全文获取类型
收费全文 | 1980篇 |
免费 | 160篇 |
国内免费 | 8篇 |
专业分类
耳鼻咽喉 | 10篇 |
儿科学 | 35篇 |
妇产科学 | 38篇 |
基础医学 | 397篇 |
口腔科学 | 51篇 |
临床医学 | 231篇 |
内科学 | 376篇 |
皮肤病学 | 33篇 |
神经病学 | 197篇 |
特种医学 | 50篇 |
外科学 | 190篇 |
综合类 | 6篇 |
一般理论 | 3篇 |
预防医学 | 188篇 |
眼科学 | 40篇 |
药学 | 117篇 |
中国医学 | 2篇 |
肿瘤学 | 184篇 |
出版年
2024年 | 5篇 |
2023年 | 20篇 |
2022年 | 30篇 |
2021年 | 47篇 |
2020年 | 40篇 |
2019年 | 61篇 |
2018年 | 45篇 |
2017年 | 52篇 |
2016年 | 67篇 |
2015年 | 72篇 |
2014年 | 86篇 |
2013年 | 118篇 |
2012年 | 198篇 |
2011年 | 157篇 |
2010年 | 96篇 |
2009年 | 113篇 |
2008年 | 139篇 |
2007年 | 123篇 |
2006年 | 105篇 |
2005年 | 107篇 |
2004年 | 102篇 |
2003年 | 104篇 |
2002年 | 92篇 |
2001年 | 17篇 |
2000年 | 10篇 |
1999年 | 16篇 |
1998年 | 13篇 |
1997年 | 7篇 |
1996年 | 12篇 |
1995年 | 12篇 |
1994年 | 6篇 |
1993年 | 7篇 |
1992年 | 6篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 5篇 |
1982年 | 8篇 |
1981年 | 5篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1974年 | 3篇 |
1966年 | 2篇 |
1949年 | 1篇 |
排序方式: 共有2148条查询结果,搜索用时 0 毫秒
41.
Shirley K. Knauer Britta Unruhe Sarah Karczewski Rouven Hecht Verena Fetz Carolin Bier Sandra Friedl Barbara Wollenberg Ralph Pries Negusse Habtemichael Ulf‐Rüdiger Heinrich Roland H. Stauber 《Human mutation》2013,34(2):395-404
Survivin (BIRC5) is an acknowledged cancer therapy‐resistance factor and overexpressed in head and neck squamous cell carcinomas (HNSCC). Driven by its nuclear export signal (NES), Survivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. Although predominantly nuclear Survivin is considered a favorable prognostic disease marker for HNSCC patients, the underlying molecular mechanisms are not resolved. Hence, we performed immunohistochemical and mutational analyses using laser capture microdissection on HNSCC biopsies from patients displaying high levels of nuclear Survivin. We found somatic BIRC5 mutations, c.278T>C (p.Phe93Ser), c.292C>T (p.Leu98Phe), and c.288A>G (silent), in tumor cells, but not in corresponding normal tissues. Comprehensive functional characterization of the Survivin mutants by ectopic expression and microinjection experiments revealed that p.Phe93Ser, but not p.Leu98Phe inactivated Survivin's NES, resulted in a predominantly nuclear protein, and attenuated Survivin's dual cytoprotective activity against chemoradiation‐induced apoptosis. Notably, in xenotransplantation studies, HNSCC cells containing the p.Phe93Ser mutation responded significantly better to cisplatin‐based chemotherapy. Collectively, our results underline the disease relevance of Survivin's nucleocytoplasmic transport, and provide first evidence that genetic inactivation of Survivin's NES may account for predominantly nuclear Survivin and increased therapy response in cancer patients. 相似文献
42.
Beate Vajen Ute Modlich Andrea Schienke Susanne Wolf Britta Skawran Winfried Hofmann Guntram Büsche Hans Kreipe Christopher Baum Irene Santos‐Barriopedro Alejandro Vaquero Brigitte Schlegelberger Cornelia Rudolph 《Genes, chromosomes & cancer》2013,52(4):423-430
Suv39h1 mediates heterochromatin formation in pericentric and telomeric regions by trimethylation of lysine 9 of histone 3 (H3K9me3). Yet, its role in the induction of chromosomal instability is poorly understood. We established a leukemia model by retrovirally expressing Myc in wild‐type and histone methyltransferase Suv39h1‐deficient hematopoietic cells and characterized the resulting leukemias for chromosomal instability. All mice that received cells overexpressing Myc developed myeloid leukemia with a median survival of 44 days posttransplantation. Myc‐overexpressing wild‐type leukemias demonstrated clones with numerical chromosomal aberrations (5/16). In secondary transplantations of these leukemic cells, structural changes, mostly end‐to‐end fusions of chromosomes, appeared (10/12). In contrast, leukemic cells overexpressing Myc with reduced or no Suv39h1 expression had a normal karyotype in primary, secondary, and tertiary transplantations (16/16). Myc‐transduced Suv39h1‐deficient cells showed less critically short telomeres (P < 0.05) compared with Myc‐transduced wild‐type bone marrow cells. Gene expression analysis showed upregulation of genes involved in the alternative lengthening of telomeres (ALT) mechanism. Thus, we hypothesize that loss of Suv39h1 implies activation of the ALT mechanism, in turn ensuring telomere length and stability. Our data show for the first time that Suv39h1 deficiency may prevent chromosomal instability by more efficient telomere stabilization in hematopoietic bone marrow cells overexpressing Myc. © 2013 Wiley Periodicals, Inc. 相似文献
43.
44.
Alterations in intervertebral disc composition,matrix homeostasis and biomechanical behavior in the UCD‐T2DM rat model of type 2 diabetes 下载免费PDF全文
Aaron J. Fields Britta Berg‐Johansen Lionel N. Metz Stephanie Miller Brandan La Ellen C. Liebenberg Dezba G. Coughlin James L. Graham Kimber L. Stanhope Peter J. Havel Jeffrey C. Lotz 《Journal of orthopaedic research》2015,33(5):738-746
Type 2 diabetes (T2D) adversely affects many tissues, and the greater incidence of discogenic low back pain among diabetic patients suggests that the intervertebral disc is affected too. Using a rat model of polygenic obese T2D, we demonstrate that diabetes compromises several aspects of disc composition, matrix homeostasis, and biomechanical behavior. Coccygeal motion segments were harvested from 6‐month‐old lean Sprague‐Dawley rats, obese Sprague‐Dawley rats, and diabetic obese UCD‐T2DM rats (diabetic for 69 ± 7 days). Findings indicated that diabetes but not obesity reduced disc glycosaminoglycan and water contents, and these degenerative changes correlated with increased vertebral endplate thickness and decreased endplate porosity, and with higher levels of the advanced glycation end‐product (AGE) pentosidine. Consistent with their diminished glycosaminoglycan and water contents and their higher AGE levels, discs from diabetic rats were stiffer and exhibited less creep when compressed. At the matrix level, elevated expression of hypoxia‐inducible genes and catabolic markers in the discs from diabetic rats coincided with increased oxidative stress and greater interactions between AGEs and one of their receptors (RAGE). Taken together, these findings indicate that endplate sclerosis, increased oxidative stress, and AGE/RAGE‐mediated interactions could be important factors for explaining the greater incidence of disc pathology in T2D. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:738–746, 2015. 相似文献
45.
Higher gastric mucin secretion and lower gastric acid output in first-degree relatives of gastric cancer patients 总被引:1,自引:0,他引:1
Vilkin A Levi Z Morgenstern S Shmuely H Gal E Hadad B Hardi B Niv Y 《Journal of clinical gastroenterology》2008,42(1):36-41
BACKGROUND: Patients infected by Helicobacter pylori who have first-degree relatives with gastric cancer have an 8-fold increased risk of developing gastric cancer themselves. Mucins are high-molecular-weight glycoproteins that play a cardinal role in the protective mechanism of the gastric epithelium. AIM: To study gastric acid and mucin secretion in dyspeptic patients with and without a family history of gastric cancer and H. pylori infection. MATERIALS AND METHODS: Twenty-six dyspeptic patients underwent esophago-gastro-duodenoscopy, gastric biopsies, and acid and mucin secretory tests. The sample was divided by family history of gastric cancer and H. pylori status. RESULTS: Patients who were infected by H. pylori had a significantly higher degree of inflammation than those who were not. H. pylori-positive patients with a positive family history had a lower basal and maximal gastric acid output than infected patients with no family history and noninfected controls, and a higher basal and maximal mucin output than infected patients with no family history. MUC5AC was the major mucin species expressed in gastric juice. CONCLUSIONS: In patients with relatives with gastric cancer, H. pylori infection is associated with a more severe inflammatory reaction consisting of decreased gastric acid secretion and increased mucin secretion. 相似文献
46.
Arner P Stenson BM Dungner E Näslund E Hoffstedt J Ryden M Dahlman I 《The Journal of clinical endocrinology and metabolism》2008,93(6):2249-2254
CONTEXT: Six transmembrane protein of prostate 2 (STAMP2) is a counterregulator of adipose inflammation and insulin resistance in mice. Our hypothesis was that STAMP2 could be involved in human obesity and insulin resistance. OBJECTIVE: The objective of the study was to elucidate the role of adipose STAMP2 expression in human obesity and insulin resistance. DESIGN: The design was to quantify STAMP2 in human abdominal sc and omental white adipose tissue (WAT), isolated adipocytes, and stroma and in vitro differentiated preadipocytes and relate levels of STAMP2 in sc WAT to clinical and adipocyte phenotypes involved in insulin resistance. PARTICIPANTS: Nonobese and obese women and men (n = 236) recruited from an obesity clinic or through local advertisement. MAIN OUTCOME MEASUREMENT: Clinical measures included body mass index, body fat, total adiponectin, and homeostasis model assessment as measure of overall insulin resistance. In adipocytes we determined cell size, sensitivity of lipolysis and lipogenesis to insulin, adiponectin secretion, and inflammatory gene expression. RESULTS: STAMP2 levels in sc and visceral WAT and adipocytes were increased in obesity (P = 0.0008-0.05) but not influenced by weight loss. Increased WAT STAMP2 levels associated with a high amount of body fat (P = 0.04), high homeostasis model assessment (P = 0.01), and large adipocytes (P = 0.02). Subjects with high STAMP2 levels displayed reduced sensitivity of adipocyte lipogenesis (P = 0.04) and lipolysis (P = 0.03) to insulin but had normal adiponectin levels. WAT STAMP2 levels correlated with expression of the macrophage marker CD68 (P = 0.0006). CONCLUSION: Human WAT STAMP2 associates with obesity and insulin resistance independently of adiponectin, but the role of STAMP2 in obesity and its complications seems different from that in mice. 相似文献
47.
48.
PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE 下载免费PDF全文
Karthik Sathiyanadan Caroline Coisne Gaby Enzmann Urban Deutsch Britta Engelhardt 《European journal of immunology》2014,44(8):2287-2294
T‐cell migration across the blood‐brain barrier is a crucial step in the pathogenesis of EAE, an animal model for MS. Live cell imaging studies demonstrated that P‐selectin glycoprotein ligand‐1 (PSGL‐1) and its endothelial ligands E‐ and P‐selectin mediate the initial rolling of T cells in brain vessels during EAE. As functional absence of PSGL‐1 or E/P‐selectins does not result in ameliorated EAE, we speculated that T‐cell entry into the spinal cord is independent of PSGL‐1 and E/P‐selectin. Performing intravital microscopy, we observed the interaction of WT or PSGL‐1?/? proteolipid protein‐specific T cells in inflamed spinal cord microvessels of WT or E/P‐selectin?/? SJL/J mice during EAE. T‐cell rolling but not T‐cell capture was completely abrogated in the absence of either PSGL‐1 or E‐ and P‐selectin, resulting in a significantly reduced number of T cells able to firmly adhere in the inflamed spinal cord microvessels, but did not lead to reduced T‐cell invasion into the CNS parenchyma. Thus, PSGL‐1 interaction with E/P‐selectin is essential for T‐cell rolling in inflamed spinal cord microvessels during EAE. Taken together with previous observations, our findings show that T‐cell rolling is not required for successful T‐cell entry into the CNS and initiation of EAE. 相似文献
49.
50.
Aeffner S Reusch T Weinhausen B Salditt T 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(25):E1609-E1618
We have used X-ray diffraction on the rhombohedral phospholipid phase to reconstruct stalk structures in different pure lipids and lipid mixtures with unprecedented resolution, enabling a quantitative analysis of geometry, as well as curvature and hydration energies. Electron density isosurfaces are used to study shape and curvature properties of the bent lipid monolayers. We observe that the stalk structure is highly universal in different lipid systems. The associated curvatures change in a subtle, but systematic fashion upon changes in lipid composition. In addition, we have studied the hydration interaction prior to the transition from the lamellar to the stalk phase. The results indicate that facilitating dehydration is the key to promote stalk formation, which becomes favorable at an approximately constant interbilayer separation of 9.0 ± 0.5 Å for the investigated lipid compositions. 相似文献