全文获取类型
收费全文 | 2283篇 |
免费 | 159篇 |
国内免费 | 14篇 |
专业分类
耳鼻咽喉 | 15篇 |
儿科学 | 67篇 |
妇产科学 | 69篇 |
基础医学 | 354篇 |
口腔科学 | 34篇 |
临床医学 | 207篇 |
内科学 | 478篇 |
皮肤病学 | 105篇 |
神经病学 | 284篇 |
特种医学 | 77篇 |
外科学 | 210篇 |
综合类 | 10篇 |
预防医学 | 142篇 |
眼科学 | 31篇 |
药学 | 145篇 |
中国医学 | 8篇 |
肿瘤学 | 220篇 |
出版年
2024年 | 4篇 |
2023年 | 27篇 |
2022年 | 54篇 |
2021年 | 90篇 |
2020年 | 69篇 |
2019年 | 78篇 |
2018年 | 89篇 |
2017年 | 78篇 |
2016年 | 94篇 |
2015年 | 91篇 |
2014年 | 116篇 |
2013年 | 135篇 |
2012年 | 207篇 |
2011年 | 212篇 |
2010年 | 119篇 |
2009年 | 104篇 |
2008年 | 164篇 |
2007年 | 128篇 |
2006年 | 118篇 |
2005年 | 126篇 |
2004年 | 93篇 |
2003年 | 83篇 |
2002年 | 67篇 |
2001年 | 15篇 |
2000年 | 8篇 |
1999年 | 7篇 |
1998年 | 9篇 |
1997年 | 8篇 |
1996年 | 8篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1990年 | 4篇 |
1989年 | 6篇 |
1988年 | 2篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1983年 | 2篇 |
1981年 | 4篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1975年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1967年 | 1篇 |
1960年 | 1篇 |
1957年 | 1篇 |
1955年 | 1篇 |
1934年 | 1篇 |
排序方式: 共有2456条查询结果,搜索用时 15 毫秒
71.
Katharina Hess Saad H. Alzahrani Jackie F. Price Mark W. Strachan Natalie Oxley Rhodri King Tobias Gamlen Verena Schroeder Paul D. Baxter Ramzi A. Ajjan 《Diabetologia》2014,57(8):1737-1741
Aims/hypothesis
Plasminogen activator inhibitor-1 (PAI-1) has been regarded as the main antifibrinolytic protein in diabetes, but recent work indicates that complement C3 (C3), an inflammatory protein, directly compromises fibrinolysis in type 1 diabetes. The aim of the current project was to investigate associations between C3 and fibrinolysis in a large cohort of individuals with type 2 diabetes.Methods
Plasma levels of C3, C-reactive protein (CRP), PAI-1 and fibrinogen were analysed by ELISA in 837 patients enrolled in the Edinburgh Type 2 Diabetes Study. Fibrin clot lysis was analysed using a validated turbidimetric assay.Results
Clot lysis time correlated with C3 and PAI-1 plasma levels (r?=?0.24, p?<?0.001 and r?=?0.22, p?<?0.001, respectively). In a multivariable regression model involving age, sex, BMI, C3, PAI-1, CRP and fibrinogen, and using log-transformed data as appropriate, C3 was associated with clot lysis time (regression coefficient 0.227 [95% CI 0.161, 0.292], p?<?0.001), as was PAI-1 (regression coefficient 0.033 [95% CI 0.020, 0.064], p?<?0.05) but not fibrinogen (regression coefficient 0.003 [95% CI ?0.046, 0.051], p?=?0.92) or CRP (regression coefficient 0.024 [95% CI ?0.008, 0.056], p?=?0.14). No correlation was demonstrated between plasma levels of C3 and PAI-1 (r?=??0.03, p?=?0.44), consistent with previous observations that the two proteins affect different pathways in the fibrinolytic system.Conclusions/interpretation
Similarly to PAI-1, C3 plasma levels are independently associated with fibrin clot lysis in individuals with type 2 diabetes. Therefore, future studies should analyse C3 plasma levels as a surrogate marker of fibrinolysis potential in this population. 相似文献72.
Drug‐induced liver injury (DILI) is the most common cause of acute liver failure and often responsible for drug withdrawals from the market. Clinical manifestations vary, and toxicity may or may not appear dose‐dependent. We present several machine‐learning models (decision tree induction, k‐nearest neighbor, support vector machines, artificial neural networks) for the prediction of clinically relevant DILI based solely on drug structure, with data taken from published DILI cases. Our models achieved corrected classification rates of up to 89%. We also studied the association of a drug's interaction with carriers, enzymes and transporters, and the relationship of defined daily doses with hepatotoxicity. The results presented here are useful as a screening tool both in a clinical setting in the assessment of DILI as well as in the early stages of drug development to rule out potentially hepatotoxic candidates. 相似文献
73.
Nils Schweingruber Henrike J. Fischer Lisa Fischer Jens van den Brandt Anna Karabinskaya Verena Labi Andreas Villunger Benedikt Kretzschmar Peter Huppke Mikael Simons Jan P. Tuckermann Alexander Flügel Fred Lühder Holger M. Reichardt 《Acta neuropathologica》2014,127(5):713-729
Glucocorticoids (GCs) are the standard therapy for treating multiple sclerosis (MS) patients suffering from an acute relapse. One of the main mechanisms of GC action is held to be the induction of T cell apoptosis leading to reduced lymphocyte infiltration into the CNS, yet our analysis of experimental autoimmune encephalomyelitis (EAE) in three different strains of genetically manipulated mice has revealed that the induction of T cell apoptosis is not essential for the therapeutic efficacy of GCs. Instead, we identified the redirection of T cell migration in response to chemokines as a new therapeutic principle of GC action. GCs inhibited the migration of T cells towards CCL19 while they enhanced their responsiveness towards CXCL12. Importantly, blocking CXCR4 signaling in vivo by applying Plerixafor® strongly impaired the capacity of GCs to interfere with EAE, as revealed by an aggravated disease course, more pronounced CNS infiltration and a more dispersed distribution of the infiltrating T cells throughout the parenchyma. Our observation that T cells lacking the GC receptor were refractory to CXCL12 further underscores the importance of this pathway for the treatment of EAE by GCs. Importantly, methylprednisolone pulse therapy strongly increased the capacity of peripheral blood T cells from MS patients of different subtypes to migrate towards CXCL12. This indicates that modulation of T cell migration is an important mechanistic principle responsible for the efficacy of high-dose GC therapy not only of EAE but also of MS. 相似文献
74.
Matthias Watzka Christof Geisen Monika Scheer Regina Wieland Verena Wiegering Thomas Dörner Hans-Jürgen Laws Fatma Gümrük Sahin Hanalioglu Sule Ünal Davut Albayrak Johannes Oldenburg 《Thrombosis research》2014
Functional limitations for the vitamin K cycle, caused either by mutations in gamma-glutamyl carboxylase or vitamin K epoxide reductase genes, result in hereditary deficiency of vitamin K-dependent coagulation factors (VKCFD1 and VKCFD2, respectively). Patients suffering from VKCFD often share several other anatomical irregularities which are not related to haemostasis. Here we report on nine patients, eight of them previously unreported, who presented with VKCFD1. All were examined with special attention to vitamin K-dependent coagulation factors as well as to bone and heart development and to other anatomical signs of embryonal vitamin K deficiency. In total, we detected ten mutations in the gamma-glutamyl carboxylase gene of which seven have not been previously reported. Most interestingly, additional non-bleeding phenotypes were observed in all patients including midfacial hypoplasia, premature osteoporosis, cochlear hearing loss, heart valve defects, pulmonary stenosis, or pseudoxanthoma elasticum-like phenotype. Undercarboxylated matrix Gla protein, osteocalcin, and periostin appear to be responsible for these defects which are also observed in cases of fetal warfarin syndrome. 相似文献
75.
76.
Adamo A Woglar A Silva N Penkner A Jantsch V La Volpe A 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(9):3440-3445
Introduction of multiple copies of a germ-line-expressed gene elicits silencing of the corresponding endogenous gene during Caenorhabditis elegans oogenesis; this process is referred to as germ-line cosuppression. Transformed plasmids assemble into extrachromosomal arrays resembling extra minichromosomes with repetitive structures. Loss of the transgene extrachromosomal array leads to reversion of the silencing phenomenon. Cosuppression and RNAi depend upon some of the same genes. In the C. elegans germ line, about half the cells undergo a physiological programmed cell death that shares most genetic requirements with somatic apoptosis. In addition, apoptosis is stimulated by DNA damage and synaptic failure mediated through different apoptotic checkpoints. We found that both germ-line cosuppression and RNAi of germ-line-expressed genes enhance apoptosis during C. elegans oogenesis. In contrast, apoptosis is not enhanced by extrachromosomal arrays carrying genes not driven by germ-line-specific promoters that thus do not elicit transgene-mediated cosuppression/silencing. Similarly, introduction of doubled-stranded RNA that shares no homology with endogenous genes has no effect on apoptosis. "Silencing-induced apoptosis" is dependent upon sir-2.1 and cep-1 (the worm p53 ortholog), and is accompanied by a rise in RAD-51 foci, a marker for ongoing DNA repair, indicating induction of DNA double-strand breaks. This finding suggests that the DNA damage-response pathway is involved. RNAi and cosuppression have been postulated as defense mechanisms against genomic intruders. We speculate that the mechanism here described may trigger the elimination of germ cells that have undergone viral infection or transposon activation. 相似文献
77.
Salman V Amann R Shub DA Schulz-Vogt HN 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(11):4203-4208
The gene encoding the small subunit rRNA serves as a prominent tool for the phylogenetic analysis and classification of Bacteria and Archaea owing to its high degree of conservation and its fundamental function in living organisms. Here we show that the 16S rRNA genes of not-yet-cultivated large sulfur bacteria, among them the largest known bacterium Thiomargarita namibiensis, regularly contain numerous self-splicing introns of variable length. The 16S rRNA genes can thus be enlarged to up to 3.5 kb. Remarkably, introns have never been identified in bacterial 16S rRNA genes before, although they are the most frequently sequenced genes today. This may be caused in part by a bias during the PCR amplification step that discriminates against longer homologs, as we show experimentally. Such length heterogeneity of 16S rRNA genes has so far never been considered when constructing 16S rRNA-based clone libraries, even though an elongation of rRNA genes due to intervening sequences has been reported previously. The detection of elongated 16S rRNA genes has profound implications for common methods in molecular ecology and may cause systematic biases in several techniques. In this study, catalyzed reporter deposition-fluorescence in situ hybridization on both ribosomes and rRNA precursor molecules as well as in vitro splicing experiments were performed and confirmed self-splicing of the introns. Accordingly, the introns do not inhibit the formation of functional ribosomes. 相似文献
78.
Kühn MW Radtke I Bullinger L Goorha S Cheng J Edelmann J Gohlke J Su X Paschka P Pounds S Krauter J Ganser A Quessar A Ribeiro R Gaidzik VI Shurtleff S Krönke J Holzmann K Ma J Schlenk RF Rubnitz JE Döhner K Döhner H Downing JR 《Blood》2012,119(10):e67-e75
To identify cooperating lesions in core-binding factor acute myeloid leukemia, we performed single-nucleotide polymorphism-array analysis on 300 diagnostic and 41 relapse adult and pediatric leukemia samples. We identified a mean of 1.28 copy number alterations per case at diagnosis in both patient populations. Recurrent minimally deleted regions (MDRs) were identified at 7q36.1 (7.7%), 9q21.32 (5%), 11p13 (2.3%), and 17q11.2 (2%). Approximately one-half of the 7q deletions were detectable only by single-nucleotide polymorphism-array analysis because of their limited size. Sequence analysis of MLL3, contained within the 7q36.1 MDR, in 46 diagnostic samples revealed one truncating mutation in a leukemia lacking a 7q deletion. Recurrent focal gains were identified at 8q24.21 (4.7%) and 11q25 (1.7%), both containing a single noncoding RNA. Recurrent regions of copy-neutral loss-of-heterozygosity were identified at 1p (1%), 4q (0.7%), and 19p (0.7%), with known mutated cancer genes present in the minimally altered region of 1p (NRAS) and 4q (TET2). Analysis of relapse samples identified recurrent MDRs at 3q13.31 (12.2%), 5q (4.9%), and 17p (4.9%), with the 3q13.31 region containing only LSAMP, a putative tumor suppressor. Determining the role of these lesions in leukemogenesis and drug resistance should provide important insights into core-binding factor acute myeloid leukemia. 相似文献
79.
The coagulation and complement pathways simultaneously promote homeostasis in response to injury but cause tissue damage when unregulated. Mechanisms by which they cooperate are poorly understood. To delineate their interactions, we studied the effects of thrombin and C5 convertase on C5 in purified and plasma-based systems, measuring release of the anaphylatoxin C5a, and generation of C5b, the initial component of the lytic membrane attack complex. Thrombin cleaved C5 poorly at R751, yielding minimal C5a and C5b. However, thrombin efficiently cleaved C5 at a newly identified, highly conserved R947 site, generating previously undescribed intermediates C5(T) and C5b(T). Tissue factor-induced clotting of plasma led to proteolysis of C5 at a thrombin-sensitive site corresponding to R947 and not R751. Combined treatment of C5 with thrombin and C5 convertase yielded C5a and C5b(T), the latter forming a C5b(T)-9 membrane attack complex with significantly more lytic activity than with C5b-9. Our findings provide a new paradigm for complement activation, in which thrombin and C5 convertase are invariant partners, enhancing the terminal pathway via the generation of newly uncovered C5 intermediates. Delineating the molecular links between coagulation and complement will provide new therapeutic targets for diseases associated with excess fibrin deposition and complement activation. 相似文献
80.
Haufe S Utz W Engeli S Kast P Böhnke J Pofahl M Traber J Haas V Hermsdorf M Mähler A Busjahn A Wiesner S Otto C Mehling H Luft FC Boschmann M Schulz-Menger J Jordan J 《Hypertension》2012,59(1):70-75
In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.9±4.4; range, 26.5-45.4 kg/m(2)) to 6-month hypocaloric diets with either reduced carbohydrate intake or reduced fat intake. We obtained cardiac MRI and ambulatory blood pressure recordings over 24 hours before and after 6 months. Ninety subjects completing the intervention period had a full cardiac MRI data set. Subjects lost 7.3±4.0 kg (7.9±3.8%) with reduced-carbohydrate diet and 6.2±4.2 kg (6.7±4.4%) with reduced-fat diet (P<0.001 within each group; P=not significant between interventions). Caloric restriction led to similar significant decreases in left ventricular mass with low-carbohydrate diets (5.4±5.4 g) or low-fat diets (5.2±4.8 g; P<0.001 within each group; P=not significant between interventions). Systolic and diastolic left ventricular function did not change with either diet. The 24-hour systolic blood pressure decreased similarly with both interventions. Body weight change (β=0.33; P=0.02) and percentage of ingested n-3 polyunsaturated fatty acids (β=-0.27; P=0.03) predicted changes in left ventricular mass. In conclusion, weight loss induced by reduced-fat diets or reduced-carbohydrate diets similarly improved left ventricular mass in overweight and obese subjects over a 6-month period. However, n-3 polyunsaturated fatty acid ingestion may have an independent beneficial effect on left ventricular mass. 相似文献