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941.
942.
Susan Majka Moira Hagen Thomas Blackwell Julie Harral Jennifer A Johnson Robert Gendron Helene Paradis Daniel Crona James E Loyd Eva Nozik-Grayck Kurt R Stenmark James West 《Respiratory research》2011,12(1):84
Background
Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown.Methods
In vivo experiments were performed on adult mice with conditional endothelial-specific expression of the truncation mutation Bmpr2delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation.Results
Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2delx4+ and Bmpr2R899X mutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2delx4+ cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2R899X PMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells.Conclusions
Bmpr2 mutation in PMVEC in vivo may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis. 相似文献943.
944.
Notch信号通路是进化中高度保守的信号转导通路,其调控细胞增殖、分化和凋亡的功能涉及几乎所有组织和器官。血管损伤后,Notch信号通路分子表达改变,引起内皮细胞(endothelial cell,EC)和血管平滑肌细胞(vascular smooth muscle cell,VSMC)表型改变,其增殖、迁移、抗凋亡等能力也随之变化,从而参与血管的损伤修复。Notch信号通路能够促进EC和VSMC增殖以及VSMC迁移至内膜,并提高其存活能力,凶此能够促进新生内膜的形成。 相似文献
945.
946.
The circle of Willis (cW) is a major arterial collateral structure interconnecting hemispheric circulation within the brain, and in humans, anatomical variation of the cW is linked to stroke risk. Our prior studies on adult mice deficient in vascular smooth muscle cell (vSMC) Notch signaling revealed altered cerebroarterial maturation and patterning, including an anatomically incompetent cW similar to human variants. However, a developmental dependency on Notch signaling for cW formation in this model remained uncharacterized. Through temporospatial embryonic analyses, we now demonstrate that cW assembly is a pre-natal process highly sensitive to vSMC Notch signals, whose absence results in delayed nascent vascular plexus formation and under-development of the cW including the key anterior communicating artery (AComA) interconnecting anterior forebrain circulation. Mutant embryos additionally feature reduced vSMC coverage, non-uniform calibers and asymmetric branching at bifurcations of the major proximal cerebral arteries. At the cellular level, a notable reduction in vascular endothelial cell proliferation exists in the region of AComA assembly despite the presence of Vegfa. Furthermore, Notch signaling-deficient vSMCs in developing cerebral vessels feature reduced Pdgfrβ and Jagged1 levels and impaired proliferation. These collective findings in the embryonic brain support studies in adult animals demonstrating a reliance on intact vSMC Notch signaling for optimal neovascular responses to angiogenic stimuli. Importantly, the new data provide unique insights into the native formation of the cW and underscore a pioneering developmental role for vSMC Notch signaling in regulating temporospatial assembly of the clinically relevant cW. 相似文献
947.
948.
Maria G. Stathopoulou Amélie Bonnefond Ndeye Coumba Ndiaye Mohsen Azimi-Nezhad Said El Shamieh Abdelsalam Saleh Marc Rancier Gerard Siest John Lamont Peter Fitzgerald Sophie Visvikis-Siest 《Journal of lipid research》2013,54(2):535-541
Vascular endothelial growth factor A (VEGFA) is among the most-significant stimulators of angiogenesis. Its effect on cardiovascular diseases and on the variation of related risk factors such as lipid parameters is considered important, although as yet unclear. Recently, we identified four common variants (rs6921438, rs4416670, rs6993770, and rs10738760) that explain up to 50% of the heritability of plasma VEGFA levels. In the present study, we aimed at assessing the contribution of these variants to the variation of blood lipid levels (including apoE, triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol levels (LDL-C and HDL-C)] in healthy subjects. The effect of these single-nucleotide polymorphisms (SNPs) on lipid levels was assessed using linear regression in discovery and replication samples (n = 1,006 and n = 1,145; respectively), followed by a meta-analysis. Their gene×gene and gene×environment interactions were also assessed. SNP rs6921438 was associated with HDL-C (β = −0.08 mmol/l, Poverall = 1.2 × 10−7) and LDL-C (β = 0.13 mmol/l, Poverall = 1.5 × 10−4). We also identified a significant association between the interaction rs4416670×hypertension and apoE variation (Poverall = 1.7 × 10−5). Therefore, our present study shows a common genetic regulation between VEGFA and cholesterol homeostasis molecules. The SNP rs6921438 is in linkage disequilibrium with variants located in an enhancer- and promoter-associated histone mark region and could have a regulatory effect in the expression of surrounding genes, including VEGFA. 相似文献
949.
MAKIKO NAGAI MIWA OHNISHI TAKEO UEHARA MUTSUMI YAMAGAMI EIKO MIURA MAI KAMAKURA AKIRA KITAMURA SHU‐ICHI SAKAGUCHI WATARU SAKAMOTO TERUO SHIMMEN HIDEHIRO FUKAKI ROBERT J. REID TETSURO MIMURA 《Plant, cell & environment》2013,36(10):1826-1837
The concentration of ions in plant cells and tissues is an essential factor in determining physiological function. In the present study, we established that concentration gradients of mobile ions exist in both xylem exudates and tissues within a barley (Hordeum vulgare) primary leaf. For K+ and NO3?, ion concentrations generally decreased from the leaf base to the tip in both xylem exudates and tissues. Ion gradients were also found for Pi and Cl? in the xylem. The hydathode strongly absorbed Pi and re‐translocated it to the rest of the plant, whereas Cl? was extruded. The ion concentration gradients developed early during leaf growth, increased as the tissue aged and remained under both high and low transpiration conditions. Measurement of the expression profiles of Pi, K+ and NO3? transporters along the longitudinal axis of the leaf revealed that some transporters are more expressed at the hydathode, but for most transporters, there was no significant variation along the leaf. The mechanisms by which longitudinal ion gradients develop in leaves and their physiological functions are discussed. 相似文献
950.
Lin-Hui Zhang Yong-Liang Jia Xi-Xi Lin Hong-Quan Zhang Xin-Wei Dong Jun-Ming Zhao Jian Shen Hui-Juan Shen Fen-fen Li Xiao-Feng Yan Wei Li Yu-Qing Zhao Qiang-Min Xie 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013