hypersensitivity model, TASP0251078 effectively suppressed ear swelling, leukocyte infiltration, and hyperplasia. These findings provide the chemical evidence that S1P1 antagonism is responsible for lymphocyte sequestration from the blood, and suggest that the effect of S1P1 agonists on lymphocyte sequestration results from their functional antagonism. 相似文献
145.
Nguyen Tien Huy Nguyen Thanh Hong Thao Nguyen Anh Tuan Nguyen Tuan Khiem Christopher C. Moore Doan Thi Ngoc Diep Kenji Hirayama 《PloS one》2012,7(11)
Background and Purpose
Successful outcomes from bacterial meningitis require rapid antibiotic treatment; however, unnecessary treatment of viral meningitis may lead to increased toxicities and expense. Thus, improved diagnostics are required to maximize treatment and minimize side effects and cost. Thirteen clinical decision rules have been reported to identify bacterial from viral meningitis. However, few rules have been tested and compared in a single study, while several rules are yet to be tested by independent researchers or in pediatric populations. Thus, simultaneous test and comparison of these rules are required to enable clinicians to select an optimal diagnostic rule for bacterial meningitis in settings and populations similar to ours.Methods
A retrospective cross-sectional study was conducted at the Infectious Department of Pediatric Hospital Number 1, Ho Chi Minh City, Vietnam. The performance of the clinical rules was evaluated by area under a receiver operating characteristic curve (ROC-AUC) using the method of DeLong and McNemar test for specificity comparison.Results
Our study included 129 patients, of whom 80 had bacterial meningitis and 49 had presumed viral meningitis. Spanos''s rule had the highest AUC at 0.938 but was not significantly greater than other rules. No rule provided 100% sensitivity with a specificity higher than 50%. Based on our calculation of theoretical sensitivity and specificity, we suggest that a perfect rule requires at least four independent variables that posses both sensitivity and specificity higher than 85–90%.Conclusions
No clinical decision rules provided an acceptable specificity (>50%) with 100% sensitivity when applying our data set in children. More studies in Vietnam and developing countries are required to develop and/or validate clinical rules and more very good biomarkers are required to develop such a perfect rule. 相似文献146.
Yoshihiro Ida Ayaka Matsubara Toru Nemoto Manabu Saito Shigeto Hirayama Hideaki Fujii Hiroshi Nagase 《Bioorganic & medicinal chemistry》2012,20(19):5810-5831
We have reported previously the novel δ opioid agonist KNT-127 which showed high affinity and selectivity for the δ receptor. Moreover, the analgesic effect of subcutaneously administered KNT-127 was more potent than that of a prototypical δ agonist (?)-TAN-67 in the acetic acid writhing test. This study of the structure–activity relationship of KNT-127 derivatives focused on the introduction of substituents onto the 5′-, 6′-, 7′- or 8′-position of the quinoline ring and revealed that many derivatives with 5′- or 8′-substituents showed high affinities and selectivities for the δ receptor. Especially, SYK-153 with an 8′-OH group showed the highest affinity and the most balanced and highest selectivity for the δ receptor among the synthesized compounds. 相似文献
147.
Ni Hou Hideo Mogami Chisato Kubota-Murata Meng Sun Toshiyuki Takeuchi Seiji Torii 《PloS one》2012,7(10)
Newly synthesized hormones have been suggested to be preferentially secreted by various neuroendocrine cells. This observation indicates that there is a distinct population of secretory granules containing new and old hormones. Recent development of fluorescent timer proteins used in bovine adrenal chromaffin cells revealed that secretory vesicles segregate into distinct age-dependent populations. Here, we verify the preferential release of newly synthesized insulin in the pancreatic β-cell line, MIN6, using a combination of multi-labeling reporter systems with both fluorescent and biochemical procedures. This system allows hormones or granules of any age to be labeled, in contrast to the timer proteins, which require fluorescence shift time. Pulse-chase labeling with different color probes distinguishes insulin secretory granules by age, with younger granules having a predominantly intracellular localization rather than at the cell periphery. 相似文献
148.
How Drugs Interact with Transporters: SGLT1 as a Model 总被引:1,自引:0,他引:1
Drugs are transported by cotransporters with widely different turnover rates. We have examined the underlying mechanism using, as a model system, glucose and indican (indoxyl-beta-D: -glucopyranoside) transport by human Na(+)/glucose cotransporter (hSGLT1). Indican is transported by hSGLT1 at 10% of the rate for glucose but with a fivefold higher apparent affinity. We expressed wild-type hSGLT1 and mutant G507C in Xenopus oocytes and used electrical and optical methods to measure the kinetics of glucose (using nonmetabolized glucose analogue alpha-methyl-D: -glucopyranoside, alphaMDG) and indican transport, alone and together. Indican behaved as a competitive inhibitor of alphaMDG transport. To examine protein conformations, we recorded SGLT1 capacitive currents (charge movements) and fluorescence changes in response to step jumps in membrane voltage, in the presence and absence of indican and/or alphaMDG. In the absence of sugar, voltage jumps elicited capacitive SGLT currents that decayed to steady state with time constants (tau) of 3-20 ms. These transient currents were abolished in saturating alphaMDG but only slightly reduced (10%) in saturating indican. SGLT1 G507C rhodamine fluorescence intensity increased with depolarizing and decreased with hyperpolarizing voltages. Maximal fluorescence increased approximately 150% in saturating indican but decreased approximately 50% in saturating alphaMDG. Modeling indicated that the rate-limiting step for indican transport is sugar translocation, whereas for alphaMDG it is dissociation of Na(+) from the internal binding sites. The inhibitory effects of indican on alphaMDG transport are due to its higher affinity and a 100-fold lower translocation rate. Our results indicate that competition between substrates and drugs should be taken into consideration when targeting transporters as drug delivery systems. 相似文献
149.
Abstract We identified a novel neural cell adhesion molecule (NCAM)-associated protein, myo genesis-related and N CAM- a ssociated p rotein (MYONAP), the expression of which increases during the formation of myotubes in quail myoblasts transformed with a temperature-sensitive mutant of Rous sarcoma virus (QM-RSV cells). MYONAP shares homology with PL48 in human cytotrophoblasts and KIAA0386 in human brain. Excess expression of MYONAP in presumptive QM-RSV myoblasts induced long protrusions like neurites in cooperation with microtubules. Suppression of MYONAP by antisense cDNA prevented myotubes from forming in spite of the expression of myogenin, creatine kinase, and myosin, and rendered myoblast membranes resistant to fusion. Yeast two-hybrid screening showed that MYONAP interacted with NCAM specifically. Deletion of the NCAM-associated domain resulted in a loss of the function that induces neurite-like protrusions to form and disturbed the elongation of microtubules. The results suggested that MYONAP influenced the functions of microtubules and was involved in the formation of myotubes via its interaction with NCAM. 相似文献
150.