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191.
Phosphoinositide 3-kinase-γ (PI3Kγ) has been identified to play the critical roles in inflammatory cells activation and recruitment in multiply inflammatory diseases and it promised to be a prospective target for relevant inflammatory diseases therapy. AS605240, a selective PI3Kγ inhibitor, has been proved effective on several inflammatory diseases. In this study, we investigated the protective effect of AS605240 on bleomycin-induced pulmonary fibrosis in rats. Our results showed that orally administration of AS605240 significantly prevented lung inflammation and reduced collagen deposition. AS605240 also inhibited augmented expression of TNF-α and IL-1β induced by bleomycin instillation. Moreover, the mRNA levels of TNF-α and IL-1β in lung were remarkably suppressed. Histological assessment found that AS605240 reduced the expression of TGF-β1 and prevented T lymphocytes infiltration to lung. Phospho-Akt level in inflammatory cells by blocking PI3Kγ was down-regulated and the inhibition of Akt phosphorylation was further confirmed by Western blot. Our findings illustrated that AS605240 was effective for preventing pulmonary fibrosis by suppressing inflammatory cells recruitment and production of inflammatory cytokines. These findings also suggest that PI3Kγ may be a useful target in treating inflammation diseases and AS605240 may represent a promising novel agent for the future therapy of pulmonary fibrosis. 相似文献
192.
Kazuaki Homma Charles T. Anderson Guo-Guang Du MaryAnn Cheatham Jing Zheng 《生物化学与生物物理学报:生物膜》2010,1798(6):1029-4223
Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel that is present in a variety of epithelial cell types, and usually expressed in the luminal membrane. In contrast, prestin (SLC26A5) is a voltage-dependent motor protein, which is present in the basolateral membrane of cochlear outer hair cells (OHCs), and plays an important role in the frequency selectivity and sensitivity of mammalian hearing. By using in situ hybridization and immunofluorescence, we found that both mRNA and protein of CFTR are present in OHCs, and that CFTR localizes in both the apical and the lateral membranes. CFTR was not detected in the lateral membrane of inner hair cells (IHCs) or in that of OHCs derived from prestin-knockout mice, i.e., in instances where prestin is not expressed. These results suggest that prestin may interact physically with CFTR in the lateral membrane of OHCs. Immunoprecipitation experiments confirmed a prestin-CFTR interaction. Because chloride is important for prestin function and for the efferent-mediated inhibition of cochlear output, the prestin-directed localization of CFTR to the lateral membrane of OHCs has a potential physiological significance. Aside from its role as a chloride channel, CFTR is known as a regulator of multiple protein functions, including those of the solute carrier family 26 (SLC26). Because prestin is in the SLC26 family, several members of which interact with CFTR, we explored the potential modulatory relationship associated with a direct, physical interaction between prestin and CFTR. Electrophysiological experiments demonstrated that cAMP-activated CFTR is capable of enhancing voltage-dependent charge displacement, a signature of OHC motility, whereas prestin does not affect the chloride conductance of CFTR. 相似文献
193.
Pedersen PL 《Journal of bioenergetics and biomembranes》2007,39(5-6):349-355
Transport ATPases can be lumped into four distinct types, P, F, V, and ABC, with the first three designated 20 years ago (Pedersen,
P.L. and Carafoli, E., Trends Biochem. Sci.
12, 146–150, 1987) and the ABC type included more recently. The mini-reviews (>20) that comprise this volume of the Journal of
Bioenergetics and Biomembranes describe work presented at the 2007 FASEB Conference (6th) on Transport ATPases (Kathleen Sweadner,
Chair; Rajini Rao, Co-Chair). Since these conferences began in 1997, the “transport ATPase field” has seen tremendous progress.
Advances include a much better understanding of the structure, mechanism, and regulation of each of the four major ATPase
types as well as their physiological and medical relevance. In fact, the transport ATPase field has entered a new era in which
work on these enzymes is likely to contribute to new therapies for multiple diseases that affect both people and animals.
Among these are cancer and heart disease, mitochondrial diseases, osteoporosis, macromolecular degeneration, immune deficiency,
cystic fibrosis, diabetes, ulcers, nephro-toxicity, hearing loss, skin disorders, lupus, and malaria. In addition, as several
members of the transport ATPase family include those involved in drug resistance their study may help alleviate this recurring
problem in drug development. Finally, the transport ATPase field is also paving the way for nanotechnology focused on nano-motors
with work on the F-type ATPases (F0F1) leading the way. These ATPases driven in reverse by a proton gradient have the capacity to interconvert electrochemical
energy into mechanical energy and finally into chemical energy conserved in the terminal bond of ATP. In mammalian mitochondria
these events occur on a larger complex or “nano-machine” called the “ATP synthasome” that consists of the ATP synthase in
complex formation with carriers for Pi and ADP/ATP. 相似文献
194.
Cystic fibrosis (CF) is a fatal disease affecting the lungs and digestive system by impairment of the Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR). While over 1000 mutations in CFTR have been associated with CF, the majority of cases are linked
to the deletion of phenylalanine 508 (ΔF508). F508 is located in the first nucleotide binding domain (NBD1) of CFTR. This
mutation is sufficient to impair the trafficking of CFTR to the plasma membrane and, thus, its function. As an ABC transporter,
recent structural data from the family provide a framework on which to consider the effect of the ΔF508 mutation on CFTR.
There are fifty-seven known structures of ABC transporters and domains thereof. Only six of these structures are of the intact
transporters. In addition, modern bioinformatic tools provide a wealth of sequence and structural information on the family.
We will review the structural information from the RCSB structure repository and sequence databases of the ABC transporters.
The available structural information was used to construct a model for CFTR based on the ABC transporter homologue, Sav1866,
and provide a context for understanding the molecular pathology of Cystic Fibrosis. 相似文献
195.
Nucleoside diphosphate kinase A (NDPK-A) regulates the alpha1 isoform of the AMP-activated protein kinase (AMPK alpha1) selectively, independent of [AMP] and surrounding [ATP], by a process termed substrate channelling. Here, we show, using a range of empirically validated biochemical techniques, that the muscle form (M-LDH or LDH-A) and the heart form (H-LDH or LDH-B) of lactate dehydrogenase are physically associated with the liver cytosolic substrate-channelling complex such that M-LDH associates with NDPK-A, AMPK alpha1 and casein kinase 2 (CK2), whereas H-LDH associates with local NDPK-B. We find that the species of LDH bound to the substrate-channelling complex regulates the in vivo enzymatic activities of both AMPK and CK2, and has a downstream effect on the phospho-status of acetyl CoA carboxylase, a key regulator of cellular fat metabolism known to be a part of the cytosolic substrate-channelling complex in vivo. We hypothesise that the regulatory presence of LDH in the complex couples the substrate-channelling mechanism to both the glycolytic and redox states of the cell, allowing for efficient sensing of cell metabolic status, interfacing with the substrate-channelling complex and regulating the enzymatic activities of AMPK and CK2, two critical protein kinases. 相似文献
196.
Angiogenesis is not impaired in connective tissue growth factor (CTGF) knock-out mice. 总被引:3,自引:0,他引:3
Esther J Kuiper Peggy Roestenberg Christoph Ehlken Vincent Lambert Henny Bloys van Treslong-de Groot Karen M Lyons Hans-Jürgen T Agostini Jean-Marie Rakic Ingeborg Klaassen Cornelis J F Van Noorden Roel Goldschmeding Reinier O Schlingemann 《The journal of histochemistry and cytochemistry》2007,55(11):1139-1147
Connective tissue growth factor (CTGF) is a member of the CCN family of growth factors. CTGF is important in scarring, wound healing, and fibrosis. It has also been implicated to play a role in angiogenesis, in addition to vascular endothelial growth factor (VEGF). In the eye, angiogenesis and subsequent fibrosis are the main causes of blindness in conditions such as diabetic retinopathy. We have applied three different models of angiogenesis to homozygous CTGF(-/-) and heterozygous CTGF(+/-) mice to establish involvement of CTGF in neovascularization. CTGF(-/-) mice die around birth. Therefore, embryonic CTGF(-/-), CTGF(+/-), and CTGF(+/+) bone explants were used to study in vitro angiogenesis, and neonatal and mature CTGF(+/-) and CTGF(+/+) mice were used in models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. Angiogenesis in vitro was independent of the CTGF genotype in both the presence and the absence of VEGF. Oxygen-induced vascular pathology in the retina, as determined semi-quantitatively, and laser-induced choroidal neovascularization, as determined quantitatively, were also not affected by the CTGF genotype. Our data show that downregulation of CTGF levels does not affect neovascularization, indicating distinct roles of VEGF and CTGF in angiogenesis and fibrosis in eye conditions. 相似文献
197.
树突状细胞在肾小管间质纤维化中作用及缬沙坦的干预调节 总被引:1,自引:0,他引:1
探讨树突状细胞(DC)在肾纤维化大鼠肾小管间质中分布,以及缬沙坦对DC浸润聚集的干预作用。建立肾大部切除大鼠模型,随机分为正常组(n=18),假手术组(n=18),模型组(n=18),缬沙坦治疗组(n=18)。分别于建模1、4、12周取肾组织,采用HE和Masson染色评定各组肾小管间质纤维化(TIF)程度;采用免疫双染及荧光图像分析法,观察DC-SIGN DC在各组大鼠肾组织中分布变化;采用免疫组化方法,观察P-选择素以及TGF-β1、α-平滑肌肌动蛋白(α-SMA)、III型胶元(ColIII)、纤维连接蛋白(FN)在上述肾组织中表达;以及RT-PCR检测P-选择素、TGF-β1、α-SMA、ColIII、FN的mRNA水平。结果显示,(1)模型组DC-SIGN DC主要分布于肾小管、肾间质和肾血管,以肾间质最为明显;其分布数量于12周较1和4周呈明显增多,且与慢性肾功能减退呈正相关。(2)12周时手术组大鼠肾小管间质区P-选择素、TGF-β1、α-SMA、ColIII、FN mRNA转录水平和蛋白质表达均明显增加,并与TIF程度以及DC-SIGN DC分布数量呈正相关。(3)经缬沙坦治疗后,DC-SIGN DC分布减少,以及P-选择素、TGF-β1、α-SMA、ColIII、FN mRNA转录水平和蛋白质表达下降,TIF程度减轻及肾功能改善。研究结果表明,DC启动参与了肾小管间质纤维化形成,并与肾功能损害程度密切相关。缬沙坦对此具有明显的抑制和肾脏保护作用。 相似文献
198.
Ishikawa T Terai S Urata Y Marumoto Y Aoyama K Murata T Mizunaga Y Yamamoto N Nishina H Shinoda K Sakaida I 《Cell and tissue research》2007,327(3):463-470
We previously reported that fibroblast growth factor 2 (FGF2) facilitated the differentiation of transplanted bone marrow
cells (BMCs) into hepatocytes. Our earlier study also demonstrated that administration of FGF2 in combination with bone marrow
transplantation (BMT) synergistically activated tumor necrosis factor-alpha signaling and significantly improved liver function
and prognosis more than BMT alone. However, the way that it affected the extracellular matrix remained unclear. Here, we investigated
the effect of FGF2 treatment together with BMT on liver fibrosis in mice treated with carbon tetrachloride (CCl4). Transplantation of BMCs and concurrent treatment with FGF2 caused a statistically significant reduction in CCl4-induced liver fibrosis that was accompanied by strong expression of matrix metalloproteinase 9 as compared with FGF2-only
treatment or BMT alone. Moreover, in this process, the proliferation of bone-marrow-derived cells was accelerated without
causing apoptosis. Thus, the administration of FGF2 in combination with BMT synergistically improves CCl4-induced liver fibrosis in mice. This treatment has the potential of being an effective therapy for patients with liver cirrhosis.
This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (nos. 16390211
and 16590597) and for translational research from the Ministry of Health, Labor and Welfare (H-trans-5 and H17-Special-015). 相似文献
199.
Valdivieso AG Marcucci F Taminelli G Guerrico AG Alvarez S Teiber ML Dankert MA Santa-Coloma TA 《Biochemical and biophysical research communications》2007,356(3):805-809
Cystic fibrosis (CF) is a disease produced by mutations in the CFTR channel. We have previously reported that the CFTR chloride transport activity indirectly regulates the differential expression of several genes, including SRC and MUC1. Here we report that MT-ND4, a mitochondrial gene encoding a subunit of the mitochondrial Complex I (mtCx-I), is also a CFTR-dependent gene. A reduced expression of MT-ND4 was observed in CFDE cells (derived from a CF patient) when compared to CFDE cells ectopically expressing wild-type CFTR. The differential expression of MT-ND4 in CF was confirmed by RT-PCR. In situ hybridizations of deparaffinized human lung tissue slices derived from wt-CFTR or CF patients also showed downregulation of ND4 in CF. In addition, the CFTR chloride transport inhibitors glibenclamide and CFTR(inh)-172 also reduced MT-ND4 expression in CFDE cells ectopically expressing wt CFTR. These results suggest that the CFTR chloride transport activity indirectly up-regulates MT-ND4 expression. 相似文献
200.