全文获取类型
收费全文 | 2764篇 |
免费 | 139篇 |
国内免费 | 29篇 |
专业分类
耳鼻咽喉 | 14篇 |
儿科学 | 29篇 |
妇产科学 | 17篇 |
基础医学 | 439篇 |
口腔科学 | 45篇 |
临床医学 | 258篇 |
内科学 | 474篇 |
皮肤病学 | 32篇 |
神经病学 | 175篇 |
特种医学 | 290篇 |
外科学 | 483篇 |
综合类 | 24篇 |
预防医学 | 111篇 |
眼科学 | 29篇 |
药学 | 265篇 |
中国医学 | 29篇 |
肿瘤学 | 218篇 |
出版年
2023年 | 22篇 |
2022年 | 62篇 |
2021年 | 89篇 |
2020年 | 30篇 |
2019年 | 60篇 |
2018年 | 82篇 |
2017年 | 54篇 |
2016年 | 83篇 |
2015年 | 128篇 |
2014年 | 159篇 |
2013年 | 160篇 |
2012年 | 247篇 |
2011年 | 228篇 |
2010年 | 133篇 |
2009年 | 114篇 |
2008年 | 173篇 |
2007年 | 145篇 |
2006年 | 140篇 |
2005年 | 125篇 |
2004年 | 98篇 |
2003年 | 81篇 |
2002年 | 57篇 |
2001年 | 42篇 |
2000年 | 52篇 |
1999年 | 42篇 |
1998年 | 25篇 |
1997年 | 24篇 |
1996年 | 34篇 |
1995年 | 19篇 |
1994年 | 14篇 |
1993年 | 5篇 |
1992年 | 8篇 |
1991年 | 16篇 |
1990年 | 12篇 |
1989年 | 12篇 |
1988年 | 11篇 |
1987年 | 19篇 |
1986年 | 13篇 |
1985年 | 16篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 5篇 |
1981年 | 8篇 |
1980年 | 12篇 |
1979年 | 12篇 |
1978年 | 7篇 |
1977年 | 7篇 |
1976年 | 6篇 |
1973年 | 3篇 |
1967年 | 3篇 |
排序方式: 共有2932条查询结果,搜索用时 15 毫秒
91.
Jiyong Kwak Hye-Jin Shin Se-Hoon Kim Jin-Kyoung Shim Ji-Hyun Lee Yong-Min Huh Eui-Hyun Kim Eun-Kyung Park Jong Hee Chang Sun Ho Kim Yong-Kil Hong Dong-Seok Kim Su-Jae Lee Seok-Gu Kang 《Child's nervous system》2013,29(12):2229-2239
Purpose
It has been reported that cancer stem cells (CSCs) can be isolated from primitive neuroectodermal tumor (PNET) specimens. Moreover, mesenchymal stem-like cells (MSLCs) have been isolated from Korean glioma specimens. Here, we tested whether tumor spheres and MSLCs can be simultaneously isolated from a single PNET specimen, a question that has not been addressed.Methods
We isolated single-cell suspensions from PNET specimens, then cultured these cells using methods for MSLCs or CSCs. Cultured cells were analyzed for surface markers of CSCs using immunocytochemistry and for surface markers of bone marrow-derived mesenchymal stem cells (BM-MSCs) using fluorescence-activated cell sorting (FACS). Tumor spheres were exposed to neural differentiation conditions, and MSLCs were exposed to mesenchymal differentiation conditions. Possible locations of MSLCs within PNET specimens were determined by immunofluorescence analysis of tumor sections.Results
Cells similar to tumor spheres and MSLCs were independently isolated from one of two PNET specimens. Spheroid cells, termed PNET spheres, were positive for CD133 and nestin, and negative for musashi and podoplanin. PNET spheres were capable of differentiation into immature neural cells and astrocytes, but not oligodendrocytes or mature neural cells. FACS analysis revealed that adherent cells isolated from the same PNET specimen, termed PNET-MSLCs, had surface markers similar to BM-MSCs. These cells were capable of mesenchymal differentiation. Immunofluorescence labeling indicated that some CD105+ cells might be closely related to endothelial cells and pericytes.Conclusion
We showed that both tumor spheres and MSLCs can be isolated from the same PNET specimen. PNET-MSLCs occupied a niche in the vicinity of the vasculature and could be a source of stroma for PNETs. 相似文献92.
Min Ji Shin Harin Rhee Il Young Kim Sang Heon Song Dong Won Lee Soo Bong Lee Ihm Soo Kwak Eun Young Seong 《Clinical and experimental nephrology》2016,20(3):402-410
Background
The RIFLE classification is widely used to assess the severity of acute kidney injury (AKI), but its application to geriatric AKI patients complicated by medical problems has not been reported.Methods
We investigated 256 geriatric patients (≥65 years old; mean age, 74.4 ± 6.3 years) who developed AKI in the intensive care unit (ICU) according to the RIFLE classification. Etiologic, clinical, and prognostic variables were analyzed.Results
They were categorized into RIFLE-R (n = 53), RIFLE-I (n = 102), and RIFLE-F (n = 101) groups. The overall in-hospital mortality was 39.8 %. There were no significant differences in RIFLE category between survivors and non-survivors. Survivors had significantly less needs for a ventilator and vasopressor, and lower number of failing organs. Survivors had higher systolic blood pressure, hemoglobin level, and serum albumin levels. We performed a logistic regression analysis to identify the independent predictors of in-hospital mortality. In a univariate analysis, hypertension, chronic kidney disease, RIFLE classification, number of failing organs, need for a ventilator and vasopressor, systolic blood pressure, hemoglobin level, and serum albumin levels were identified as prognostic factors of in-hospital mortality. However, in a multivariate analysis, hypertension, chronic kidney disease, number of failing organs, and serum albumin levels were independent risk factors, with no significant difference for in-hospital mortality with the RIFLE classification.Conclusion
The RIFLE classification might not be associated with mortality in geriatric AKI patients in the ICU. In geriatric patients with AKI, various factors besides severity of AKI should be considered to predict mortality.93.
Cerebellar Purkinje neurons have intracellular regulatory systems including Ca2+-binding proteins, intracellular Ca2+ stores, Ca2+-ATPase and Na+-Ca2+ exchanger (NCX) that keep intracellular Ca2+ concentration ([Ca2+]i) in physiological range. Among these, NCX interacts with AMPA receptors, activation of which induces cerebellar synaptic plasticity. And the activation of metabotropic glutamate receptor 1 (mGluR1) is also involved in the induction of cerebellar long-term depression. The interaction of NCX with mGluR1 is not known yet. Thus, in this study, the functional relationship between NCX and mGluR1 in modulating the [Ca2+]i in rat Purkinje neurons was investigated. The interaction between NCX and mGluR1 in Purkinje neurons was studied by measuring intracellular Ca2+ transients induced by an agonist of group I mGluRs, 3,5-dihydroxyphenylglycine (DHPG). The DHPG-induced Ca2+ transient was significantly reduced by treatments of NCX inhibitors, bepridil and KB-R7943. When cells were pretreated with antisense oligodeoxynucleotides of NCX, the DHPG-induced Ca2+ transient was also inhibited. These results suggest that NCX modulates the activity of mGluR1 in cerebellar Purkinje neurons. Therefore, NCX appears to play an important role in the physiological function of cerebellar Purkinje neurons such as synaptic plasticity. 相似文献
94.
Although Saimiri Transforming Protein (STP)-A11, an oncoprotein of Herpesvirus saimiri, has been known to activate NF-kappaB signaling pathway, the detailed mechanism has not been reported yet. We herein report that STP-A11 activates non-canonical NF-kappaB pathway, resulting in p100 processing to p52. In addition, translocation of p52 protein (NF-kappaB2) into the nucleus is observed by the expression of STP-A11. STP-A11-mediated processing of p100 to p52 protein requires proteosome-mediated proteolysis because MG132 treatment clearly blocked p52 production in spite of the expression of STP-A11. Analysis of STP-A11 mutants to activate NF-kappaB2 pathway discloses the requirement of TRAF6-binding site not Src-binding site for STP-A11-mediated NF-kappaB2 pathway. Blockage of STP-A11-mediated p52 production using siRNA against p52 enhanced a chemotherapeutic drug-mediated cell death, suggesting that p52 production induced by the expression of STP-A11 would contribute to cellular transformation, which results from a resistance to cell death. 相似文献
95.
Duck Soo Lim Yoo Seok Youn Seung Jun Kwack Hyo Min Kwak Seong Kwang Lim Ji Yun Kim 《Journal of toxicology and environmental health. Part A》2014,77(22-24):1451-1466
Bepotastine salts (nicotinate and salicylate) were investigated for their physicochemical properties to develop novel salt forms of bepotastine, bioequivalent to the bepotastine besilate-loaded tablet (Talion). These bepotastine salts of either nicotinate- or salicylate-loaded tablets were prepared by conventional wet granulation method, and dissolution profiles and pharmacokinetics in beagle dogs were compared to those of Talion. A novel bepotastine nicotinate has a higher solubility at varying pH levels (1.2, 4, or 6.8) than salicylate-loaded or besilate-loaded salt. In addition, those bepostastine salt forms (nicotinate and salicylate) are stable in heat, light, and water. Further, the novel nicotinate- and salicylate-loaded tablets showed similar dissolution rates to Talion in several selected dissolution media and were bioequivalent to Talion in beagle dogs in terms of area under the concentration–time curve (AUC) and maximum observed concentration (Cmax). A pharmacokinetic study performed in beagle dogs demonstrated that test and reference products were found to be bioequivalent in terms of safety, efficacy, and pharmacokinetic properties. These results suggest that bepostastine nicotinate and salicylate formulations are considered applicable candidates and are well tolerated versus the conventional bepostastine besilate formulation. 相似文献
96.
Min Soo Choo Sung Yong Cho Kyungtae Ko Chang Wook Jeong Seung Bae Lee Ja Hyeon Ku Sung Kyu Hong Seok-Soo Byun Cheol Kwak Hyeon Hoe Kim Sang Eun Lee Hyeon Jeong 《World journal of urology》2014,32(6):1401-1409
Purpose
We investigated the influence of positive surgical margins (PSMs) and their locations on biochemical recurrence (BCR) according to risk stratification and surgical modality.Methods
A total of 1,874 post-radical-prostatectomy (RP) patients of pT2–T3a between 2000 and 2010 at three tertiary centers, and who did not receive neoadjuvant/adjuvant therapy, were included in this study. Patients were stratified according to BCR risk: low risk (PSA <10, pT2a-b, and pGS ≤6), intermediate risk (PSA 10–20 and/or pT2c and/or pGS 7), and high risk (PSA >20 or pT3a or pGS 8–10). The median follow-up was 43 months.Results
PSMs were a significant predictor of BCR in both the intermediate- and high-risk-disease groups (P = .001, HR 2.1, 95 % CI 1.3–3.4; P < .001, HR 2.8, 95 % CI 2.0–4.1). Positive apical margin was a significant risk factor for BCR in high-risk disease (P = .003, HR 2.0, 95 % CI 1.2–3.3), but not in intermediate-risk disease (P = .06, HR 1.7, 95 % CI 0.9–3.1). Positive bladder neck margin was a significant risk factor for BCR in both intermediate- and high-risk disease (P < .001, HR 5.4, 95 % CI 2.1–13.8; P = .001, HR 4.5, 95 % CI 1.8–11.4). In subgroup analyses, robotic RP provided comparable BCR-free survival regardless of risk stratification. Patients with PSMs showed similar BCR-free survival between open and robotic RP (log-rank, P = .897).Conclusions
Post-RP PSMs were a significantly independent predictor of disease progression in high-risk disease as well as intermediate-risk disease. Both positive apical and bladder neck margins are also significant risk factors of BCR in high-risk disease. Patients with PSMs showed similar BCR-free survival between open and robotic surgery. 相似文献97.
98.
99.
Joonhee Park Jin-Oh Kwak Brigitte Riederer Ursula Seidler Susan P.C. Cole Hwa Jeong Lee Min Goo Lee 《Journal of the American Society of Nephrology : JASN》2014,25(4):726-736
Na+/H+ exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3−/−) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3−/− mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules.Assembly of protein complexes by adaptor proteins with PSD-95/discs large/ZO-1 (PDZ) domains plays an important role in the regulation of many membrane proteins, especially in epithelial and neuronal tissues.1,2 For example, PDZ-based adapter proteins in epithelia, such as Shank2, synaptic scaffolding molecule (S-SCAM), and Na+/H+ exchanger regulatory factors (NHERFs), are known to be involved in the regulation of cell surface expression and the activity of many membrane transporters and receptors in the respiratory, digestive, urinary, and reproductive organs.3–6 The four members of the NHERF proteins (NHERF1 to 4) contain either two or four PDZ domains and were the first family of PDZ-containing proteins shown to be involved in epithelial transport. NHERF3, also known as PDZK1 or CAP70, has four PDZ domains and is normally localized to the apical microdomains of gastrointestinal and kidney epithelia. Each PDZ domain of NHERF3 has been proposed to bind independently to the PDZ binding motif of various membrane proteins, such as the cystic fibrosis transmembrane conductance regulator (CFTR), the Na+/H+ exchanger 3, the urate transporter, and the organic anion transporter 4.7–10 However, Nherf3 knockout (Nherf3−/−) mice do not have a discernible phenotype except mild hypercholesterolemia,11 and, consequently, the in vivo role of NHERF3 in transepithelial transport remains poorly understood.Transporters belonging to either the ATP binding cassette (ABC) or the solute-linked carrier superfamilies of membrane proteins play diverse roles in the pharmacokinetic and pharmacodynamic pathways of drugs and their metabolites.12 Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the C subfamily of ABC transporters and mediates the efflux of a group of organic molecules using energy generated from the binding and hydrolysis of ATP.13 Cumulative evidence suggests that MRP4 pumps out purine compounds and plays an important role in the renal elimination of purine-based antiviral and antineoplastic agents.14,15 However, the regulatory mechanisms for MRP4 expression and function have not been extensively studied.The COOH terminus of MRP4 contains a class 1 PDZ interaction motif (-S/T-X-Ф, where Ф is a hydrophobic amino acid),16 indicating that MRP4 may interact with PDZ-based adaptors in epithelia. In preliminary studies using a yeast two-hybrid assay, MRP4 was found to strongly interact with NHERF3 among several PDZ adaptor proteins expressed in epithelial tissues. The aim of the present study was to identify the physiologic and pharmacologic roles of the interaction of NHERF3 with MRP4 using a variety of in vitro and in vivo experimental approaches. The results obtained provide strong evidence that NHERF3 is a key regulator of organic transport in the kidney, particularly the MRP4-mediated clearance of purine-based drug molecules. 相似文献
100.
Minho Kwak MD Daegu Son MD PhD Junhyung Kim MD PhD Kihwan Han MD PhD 《Wound repair and regeneration》2014,22(5):678-682
This study investigated wound contraction rates according to anatomical regions and wound morphology according to skin tension line in a micropig porcine model. Of the four animals used, skin tension morphology was determined in one pig. In the remaining three pigs, six pairs of full‐thickness skin excisions were created on the dorsum (six square and six circular). The wounds were grouped, Wounds #1 through #5, according to the skin tension line and anatomical regions: Wounds #1 and #2, cephalic; Wounds #4 and #5, caudal; and Wound #3, center. Wound sizes and contraction rates were calculated for 28 days. A static tension topography of the micropig dorsum was obtained. Excisional wounds deformed along the local tension vector and healed in this fashion. Wound contraction rates were significantly higher for cephalic wounds (p = 0.004). No significant difference in wound contraction rates were observed between square and circular wounds. Final wound morphology was related to the local tension vector and initial wound shape. Cephalic wounds contracted more quickly. Further studies are needed to characterize scar formation after primarily closed surgical wounds in relation to the newly established skin tension topography and to elucidate the mechanism behind the variable wound contraction rates in the cephalocaudal gradient. 相似文献