全文获取类型
收费全文 | 1135篇 |
免费 | 70篇 |
国内免费 | 1篇 |
出版年
2024年 | 2篇 |
2023年 | 4篇 |
2022年 | 9篇 |
2021年 | 22篇 |
2020年 | 14篇 |
2019年 | 16篇 |
2018年 | 32篇 |
2017年 | 22篇 |
2016年 | 33篇 |
2015年 | 59篇 |
2014年 | 75篇 |
2013年 | 77篇 |
2012年 | 83篇 |
2011年 | 79篇 |
2010年 | 45篇 |
2009年 | 54篇 |
2008年 | 61篇 |
2007年 | 82篇 |
2006年 | 44篇 |
2005年 | 51篇 |
2004年 | 54篇 |
2003年 | 48篇 |
2002年 | 37篇 |
2001年 | 28篇 |
2000年 | 31篇 |
1999年 | 22篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 5篇 |
1993年 | 2篇 |
1992年 | 11篇 |
1991年 | 6篇 |
1990年 | 9篇 |
1989年 | 16篇 |
1988年 | 5篇 |
1987年 | 10篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 7篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1976年 | 3篇 |
1973年 | 2篇 |
1971年 | 3篇 |
1970年 | 1篇 |
1965年 | 2篇 |
1934年 | 1篇 |
排序方式: 共有1206条查询结果,搜索用时 15 毫秒
991.
992.
Structure–activity relationships of heteroaromatic esters as human rhinovirus 3C protease inhibitors
Isak Im Eui Seung Lee Soo Jeong Choi Ju-Yeon Lee Yong-Chul Kim 《Bioorganic & medicinal chemistry letters》2009,19(13):3632-3636
Human rhinovirus 3C protease (HRV 3Cpro) is known to be a promising target for development of therapeutic agents against the common cold because of the importance of the protease in viral replication as well as its expression in a large number of serotypes. To explore non-peptidic inhibitors of HRV 3Cpro, a series of novel heteroaromatic esters was synthesized and evaluated for inhibitory activity against HRV 3Cpro, to determine the structure–activity relationships. The most potent inhibitor, 7, with a 5-bromopyridinyl group, had an IC50 value of 80 nM. In addition, the binding mode of a novel analog, 19, with the 4-hydroxyquinolinone moiety, was explored by molecular docking, suggesting a new interaction in the S1 pocket. 相似文献
993.
Geetha Velmourougane Ravinder Raju Gabriel Bricard Jin S. Im Gurdyal S. Besra Steven A. Porcelli Amy R. Howell 《Bioorganic & medicinal chemistry letters》2009,19(13):3386-3388
An α-galactosyl ceramide (α-GalCer) 2 was synthesized and evaluated for its ability to stimulate iNKT-cell proliferation and elicit T-helper cytokines, IL-4 and IFNγ. Compound 2 combines the acyl chain of the potent, Th2 biasing α-GalCer 1 with a sphingoid base of the same length as that found in OCH, which also exhibits Th2 skewing, Such complementation may enhance cytokine bias, which is thought to be important for therapeutic applications of iNKT cell stimulation. Two related α-GalCers, 3 and 4, with saturated acyl chains were prepared for comparison. 相似文献
994.
The carbazole assay has been used for determination of the percentage of hyaluronic acid in biological fluids. However, it is difficult to measure the concentration of hyaluronic acid in culture broth because glucose and polysaccharides remaining after cultures can react with sulfuric acid and carbazole. The glucose and polysaccharide remnants must be completely removed in order to get the correct value for hyaluronic acid. The turbidity assay, another method for estimating the concentration of hyaluronic acid, is based on the formation of insoluble complexes between hyaluronic acid and cetyltrimethylammonium bromide. This method is very easy and fast compared with the carbazole assay. Because concentrations of hyaluronic acid measured by the turbidity assay were ranged around 100% of those measured by the carbazole assay, the content of hyaluronic acid in culture broth can be determined by the turbidity assay. The turbidity method also has the advantage of being safer than the carbazole assay. 相似文献
995.
Young-Jae Kim Oyunbileg Galindev Jun Han Sei Su-Mi Bae Hosub Im Lanying Wen Young Rok Seo Woong Shick Ahn 《Biological trace element research》2009,131(2):103-109
Of trace elements in the serum of living organisms, selenium (Se) is an essential mineral and plays the role of an antioxidant
as selenoproteins protecting the organism against oxidative damage induced by hydrogen peroxide, other lipid hydroperoxides,
and their derivatives. The aim of this study was to determine the mean serum Se levels in healthy Korean volunteers (50 males
and 50 females) by using an inductively coupled plasma-mass spectrometry method. The samples were collected at the Health
Promotion Centre of Kangnam St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Kangnam District,
Seoul in accordance with procedures approved by the Institutional Review Board of the Catholic University of Korea. The mean
serum Se level in healthy subjects was 112.05 ± 30.42 μg/l. For gender, it was 120.81 ± 27.37 μg/l for females and 103.29 ± 31.05 μg/l
for males. From the study result, there was a significant difference between the mean Se concentrations of gender groups (p = 0.0035). Also, the study indicated no effect of age on Se levels (p > 0.05) in the healthy individuals. 相似文献
996.
Amanda Reider Sarah L Barker Sanjay K Mishra Young Jun Im Lymarie Maldonado‐Báez James H Hurley Linton M Traub Beverly Wendland 《The EMBO journal》2009,28(20):3103-3116
Internalization of diverse transmembrane cargos from the plasma membrane requires a similarly diverse array of specialized adaptors, yet only a few adaptors have been characterized. We report the identification of the muniscin family of endocytic adaptors that is conserved from yeast to human beings. Solving the structures of yeast muniscin domains confirmed the unique combination of an N‐terminal domain homologous to the crescent‐shaped membrane‐tubulating EFC/F‐BAR domains and a C‐terminal domain homologous to cargo‐binding μ homology domains (μHDs). In vitro and in vivo assays confirmed membrane‐tubulation activity for muniscin EFC/F‐BAR domains. The μHD domain has conserved interactions with the endocytic adaptor/scaffold Ede1/eps15, which influences muniscin localization. The transmembrane protein Mid2, earlier implicated in polarized Rho1 signalling, was identified as a cargo of the yeast adaptor protein. These and other data suggest a model in which the muniscins provide a combined adaptor/membrane‐tubulation activity that is important for regulating endocytosis. 相似文献
997.
Hye-Ryun Kim So-Hee Jeong Young-Sam Im Sung Yun Cho Joong-Kwon Choi Hea Kyeong Shin Yong-Min Kim Jin-Ook Song Seong-Ho Jeon Joong-Kook Choi 《Genes & genomics.》2009,31(3):261-266
Purmorphamine is a purine analog and it affects osteogenesis, in part, through the modulation of Sonic Hedgehog signaling pathway. However, the underlying mechanism has remained elusive. Previously, we identified two purmorphamine derivatives that modulate the expression of osteogenic markers includingRunx2, Dlx2 andHes1. However, the extents of osteogenesis varied depending on the assay employed, and this necessitates the identification of reliable markers. Here, we report that the expression of osteocalcin was most sensitive to the treatment of purmorphamine derivatives among genes we analyzed by RT-PCR. Purmorphamine derivatives differentially modulated the expression of early and late osteogenic markers; alkaline phosphatase and osteocalcin gene respectively. In addition, the expression of osteocalcin is also modulated differentially by purmorphamine derivatives over time. Although JNK activity is reported to be necessary for osteocalcin expression, its requirement varied among purmorphamine derivatives. Also the overall cytotoxic response to purmorphamine derivatives appeared slightly different. 相似文献
998.
Yoon Jeong Choi Eunok Im Hyo Kyun Chung Charalabos Pothoulakis Sang Hoon Rhee 《The Journal of biological chemistry》2010,285(48):37570-37578
Toll-like receptors (TLRs) associate with adaptor molecules (MyD88, Mal/TIRAP, TRAM, and TRIF) to mediate signaling of host-microbial interaction. For instance, TLR4 utilizes the combination of both Mal/TIRAP-MyD88 (MyD88-dependent pathway) and TRAM-TRIF (MyD88-independent pathway). However, TLR5, the specific receptor for flagellin, is known to utilize only MyD88 to elicit inflammatory responses, and an involvement of other adaptor molecules has not been suggested in TLR5-dependent signaling. Here, we found that TRIF is involved in mediating TLR5-induced nuclear factor κB (NFκB) and mitogen-activated protein kinases (MAPKs), specifically JNK1/2 and ERK1/2, activation in intestinal epithelial cells. TLR5 activation by flagellin permits the physical interaction between TLR5 and TRIF in human colonic epithelial cells (NCM460), whereas TLR5 does not interact with TRAM upon flagellin stimulation. Both primary intestinal epithelial cells from TRIF-KO mice and TRIF-silenced NCM460 cells significantly reduced flagellin-induced NFκB (p105 and p65), JNK1/2, and ERK1/2 activation compared with control cells. However, p38 activation by flagellin was preserved in these TRIF-deficient cells. TRIF-KO intestinal epithelial cells exhibited substantially reduced inflammatory cytokine (keratinocyte-derived cytokine, macrophage inflammatory protein 3α, and IL-6) expression upon flagellin, whereas control cells from TRIF-WT mice showed robust cytokine expression by flagellin. Compare with TRIF-WT mice, TRIF-KO mice were resistant to in vivo intestinal inflammatory responses: flagellin-mediated exacerbation of colonic inflammation and dextran sulfate sodium-induced experimental colitis. We conclude that in addition to MyD88, TRIF mediates TLR5-dependent responses and, thereby regulates inflammatory responses elicited by flagellin/TLR5 engagement. Our findings suggest an important role of TRIF in regulating host-microbial communication via TLR5 in the gut epithelium. 相似文献
999.
Jikyoung Park Soo Im Kang Sun-Young Lee Xian F. Zhang Myoung Shin Kim Lisa F. Beers Dae-Sik Lim Joseph Avruch Ho-Shik Kim Sean Bong Lee 《The Journal of biological chemistry》2010,285(45):35029-35038
Epigenetic silencing of RASSF (Ras association domain family) genes RASSF1 and RASSF5 (also called NORE1) by CpG hypermethylation is found frequently in many cancers. Although the physiological roles of RASSF1 have been studied in some detail, the exact functions of RASSF5 are not well understood. Here, we show that RASSF5 plays an important role in mediating apoptosis in response to death receptor ligands, TNF-α and TNF-related apoptosis-inducing ligand. Depletion of RASSF5 by siRNA significantly reduced TNF-α-mediated apoptosis, likely through its interaction with proapoptotic kinase MST1, a mammalian homolog of Hippo. Consistent with this, siRNA knockdown of MST1 also resulted in resistance to TNF-α-induced apoptosis. To further study the role of Rassf5 in vivo, we generated Rassf5-deficient mouse. Inactivation of Rassf5 in mouse embryonic fibroblasts (MEFs) resulted in resistance to TNF-α- and TNF-related apoptosis-inducing ligand-mediated apoptosis. Importantly, Rassf5-null mice were significantly more resistant to TNF-α-induced apoptosis and failed to activate Mst1. Loss of Rassf5 also resulted in spontaneous immortalization of MEFs at earlier passages than the control MEFs, and Rassf5-null immortalized MEFs, but not the immortalized wild type MEFs, were fully transformed by K-RasG12V. Together, our results demonstrate a direct role for RASSF5 in death receptor ligand-mediated apoptosis and provide further evidence for RASSF5 as a tumor suppressor. 相似文献
1000.
Imène Ben Salah Tarek Slatni Alfonso Albacete Mhemmed Gandour Cristina Martínez Andújar Hayet Houmani Karim Ben Hamed Vicente Martinez Francisco Pérez-Alfocea Chedly Abdelly 《Symbiosis (Philadelphia, Pa.)》2010,51(2):187-195
In this study, the effect of 100 mM NaCl on physiological and biochemical responses were investigated in nodules of two Medicago ciliaris lines differing in salt tolerance (TNC 1.8 and TNC 11.9). Results showed that, on the basis of growth and nitrogen fixation,
the line TNC 1.8 proved more salt tolerant than TNC 11.9. The salt-induced oxidative stress (membrane lipid peroxidation,
leghemoglobin degradation, antioxidant activities reduction) occurred similarly in nodules of both lines. The tolerant line
TNC 1.8 showed a better capacity to preserve higher sucrolytic activities and maintained higher nodule malate concentration,
although total organic acids decreased in both lines. The higher amount of organic acids in the tolerant line seems to be
related to its capacity to maintain higher NH4 nodule concentration in comparison with the sensitive line. Although salt stress reduced concentrations of the majority of
amino acid in both lines, the decrease of the most preponderant amino acids glycine, valine, aspartate and glutamate was more
accentuated in the sensitive line TNC 11.9. However, alanine concentration increased in the nodules of this sensitive line,
suggesting a higher incidence of stress-induced hypoxia. The present study provides further evidence that salt tolerance of
nitrogen fixation in the tolerant line is linked to a more effective supply of malate to bacteroids which allows the synthesis
of amino acids required to maintain both plant and nodule growth. 相似文献