全文获取类型
收费全文 | 1102篇 |
免费 | 76篇 |
国内免费 | 1篇 |
专业分类
1179篇 |
出版年
2023年 | 4篇 |
2022年 | 11篇 |
2021年 | 13篇 |
2020年 | 6篇 |
2019年 | 10篇 |
2018年 | 23篇 |
2017年 | 12篇 |
2016年 | 29篇 |
2015年 | 46篇 |
2014年 | 51篇 |
2013年 | 59篇 |
2012年 | 78篇 |
2011年 | 88篇 |
2010年 | 72篇 |
2009年 | 57篇 |
2008年 | 72篇 |
2007年 | 70篇 |
2006年 | 70篇 |
2005年 | 59篇 |
2004年 | 54篇 |
2003年 | 60篇 |
2002年 | 54篇 |
2001年 | 14篇 |
2000年 | 8篇 |
1999年 | 11篇 |
1998年 | 16篇 |
1997年 | 10篇 |
1996年 | 7篇 |
1995年 | 5篇 |
1994年 | 7篇 |
1993年 | 12篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1990年 | 6篇 |
1989年 | 10篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 7篇 |
1984年 | 3篇 |
1982年 | 7篇 |
1980年 | 3篇 |
1977年 | 2篇 |
1975年 | 2篇 |
1972年 | 3篇 |
1971年 | 4篇 |
1969年 | 2篇 |
1968年 | 2篇 |
1963年 | 2篇 |
1957年 | 2篇 |
排序方式: 共有1179条查询结果,搜索用时 0 毫秒
91.
Jan Gundlach Achim Dickmanns Kathrin Schr?der-Tittmann Piotr Neumann Jan Kaesler Jan Kampf Christina Herzberg Elke Hammer Frank Schwede Volkhard Kaever Kai Tittmann J?rg Stülke Ralf Ficner 《The Journal of biological chemistry》2015,290(5):3069-3080
The cyclic dimeric AMP nucleotide c-di-AMP is an essential second messenger in Bacillus subtilis. We have identified the protein DarA as one of the prominent c-di-AMP receptors in B. subtilis. Crystal structure analysis shows that DarA is highly homologous to PII signal transducer proteins. In contrast to PII proteins, the functionally important B- and T-loops are swapped with respect to their size. DarA is a homotrimer that binds three molecules of c-di-AMP, each in a pocket located between two subunits. We demonstrate that DarA is capable to bind c-di-AMP and with lower affinity cyclic GMP-AMP (3′3′-cGAMP) but not c-di-GMP or 2′3′-cGAMP. Consistently the crystal structure shows that within the ligand-binding pocket only one adenine is highly specifically recognized, whereas the pocket for the other adenine appears to be promiscuous. Comparison with a homologous ligand-free DarA structure reveals that c-di-AMP binding is accompanied by conformational changes of both the fold and the position of the B-loop in DarA. 相似文献
92.
Thomas O. Eichmann Lukas Grumet Ulrike Taschler Jürgen Hartler Christoph Heier Aaron Woblistin Laura Pajed Manfred Kollroser Gerald Rechberger Gerhard G. Thallinger Rudolf Zechner Günter Haemmerle Robert Zimmermann Achim Lass 《Journal of lipid research》2015,56(10):1972-1984
Lipid droplets (LDs) of hepatic stellate cells (HSCs) contain large amounts of vitamin A [in the form of retinyl esters (REs)] as well as other neutral lipids such as TGs. During times of insufficient vitamin A availability, RE stores are mobilized to ensure a constant supply to the body. To date, little is known about the enzymes responsible for the hydrolysis of neutral lipid esters, in particular of REs, in HSCs. In this study, we aimed to identify LD-associated neutral lipid hydrolases by a proteomic approach using the rat stellate cell line HSC-T6. First, we loaded cells with retinol and FAs to promote lipid synthesis and deposition within LDs. Then, LDs were isolated and lipid composition and the LD proteome were analyzed. Among other proteins, we found perilipin 2, adipose TG lipase (ATGL), and comparative gene identification-58 (CGI-58), known and established LD proteins. Bioinformatic search of the LD proteome for α/β-hydrolase fold-containing proteins revealed no yet uncharacterized neutral lipid hydrolases. In in vitro activity assays, we show that rat (r)ATGL, coactivated by rat (r)CGI-58, efficiently hydrolyzes TGs and REs. These findings suggest that rATGL and rCGI-58 are LD-resident proteins in HSCs and participate in the mobilization of both REs and TGs. 相似文献
93.
94.
Franziska Volland-Voigt Achim Br?uning Oswaldo Ganzhi Thorsten Peters Hector Maza 《Trees - Structure and Function》2011,25(1):39-48
Stem diameter increments of the broadleaved deciduous tree species Tabebuia chrysantha were measured with high-resolution dendrometers in a tropical lower montane forest and in a dry forest in southern Ecuador,
the latter showing a distinct dry season. Those analyses were complemented by wood anatomical studies on regularly collected
microcores to determine the season of active cambial growth and the time of formation of annual growth boundaries. The length
of the cambial active period varied between 3 and 7 months at the tropical lower montane forest and 2 and 4 months in the
dry forest, respectively. During dry days, amplitudes of daily stem diameter variations correlated with vapour pressure deficit.
During October and November, inter-annual climate variations may lead to dry and sunny conditions in the tropical lower montane
forest, causing water deficit and stem diameter shrinkage in T. chrysantha. The results of the climate–growth analysis show a positive relationship between tree growth and rainfall as well as vapour
pressure deficit in certain periods of the year, indicating that rainfall plays a major role for tree growth. 相似文献
95.
Rose AJ Díaz MB Reimann A Klement J Walcher T Krones-Herzig A Strobel O Werner J Peters A Kleyman A Tuckermann JP Vegiopoulos A Herzig S 《Cell metabolism》2011,14(1):123-130
Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition. Fasted mice with hepatocyte-specific GR knockdown had smaller gallbladder BA content and were more susceptible to developing cholesterol gallstones when fed a cholesterol-rich diet. Hepatic GR deficiency impaired liver BA uptake/transport via lower expression of the major hepatocyte basolateral BA transporter, Na(+)-taurocholate transport protein (Ntcp/Slc10a1), which affected dietary fat absorption and brown adipose tissue activation. Our results demonstrate a role of the HPA axis in the endocrine regulation of BA homeostasis through the liver GR control of enterohepatic BA recycling. 相似文献
96.
von Boehmer L Keller L Mortezavi A Provenzano M Sais G Hermanns T Sulser T Jungbluth AA Old LJ Kristiansen G van den Broek M Moch H Knuth A Wild PJ 《PloS one》2011,6(7):e21366
The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p<0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p<0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer. 相似文献
97.
Gutierrez E Tkachenko E Besser A Sundd P Ley K Danuser G Ginsberg MH Groisman A 《PloS one》2011,6(9):e23807
Substrate rigidity profoundly impacts cellular behaviors such as migration, gene expression, and cell fate. Total Internal Reflection Fluorescence (TIRF) microscopy enables selective visualization of the dynamics of substrate adhesions, vesicle trafficking, and biochemical signaling at the cell-substrate interface. Here we apply high-refractive-index silicone gels to perform TIRF microscopy on substrates with a wide range of physiological elastic moduli and simultaneously measure traction forces exerted by cells on the substrate. 相似文献
98.
Hauser S Bickel L Weinspach D Gerg M Schäfer MK Pfeifer M Hazin J Schelter F Weidle UH Ramser J Volkmann J Meindl A Schmitt M Schrötzlmair F Altevogt P Krüger A 《PloS one》2011,6(4):e18989
Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression. 相似文献
99.
Holger Hackstein Sabine Kranz Anne Lippitsch Andreas Wachtendorf Olivia Kershaw Achim D Gruber Gabriela Michel Jürgen Lohmeyer Gregor Bein Nelli Baal Susanne Herold 《Respiratory research》2013,14(1):91
Background
Klebsiella pneumoniae is a leading cause of severe hospital-acquired respiratory tract infections and death but little is known regarding the modulation of respiratory dendritic cell (DC) subsets. Plasmacytoid DC (pDC) are specialized type 1 interferon producing cells and considered to be classical mediators of antiviral immunity.Method
By using multiparameter flow cytometry analysis we have analysed the modulation of respiratory DC subsets after intratracheal Klebsiella pneumonia infection.Results
Data indicate that pDCs and MoDC were markedly elevated in the post acute pneumonia phase when compared to mock-infected controls. Analysis of draining mediastinal lymph nodes revealed a rapid increase of activated CD103+ DC, CD11b+ DC and MoDC within 48 h post infection. Lung pDC identification during bacterial pneumonia was confirmed by extended phenotyping for 120G8, mPDCA-1 and Siglec-H expression and by demonstration of high Interferon-alpha producing capacity after cell sorting. Cytokine expression analysis of ex vivo-sorted respiratory DC subpopulations from infected animals revealed elevated Interferon-alpha in pDC, elevated IFN-gamma, IL-4 and IL-13 in CD103+ DC and IL-19 and IL-12p35 in CD11b+ DC subsets in comparison to CD11c+ MHC-class IIlow cells indicating distinct functional roles. Antigen-specific naive CD4+ T cell stimulatory capacity of purified respiratory DC subsets was analysed in a model system with purified ovalbumin T cell receptor transgenic naive CD4+ responder T cells and respiratory DC subsets, pulsed with ovalbumin and matured with Klebsiella pneumoniae lysate. CD103+ DC and CD11b+ DC subsets represented the most potent naive CD4+ T helper cell activators.Conclusion
These results provide novel insight into the activation of respiratory DC subsets during Klebsiella pneumonia infection. The detection of increased respiratory pDC numbers in bacterial pneumonia may indicate possible novel pDC functions with respect to lung repair and regeneration. 相似文献100.
The rise kinetics of the absorption changes induced at 515 nm and 480 nm by a flash were studied using two types of xenon flashes of different durations. The ‘slow’ rise of the absorption change () observed by Cox and Delosme (1978 C.R. Acad. Sci. (Paris) Sér. D 282, 775–778) and Joliot P., Delosme, R. and Joliot, A. ((1977) Biochim. Biophys. Acta 459, 47–57) was found to be due to double hits occurring in the reaction centers of System I during the flash.The turnover kinetics of the reaction centers of System I after a short flash were studied by a double flash method. They are in agreement with a second order reaction between P+-700 and its electron donor. 相似文献