全文获取类型
收费全文 | 11383篇 |
免费 | 864篇 |
国内免费 | 545篇 |
专业分类
12792篇 |
出版年
2024年 | 22篇 |
2023年 | 113篇 |
2022年 | 276篇 |
2021年 | 442篇 |
2020年 | 326篇 |
2019年 | 399篇 |
2018年 | 445篇 |
2017年 | 354篇 |
2016年 | 481篇 |
2015年 | 708篇 |
2014年 | 756篇 |
2013年 | 904篇 |
2012年 | 1069篇 |
2011年 | 931篇 |
2010年 | 547篇 |
2009年 | 507篇 |
2008年 | 592篇 |
2007年 | 519篇 |
2006年 | 442篇 |
2005年 | 386篇 |
2004年 | 355篇 |
2003年 | 294篇 |
2002年 | 253篇 |
2001年 | 201篇 |
2000年 | 187篇 |
1999年 | 169篇 |
1998年 | 86篇 |
1997年 | 97篇 |
1996年 | 92篇 |
1995年 | 76篇 |
1994年 | 72篇 |
1993年 | 72篇 |
1992年 | 89篇 |
1991年 | 87篇 |
1990年 | 66篇 |
1989年 | 53篇 |
1988年 | 47篇 |
1987年 | 48篇 |
1986年 | 36篇 |
1985年 | 39篇 |
1984年 | 22篇 |
1983年 | 21篇 |
1982年 | 12篇 |
1981年 | 12篇 |
1979年 | 11篇 |
1978年 | 15篇 |
1975年 | 7篇 |
1974年 | 7篇 |
1972年 | 12篇 |
1971年 | 6篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
181.
182.
Wan Yun Ho Jer-Cherng Chang Kenneth Lim Amaury Cazenave-Gassiot Aivi T. Nguyen Juat Chin Foo Sneha Muralidharan Ashley Viera-Ortiz Sarah J.M. Ong Jin Hui Hor Ira Agrawal Shawn Hoon Olubankole Aladesuyi Arogundade Maria J. Rodriguez Su Min Lim Seung Hyun Kim John Ravits Shi-Yan Ng Markus R. Wenk Edward B. Lee Greg Tucker-Kellogg Shuo-Chien Ling 《The Journal of cell biology》2021,220(9)
183.
We evaluated the association between GSTM1 and GSTT1 gene polymorphisms and susceptibility to chronic obstructive pulmonary
disease (COPD) in smokers. A meta-analysis of the published case–control studies was performed. Published literature was retrieved
from PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI), with last update in February, 2011. Data were extracted
and a fixed- or random-effects model was used to calculate pooled odds ratios with 95% confidence intervals depending on statistical
heterogeneity. Fourteen eligible studies, comprising 1,665 COPD cases and 1,614 controls, were included in the meta-analysis.
The combined analyses showed that there was a significant difference in GSTM1 genotype distribution between COPD cases and
controls among Caucasians, but not among Asians. The combined GSTM1/GSTT1 null genotype conferred a 1.36-fold greater risk
for COPD in Asian smokers. The GSTT1 null genotype alone was not associated with enhanced risk for COPD. The GSTM1 null genotype
is significantly associated with an increasing susceptibility to COPD in Caucasian smokers, but not in Asian smokers. The
GSTM1/GSTT1 null genotype is a significant risk factor for developing COPD in Asian smokers. The GSTT1 null genotype, however,
was not associated with COPD. 相似文献
184.
L-serine degradation in Escherichia coli K-12: cloning and sequencing of the sdaA gene. 总被引:2,自引:8,他引:2 下载免费PDF全文
A new mutant of Escherichia coli K-12 unable to grow with L-serine, glycine, and L-leucine has been isolated by lambda plac Mu insertion and shown to be deficient in L-serine deaminase activity. The corresponding gene, sdaA, has been cloned from a prototrophic strain, and the clone has been characterized and sequenced. The evidence is consistent with the hypothesis that sdaA is the structural gene for L-serine deaminase. However, other possibilities are also considered. No significant homology with previously reported DNA or protein sequences was detected. 相似文献
185.
Phosphatidylinositol 3-kinase/Akt activation by integrin-tumor matrix interaction suppresses Fas-mediated apoptosis in T cells 总被引:1,自引:0,他引:1
Su CC Lin YP Cheng YJ Huang JY Chuang WJ Shan YS Yang BC 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(7):4589-4597
It has recently become apparent that the microenvironment made up of the extracellular matrix may affect cell signaling. In this study, we evaluated Fas-triggered apoptosis in T cells in contact with tumor cells, which resembles the cell-to-cell interactions found in tumor regions. Jurkat cells were less susceptible to the Fas-mediated apoptosis when cocultured with U118, HeLa, A549, and Huh-7 tumor cells. This was indicated by less plasma membrane alteration, an amelioration of the loss of mitochondria membrane potential, a decrease in caspase-8 and caspase-3 activation, a decrease in DNA fragmentation factor-45/35 cleavage, and a reduction in the breakage of DNA when compared with Jurkat cells cultured alone. In contrast, the tumor cell lines MCF-7 and HepG2 produced no such protective effect. This protective event was independent of the expression of Fas ligand on the tumor cells. Interrupting the beta integrins-matrix interaction diminished the coculture effect. In Jurkat cells, cell matrix contact reduced the assembly of the Fas death-inducing signaling complex and Bcl-x(L) cleavage, but enhanced the phosphorylation of ERK1/2, p38 MAPK, and Akt. Only PI3K inhibitor, but not kinase inhibitors for MEK, ERK1/2, p38 MAPK, JNK, protein kinase C, and protein kinase A, completely abolished this tumor cell contact-associated protection and in parallel restored Fas-induced Bcl-x(L) cleavage as well as decreasing the phosphorylation of Bad at serine 136. Together, our results indicate that stimulation of the beta integrin signal of T cells by contact with tumor cells may trigger a novel protective signaling through the PI3K/Akt pathway of T cells against Fas-mediated apoptosis. 相似文献
186.
Chang YT Cheng CM Su YZ Lee WT Hsu JS Liu GC Cheng TL Wang YM 《Bioconjugate chemistry》2007,18(6):1716-1727
A smart contrast agent for magnetic resonance imaging (MRI) can be used to exploit an enzymatic activity specific to the tissue or disease state signified by converting an MRI-inactivated agent to an activated MRI agent. In this study, a beta-galactopyranose-containing gadolinium(III) complex [Gd(DOTA-FPG)(H 2O)] was designed, synthesized, and characterized as being potentially suitable for a bioactivated MRI contrast agent. The (17)O NMR experiments were conducted to estimate the water exchange rate k e x 298 and rotational correlation time tau R 298 . The k ex 298 value of [Gd(DOTA-FPG)(H 2O)] is similar to that of [Gd(DO3A-bz-NO 2)(H 2O)]. The rotational correlation time value of [Gd(DOTA-FPG)(H 2O)] is dramatically longer than that of [Gd(DOTA)(H 2O)] (-) Relaxometric studies show that the percentage change in the T 1 value of [Gd(DOTA-FPG)(H 2O)] decreases dramatically in the presence of beta-galactosidase and human serum albumin. The T(1) change percentage of [Gd(DOTA-FPG)(H 2O)] (60%) is significantly higher than those of Egad and gadolinium(III)-1-(4-(2-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl)))-ethylcarbamoyloxymethyl)-2-nitrophenyl)-beta- d-glucopyronuronate. The signal intensity of the MR image for [Gd(DOTA-FPG)(H 2O)] in the presence of human serum albumin and beta-galactosidase (2670 +/- 210) is significantly higher than that of [Gd(DOTA-FPG)(H 2O)] in the sodium phosphate buffer solution (1490 +/- 160). In addition, the MR images show a higher-intensity enhancement in CT26/beta-gal tumor with beta-galactosidase gene expression but not for the CT26 tumor without beta-galactosidase gene expression. We conclude that [Gd(DOTA-FPG)(H 2O)] is a suitable candidate for a bioactivated MRI contrast agent in tracing gene expression. 相似文献
187.
We investigated the effects of homocysteine (Hcy) and oxidized low density lipoprotein (ox-LDL) on DNA methylation in the promoter region of the estrogen receptor α (ERos) gene,and its potentialmechanism in the pathogenesis of atherosclerosis.Cultured smooth muscle cells (SMCs) of humans weretreated by Hcy and ox-LDL with different concentrations for different periods of time.The DNA methylationstatus was assayed by nested methylation-specific polymerase chain reaction,the lipids that accumulated inthe SMCs and foam cell formations were examined with Oil red O staining.The proliferation of SMCs wasassayed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method.The results showedthat ox-LDL in moderate concentrations (10-40 mg/L) induced de novo methylation in the promoter regionof the ERα gene of SMCs.However,high concentrations (50 mg/L) of ox-LDL,resulted in demethylation ofERα.The Hcy treatment resulted in de novo methylation in the promoter region of the ERα gene with aconcentration- and treating time-dependent manner,and a dose-dependent promoting effect on SMCproliferation.These data indicated that the two risk factors for atherosclerosis had the function of inducingde novo methylation in the promoter region of the ERα gene of SMCs. However,high concentrations (50rag/L) of ox-LDL induced demethylation,indicating that different risk factors of atherosclerosis with differentpotency might cause different aberrant methylation patterns in the promoter region of the ERα gene.Theatherogenic mechanism of Hcy might involve the hypermethylation of the ERα gene,leading to the proliferationof SMCs in atherosclerotic lesions. 相似文献
188.
大剂量国产胸腺肽联合干扰素治疗慢性乙肝疗效及其机理初探 总被引:3,自引:0,他引:3
本文研究大剂量胸腺肽联合干扰素对慢性乙肝患者的治疗作用,发现胸腺肽联合干扰素治疗三个月后,患者的ALT复常率、HBeAg转阴率、HBVDNA阴转率和HBVDNA有效下降率分别为760%、440%、560%和960%。T淋巴细胞亚群分析结果表明,联合治疗后,患者外周血CD4+淋巴细胞亚群上调,CD8+亚群下调,二者比值趋于正常,说明国产胸腺肽联合干扰素治疗慢性乙肝的治疗机理与免疫调节作用有关。 相似文献
189.
Ming-Jai Su PhD Wen-Pin Chen Tase-Yueh Lo Tian-Shung Wu 《Journal of biomedical science》1999,6(6):376-386
We investigated the electrophysiological effect and antiarrhythmic potential of cinnamophilin (Cinn), a thromboxane A2 antagonist isolated fromCinnamomum philippinense, on rat cardiac tissues. Action potential and ionic currents in single rat ventricular cells were examined by current clamp or voltage clamp in a whole-cell configuration. In 9 episodes of ischemia-reperfusion arrhythmia, 10 µM Cinn converted 6 of them to normal sinus rhythm. Cinn suppressed the maximal rate of rise of the action potential upstroke (Vmax) and prolonged the action potential duration at 50% repolarization (APD50). Voltage clamp study showed that the suppression of Vmax by Cinn was associated with an inhibition of sodium inward current (INa, IC50=10.0 ± 0.4 µM). At 30 µM, V1/2 for the steady-state inactivation curve of INa was shifted from –84.1 ± 0.2 to –93.0 ± 0.5 mV. Cinn also reduced calcium inward current (ICa) dose-dependently with an IC50 value of 9.5 ± 0.3 µM. Cinn (10 µM) reduced the ICa with a negative shift of V1/2 for the steady-state inactivation curve of ICa from –32.2 ± 0.3 to –50.7 ± 0.4 mV. The prolongation of APD50 was associated with an inhibition of the integral of potassium outward current with IC50 values between 4.8 and 7.1 µM. At 10 µM, Cinn reduced INa without a negative shift of its voltage-dependent steady-state inactivation curves. The inhibition of transient outward current (Ito) by Cinn (3–30 µM) was associated with an acceleration of its time constant of inactivation and negative shift of its potential-dependent steady-state inactivation curves. The equilibrium dissociation constant (Kd) of Cinn to inhibit open state Ito channels, as calculated from the time constant of developing block, was 18.3 µM. The time constant of recovery of Ito from inactivation state was unaffected by Cinn. The rate constant for the relief from the depolarization-dependent block of Ito was calculated to be 23.9 ms. As compared with its effect on Ito, Cinn exerted about half the potency to block INa and ICa. These results indicate that the inhibition of INa, ICa and Ito may contribute to the antiarrhythmic activity of Cinn against ischemia-reperfusion arrhythmia. 相似文献
190.
C Luo X Yao J Li B He Q Liu H Ren F Liang M Li H Lin J Peng T F Yuan Z Pei H Su 《Cell death & disease》2016,7(3):e2160
Subarachnoid hemorrhage (SAH) is a devastating disease with high mortality. The mechanisms underlying its pathological complications have not been fully identified. Here, we investigate the potential involvement of the glymphatic system in the neuropathology of SAH. We demonstrate that blood components rapidly enter the paravascular space following SAH and penetrate into the perivascular parenchyma throughout the brain, causing disastrous events such as cerebral vasospasm, delayed cerebral ischemia, microcirculation dysfunction and widespread perivascular neuroinflammation. Clearance of the paravascular pathway with tissue-type plasminogen activator ameliorates the behavioral deficits and alleviates histological injury of SAH. Interestingly, AQP4−/− mice showed no improvements in neurological deficits and neuroinflammation at day 7 after SAH compared with WT control mice. In conclusion, our study proves that the paravascular pathway dynamically mediates the pathological complications following acute SAH independently of glymphatic control.Cerebral aneurysm rupture causes subarachnoid hemorrhage (SAH), which is associated with a high mortality due to its secondary complications, including hemorrhage, hydrocephalus and delayed cerebral ischemia (DCI).1, 2, 3 Therapeutic interventions against the secondary complications, especially DCI, are yet limited, as the pathological mechanism underlying that is not fully understood.2, 3, 4, 5, 6, 7 Current hypotheses of the development of the secondary complications mainly include cerebral vasospasm (CVS) and the microcirculation disturbance, as well as parenchymal arterial lesions, microthrombosis and neuroinflammation.1, 2, 4, 7, 8, 9Previous studies have shown that the blockade of cerebral lymphatic drainage deteriorated the secondary cerebral ischemia after SAH, suggesting that the cerebral lymphatic drainage pathway could be involved in the pathological mechanism of SAH.10, 11 However, the central nervous system (CNS) was considered lack of a conventional lymphatic drainage system in the past. Recently, several studies have shown that the brain has in fact the proper lymphatic system, including sinus-associated lymphatic vessels and the glymphatic system (GS).12, 13, 14, 15 Sinus-associated lymphatic vessels express all of the molecular hallmarks of lymphatic endothelial cells, contain cerebrospinal fluid (CSF) and immune cells, and drain into the deep cervical lymph nodes.12, 13There is a histologically defined space in the brain, the Virchow–Robin space, where the subarachnoid space meets the paravascular space (or perivascular space in somewhere, PVS).16 The GS is a specialized brain-wide anatomic structure locating at the PVS surrounding the brain vasculature, which is ensheathed with the astroglial endfeet and astroglial water channel aquaporin-4 (AQP4).14, 15 The GS facilitates the efficient lymphatic clearance of extracellular solutes and fluid in the brain through astroglial-mediated interstitial fluid bulk flow.14Impairment of GS involves neurological conditions including traumatic brain injuries,17 ischemic stroke18 and aged brain.19 Interestingly, brain imaging study with magnetic resonance imaging reported weakened GS perfusion following acute stroke or SAH.18, 20 However, little is known about whether the GS is involved in the secondary complications of SAH. Here, we examined the potential involvement of GS in SAH-associated pathology progression with in vivo two-photon microscopy and CLARITY technique.21, 22 Our data showed that subarachnoid blood flowed into the brain parenchyma rapidly through the PVS, causing CVS, vasculitis, widespread microinfraction and neuroinflammation in the animal model of SAH and SAH patients. Prevention of CVS with Fasudil23 did not improve the neurological impairment nor alleviated the pathology, while the PVS clearance with tissue-type plasminogen activator (tPA) infusion improved the behavioral recovery and reduced neuroinflammation in the brain. Interestingly, AQP4−/− mice showed no improvements in neurological deficits and neuroinflammation at day 7 after SAH compared with WT control mice. Our study therefore suggested that the paravacular pathway dynamically mediates the pathological complications following acute SAH independently of glymphatic control. 相似文献