全文获取类型
收费全文 | 1386篇 |
免费 | 110篇 |
国内免费 | 5篇 |
出版年
2021年 | 24篇 |
2020年 | 21篇 |
2019年 | 17篇 |
2018年 | 36篇 |
2017年 | 32篇 |
2016年 | 46篇 |
2015年 | 64篇 |
2014年 | 67篇 |
2013年 | 94篇 |
2012年 | 100篇 |
2011年 | 86篇 |
2010年 | 56篇 |
2009年 | 38篇 |
2008年 | 56篇 |
2007年 | 55篇 |
2006年 | 49篇 |
2005年 | 45篇 |
2004年 | 29篇 |
2003年 | 29篇 |
2002年 | 34篇 |
2001年 | 29篇 |
2000年 | 30篇 |
1999年 | 22篇 |
1998年 | 19篇 |
1997年 | 9篇 |
1995年 | 10篇 |
1994年 | 16篇 |
1993年 | 13篇 |
1992年 | 17篇 |
1991年 | 24篇 |
1990年 | 16篇 |
1989年 | 14篇 |
1988年 | 20篇 |
1987年 | 31篇 |
1986年 | 21篇 |
1985年 | 27篇 |
1984年 | 17篇 |
1983年 | 13篇 |
1982年 | 15篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 13篇 |
1978年 | 9篇 |
1976年 | 8篇 |
1974年 | 9篇 |
1973年 | 14篇 |
1972年 | 8篇 |
1971年 | 8篇 |
1970年 | 10篇 |
1968年 | 8篇 |
排序方式: 共有1501条查询结果,搜索用时 15 毫秒
101.
Nam-On Ku Sara A. Michie Roy M. Soetikno Evelyn Z. Resurreccion Rosemary L. Broome M. Bishr Omary 《The Journal of cell biology》1998,143(7):2023-2032
Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that overexpress a human genomic K18 ser52→ ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18-expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress. 相似文献
102.
103.
Phosphorylation of human keratin 18 serine 33 regulates binding to 14-3-3 proteins. 总被引:19,自引:0,他引:19 下载免费PDF全文
Members of the 14-3-3 protein family bind the human intermediate filament protein keratin 18 (K18) in vivo, in a cell-cycle- and phosphorylation-dependent manner. We identified K18 Ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. Comparison of wild-type versus K18 Ser33-->Ala/Asp transfected cells showed that K18 Ser33 phosphorylation is essential for the association of K18 with 14-3-3 proteins, and plays a role in keratin organization and distribution. Mutation of another K18 major phosphorylation site (Ser52) or K18 glycosylation sites had no effect on the binding of K18 to 14-3-3 proteins. The K18 phospho-Ser33 motif is different from several 14-3-3-binding phosphomotifs already described. Antibodies that are specific to K18 phospho-Ser33 or phospho-Ser52 show that although Ser52 and Ser33 phosphorylated K18 molecules manifest partial colocalization, these phosphorylation events reside predominantly on distinct K18 molecules. Our results demonstrate a unique K18 phosphorylation site that is necessary but not sufficient for K18 binding to 14-3-3 proteins. This binding is likely to involve one or more mitotic events coupled to K18 Ser33 phosphorylation, and plays a role in keratin subcellular distribution. Physiological Ser52 or Ser33 phosphorylation on distinct K18 molecules suggests functional compartmentalization of these modifications. 相似文献
104.
Eun-Kyung Yoon Sae-Kwang Ku Wonhwa Lee Soyoung Kwak Hyejin Kang Byeongjin Jung Jong-Sup Bae 《BMB reports》2015,48(10):577-582
Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain. Here, the anticoagulant effects of scolymoside, an active compound in C. subternata, were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). The effects of scolymoside on plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) expression were evaluated in tumor necrosis factor (TNF)-α-activated human endothelial cells. Treatment with scolymoside resulted in prolonged aPTT and PT and the inhibition of thrombin and FXa activities and production. In addition, scolymoside inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. Scolymoside also elicited anticoagulant effects in mice, including a significant reduction in the PAI-1 to t-PA ratio. Collectively, these findings indicate that scolymoside possesses anticoagulant activities and could be developed as a novel anticoagulant. [BMB Reports 2015; 48(10): 577-582] 相似文献
105.
Dae Won Kim Sung Ho Lee Min Jea Shin Kibom Kim Sae Kwang Ku Jong Kyu Youn Su Bin Cho Jung Hwan Park Chi Hern Lee Ora Son Eun Jeong Sohn Sung-Woo Cho Jong Hoon Park Hyun Ah Kim Kyu Hyung Han Jinseu Park Won Sik Eum Soo Young Choi 《BMB reports》2015,48(11):618-623
FK506 binding protein 12 (FK506BP) is a small peptide with a single FK506BP domain that is involved in suppression of immune response and reactive oxygen species. FK506BP has emerged as a potential drug target for several inflammatory diseases. Here, we examined the protective effects of directly applied cell permeable FK506BP (PEP-1-FK506BP) on corneal alkali burn injury (CAI). In the cornea, there was a significant decrease in the number of cells expressing pro-inflammation, apoptotic, and angiogenic factors such as TNF-α, COX-2, and VEGF. Both corneal opacity and corneal neovascularization (CNV) were significantly decreased in the PEP-1-FK506BP treated group. Our results showed that PEP-1-FK506BP can significantly inhibit alkali burn-induced corneal inflammation in rats, possibly by accelerating corneal wound healing and by reducing the production of angiogenic factors and inflammatory cytokines. These results suggest that PEP-1-FK506BP may be a potential therapeutic agent for CAI. [BMB Reports 2015; 48(11): 618-623] 相似文献
106.
Kate?ina Ku?elová Barbora Brodská Ota Fuchs Marie Dobrovolná Petr Soukup Petr Cetkovsky 《PloS one》2015,10(5)
Nucleophosmin 1 (NPM1) mutations are frequently found in patients with acute myeloid leukemia (AML) and the newly generated sequences were suggested to induce immune response contributing to the relatively favorable outcome of patients in this AML subset. We hypothesized that if an efficient immune response against mutated nucleophosmin can be induced in vivo, the individuals expressing HLA alleles suitable for presenting NPM-derived peptides should be less prone to developing AML associated with NPM1 mutation. We thus compared HLA class I frequencies in a cohort of patients with mutated NPM1 (63 patients, NPMc+), a cohort of patients with wild-type NPM1 (94 patients, NPMwt) and in normal individuals (large datasets available from Allele Frequency Net Database). Several HLA allelic groups were found to be depleted in NPMc+ patients, but not in NPMwt compared to the normal distribution. The decrease was statistically significant for HLA B*07, B*18, and B*40. Furthermore, statistically significant advantage in the overall survival was found for patients with mutated NPM1 expressing at least one of the depleted allelic groups. The majority of the depleted alleles were predicted to bind potent NPM-derived immunopeptides and, importantly, these peptides were often located in the unmutated part of the protein. Our analysis suggests that individuals expressing specific HLA allelic groups are disposed to develop an efficient anti-AML immune response thanks to aberrant cytoplasmic localization of the mutated NPM protein. 相似文献
107.
We recently published two papers detailing the structures of fluid phase phosphatidylglycerol (PG) lipid bilayers (Ku?erka et al., 2012 J. Phys. Chem. B 116: 232–239; Pan et al., 2012 Biochim. Biophys. Acta Biomembr. 1818: 2135–2148), which were determined using the scattering density profile model. This hybrid experimental/computational technique utilizes molecular dynamics simulations to parse a lipid bilayer into components whose volume probabilities follow simple analytical functional forms. Given the appropriate scattering densities, these volume probabilities are then translated into neutron scattering length density (NSLD) and electron density (ED) profiles, which are used to jointly refine experimentally obtained small angle neutron and X-ray scattering data. However, accurate NSLD and ED profiles can only be obtained if the bilayer's chemical composition is known. Specifically, in the case of neutron scattering, the lipid's exchangeable hydrogens with aqueous D2O must be accounted for, as they can have a measureable effect on the resultant lipid bilayer structures. This was not done in our above-mentioned papers. Here we report on the molecular structures of PG lipid bilayers by appropriately taking into account the exchangeable hydrogens. Analysis indicates that the temperature-averaged PG lipid areas decrease by 1.5 to 3.8 Å2, depending on the lipid's acyl chain length and unsaturation, compared to PG areas when hydrogen exchange was not taken into account. 相似文献
108.
Lee HS Chang JH Ku SK 《Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society》2010,48(3):387-393
The regional distribution and frequency of the pancreatic endocrine cells in the ddN mouse were studied using specific antisera against insulin, glucagon, somatostatin and human pancreatic polypeptide (hPP). In the pancreatic islets, most of insulin-immunoreactive (IR) cells were located in the central region, and glucagon-, somatostatin and hPP-IR cells were located in the peripheral region regardless of the lobe. In the splenic part, glucagon-IR cells were also located in the central regions, and more numerous somatostatin-IR cells were detected in the central regions as compared with the duo-denal part. hPP-IR cells were restricted to the peripheral regions in both lobes but more numerous cells were detected in the duodenal portion. In the exocrine parenchyma of the splenic lobe, only insulin- and glucagon-IR cells were detected but all four kinds of IR cells were observed in the duodenal portion. In addition, insulin and hPP-IR cells were also demonstrated in the pancreatic duct regions. In conclusion, some strain-dependent characteristic distributional patterns of pancreatic endocrine cells were found in the ddN mouse with somewhat different distributional patterns between the two pancreatic lobes. 相似文献
109.
Influence of the acetylcholinesterase active site protonation on omega loop and active site dynamics
Wiesner J Kříž Z Kuča K Jun D Koča J 《Journal of biomolecular structure & dynamics》2010,28(3):393-403
Existence of alternative entrances in acetylcholinesterase (AChE) could explain the contrast between the very high AChE catalytic efficiency and the narrow and long access path to the active site revealed by X-ray crystallography. Alternative entrances could facilitate diffusion of the reaction products or at least water and ions from the active site. Previous molecular dynamics simulations identified side door and back door as the most probable alternative entrances. The simulations of non-inhibited AChE suggested that the back door opening events occur only rarely (0.8% of the time in the 10ns trajectory). Here we present a molecular dynamics simulation of non-inhibited AChE, where the back door opening appears much more often (14% of the time in the 12ns trajectory) and where the side door opening was observed quite frequently (78% of trajectory time). We also present molecular dynamics, where the back door does not open at all, or where large conformational changes of the AChE omega loop occur together with alternative passage opening events. All these differences in AChE dynamical behavior are caused by different protonation states of two glutamate residues located on bottom of the active site gorge (Glu202 and G450 in Mus musculus AChE). Our results confirm the results of previous molecular dynamics simulations, expand the view and suggest the probable reasons for the overall conformational behavior of AChE omega loop. 相似文献
110.
Mirjana Dimitrijević Stanislava Stanojević Katarina Mitić Nataša Kuštrimović Vesna Vujić Tatjana Miletić Vesna Kovačević-Jovanović 《Regulatory peptides》2010,159(1-3):100-109
It has been acknowledged that aging exerts detrimental effects on cells of the innate immune system and that neuropeptides, including neuropeptide Y (NPY) and NPY-related peptides fine-tune the activity of these cells through a receptor specific mechanism. The present study investigated the age-dependent potential of peptide YY (PYY) to modulate different granulocyte functions. The PYY reduced the carrageenan-elicited granulocyte accumulation into the air-pouch of aged (24 months) rats, and markedly decreased the phagocytosis of zymosan, as well as the H2O2 production, when applied in vivo (20 μg/air-pouch). The anti-inflammatory effect of PYY was less prominent in adult (8 months) and young (3 months) rats. However, the proportions of granulocytes expressing Y1, Y2 and Y5 receptor subtypes were significantly lower in both aged and young rats when compared to adult rats. Furthermore, the aging was found to be associated with the diminished dipeptidyl peptidase 4 (DP4, an enzyme converting the NPY and PYY to Y2/Y5 receptor selective agonists) activity in plasma. In conclusion, the diverse age-related anti-inflammatory effect of PYY in rats originates from different expression levels of Y1, Y2, and Y5 receptor subtypes in addition to different plasma DP4 activity. 相似文献