全文获取类型
收费全文 | 6194篇 |
免费 | 363篇 |
国内免费 | 1篇 |
专业分类
6558篇 |
出版年
2022年 | 35篇 |
2021年 | 71篇 |
2019年 | 44篇 |
2018年 | 66篇 |
2017年 | 59篇 |
2016年 | 87篇 |
2015年 | 145篇 |
2014年 | 213篇 |
2013年 | 296篇 |
2012年 | 285篇 |
2011年 | 315篇 |
2010年 | 166篇 |
2009年 | 162篇 |
2008年 | 275篇 |
2007年 | 293篇 |
2006年 | 283篇 |
2005年 | 310篇 |
2004年 | 261篇 |
2003年 | 265篇 |
2002年 | 287篇 |
2001年 | 239篇 |
2000年 | 251篇 |
1999年 | 184篇 |
1998年 | 101篇 |
1997年 | 64篇 |
1996年 | 53篇 |
1995年 | 57篇 |
1994年 | 57篇 |
1993年 | 54篇 |
1992年 | 124篇 |
1991年 | 139篇 |
1990年 | 106篇 |
1989年 | 108篇 |
1988年 | 122篇 |
1987年 | 101篇 |
1986年 | 91篇 |
1985年 | 85篇 |
1984年 | 62篇 |
1983年 | 63篇 |
1982年 | 46篇 |
1980年 | 36篇 |
1979年 | 49篇 |
1978年 | 43篇 |
1977年 | 27篇 |
1976年 | 30篇 |
1975年 | 36篇 |
1974年 | 33篇 |
1973年 | 36篇 |
1971年 | 34篇 |
1970年 | 30篇 |
排序方式: 共有6558条查询结果,搜索用时 0 毫秒
151.
Kim J Hirasawa T Saito M Furusawa C Shimizu H 《Applied microbiology and biotechnology》2011,91(1):143-151
Glutamate overproduction by Corynebacterium glutamicum is triggered by treatment with penicillin or Tween 40 and is accompanied by a decrease in 2-oxoglutarate dehydrogenase complex
(ODHC) activity. We have reported that de novo synthesis of OdhI, which inhibits ODHC activity by interacting specifically
with the E1o subunit of ODHC (OdhA), is induced by penicillin, and that odhI overexpression induces glutamate overproduction in the absence of any triggers for glutamate overproduction. In this study,
to determine the function of OdhI in glutamate overproduction by C. glutamicum, changes in OdhI levels and phosphorylation status during penicillin- and Tween 40-induced glutamate overproduction were
examined by western blot. The synthesis of both unphosphorylated and phosphorylated OdhI was increased by addition of Tween
40 or penicillin and the levels of unphosphorylated OdhI, which can inhibit ODHC activity, was significantly higher than those
of phosphorylated OdhI, which is unable to inhibit ODHC activity. Meanwhile, the OdhA levels were maintained throughout the
culture. These results indicate that OdhI synthesis is induced by additions of penicillin and Tween 40 and most synthesized
OdhI is unphosphorylated, resulting in the decrease in ODHC activity and glutamate overproduction. Similarly, in the odhI-overexpressing strain, both unphosphorylated and phosphorylated OdhI were synthesized, while the levels of OdhA were nearly
constant throughout culture. Our results suggest that high level of unphosphorylated OdhI regulates glutamate overproduction
by C. glutamicum. 相似文献
152.
Maeda S Sahara N Saito Y Murayama M Yoshiike Y Kim H Miyasaka T Murayama S Ikai A Takashima A 《Biochemistry》2007,46(12):3856-3861
Neurofibrillary tangles (NFTs) are pathological hallmarks of several neurodegenerative disorders, including Alzheimer's disease (AD). NFTs are composed of microtubule-binding protein tau, which assembles to form paired helical filaments (PHFs) and straight filaments. Here we show by atomic force microscopy that AD brain tissue and in vitro tau form granular and fibrillar tau aggregates. CD spectral analysis and immunostaining with conformation-dependent antibodies indicated that tau may undergo conformational changes during fibril formation. Enriched granules generated filaments, suggesting that granular tau aggregates may be an intermediate form of tau fibrils. The amount of granular tau aggregates was elevated in prefrontal cortex of Braak stage I cases compared to that of Braak stage 0 cases, suggesting that granular tau aggregation precedes PHF formation. Thus, granular tau aggregates may be a relevant marker for the early diagnosis of tauopathy. Reducing the level of these aggregates may be a promising therapy for tauopathies and for promoting healthy brain aging. 相似文献
153.
Kawase T Okuda K Saito Y Amizuka N Suzuki H Yoshie H 《In vitro cellular & developmental biology. Animal》2005,41(5-6):171-176
Summary Platelet-rich plasma (PRP) has been used to promote periodontal regeneration following the premise that constituent transforming
growth factor-β1 (TGF-β1) and platelet-derived growth factor-AB will stimulate cell proliferation at the site of application.
In previous studies, we demonstrated that PRP mimics TGF-β1 to modulate proliferation in a cell type-specific manner, that
fibrin clot formation by PRP upregulates type I collagen, and that an unidentified factor(s) in PRP increases alkaline phosphatase
(ALP) activity in human periodontal ligament (PDL) cell cultures. We have now examined the effects of PRP on in vitro mineralization.
Platelet-rich plasma and PDL cells were prepared from human adult volunteers or rats. After 20 d of continuous treatment with
PRP in dexamethazone (Dex)-containing osteogenic medium, PRP time dependently promoted mineralization by rat PDL cells but
failed to fully induce the osteoblastic phenotype. Furthermore, when human PDL cells were induced to increase ALP activity
in osteogenic medium that lacked Dex, a condition that should delay (or suppress) osteoblastic differentiation, transmission
electron microscopy revealed that mineralized spicules were initially deposited onto PRP-derived platelet aggregates. Taken
together with our previous data, these findings suggest that PRP provides platelet aggregates as nuclei to initiate mineralization
while stimulating PDL cell proliferation, differentiation, and collagen production. The combination of these effects may effectively
mediate PRP's ability to promote regeneration of periodontal tissue, including skeletal tissue, at the site of injury. 相似文献
154.
Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression 总被引:12,自引:0,他引:12
Bandyopadhyay S Zhan R Chaudhuri A Watabe M Pai SK Hirota S Hosobe S Tsukada T Miura K Takano Y Saito K Pauza ME Hayashi S Wang Y Mohinta S Mashimo T Iiizumi M Furuta E Watabe K 《Nature medicine》2006,12(8):933-938
CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models. To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis. 相似文献
155.
Various mutant lysozymes were constructed by genetic modification and secreted in yeast expression system to evaluate the changes in the antigenicity of hen egg lysozyme (HEL). Although Arg68, the most critical residue to antigenicity of HEL, was substituted with Gln, the binding of monoclonal antibodies (mAbs) with the mutant lysozyme did not critically reduce, remaining 60% of the binding with mAb. In contrast, glycosylated mutant lysozyme G49N whose glycine was substituted with asparagine dramatically reduced the binding with mAb. The oligomannosyl type of G49N lysozyme reduced binding with mAb to one-fifth, while the polymannosyl type of G49N lysozyme completely diminished the binding with mAb. This suggests that the site-specific glycosylation of lysozyme in the interfacial region of lysozyme-antibody complex is more effective to reduce the antigenicity than the mutation of single amino acid substitution in the interfacial region. 相似文献
156.
Y Ohyama K Miyamoto Y Saito N Minamino K Kangawa H Matsuo 《Biochemical and biophysical research communications》1992,183(2):743-749
Two similar membrane bound guanylate cyclases (GC-A and GC-B) are known as natriuretic peptide receptors, but have not been well characterized yet. In this study, we have isolated two forms of GC-B cDNA clones along with GC-A cDNA clones from rat brain. The two forms of rat GC-B differ from each other only by 75bp deletion at 3'-flanking region of the putative transmembrane domain, the shorter form lacking the nucleotide binding site by the deletion. Expression of these cDNAs on mammalian cells revealed that (1) GC-B is a specific receptor for CNP whereas GC-A is stimulated effectively both by ANP and BNP, and (2) the two forms of GC-B possess practically the same high binding affinity for CNP while the shorter form could not induce cGMP production by the binding of CNP. These data indicate that in rat brain is present the non-functional receptor for CNP caused by the short deletion. 相似文献
157.
Y Saito K Nakao G Shirakami M Jougasaki T Yamada H Itoh M Mukoyama H Arai K Hosoda S Suga 《Biochemical and biophysical research communications》1989,163(3):1512-1516
Using two radioimmunoassays (RIAs) for endothelin-1 (ET-1) with and without a substantial cross-reactivity with ET-3, we have measured the plasma ET-1-like immunoreactivity (-LI) level in rat plasma. ET-1-LI was detected in plasma from male Wistar rats. ET-1-LI in rat plasma consisted of three components with molecular weights of 6K, 4K and 2.5K daltons by gel permeation chromatography. Two of the components were eluted at positions of big ET (4K) and synthetic ET-1 (2.5K). The remaining component was eluted at the preceding fraction (6K). No difference was observed in ET-1-LI of the small molecular form of ET (2.5K) between the two RIAs. Thus, there is little or no ET-3 in rat plasma, which has the sequence found originally in the rat genome. The concentration of the small molecular form of ET, presumably ET-1, in rat plasma was about 4 pg/ml. 相似文献
158.
159.
Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration 总被引:11,自引:0,他引:11
Watanabe T Wang S Noritake J Sato K Fukata M Takefuji M Nakagawa M Izumi N Akiyama T Kaibuchi K 《Developmental cell》2004,7(6):871-883
Rho family GTPases, particularly Rac1 and Cdc42, are key regulators of cell polarization and directional migration. Adenomatous polyposis coli (APC) is also thought to play a pivotal role in polarized cell migration. We have found that IQGAP1, an effector of Rac1 and Cdc42, interacts directly with APC. IQGAP1 and APC localize interdependently to the leading edge in migrating Vero cells, and activated Rac1/Cdc42 form a ternary complex with IQGAP1 and APC. Depletion of either IQGAP1 or APC inhibits actin meshwork formation and polarized migration. Depletion of IQGAP1 or APC also disrupts localization of CLIP-170, a microtubule-stabilizing protein that interacts with IQGAP1. Taken together, these results suggest a model in which activation of Rac1 and Cdc42 in response to migration signals leads to recruitment of IQGAP1 and APC which, together with CLIP-170, form a complex that links the actin cytoskeleton and microtubule dynamics during cell polarization and directional migration. 相似文献
160.
Saito A Sugisawa A Umegaki K Sunagawa H 《Bioscience, biotechnology, and biochemistry》2004,68(2):271-276
We investigated chromosomal damage caused by a typical flavonoid, quercetin, and its two conjugates, quercetin-3-O-sulfate and isorhamnetin, and their protective effects against chromosomal damage induced by H2O2. The chromosomal damage was detected by the cytokinesis-block micronucleus (CBMN) assay using a lymphoblastoid cell line, WIL2-NS. We found that quercetin itself induced chromosomal damage at 10 microM, but quercetin-3-O-sulfate and isorhamnetin did not induce damage up to 30 microM. In the medium used for the CBMN assay, quercetin (at 100 microM) generated a high concentration of H2O2, but the two conjugates did not at the same concentration. On the other hand, pretreatment with quercetin (at 1 microM), quercetin-3-O-sulfate (at 10 microM), and isorhamnetin (at 5 microM) prevented H2O2-induced chromosomal damage to WIL2-NS cells. These findings suggest that the induction and prevention of H2O2-induced chromosomal damage are different between quercetin and its metabolites. 相似文献