全文获取类型
收费全文 | 11193篇 |
免费 | 852篇 |
国内免费 | 6篇 |
出版年
2023年 | 63篇 |
2022年 | 144篇 |
2021年 | 286篇 |
2020年 | 179篇 |
2019年 | 183篇 |
2018年 | 245篇 |
2017年 | 216篇 |
2016年 | 419篇 |
2015年 | 624篇 |
2014年 | 659篇 |
2013年 | 778篇 |
2012年 | 1005篇 |
2011年 | 920篇 |
2010年 | 566篇 |
2009年 | 493篇 |
2008年 | 614篇 |
2007年 | 646篇 |
2006年 | 622篇 |
2005年 | 515篇 |
2004年 | 462篇 |
2003年 | 375篇 |
2002年 | 395篇 |
2001年 | 106篇 |
2000年 | 76篇 |
1999年 | 90篇 |
1998年 | 112篇 |
1997年 | 45篇 |
1996年 | 71篇 |
1995年 | 69篇 |
1994年 | 56篇 |
1993年 | 58篇 |
1992年 | 56篇 |
1991年 | 51篇 |
1990年 | 42篇 |
1989年 | 42篇 |
1988年 | 39篇 |
1987年 | 52篇 |
1986年 | 40篇 |
1985年 | 44篇 |
1984年 | 43篇 |
1983年 | 58篇 |
1982年 | 47篇 |
1981年 | 46篇 |
1980年 | 30篇 |
1979年 | 38篇 |
1978年 | 23篇 |
1977年 | 41篇 |
1976年 | 24篇 |
1975年 | 21篇 |
1973年 | 19篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
951.
Mazzei JC Zhou H Brayfield BP Hontecillas R Bassaganya-Riera J Schmelz EM 《The Journal of nutritional biochemistry》2011,22(12):1160-1171
Inflammation of the gastrointestinal tract increases the risk of developing colon cancer especially in younger adults. Dietary compounds are not only associated with the etiology of inflammation and colon cancer but also in their prevention. Sphingolipid metabolites have been shown to play a role in the initiation and perpetuation of inflammatory responses. In the present study, we investigated the suppression of dextran sodium sulfate-induced colitis and azoxymethane-induced colon cancer by dietary sphingomyelin (SM) in mice that lack functional peroxisome proliferator-activated receptor γ (PPAR-γ) in intestinal epithelial and immune cells. Dietary SM decreased disease activity and colonic inflammatory lesions in mice of both genotypes but more efficiently in mice expressing PPAR-γ. The increased survival and suppression of tumor formation in the SM-fed mice appeared to be independent of PPAR-γ expression in immune and epithelial cells. Using a real-time polymerase chain reaction array, we detected an up-regulation in genes involved in Th1 (interferon γ) and Th17 (interleukin [IL]-17 and IL-23) responses despite the reduced inflammation scores. However, the genes involved in Th2 (IL-4, IL-13 and IL-13ra2) and Treg (IL-10rb) anti-inflammatory responses were up-regulated in a PPAR-γ-dependent manner. In line with the PPAR-γ dependency of our in vivo findings, treatment of RAW macrophages with sphingosine increased the PPAR-γ reporter activity. In conclusion, dietary SM modulated inflammatory responses at the early stages of the disease by activating PPAR-γ, but its anticarcinogenic effects followed a PPAR-γ-independent pattern. 相似文献
952.
González-Fernández E de-los-Santos-Álvarez N Lobo-Castañón MJ Miranda-Ordieres AJ Tuñón-Blanco P 《Biosensors & bioelectronics》2011,26(5):2354-2360
An RNA aptamer is proposed as a recognition element for the detection of tobramycin in human serum. A displacement assay was developed using faradaic-electrochemical impedance spectroscopy (F-EIS) as a detection technique. Two modified aptamers, a partially (ATA) and a fully O-methylated aptamer (FATA) were evaluated and compared. The affinity constant, K(D), for both aptamers was estimated by F-EIS resulting virtually identical within the experimental error. The selectivity towards other aminoglycosides was also studied. The analytical characteristics were evaluated in aqueous solution using both aptamers and FATA was selected for human serum experiments. Using a 1:0.5 dilution of the serum, a linear range between 3 μM and 72.1 μM was obtained, which included the therapeutic range of the antibiotic. 相似文献
953.
Stolz A Riefler M Lomin SN Achazi K Romanov GA Schmülling T 《The Plant journal : for cell and molecular biology》2011,67(1):157-168
Arabidopsis thaliana has three membrane‐located cytokinin receptors (AHK2, AHK3 and CRE1/AHK4), which are sensor histidine kinases containing a ligand‐binding CHASE domain. Despite their structural similarity the role of these receptors differs in planta. Here we have explored which parameters contribute to signal specification. In a bacterial assay, the CHASE domain of AHK2 has a similar ligand binding spectrum as CRE1/AHK4. It shows the highest affinity for isopentenyladenine (iP) and trans‐zeatin (tZ) with an apparent KD of 1.4 and 4.0 nm , respectively. Real‐time PCR analysis of cytokinin primary response genes in double mutants retaining only single receptors revealed that all receptors are activated in planta by cytokinin concentrations in the low nanomolar range. However, there are differences in sensitivity towards the principal cytokinins iP and tZ. The activation of the cytokinin‐sensitive PARR5:GUS reporter gene in three different double mutants shows specific, but also overlapping, spatial domains of activity, which were for all receptors predominantly in the shoot apical meristems and root cap columella. AHK2 and AHK3 signal specifically in leaf parenchyma cells, AHK3 in stomata cells, and CRE1/AHK4 in the root vasculature. Promoter‐swap experiments demonstrate that CRE1/AHK4 can functionally replace AHK2 but not AHK3. However, the cytoplasmic AHK3 histidine kinase (Hk) domain can be replaced by the CRE1/AHK4 Hk domain, which suggests that functionality is mediated in this case by the extracytosolic domain. Together, the data show that both differential gene expression and ligand preference contribute to specify the receptor activity. 相似文献
954.
Three optional pellet production processes integrated with an existing biomass-based CHP plant using different raw materials (wood chips and solid hydrolysis residues) are studied. The year is divided into 12 periods, and the integrated biorefinery systems are modeled and simulated for each period. The annual economic performance of three integrated biorefinery systems is analyzed based on the simulation results. The option of pellet production integrated with the existing CHP plant with the exhaust flue gas and superheated steam as drying mediums has the lowest specific pellet production cost of 105 €/t(pellet), the shortest payback time of less than 2 years and the greatest CO(2) reduction of the three options. An advantage in common among the three options is a dramatic increase of the total annual power production and significant CO(2) reduction in spite of a small decrease of power efficiency. 相似文献
955.
Toshiyuki Fukao Jörn Oliver SassPetri Kursula Eva ThimmUdo Wendel Can FiciciogluKamel Monastiri Nathalie GuffonIvo Bari? Marie-therese ZabotNaomi Kondo 《生物化学与生物物理学报:疾病的分子基础》2011,1812(5):619-624
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37 °C. They were more stable at 30 °C than 37 °C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild-type residual activities at 37 and 30 °C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH < 7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors. 相似文献
956.
Hedgehog signalling is required for perichondral osteoblast differentiation in zebrafish 总被引:1,自引:0,他引:1
In tetrapod long bones, Hedgehog signalling is required for osteoblast differentiation in the perichondrium. In this work we analyse skeletogenesis in zebrafish larvae treated with the Hedgehog signalling inhibitor cyclopamine. We show that cyclopamine treatment leads to the loss of perichondral ossification of two bones in the head. We find that the Hedgehog co-receptors patched1 and patched2 are expressed in regions of the perichondrium that will form bone before the onset of ossification. We also show that cyclopamine treatment strongly reduces the expression of osteoblast markers in the perichondrium and that perichondral ossification is enhanced in patched1 mutant fish. This data suggests a conserved role for Hedgehog signalling in promoting perichondral osteoblast differentiation during vertebrate skeletal development. However, unlike what is seen during long bone development, we did not observe ectopic chondrocytes in the perichondrium when Hedgehog signalling is blocked. This result may point to subtle differences between the development of the skeleton in the skull and limb. 相似文献
957.
TRP channels have emerged as key biological sensors in vision, taste, olfaction, hearing, and touch. Despite their importance, virtually nothing is known about the folding and transport of TRP channels during biosynthesis. Here, we identify XPORT (exit protein of rhodopsin and TRP) as a critical chaperone for TRP and its G protein-coupled receptor (GPCR), rhodopsin (Rh1). XPORT is a resident ER and secretory pathway protein that interacts with TRP and Rh1, as well as with Hsp27 and Hsp90. XPORT promotes the targeting of TRP to the membrane in Drosophila S2 cells, a finding that provides a critical first step toward solving a longstanding problem in?the successful heterologous expression of TRP. Mutations in xport result in defective transport of TRP and Rh1, leading to retinal degeneration. Our results identify XPORT as a molecular chaperone and provide a mechanistic link between TRP channels and their GPCRs during biosynthesis and transport. 相似文献
958.
Reactive oxygen species (ROS) play an important role in normal signaling events and excessive ROS are associated with many pathological conditions. The amount of ROS in cells is dependent on both the production of ROS by the mitochondrial electron transport chain and their removal by ROS-detoxifying enzymes. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of mitochondrial functions and a key regulator of the ROS-detoxifying program. However, the impact of PGC-1α on the topology and rate of superoxide production by the mitochondrial electron transport chain is not known. We report here, using mitochondria from muscle creatine kinase–PGC-1α transgenic mice, that PGC-1α does not affect the topology of ROS production, but increases the capacity of complexes I and III to generate ROS. These changes are associated with increased mitochondrial respiration and content of respiratory chain complexes. When normalizing ROS production to mitochondrial respiration, we find that PGC-1α preserves the percentage of free radical leak by the electron transport chain. Together, these data demonstrate that PGC-1α regulates the intrinsic properties of mitochondria in such a way as to preserve a tight coupling between mitochondrial respiration and ROS production. 相似文献
959.
960.
Sielaff F Böttcher-Friebertshäuser E Meyer D Saupe SM Volk IM Garten W Steinmetzer T 《Bioorganic & medicinal chemistry letters》2011,21(16):4860-4864
A series of substrate analogue inhibitors of the serine protease HAT, containing a 4-amidinobenzylamide moiety as the P1 residue, was prepared. The most potent compounds possess a basic amino acid in the d-configuration as P3 residue. Whereas inhibitor 4 (Ki 13 nM) containing proline as the P2 residue completely lacks selectivity, incorporation of norvaline leads to a potent inhibitor (15, Ki 15 nM) with improved selectivity for HAT in comparison to the coagulation proteases thrombin and factor Xa or the fibrinolytic plasmin. Selected inhibitors were able to suppress influenza virus replication in a HAT-expressing MDCK cell model. 相似文献