全文获取类型
收费全文 | 1181篇 |
免费 | 126篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 24篇 |
2020年 | 15篇 |
2019年 | 12篇 |
2018年 | 33篇 |
2017年 | 32篇 |
2016年 | 43篇 |
2015年 | 82篇 |
2014年 | 85篇 |
2013年 | 95篇 |
2012年 | 103篇 |
2011年 | 121篇 |
2010年 | 78篇 |
2009年 | 56篇 |
2008年 | 78篇 |
2007年 | 62篇 |
2006年 | 71篇 |
2005年 | 64篇 |
2004年 | 52篇 |
2003年 | 53篇 |
2002年 | 56篇 |
2001年 | 15篇 |
2000年 | 9篇 |
1999年 | 12篇 |
1998年 | 9篇 |
1997年 | 7篇 |
1996年 | 7篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 5篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1982年 | 1篇 |
1977年 | 2篇 |
1974年 | 1篇 |
1969年 | 1篇 |
1967年 | 2篇 |
1961年 | 1篇 |
排序方式: 共有1307条查询结果,搜索用时 15 毫秒
91.
Kim HS Kim Y Doddareddy MR Seo SH Rhim H Tae J Pae AN Choo H Cho YS 《Bioorganic & medicinal chemistry letters》2007,17(2):476-481
A small molecule library of 1,3-dioxoisoindoline-5-carboxamides 4 was designed based on the pharmacophore model, synthesized and biologically evaluated as potential T-type calcium channel blockers. The most active compounds 4d and 4n show T-type calcium channel blocking activity with IC50 values of 0.93 and 0.96 microM, respectively. 相似文献
92.
Eswaran J Lee WH Debreczeni JE Filippakopoulos P Turnbull A Fedorov O Deacon SW Peterson JR Knapp S 《Structure (London, England : 1993)》2007,15(2):201-213
p21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4-6) regulate a wide variety of cellular functions, and PAK deregulation has been linked to tumor development. Structural comparison of five high-resolution structures comprising all active, monophosphorylated group II catalytic domains revealed a surprising degree of domain plasticity, including a number of catalytically productive and nonproductive conformers. Rearrangements of helix alphaC, a key regulatory element of kinase function, resulted in an additional helical turn at the alphaC N terminus and a distortion of its C terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues that structurally link the glycine-rich loop, alphaC, and the activation segment and firmly anchor alphaC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5. 相似文献
93.
Lee JO Park MH Choi YH Ha YL Ryu CH 《Journal of microbiology and biotechnology》2007,17(11):1904-1907
The aim of this study was to develop a new fermentation method in order to improve the digestion of soybean protein, and to promote normal fermentation of soybean. A proximate composition, such as moisture, pH, and reducing sugar, of fermented soybeans by the new fermentation was similar to those of controls. Neutral protease activity, the most important factor for fermented soybean products, was the highest, having about 636 U/g at 54 h fermentation. The content of total free amino acid was almost 3-18 times higher than controls. The three-step fermented soybeans can be used as a functional food ingredient for human consumption, with higher protein digestibility. 相似文献
94.
Kim SW Kim YH Yoo AY Yu JE Hur J Lee JH Cha J Kang HY 《Journal of microbiology and biotechnology》2007,17(8):1316-1323
In order to induce high levels of protein secretion, we have constructed a recombinant plasmid, designated pBP244, into which was incorporated key components of the type-II Sec-dependent secretion system, including LepB (signal peptidase), SecA (ATPase), and SecB (chaperone). The biological activities of the LepB, SecA, and SecB components expressed from genes harbored by pBP244 appeared to play their normal roles. In order to evaluate the protein secretion, a pspA (Streptococcus pneumoniae surface protein A) gene was cloned into pBP244, resulting in pBP438. S. typhimurium harboring pBP438 grown until the stationary phase, secreted a higher level of PspA into the culture supernatants than did the strain harboring pYA3494. The strain harboring pBP438 secreted a supernatant amount 1.71-fold, a periplasmic space amount 1.47-fold, and an outer membrane amount 1.49-fold higher than that of pYA3494. S. typhimurium chi8554 kept the Asd+ plasmid pBP244 and pBP438 for 60 generations in LB broth harboring DAP, thereby indicating that pBP244 and pBP438 were quite stable in the Salmonella strain. 相似文献
95.
Bo Yong Kim Hwa Young Song Mi Young Kim Bong Hee Lee Kyung Joo Kim Kyung Jin Jo Suhng Wook Kim Seung Gwan Lee Boo Hyung Lee 《Archives of insect biochemistry and physiology》2015,89(3):169-180
Despite numerous studies on late embryogenesis abundant (LEA) proteins, their functions, roles, and localizations during developmental stages in arthropods remain unknown. LEA proteins protect crucial proteins against osmotic stress during the development and growth of various organisms. Thus, in this study, fluorescence in situ hybridization was used to determine the crucial regions protected against osmotic stress as well as the distinctive localization of group 3 (G3) LEA+ cells during brine shrimp development. Several cell types were found to synthesize G3 LEA RNA, including neurons, muscular cells, APH‐1+ cells, and renal cells. The G3 LEA+ neuronal cell bodies outside of the mushroom body projected their axonal bundles to the central body, but those inside the mushroom body projected their axonal bundles toward the deutocerebrum without innervating the central body. The cell bodies inside the mushroom body received axons of the G3 LEA+ sensory cells at the medial ventral cup of the nauplius eye. Several glands were found to synthesize G3 LEA RNA during the nauplius stages of brine shrimp, including the sinus, antennal I and II, salt, and three ectodermal glands. This study provides the first demonstration of the formation of G3 LEA+ sinus glands at the emergence stages of brine shrimp. These results suggest that G3 LEA protein is synthesized in several cell types. In particular, specific glands play crucial roles during the emergence and nauplius stages of brine shrimp. 相似文献
96.
Naoyuki Kondo Mariana Marin Jeong Hwa Kim Tanay M. Desai Gregory B. Melikyan 《The Journal of biological chemistry》2015,290(10):6558-6573
Whether HIV-1 enters cells by fusing with the plasma membrane or with endosomes is a subject of active debate. The ability of HIV-1 to mediate fusion between adjacent cells, a process referred to as “fusion-from-without” (FFWO), shows that this virus can fuse with the plasma membrane. To compare FFWO occurring at the cell surface with HIV-cell fusion through a conventional entry route, we designed an experimental approach that enabled the measurements of both processes in the same sample. The following key differences were observed. First, a very small fraction of viruses fusing with target cells participated in FFWO. Second, whereas HIV-1 fusion with adherent cells was insensitive to actin inhibitors, post-CD4/coreceptor binding steps during FFWO were abrogated. A partial dependence of HIV-cell fusion on actin remodeling was observed in CD4+ T cells, but this effect appeared to be due to the actin dependence of virus uptake. Third, deletion of the cytoplasmic tail of HIV-1 gp41 dramatically enhanced the ability of the virus to promote FFWO, while having a modest effect on virus-cell fusion. Distinct efficiencies and actin dependences of FFWO versus HIV-cell fusion are consistent with the notion that, except for a minor fraction of particles that mediate fusion between the plasma membranes of adjacent cells, HIV-1 enters through an endocytic pathway. We surmise, however, that cell-cell contacts enabling HIV-1 fusion with the plasma membrane could be favored at the sites of high density of target cells, such as lymph nodes. 相似文献
97.
Nami Kim Jung Ok Lee Hye Jeong Lee Hyung Ip Kim Joong Kwan Kim Yong Woo Lee Soo Kyung Lee Su Jin Kim Sun Hwa Park Hyeon Soo Kim 《The Journal of biological chemistry》2015,290(33):20438-20447
Docosahexaenoic acid (DHA) is an endogenous ligand of G protein-coupled receptor 120 (GPR120). However, the mechanisms underlying DHA action are poorly understood. In this study, DHA stimulated glucose uptake in the skeletal muscles in an AMP-activated protein kinase (AMPK)-dependent manner. GPR120-mediated increase in intracellular Ca2+ was critical for DHA-mediated AMPK phosphorylation and glucose uptake. In addition, DHA stimulated GLUT4 translocation AMPK-dependently. Inhibition of AMPK and Ca2+/calmodulin-dependent protein kinase kinase blocked DHA-induced glucose uptake. DHA and GW9508, a GPR120 agonist, increased GPR120 expression. DHA-mediated glucose uptake was not observed in GPR120 knockdown conditions. DHA increased AMPK phosphorylation, glucose uptake, and intracellular Ca2+ concentration in primary cultured myoblasts. Taken together, these results indicated that the beneficial metabolic role of DHA was attributed to its ability to regulate glucose via the GPR120-mediated AMPK pathway in the skeletal muscles. 相似文献
98.
Jihwa Chung Kyoung Hwa Kim Seok Cheol Lee Shung Hyun An Kihwan Kwon 《Molecules and cells》2015,38(10):851-858
Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis. 相似文献
99.
Gontang AC Hwa JJ Mast JD Schwabe T Clandinin TR 《Development (Cambridge, England)》2011,138(22):4899-4909
A defining characteristic of neuronal cell type is the growth of axons and dendrites into specific layers and columns of the brain. Although differences in cell surface receptors and adhesion molecules are known to cause differences in synaptic specificity, differences in downstream signaling mechanisms that determine cell type-appropriate targeting patterns are unknown. Using a forward genetic screen in Drosophila, we identify the GTPase effector Genghis khan (Gek) as playing a crucial role in the ability of a subset of photoreceptor (R cell) axons to innervate appropriate target columns. In particular, single-cell mosaic analyses demonstrate that R cell growth cones lacking Gek function grow to the appropriate ganglion, but frequently fail to innervate the correct target column. Further studies reveal that R cell axons lacking the activity of the small GTPase Cdc42 display similar defects, providing evidence that these proteins regulate a common set of processes. Gek is expressed in all R cells, and a detailed structure-function analysis reveals a set of regulatory domains with activities that restrict Gek function to the growth cone. Although Gek does not normally regulate layer-specific targeting, ectopic expression of Gek is sufficient to alter the targeting choices made by another R cell type, the targeting of which is normally Gek independent. Thus, specific regulation of cytoskeletal responses to targeting cues is necessary for cell type-appropriate synaptic specificity. 相似文献
100.
Quantitative empirical relationships between cell composition and growth rate played an important role in the early days of microbiology. Gradually, the focus of the field began to shift from growth physiology to the ever more elaborate molecular mechanisms of regulation employed by the organisms. Advances in systems biology and biotechnology have renewed interest in the physiology of the cell as a whole. Furthermore, gene expression is known to be intimately coupled to the growth state of the cell. Here, we review recent efforts in characterizing such couplings, particularly the quantitative phenomenological approaches exploiting bacterial 'growth laws.' These approaches point toward underlying design principles that can guide the predictive manipulation of cell behavior in the absence of molecular details. 相似文献