全文获取类型
收费全文 | 899篇 |
免费 | 63篇 |
出版年
2023年 | 4篇 |
2022年 | 18篇 |
2021年 | 30篇 |
2020年 | 13篇 |
2019年 | 17篇 |
2018年 | 25篇 |
2017年 | 16篇 |
2016年 | 33篇 |
2015年 | 48篇 |
2014年 | 56篇 |
2013年 | 50篇 |
2012年 | 86篇 |
2011年 | 88篇 |
2010年 | 55篇 |
2009年 | 41篇 |
2008年 | 51篇 |
2007年 | 65篇 |
2006年 | 57篇 |
2005年 | 43篇 |
2004年 | 32篇 |
2003年 | 33篇 |
2002年 | 27篇 |
2001年 | 2篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 8篇 |
1995年 | 2篇 |
1993年 | 3篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1964年 | 2篇 |
1961年 | 1篇 |
1957年 | 1篇 |
1936年 | 2篇 |
1932年 | 1篇 |
1931年 | 1篇 |
排序方式: 共有962条查询结果,搜索用时 31 毫秒
151.
152.
Hecht J Stricker S Wiecha U Stiege A Panopoulou G Podsiadlowski L Poustka AJ Dieterich C Ehrich S Suvorova J Mundlos S Seitz V 《PLoS genetics》2008,4(3):e1000025
The skeleton is one of the most important features for the reconstruction of vertebrate phylogeny but few data are available to understand its molecular origin. In mammals the Runt genes are central regulators of skeletogenesis. Runx2 was shown to be essential for osteoblast differentiation, tooth development, and bone formation. Both Runx2 and Runx3 are essential for chondrocyte maturation. Furthermore, Runx2 directly regulates Indian hedgehog expression, a master coordinator of skeletal development. To clarify the correlation of Runt gene evolution and the emergence of cartilage and bone in vertebrates, we cloned the Runt genes from hagfish as representative of jawless fish (MgRunxA, MgRunxB) and from dogfish as representative of jawed cartilaginous fish (ScRunx1–3). According to our phylogenetic reconstruction the stem species of chordates harboured a single Runt gene and thereafter Runt locus duplications occurred during early vertebrate evolution. All newly isolated Runt genes were expressed in cartilage according to quantitative PCR. In situ hybridisation confirmed high MgRunxA expression in hard cartilage of hagfish. In dogfish ScRunx2 and ScRunx3 were expressed in embryonal cartilage whereas all three Runt genes were detected in teeth and placoid scales. In cephalochordates (lancelets) Runt, Hedgehog and SoxE were strongly expressed in the gill bars and expression of Runt and Hedgehog was found in endo- as well as ectodermal cells. Furthermore we demonstrate that the lancelet Runt protein binds to Runt binding sites in the lancelet Hedgehog promoter and regulates its activity. Together, these results suggest that Runt and Hedgehog were part of a core gene network for cartilage formation, which was already active in the gill bars of the common ancestor of cephalochordates and vertebrates and diversified after Runt duplications had occurred during vertebrate evolution. The similarities in expression patterns of Runt genes support the view that teeth and placoid scales evolved from a homologous developmental module. 相似文献
153.
Pingel LC Kohlgraf KG Hansen CJ Eastman CG Dietrich DE Burnell KK Srikantha RN Xiao X Bélanger M Progulske-Fox A Cavanaugh JE Guthmiller JM Johnson GK Joly S Kurago ZB Dawson DV Brogden KA 《Immunology and cell biology》2008,86(8):643-649
Regulatory mechanisms in mucosal secretions and tissues recognize antigens and attenuate pro-inflammatory cytokine responses. Here, we asked whether human beta-defensin 3 (HBD3) serves as an upstream suppressor of cytokine signaling that binds and attenuates pro-inflammatory cytokine responses to recombinant hemagglutinin B (rHagB), a non-fimbrial adhesin from Porphyromonas gingivalis strain 381. We found that HBD3 binds to immobilized rHagB and produces a significantly higher resonance unit signal in surface plasmon resonance spectroscopic analysis, than HBD2 and HBD1 that are used as control defensins. Furthermore, we found that HBD3 significantly attenuates (P<0.05) the interleukin (IL)-6, IL-10, granulocyte macrophage colony stimulating factor (GM-CSF) and tumor-necrosis factor-alpha (TNF-alpha) responses induced by rHagB in human myeloid dendritic cell culture supernatants and the extracellular signal-regulated kinases (ERK 1/2) response in human myeloid dendritic cell lysates. Thus, HBD3 binds rHagB and this interaction may be an important initial step to attenuate a pro-inflammatory cytokine response and an ERK 1/2 response. 相似文献
154.
155.
Nikolaos Venetsaneas Georgia AntonopoulouKaterina Stamatelatou Michael KornarosGerasimos Lyberatos 《Bioresource technology》2009,100(15):3713-3717
This study focuses on the exploitation of cheese whey as a source for hydrogen and methane, in a two-stage continuous process. Mesophilic fermentative hydrogen production from undiluted cheese whey was investigated at a hydraulic retention time (HRT) of 24 h. Alkalinity addition (NaHCO3) or an automatic pH controller were used, to maintain the pH culture at a constant value of 5.2. The hydrogen production rate was 2.9 ± 0.2 L/Lreactor/d, while the yield of hydrogen produced was approximately 0.78 ± 0.05 mol H2/mol glucose consumed, with alkalinity addition, while the respective values when using pH control were 1.9 ± 0.1 L/Lreactor/d and 0.61 ± 0.04 mol H2/mol glucose consumed. The corresponding yields of hydrogen produced were 2.9 L of H2/L cheese whey and 1.9 L of H2/L cheese whey, respectively. The effluent from the hydrogenogenic reactor was further digested to biogas in a continuous mesophilic anaerobic bioreactor. The anaerobic digester was operated at an HRT of 20d and produced approximately 1 L CH4/d, corresponding to a yield of 6.7 L CH4/L of influent. The chemical oxygen demand (COD) elimination reached 95.3% demonstrating that cheese whey could be efficiently used for hydrogen and methane production, in a two-stage process. 相似文献
156.
Christopher D. Cox Georgia B. McGaughey Michael J. Bogusky David B. Whitman Richard G. Ball Christopher J. Winrow John J. Renger Paul J. Coleman 《Bioorganic & medicinal chemistry letters》2009,19(11):2997-3001
NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular π-stacking interaction and a twist-boat ring conformation. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation. 相似文献
157.
Geographical variation in carbon dioxide fluxes from soils in agro-ecosystems and its implications for life-cycle assessment 总被引:1,自引:0,他引:1
158.
Innokentiy Maslennikov Martin Krupa Christopher Dickson Luis Esquivies Katherine Blain Georgia Kefala Senyon Choe Witek Kwiatkowski 《Journal of structural and functional genomics》2009,10(1):25-35
Abstract Bottlenecks in expression, solubilization, purification and crystallization hamper the structural study of integral membrane
proteins (IMPs). Successful crystallization is critically dependent on the purity, stability and oligomeric homogeneity of
an IMP sample. These characteristics are in turn strongly influenced by the type and concentration of the detergents used
in IMP preparation. By utilizing the techniques and analytical tools we earlier developed for the characterization of protein-detergent
complexes (PDCs) [21], we demonstrate that for successful protein extraction from E. coli membrane fractions, the solubilizing detergent associates preferentially to IMPs rather than to membrane lipids. Notably,
this result is contrary to the generally accepted mechanism of detergent-mediated IMP solubilization. We find that for one
particular member of the family of proteins studied (E. coli receptor kinases, which is purified in mixed multimeric states and oligomerizes through its transmembrane region), the protein
oligomeric composition is largely unaffected by a 10-fold increase in protein concentration, by alteration of micelle properties
through addition of other detergents to the PDC sample, or by a 20-fold variation in the detergent concentration used for
solubilization of the IMP from the membrane. We observed that the conditions used for expression of the IMP, which impact
protein density in the membrane, has the greatest influence on the IMP oligomeric structure. Finally, we argue that for concentrating
PDCs smaller than 30 kDa, stirred concentration cells are less prone to over-concentration of detergent and are therefore
more effective than centrifugal ultrafiltration devices. 相似文献
159.
Georgia Chalkiadaki Dragana Nikitovic Aikaterini Berdiaki Maria Sifaki Kostantinos Krasagakis Pavlos Katonis Nikos K. Karamanos George N. Tzanakakis 《The international journal of biochemistry & cell biology》2009,41(6):1323-1331
Fibroblast growth factor-2 (FGF-2), the most abundant growth factor produced by melanoma cells but not by normal melanocytes, is an important regulator of cell proliferation, migration and differentiation. In this study we show that M5 human metastatic melanoma cells’ ability to migrate is significantly enhanced by exogenously added FGF-2 while, neutralization of endogenous FGF-2 stimulates their adhesion. Previously, we have demonstrated that FGF-2 distinctly modulates the synthesis of individual glycosaminoglycans/proteoglycans (GAGs/PGs) subclasses, changing both their amounts and distribution in M5 cells. Here, treatment with FGF-2 strongly reduces the expression levels of the heparan sulfate-containing proteoglycan, syndecan-4. Syndecan-4 is a focal adhesion component in a range of cell types, adherent to several different matrix molecules, including fibronectin (FN). The reduction in syndecan-4 expression by utilizing specific siRNA discriminately increased melanoma cell motility and decreased their attachment on FN, demonstrating a regulatory role of syndecan-4 on these cell functions. Syndecan-4 has previously been demonstrated to regulate focal adhesion kinase (FAK) phosphorylation. In this study FGF-2 was shown to downregulate FAK Y397-phosphorylation during FN-mediated M5 cell adhesion, promoting their migration. The observed decrease in FAK Y397 activation was correlated to syndecan-4 expression levels. Thus, a balance in syndecan-4 expression perpetrated by FGF-2 may be required for optimal M5 cell migration.These results suggest that essential in melanoma progression FGF-2, specifically regulates melanoma cell ability to migrate through a syndecan-4-dependent mechanism. 相似文献
160.
Erica S. Martins-Duarte Simon M. Jones Ian H Gilbert Georgia C. Atella Wanderley de Souza Rossiane C. Vommaro 《Parasitology international》2009,58(4):411-415
The discovery of new compounds active against Toxoplasma gondii is extremely important due to the severe disease caused by this pathogen in immunocompromised hosts and to congenital infection. Type II fatty acid biosynthesis has shown to be a promising target for drug intervention in toxoplasmosis. Here we describe the inhibitory effect of 8 thiolactomycin (TLM) analogues against tachyzoite-infected LLC-MK2 cells. The TLM analogues demonstrated anti-T. gondii activity, arresting tachyzoite proliferation with IC50 values in the micromolar level after 24 h and 48 h of treatment. Metabolic labelling of extracellular parasites treated with TLM analogues using [3H]acetate demonstrated that these drugs affected acylglycerol synthesis. The rapid reduction of parasite load suggests that these compounds have selective cytotoxic effects against T. gondii. Transmission electron microscopy demonstrated that TLM analogues interfered with membrane-bounded organelles and parasite division and this in turn affected parasite development and survival. 相似文献