全文获取类型
收费全文 | 2244篇 |
免费 | 307篇 |
国内免费 | 47篇 |
出版年
2024年 | 8篇 |
2023年 | 67篇 |
2022年 | 60篇 |
2021年 | 193篇 |
2020年 | 175篇 |
2019年 | 185篇 |
2018年 | 153篇 |
2017年 | 86篇 |
2016年 | 81篇 |
2015年 | 116篇 |
2014年 | 179篇 |
2013年 | 151篇 |
2012年 | 122篇 |
2011年 | 113篇 |
2010年 | 88篇 |
2009年 | 85篇 |
2008年 | 84篇 |
2007年 | 88篇 |
2006年 | 86篇 |
2005年 | 58篇 |
2004年 | 46篇 |
2003年 | 42篇 |
2002年 | 42篇 |
2001年 | 29篇 |
2000年 | 25篇 |
1999年 | 17篇 |
1998年 | 18篇 |
1997年 | 29篇 |
1996年 | 16篇 |
1995年 | 16篇 |
1994年 | 21篇 |
1993年 | 11篇 |
1992年 | 17篇 |
1991年 | 21篇 |
1990年 | 15篇 |
1989年 | 12篇 |
1988年 | 7篇 |
1987年 | 6篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 10篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1974年 | 3篇 |
1971年 | 1篇 |
排序方式: 共有2598条查询结果,搜索用时 31 毫秒
991.
Chronic Opisthorchis viverrini-induced hepatobiliary disease is associated with significant leukocyte infiltration, including activated macrophages; however, the polarization of infiltrating macrophages remains to be fully characterized. In this study, we characterized macrophage polarization and phenotype in chronic O. viverrini-induced hepatobiliary disease in humans and hamsters using gene expression and histochemical analysis. Chronic O. viverrini infection and associated hepatobiliary diseases were associated with iron loaded M2-like macrophages in both humans and hamsters. This study provides suggestive evidence that iron loaded M2-like macrophages promote hepatobiliary disease in chronic O. viverrini infection. 相似文献
992.
Shu-Yan Gao Xue Zhou You-Jie Li Wei-Li Liu Ping-Yu Wang Min Pang Shu-Yang Xie Chang-Jun Lv 《Life sciences》2014
Aims
This study aimed to investigate the pathogenesis mechanisms of bleomycin (BLM)-induced pulmonary fibrosis (PF) in Sprague–Dawley rats and explore the anti-fibrotic role of arsenic trioxide (As2O3) in preventing PF.Main methods
Intratracheal instillation of BLM was performed to establish PF rat models. The treatment group was treated with As2O3 (0.4 mg/kg/day). Morphological changes were observed by hematoxylin–eosin and Masson staining. Related proteins were determined by immunohistochemistry, immunofluorescence, and Western blot. MicroRNA detection was performed by quantitative real-time polymerase chain reaction.Key findings
As a novel miRNA in PF, miR-98 decreased in the fibrotic lung tissues. Based on microRNA analysis software, we found that Stat3-3′-UTR is targeted by miR-98. Then, we found that Stat3 was activated with PF development and the expression of Stat3 and p-Stat3 was significantly increased in BLM-induced PF at day 28 compared with saline-treated rats. Our results showed that both Stat3 and p-Stat3 were significantly decreased in miR-98-treated A549 cells compared with that in mu-98-treated cultures or untreated controls. The fibrotic marker α-SMA was upregulated, whereas E-cadherin was inhibited in fibrotic lung tissues. The ratio of apoptotic factors Bax/Bcl-2 increased with the development of fibrosis. Furthermore, As2O3 treatment prevented lung interstitial thickening and inhibited the collagen type I and hydroxyproline, thereby preventing the development of PF. As2O3 also significantly down-regulated α-SMA but increased E-cadherin and miR-98 levels.Significance
The study revealed that arsenic trioxide prevented rat PF by up-regulation of miR-98 and inhibition of its downstream Stat3 signals. 相似文献993.
Wenbing Yang Haitao Shen Guodong Fang Hui Li Lan Li Fang Deng Wei Gu Kangsheng Li Lian Ma Jiang Gu Yongyu Wang 《Life sciences》2014
Aims
Surfactant protein A (SP-A) plays critical roles in the innate immune system and surfactant homeostasis of the lung. Mutations in SP-A2 of the carbohydrate recognition domain (CRD) impair its glycosylation and are associated with pulmonary fibrosis in humans. We aim to examine how mutations in SP-A that impair its glycosylation affect its biological properties and lead to disease.Main methods
We generated rat SP-A constructs with two types of mutations that impair its glycosylation: N-glycosylation site mutations (N21T, N207S and N21T/N207S) and disease-associated CRD mutations (G231V, F198S). We transfected these constructs into Chinese hamster ovary (CHO)-K1 cells and assessed biochemical differences in cellular and secreted wild-type and mutant SP-As by western blot, immunofluorescence, and sensitivity to enzymatic digestion.Key findings
Mutations of the CRD completely impaired SP-A secretion, whereas mutations of N-glycosylation sites had little effect. Both types of mutations formed nonidet p-40 (NP-40) insoluble aggregates, but the aggregates only from CRD mutations could be partially rescued by a chemical chaperone, 4-phenylbutyrate acid (4-PBA). The majority of CRD mutant SP-A was retained in the endoplasmic reticulum. Moreover, both types of mutations reduced SP-A stability, with CRD mutant SP-A being more sensitive to chymotrypsin digestion. Both types of soluble mutant SP-A could be degraded by the proteasome pathway, while insoluble aggregates could be additionally degraded by the lysosomal pathway.Significance
Our data provide evidence that the differential glycosylation of SP-A may play distinct roles in SP-A secretion, aggregation and degradation which may contribute to familial pulmonary fibrosis caused by SP-A2 mutations. 相似文献994.
Nikolaos N. Louros Vassiliki A. Iconomidou Paraskevi L. Tsiolaki Evangelia D. Chrysina Georgios E. Baltatzis Efstratios S. Patsouris Stavros J. Hamodrakas 《FEBS letters》2014
Isolated atrial amyloidosis (IAA) is a common localized form of amyloid deposition within the atria of the aging heart. The main constituents of amyloid fibrils are atrial natriuretic peptide (ANP) and the N-terminal part of its precursor form (NT-proANP). An ‘aggregation-prone’ heptapeptide (114KLRALLT120) was located within the NT-proANP sequence. This peptide self-assembles into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and Congo red staining studies reveal. Consequently, remedies/drugs designed to inhibit the aggregation tendency of this ‘aggregation-prone’ segment of NT-proANP may assist in prevention/treatment of IAA, congestive heart failure (CHF) or atrial fibrillation (AF). 相似文献
995.
Min Liu Jiantao Ye Si Gao Wei Fang Hong Li Biao Geng Jian Zou Xi Chen Shaorui Chen Luankun Zhang Zhongbao Yue Yunzi Ma Hui Gao Zhuoming Li Peiqing Liu 《Biochemical and biophysical research communications》2014
Salvianolic acid B (SalB), one of the major bioactive components in Salviamiltiorrhiza, has plenty of cardioprotective effects. The present study was designed to investigate the effect of SalB on angiotensin II (AngII)-induced hypertrophy in neonatal rat cardiomyocytes, and to find out whether or not this effect is attributed to inhibition of poly (ADP-ribose) polymerase-1 (PARP-1), which plays a key role in cardiac hypertrophy. Our results showed that SalB prevented the cardiomyocytes from AngII-induced hypertrophy, associated with attenuation of the mRNA expressions of atrial natriuretic factor and brain natriuretic peptide, and reduction in the cell surface area. SalB inhibited the activity of PARP-1. The inhibitory effect was comparable to that of the PARP-1 inhibitor 3-Aminobenzamide (3-AB). In addition, SalB reversed the depletion of cellular NAD+ induced by AngII. Moreover, overexpression of PARP-1 attenuated the anti-hypertrophic effect of SalB. These observations suggested that SalB prevented the cardiomyocytes from AngII-induced hypertrophy, at least partially through inhibition of PARP-1. Moreover, SalB attenuated the generation of oxidative stress via suppression of NADPH oxidase 2 and 4, which might probably contribute to the inhibition of PARP-1. These present findings may shed new light on the understanding of the cardioprotective effect of SalB. 相似文献
996.
Vikram Prasad Shivani Chirra Rohit Kohli Gary E. Shull 《Biochemical and biophysical research communications》2014
Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na+/H+ exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors. 相似文献
997.
Kotaro Sakata Satoshi Eda Eun-Seo Lee Mitsuko Hara Masaya Imoto Soichi Kojima 《Biochemical and biophysical research communications》2014
Aim
Hepatic fibrosis and angiogenesis occur in parallel during the progression of liver disease. Fibrosis promotes angiogenesis via inducing vascular endothelial growth factor (VEGF) from the activated hepatic stellate cells (HSCs). In turn, increased neovessel formation causes fibrosis, although the underlying molecular mechanism remains undetermined. In the current study, we aimed to address a role of endothelial cells (ECs) as a source of latent transforming growth factor (TGF)-β, the precursor of the most fibrogenic cytokine TGF-β.Methods
After recombinant VEGF was administered to mice via the tail vein, hepatic angiogenesis and fibrogenesis were evaluated using immunohistochemical and biochemical analyses in addition to investigation of TGF-β activation using primary cultured HSCs and liver sinusoidal ECs (LSECs).Results
In addition to increased hepatic levels of CD31 expression, VEGF-treated mice showed increased α-smooth muscle actin (α-SMA) expression, hepatic contents of hydroxyproline, and latency associated protein degradation products, which reflects cell surface activation of TGF-β via plasma kallikrein (PLK). Liberating the PLK-urokinase plasminogen activator receptor complex from the HSC surface by cleaving a tethering phosphatidylinositol linker with its specific phospholipase C inhibited the activating latent TGF-β present in LSEC conditioned medium and subsequent HSC activation.Conclusion
Neovessel formation (angiogenesis) accelerates liver fibrosis at least in part via provision of latent TGF-β that activated on the surface of HSCs by PLK, thereby resultant active TGF-β stimulates the activation of HSCs. 相似文献998.
《Journal of trace elements in medicine and biology》2014,28(1):60-64
BackgroundZinc status has been previously documented in cystic fibrosis (CF) infants, children and adolescents. However, despite the increasing life expectancy observed in CF populations, data regarding zinc status of CF adults are surprisingly lacking. The objectives of this study were to (1) characterize zinc status and (2) explore associations between zinc status and clinical outcomes of CF adult patients.MethodsA retrospective chart review was performed for patients who had their plasma zinc measured between 2009 and 2012. Data included demographics, clinical characteristics, biochemical parameters and co-morbid conditions.ResultsA total of 304 CF patients were included in the study. These patients displayed a good nutritional status (mean BMI ± SD: 22.7 ± 3.5) and moderate lung disease (mean FEV1 ± SD: 66.3 ± 22.2). Low plasma zinc concentration (<9.2 μmol/L) was found in 68 out of 304 CF patients (22.4%). Compared to patients with normal zinc, those with low zinc had significantly lower forced vital capacity and forced expiratory volume in one second. 72% of CF adults with low zinc suffered from bone disease (vs 49% with normal zinc, p = 0.037) and 79% had impaired glycemic status (vs 58%, p = 0.016). Accordingly, negative correlations were found between plasma zinc and glucose (r = −0.139, p = 0.0001), HbA1c (r = −0.237, p = 0.0001) and fructosamine (r = −0.134, p = 0.034). In multiple linear regression, albumin and glycemic status were significant predictors of plasma zinc.ConclusionOur data indicated that nearly one quarter of CF adults with good nutritional status and moderate lung disease had low plasma zinc concentration and that low zinc status was associated with worse clinical outcomes. 相似文献
999.
Michele Ettorre Genny Verzè Sara Caldrer Jan Johansson Elisa Calcaterra Baroukh Maurice Assael Paola Melotti Claudio Sorio Mario Buffelli 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Cystic fibrosis is caused by mutations of CFTR gene, a protein kinase A-activated anion channel, and is associated to a persistent and excessive chronic lung inflammation, suggesting functional alterations of immune cells. Leukocytes express detectable levels of CFTR but the molecule has not been fully characterized in these cells.Methods
Freshly isolated monocytes from healthy individuals and CF patients were assessed by protein expression, single cell electrophysiological and membrane depolarization assays.Results
We recorded chloride currents by patch clamp in healthy monocytes, after the administration of a CFTR stimulus. Currents were sensitive to a specific blocker of the CFTR channel, CFTRinh-172 and were absent in CF monocytes. Next, we evaluated the effects of ex vivo exposure of monocytes from cystic fibrosis patients carrying the F508del mutation to a chemical corrector, Vertex-325. We found an increase in CFTR expression by confocal microscopy and a recovery of CFTR function by both patch clamp and single cell fluorescence analysis.Conclusions
We confirm the expression of functional CFTR in human monocytes and demonstrate that blood monocytes can represent an adequate source of primary cells to assess new therapies and define diagnosis of CF.General significance
Tests to evaluate CFTR functional abnormalities in CF disease might greatly benefit from the availability of a convenient source of primary cells. This electrophysiological study promotes the use of monocytes as a minimally invasive tool to study and monitor CFTR function in individual patients. 相似文献1000.
Anna Caretti Alessandra Bragonzi Marcella Facchini Ida De Fino Camilla Riva Paolo Gasco Claudia Musicanti Josefina Casas Gemma Fabriàs Riccardo Ghidoni Paola Signorelli 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014