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91.
Annika S?derholm Xiaohu Guo Matilda S. Newton Gary B. Evans Joakim N?svall Wayne M. Patrick Maria Selmer 《The Journal of biological chemistry》2015,290(41):24657-24668
HisA is a (βα)8 barrel enzyme that catalyzes the Amadori rearrangement of N′-[(5′-phosphoribosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide (ProFAR) to N′-((5′-phosphoribulosyl) formimino)-5-aminoimidazole-4-carboxamide-ribonucleotide (PRFAR) in the histidine biosynthesis pathway, and it is a paradigm for the study of enzyme evolution. Still, its exact catalytic mechanism has remained unclear. Here, we present crystal structures of wild type Salmonella enterica HisA (SeHisA) in its apo-state and of mutants D7N and D7N/D176A in complex with two different conformations of the labile substrate ProFAR, which was structurally visualized for the first time. Site-directed mutagenesis and kinetics demonstrated that Asp-7 acts as the catalytic base, and Asp-176 acts as the catalytic acid. The SeHisA structures with ProFAR display two different states of the long loops on the catalytic face of the structure and demonstrate that initial binding of ProFAR to the active site is independent of loop interactions. When the long loops enclose the substrate, ProFAR adopts an extended conformation where its non-reacting half is in a product-like conformation. This change is associated with shifts in a hydrogen bond network including His-47, Asp-129, Thr-171, and Ser-202, all shown to be functionally important. The closed conformation structure is highly similar to the bifunctional HisA homologue PriA in complex with PRFAR, thus proving that structure and mechanism are conserved between HisA and PriA. This study clarifies the mechanistic cycle of HisA and provides a striking example of how an enzyme and its substrate can undergo coordinated conformational changes before catalysis. 相似文献
92.
Noelia Inés Burgardt Andreas Schmidt Annika Manns Alexandra Schutkowski Günther Jahreis Yi-Jan Lin Bianca Schulze Antonia Masch Christian Lücke Matthias Weiwad 《The Journal of biological chemistry》2015,290(27):16708-16722
Recently we have shown that the peptidyl-prolyl cis/trans isomerase parvulin 17 (Par17) interacts with tubulin in a GTP-dependent manner, thereby promoting the formation of microtubules. Microtubule assembly is regulated by Ca2+-loaded calmodulin (Ca2+/CaM) both in the intact cell and under in vitro conditions via direct interaction with microtubule-associated proteins. Here we provide the first evidence that Ca2+/CaM interacts also with Par17 in a physiologically relevant way, thus preventing Par17-promoted microtubule assembly. In contrast, parvulin 14 (Par14), which lacks only the first 25 N-terminal residues of the Par17 sequence, does not interact with Ca2+/CaM, indicating that this interaction is exclusive for Par17. Pulldown experiments and chemical shift perturbation analysis with 15N-labeled Par17 furthermore confirmed that calmodulin (CaM) interacts in a Ca2+-dependent manner with the Par17 N terminus. The reverse experiment with 15N-labeled Ca2+/CaM demonstrated that the N-terminal Par17 segment binds to both CaM lobes simultaneously, indicating that Ca2+/CaM undergoes a conformational change to form a binding channel between its two lobes, apparently similar to the structure of the CaM-smMLCK796–815 complex. In vitro tubulin polymerization assays furthermore showed that Ca2+/CaM completely suppresses Par17-promoted microtubule assembly. The results imply that Ca2+/CaM binding to the N-terminal segment of Par17 causes steric hindrance of the Par17 active site, thus interfering with the Par17/tubulin interaction. This Ca2+/CaM-mediated control of Par17-assisted microtubule assembly may provide a mechanism that couples Ca2+ signaling with microtubule function. 相似文献
93.
94.
(Eco)toxicity studies conducted according to internationally standardized test guidelines are often considered reliable by default and preferred as key evidence in regulatory risk assessment. At the same time regulatory agencies emphasize the use of all relevant (eco)toxicity data in the risk assessment process, including non-standard studies. However, there is a need to facilitate the use of such studies in regulatory risk assessment. Therefore, we propose a framework that facilitates a systematic and transparent evaluation of the reliability and relevance of (eco)toxicity in vivo studies for health and environmental risk assessment. The framework includes specific criteria to guide study evaluation, as well as a color-coding tool developed to aid the application of these criteria. In addition we provide guidance intended for researchers on how to report non-standard studies to ensure that they meet regulatory requirements. The intention of the evaluating and reporting criteria is to increase the usability of all relevant data that may fill information gaps in chemical risk assessments. The framework is publically available online, free of charge, at the Science in Risk Assessment and Policy (SciRAP) website: www.scirap.org. The aim of this article is to present the framework and resources available at the SciRAP website. 相似文献
95.
Giordanetto F Knerr L Selmi N Llinàs A Lindqvist A Wang QD Ståhlberg P Thorstensson F Ullah V Nilsson K O'Mahony G Högberg G Lindhardt E Strand A Duker G 《Bioorganic & medicinal chemistry letters》2011,21(18):5557-5561
Chemical evolution of a HTS-based fragment hit resulted in the identification of N-(1-adamantyl)-2-[4-(2-tetrahydropyran-4-ylethyl)piperazin-1-yl]acetamide, a novel, selective T-type calcium channel (Ca(v)3.2) inhibitor with in vivo antihypertensive effect in rats. 相似文献
96.
97.
We tested whether mixotrophic ciliates are more resistant to solar ultraviolet radiation (UVR) than heterotrophic ones because symbiotic algae can provide self-shading by cell matter absorption and eventually by direct UV screening from mycosporine-like amino acids (MAAs). Sensitivity of a natural assemblage to solar radiation was tested in experiments in the original lake and in a more UV transparent alpine lake after transplantation of the ciliates. In both lakes, the assemblage was exposed either to full sunlight, to photosynthetically active radiation only, or kept in the dark. In each lake, exposure was for 5 h at the surface and at the depth corresponding to the 10% attenuation depth at 320 nm. Overall, when the assemblage was exposed to surface UVR, only one out of four dominant mixotrophic ciliates, Vorticella chlorellata, was more resistant than heterotrophic species. The higher UV resistance in V. chlorellata was related to the presence of MAAs and the high percentage of ciliate volume occupied by algal symbionts. Our results indicate that effects of UVR were species-specific and depended on efficient screening of these wavelengths, but also on the depth preference of the ciliates and thus, on their previous exposure history to UVR. 相似文献
98.
Anna Meuronen Piia Karisola Marina Leino Terhi Savinko Kristiina Sirola Marja-Leena Majuri P?ivi Piiril? Ismo Virtanen Mika M?kel? Annika Laitinen Lauri A Laitinen Harri Alenius 《Respiratory research》2011,12(1):2
Background
Asthma leads to structural changes in the airways, including the modification of extracellular matrix proteins such as tenascin-C. The role of tenascin-C is unclear, but it might act as an early initiator of airway wall remodelling, as its expression is increased in the mouse and human airways during allergic inflammation. In this study, we examined whether Th1 or Th2 cells are important regulators of tenascin-C in experimental allergic asthma utilizing mice with impaired Th1 (STAT4-/-) or Th2 (STAT6-/-) immunity.Methods
Balb/c wildtype (WT), STAT4-/- and STAT6-/- mice were sensitized with intraperitoneally injected ovalbumin (OVA) followed by OVA or PBS airway challenge. Airway hyperreactivity (AHR) was measured and samples were collected. Real time PCR and immunohistochemistry were used to study cytokines and differences in the expression of tenascin-C. Tenascin-C expression was measured in human fibroblasts after treatment with TNF-α and IFN-γ in vitro.Results
OVA-challenged WT mice showed allergic inflammation and AHR in the airways along with increased expression of TNF-α, IFN-γ, IL-4 and tenascin-C in the lungs. OVA-challenged STAT4-/- mice exhibited elevated AHR and pulmonary eosinophilia. The mRNA expression of TNF-α and IFN-γ was low, but the expression of IL-4 was significantly elevated in these mice. OVA-challenged STAT6-/- mice had neither AHR nor pulmonary eosinophilia, but had increased expression of mRNA for TNF-α, IFN-γ and IL-4. The expression of tenascin-C in the lungs of OVA-challenged STAT4-/- mice was weaker than in those of OVA-challenged WT and STAT6-/- mice suggesting that TNF-α and IFN-γ may regulate tenascin-C expression in vivo. The stimulation of human fibroblasts with TNF-α and IFN-γ induced the expression of tenascin-C confirming our in vivo findings.Conclusions
Expression of tenascin-C is significantly attenuated in the airways of STAT4-/- mice, which may be due to the impaired secretion of TNF-α and IFN-γ in these mice. 相似文献99.
Romaguera D Ängquist L Du H Jakobsen MU Forouhi NG Halkjær J Feskens EJ van der A DL Masala G Steffen A Palli D Wareham NJ Overvad K Tjønneland A Boeing H Riboli E Sørensen TI 《PloS one》2011,6(8):e23384
Background
Dietary factors such as low energy density and low glycemic index were associated with a lower gain in abdominal adiposity. A better understanding of which food groups/items contribute to these associations is necessary.Objective
To ascertain the association of food groups/items consumption on prospective annual changes in “waist circumference for a given BMI” (WCBMI), a proxy for abdominal adiposity.Design
We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WCBMI was defined as the residuals of waist circumference regressed on BMI, and annual change in WCBMI (ΔWCBMI, cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between food groups/items and ΔWCBMI was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates.Results
Higher fruit and dairy products consumption was associated with a lower gain in WCBMI whereas the consumption of white bread, processed meat, margarine, and soft drinks was positively associated with ΔWCBMI. When these six food groups/items were analyzed in combination using a summary score, those in the highest quartile of the score – indicating a more favourable dietary pattern –showed a ΔWCBMI of −0.11 (95% CI −0.09 to −0.14) cm/y compared to those in the lowest quartile.Conclusion
A dietary pattern high in fruit and dairy and low in white bread, processed meat, margarine, and soft drinks may help to prevent abdominal fat accumulation. 相似文献100.
von Ruesten A Steffen A Floegel A van der A DL Masala G Tjønneland A Halkjaer J Palli D Wareham NJ Loos RJ Sørensen TI Boeing H 《PloS one》2011,6(11):e27455