全文获取类型
收费全文 | 1291篇 |
免费 | 225篇 |
国内免费 | 18篇 |
出版年
2024年 | 7篇 |
2023年 | 29篇 |
2022年 | 56篇 |
2021年 | 64篇 |
2020年 | 49篇 |
2019年 | 83篇 |
2018年 | 50篇 |
2017年 | 56篇 |
2016年 | 53篇 |
2015年 | 63篇 |
2014年 | 138篇 |
2013年 | 128篇 |
2012年 | 98篇 |
2011年 | 87篇 |
2010年 | 40篇 |
2009年 | 49篇 |
2008年 | 54篇 |
2007年 | 45篇 |
2006年 | 55篇 |
2005年 | 44篇 |
2004年 | 34篇 |
2003年 | 28篇 |
2002年 | 25篇 |
2001年 | 24篇 |
2000年 | 24篇 |
1999年 | 15篇 |
1998年 | 22篇 |
1997年 | 13篇 |
1996年 | 13篇 |
1995年 | 12篇 |
1994年 | 12篇 |
1993年 | 13篇 |
1992年 | 8篇 |
1991年 | 5篇 |
1990年 | 8篇 |
1989年 | 7篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 3篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有1534条查询结果,搜索用时 16 毫秒
191.
Kim JS Romero R Tarca AL LaJeunesse C Han YM Kim MJ Suh YL Draghici S Mittal P Gotsch F Kusanovic JP Hassan S Kim CJ 《Journal of cellular and molecular medicine》2008,12(4):1317-1330
There is a difference in the susceptibility to inflammation between the umbilical vein (UV) and the umbilical arteries (UAs). This led us to hypothesize that there is an intrinsic difference in the pro-inflammatory response between UA and UV. Real-time quantitative RT-PCR and microarray analysis revealed higher expression of interleukin (IL)-1β and IL-8 mRNA in the UV and differential expression of 567 genes between the UA and UV associated with distinct biological processes, including the immune response. Differential expression of human leukocyte antigen (HLA)-DRA mRNA between the UA and UV was due to unexpected HLA-DR+ cells migrating via the umbilical vessels into Wharton's jelly, more frequently in the UV. A significant proportion of these cells co-expressed CD45 and type I pro-collagen, and acquired CD163 or α-smooth muscle actin immunoreactivity in Wharton's jelly. Migrating cells were also found in the chorionic and stem villous vessels. Furthermore, the extent of migration increased with progression of gestation, but diminished in intrauterine growth restriction (IUGR). The observations herein strongly suggest that circulating foetal fibrocytes, routing via umbilical and placental vessels, are a reservoir for key cellular subsets in the placenta. This study reports fibrocytes in the human umbilical cord and placenta for the first time, and a novel role for both circulating foetal cells and the umbilical vessels in placental development, which is deranged in IUGR. 相似文献
192.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding
of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective
agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview
of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine
ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N
6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions.
Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1
K
i = 1050 nM, hA2A
K
i = 1550 nM, hA2B EC50 = 82 nM, hA3
K
i > 5 μM) and its 2-chloro analogue 23 (hA1
K
i = 3500 nM, hA2A
K
i = 4950 nM, hA2B EC50 = 210 nM, hA3
K
i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay
in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide
(BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis. 相似文献
193.
Ongkana N Tohno S Mahakkanukrauh P Minami T Tohno Y 《Biological trace element research》2008,124(3):236-242
To elucidate compositional changes of the uterine artery with aging, the authors investigated age-related changes of elements in the uterine arteries of Thai. After ordinary dissection by medical students at Chiang Mai University was finished, the uterine arteries were resected from Thai subjects. Thai subjects ranged in age from 27 to 86 years (average age = 63.3 +/- 17.7 years). The element content of the uterine arteries was analyzed by inductively coupled plasma-atomic emission spectrometry. It was found that the Ca, P, and Na contents increased progressively in the uterine arteries of Thai with aging. A significant accumulation of Ca and P in the uterine arteries of Thai was found in the sixties patients, and the accumulation increased markedly in the seventies. Regarding the uterine arteries in subjects more than 60 years, the extent of accumulation of Ca and P in the uterine arteries of Thai was one half of that in the uterine arteries of Japanese. Regarding the relationships among elements, extremely significant direct correlations were found among the contents of Ca, P, Mg, Zn, and Na in the uterine arteries of Thai. As Ca increased in the uterine arteries of Thai, P, Mg, Zn, and Na increased simultaneously in the arteries. 相似文献
194.
Disruption of Smad4 in neural crest cells leads to mid-gestation death with pharyngeal arch, craniofacial and cardiac defects 总被引:1,自引:0,他引:1
TGFβ/BMP signaling pathways are essential for normal development of neural crest cells (NCCs). Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of TGFβ/BMP signaling. In this work, we sought to investigate the roles of Smad4 for development of NCCs. To overcome the early embryonic lethality of Smad4 null mice, we specifically disrupted Smad4 in NCCs using a Cre/loxP system. The mutant mice died at mid-gestation with defects in facial primordia, pharyngeal arches, outflow tract and cardiac ventricles. Further examination revealed that mutant embryos displayed severe molecular defects starting from E9.5. Expression of multiple genes, including Msx1, 2, Ap-2α, Pax3, and Sox9, which play critical roles for NCC development, was downregulated by NCC disruption of Smad4. Moreover, increased cell death was observed in pharyngeal arches from E10.5. However, the cell proliferation rate in these areas was not substantially altered. Taken together, these findings provide compelling genetic evidence that Smad4-mediated activities of TGFβ/BMP signals are essential for appropriate NCC development. 相似文献
195.
Durmaz R Ozden H Kanbak G Aral E Arslan OC Kartkaya K Uzuner K 《Neurochemical research》2008,33(9):1683-1691
We hypothesized that dexanabinol can prevent neuronal death by protecting neuronal lysosomes from nitric oxide (NO)-mediated
toxicity, and in turn, by suppressing the release of cathepsins during cerebral ischemia. Focal cerebral ischemia was induced
in two sets of animals by permanent middle cerebral artery occlusion. The first set was used to monitor NO concentration and
cathepsin activity, while the second was used for histological examination with hematoxylin and eosin, and TUNEL staining.
In post-ischemic brain tissue, NO content and cathepsin B and L activity increased (p < 0.05). Dexanabinol treatment reduced NO concentration and cathepsin activity to the control level (p > 0.05). The number of eosinophilic and apoptotic neurons increased in the post-ischemic cerebral cortex (p < 0.05). However, dexanabinol treatment lowered both of these (p < 0.05). We conclude that dexanabinol might be a useful agent for the treatment of stroke patients. 相似文献
196.
Induction of iNOS restricts functional activity of both eNOS and nNOS in pig cerebral artery 总被引:1,自引:0,他引:1
The aim of the study was to investigate the effect of iNOS expression on eNOS and nNOS functional activity in porcine cerebral arteries. iNOS was induced in pig basilar arteries using lipopolysaccharide (LPS). Arteries expressing iNOS generated NO and relaxed when challenged with L-arginine (30 microM), an effect that was reduced by treatment with dexamethasone (coincubated with LPS) and prevented by the iNOS inhibitor 1400 W (administered 10 min prior to precontraction). eNOS was activated by A23187 and was found to be impaired in arteries that had iNOS induced (A23187 1 microM relaxation: control 110+/-8%, LPS-treated 50+/-16% ; p<0.05, N=5-6). This was due mainly to reduced formation of NO by A23187 (NO concentration in response to A23187 1 microM: control 25+/-6 nM, LPS-treated 0.8+/-1.2 nM; p<0.001, N=5-6), in addition to a small reduction in the vasodilator response to the NO-donors NOC-22 and SIN-1. Cerebral vasodilation produced by stimulation of intramural nitrergic nerves was impaired in arteries that had iNOS induced, and this was reversed by 1400 W (control 23+/-4% relaxation, LPS-treated 11+/-1% relaxation, LPS plus 1400 W 10 microM treated 25+/-2% relaxation; p<0.01 for control versus LPS, N=6). It is concluded that the induction of iNOS in cerebral arteries reduces NO-mediated vasodilation initiated by eNOS and by nNOS, primarily by modulation of NO formation. 相似文献
197.
Anagli J Abounit K Stemmer P Han Y Allred L Weinsheimer S Movsisyan A Seyfried D 《Biochemical and biophysical research communications》2008,366(1):86-91
The effects of selective inhibition of cathepsins B and L on postischemic protein alterations in the brain were investigated in a rat model of middle cerebral artery occlusion (MCAO). Cathepsin B activity increased predominantly in the subcortical region of the ischemic hemisphere where the levels of collapsing mediator response protein 2, heat shock cognate 70 kDa protein, 60 kDa heat shock protein, protein disulfide isomerase A3 and albumin, were found to be significantly elevated. Postischemic treatment with Cbz-Phe-Ser(OBzl)-CHN2, cysteine protease inhibitor 1 (CP-1), reduced infarct volume, neurological deficits and cathepsin B activity as well as the amount of heat shock proteins and albumin found in the brain. Our data strongly suggests that the decrease in heat shock protein levels and the significant reduction of serum albumin leakage into the brain following acute treatment with CP-1 is indicative of less secondary ischemic damage, which ultimately, is related to less cerebral tissue loss and improved neurological recovery of the animals. 相似文献
198.
Objective of this study was to develop a novel in vitro artery culture system to study vascular smooth muscle cell (SMC) proliferation of porcine carotid arteries in response to injury, basic fibroblast growth factor (FGF2), and FGF2 conjugated with cytotoxin saporin (SAP). Perfusion-cultured porcine carotid arteries remained contractile in response to norepinephrine and relaxant to acetylcholine for up to 96 h. SMC proliferation of cultured arteries was detected by bromodeoxyuridine incorporation in both non-injured and balloon-injured arteries. In the inner layer of the vessel wall near the lumen, SMC proliferation were less than 10% in uninjured vessels, 66% in injured vessels, 80% in injured vessels with FGF2 treatment, and 5% in injured vessels with treatment of FGF2-SAP. Thus, the cultured porcine carotid arteries were viable; and the injury stimulated SMC proliferation, which was significantly enhanced by FGF2 and inhibited by FGF2-SAP. 相似文献
199.
Werner C Böhm M Friedrich EB 《Biochemical and biophysical research communications》2008,377(2):331-336
Number and function of endothelial progenitor cells (EPCs) are down-regulated in patients with coronary artery disease (CAD). Integrin-linked kinase (ILK) is a signal and adaptor protein that regulates survival of mature endothelial cells and vascular development.Here we show that EPC dysfunction in patients with CAD is paralleled by down-regulation of ILK while restoration of ILK expression rescues the migratory defect of CAD-EPCs. Human EPCs transduced with dominant-negative ILK (DN-ILK) display significantly reduced expression of CD34+/VEGFR-2+, DiI-Ac-LDL uptake, and Ulex europaeus lectin binding. Mechanistically, DN-ILK-transfected EPCs are characterized by decreased proliferation, while proliferation is increased in wild-type ILK-transfected EPCs. These effects are paralleled by changes in cyclin D1 expression, colony forming units, and cytoskeletal rearrangement. Functionally, ILK is necessary and sufficient for SDF-1-triggered migration and adhesion in EPCs.These data extend current knowledge about the role of ILK in EPC biology and implicate ILK as a therapeutic target in CAD. 相似文献
200.
Alenka Mavri Mojca Stegnar Joica T. Sento
nik Viktor Vide
nik 《Obesity (Silver Spring, Md.)》2001,9(9):511-516
Objective: To investigate the extent of carotid atherosclerosis and the effect of weight loss on carotid intima‐media thickness (IMT) in obese premenopausal women. Research Methods and Procedures: In 43 obese premenopausal women who participated in a 3‐month weight reduction program with a hypocaloric diet, IMT was measured by B‐mode high‐resolution ultrasound at entry and after 5 months of follow‐up. Blood samples were analyzed at entry, after intervention, and after 5 months of follow‐up. Nineteen lean women served as control subjects. Results: At entry, common carotid IMT (0.72 vs. 0.59 mm), carotid bulb IMT (0.90 vs. 0.71 mm), and overall mean IMT (0.81 vs. 0.65 mm) were greater in obese women than in lean women (all p < 0.01). After dietary intervention decreases in blood pressure, low density lipoprotein to high density lipoprotein cholesterol ratio, triglycerides, fibrinogen, plasminogen activator inhibitor‐1, and an increase in tissue‐type plasminogen activator activity levels were observed. These effects persisted after follow‐up in 14 women who maintained reduced weight. Reduction in carotid bulb IMT (to 0.81 mm, p < 0.01) and overall mean IMT (to 0.79 mm, p < 0.05) was observed in this subgroup. No significant change of carotid IMT was detected in eight women who regained weight. Changes in IMT were associated independently and significantly with changes in body mass index, low density lipoprotein to high density lipoprotein cholesterol ratio, and plasminogen activator inhibitor‐1 antigen. Discussion: Obese premenopausal women had greater IMT than did age‐matched lean controls. It seems that this early atherosclerotic changes may be reversed by normalization of body weight. 相似文献