全文获取类型
收费全文 | 5259篇 |
免费 | 461篇 |
国内免费 | 3篇 |
专业分类
5723篇 |
出版年
2024年 | 3篇 |
2023年 | 24篇 |
2022年 | 53篇 |
2021年 | 101篇 |
2020年 | 65篇 |
2019年 | 52篇 |
2018年 | 80篇 |
2017年 | 68篇 |
2016年 | 125篇 |
2015年 | 236篇 |
2014年 | 275篇 |
2013年 | 351篇 |
2012年 | 426篇 |
2011年 | 434篇 |
2010年 | 282篇 |
2009年 | 265篇 |
2008年 | 334篇 |
2007年 | 354篇 |
2006年 | 358篇 |
2005年 | 347篇 |
2004年 | 309篇 |
2003年 | 338篇 |
2002年 | 300篇 |
2001年 | 50篇 |
2000年 | 33篇 |
1999年 | 55篇 |
1998年 | 74篇 |
1997年 | 43篇 |
1996年 | 45篇 |
1995年 | 32篇 |
1994年 | 34篇 |
1993年 | 29篇 |
1992年 | 26篇 |
1991年 | 21篇 |
1990年 | 14篇 |
1989年 | 12篇 |
1988年 | 5篇 |
1987年 | 9篇 |
1986年 | 11篇 |
1985年 | 9篇 |
1984年 | 8篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1979年 | 5篇 |
1978年 | 6篇 |
1973年 | 4篇 |
1972年 | 1篇 |
1966年 | 1篇 |
1936年 | 1篇 |
排序方式: 共有5723条查询结果,搜索用时 15 毫秒
31.
Clermont E. Dionne Renée Bourbonnais Pierre Frémont Michel Rossignol Susan R. Stock Isabelle Larocque 《CMAJ》2005,172(12):1559-1567
Background
Tools for early identification of workers with back pain who are at high risk of adverse occupational outcome would help concentrate clinical attention on the patients who need it most, while helping reduce unnecessary interventions (and costs) among the others. This study was conducted to develop and validate clinical rules to predict the 2-year work disability status of people consulting for nonspecific back pain in primary care settings.Methods
This was a 2-year prospective cohort study conducted in 7 primary care settings in the Quebec City area. The study enrolled 1007 workers (participation, 68.4% of potential participants expected to be eligible) aged 18–64 years who consulted for nonspecific back pain associated with at least 1 day''s absence from work. The majority (86%) completed 5 telephone interviews documenting a large array of variables. Clinical information was abstracted from the medical files. The outcome measure was “return to work in good health” at 2 years, a variable that combined patients'' occupational status, functional limitations and recurrences of work absence. Predictive models of 2-year outcome were developed with a recursive partitioning approach on a 40% random sample of our study subjects, then validated on the rest.Results
The best predictive model included 7 baseline variables (patient''s recovery expectations, radiating pain, previous back surgery, pain intensity, frequent change of position because of back pain, irritability and bad temper, and difficulty sleeping) and was particularly efficient at identifying patients with no adverse occupational outcome (negative predictive value 78%– 94%).Interpretation
A clinical prediction rule accurately identified a large proportion of workers with back pain consulting in a primary care setting who were at a low risk of an adverse occupational outcome.Since the 1950s, back pain has taken on the proportions of a veritable epidemic, counting now among the 5 most frequent reasons for visits to physicians'' offices in North America1,2,3 and ranking sixth among health problems generating the highest direct medical costs.4 Because of its high incidence and associated expense, effective intervention for back pain has great potential for improving population health and for freeing up extensive societal resources.So-called red flags to identify pain that is specific (i.e., pain in the back originating from tumours, fractures, infections, cauda equina syndrome, visceral pain and systemic disease)5 account for about 3% of all cases of back pain.6 The overwhelming majority of back-pain problems are thus nonspecific. One important feature of nonspecific back pain among workers is that a small proportion of cases (< 10%) accounts for most of the costs (> 70%).7,8,9,10,11,12,13,14 This fact has led investigators to focus on the early identification of patients who are at higher risk of disability, so that specialized interventions can be provided earlier, whereas other patients can be expected to recover with conservative care.9,15,16,17,18,19,20,21,22,23,24,25 Although this goal has become much sought-after in back-pain research, most available studies in this area have 3 methodological problems:- Potential predictors are often limited to administrative or clinical data, whereas it is clear that back pain is a multidimensional health problem.
- The outcome variable is most often a 1-point dichotomous measure of return to work, time off work or duration of compensation, although some authors have warned against the use of first return to work as a measure of recovery. Baldwin and colleagues,26 for instance, point out that first return to work is frequently followed by recurrences of work absence.
- Most published prediction rules developed for back pain have not been successfully validated on any additional samples of patients.
32.
Boonen M Rezende de Castro R Cuvelier G Hamer I Jadot M 《The Biochemical journal》2008,416(3):431-440
The suicide inactivation mechanism of tyrosinase acting on its substrates has been studied. The kinetic analysis of the proposed mechanism during the transition phase provides explicit analytical expressions for the concentrations of o-quinone against time. The electronic, steric and hydrophobic effects of the substrates influence the enzymatic reaction, increasing the catalytic speed by three orders of magnitude and the inactivation by one order of magnitude. To explain the suicide inactivation, we propose a mechanism in which the enzymatic form E(ox) (oxy-tyrosinase) is responsible for such inactivation. A key step might be the transfer of the C-1 hydroxyl group proton to the peroxide, which would act as a general base. Another essential step might be the axial attack of the o-diphenol on the copper atom. The rate constant of this reaction would be directly related to the strength of the nucleophilic attack of the C-1 hydroxyl group, which depends on the chemical shift of the carbon C-1 (delta(1)) obtained by (13)C-NMR. Protonation of the peroxide would bring the copper atoms together and encourage the diaxial nucleophilic attack of the C-2 hydroxyl group, facilitating the co-planarity with the ring of the copper atoms and the concerted oxidation/reduction reaction, and giving rise to an o-quinone. The suicide inactivation would occur if the C-2 hydroxyl group transferred the proton to the protonated peroxide, which would again act as a general base. In this case, the co-planarity between the copper atom, the oxygen of the C-1 and the ring would only permit the oxidation/reduction reaction on one copper atom, giving rise to copper(0), hydrogen peroxide and an o-quinone, which would be released, thus inactivating the enzyme. 相似文献
33.
Callebaut I Malivert L Fischer A Mornon JP Revy P de Villartay JP 《The Journal of biological chemistry》2006,281(20):13857-13860
DNA double strand breaks are considered as the most harmful DNA lesions and are repaired by either homologous recombination or nonhomologous end joining (NHEJ). A new NHEJ factor, Cernunnos, has been identified, the defect of which leads to a severe immunodeficiency condition associated with microcephaly and other developmental defects in humans. This presentation is reminiscent to that of DNA-ligase IV deficiency and suggests a possible interplay between Cernunnos and the XRCC4 x DNA-ligase IV complex. We show here that Cernunnos physically interacts with the XRCC4 x DNA-ligase IV complex. Moreover, a combination of sensitive methods of sequence analysis revealed that Cernunnos can be associated with the XRCC4 family of proteins and that it corresponds to the genuine homolog of the yeast Nej1 protein. Altogether these results shed new lights on the last step, the DNA religation, of the NHEJ pathway. 相似文献
34.
Yao Shi Juan Yuan Vilma Rraklli Eva Maxymovitz Miriam Cipullo Mingzhi Liu Shuijie Li Isabelle Westerlund Oscar C Bedoya-Reina Petra Bullova Joanna Rorbach C Christofer Juhlin Adam Stenman Catharina Larsson Per Kogner Maureen J OSullivan Susanne Schlisio Johan Holmberg 《Nucleic acids research》2021,49(5):2509
35.
In recent years, the diagnostic and therapeutic uses of radioisotopes have shown significant progress. Immunoglobulin (Ig) appears to be a promising tracer, particularly due to its ability to target selected antigens. The main objective of this study is to optimize and assess an Ig radiolabeling method with Technetium 99m (99mTc), an attractive radioelement used widely for diagnostic imaging. Monoclonal anti-CD20 IgG was retained to study in vitro and in vivo radiolabeling impact. After IgG derivatization with 2-iminothiolane, IgG-SH was radiolabeled by an indirect method, using a 99mTc-tricarbonyl core. Radiolabeling stability was evaluated over 24h by thin-layer chromatography. IgG integrity was checked by sodium dodecyl sulfate—polyacrylamide gel electrophoresis coupled with Western blot and autoradiography. The radiolabeled Ig’s immunoaffinity was assessed in vitro by a radioimmunoassay method and binding experiments with cells (EL4-hCD20 and EL4-WT). Biodistribution studies were performed in normal BALB/c mice. Tumor uptake was assessed in mice bearing EL4-hCD20 and EL4-WT subcutaneous xenografts. With optimized method, high radiolabeling yields were obtained (95.9 ± 3.5%). 99mTc-IgG-SH was stable in phosphate-buffered saline (4°C and 25°C) and in serum (37°C), even if important sensitivity to transchelation was observed. IgG was not degraded by derivatization and radiolabeling, as shown by Western blot and autoradiography results. 99mTc-anti-CD20 IgG-SH immunoaffinity was estimated with Kd = 35 nM by both methods. In vivo biodistribution studies for 48h showed significant accumulation of radioactivity in plasma, liver, spleen, lungs and kidneys. Planar scintigraphy of mice bearing tumors showed a significant uptake of 99mTc-anti-CD20 IgG-SH in CD20+ tumor versus CD20- tumor. Radiolabeling of derivatized IgG with 99mTc-tricarbonyl was effective, stable and required few antibody amounts. This attractive radiolabeling method is “antibody safe” and preserves Ig affinity for antigen, as shown by both in vitro and in vivo experiments. This method could easily be used with noncommercial IgG or other antibody isotypes. 相似文献
36.
ElFihry Raouia Elmessaoudi-Idrissi Mohcine Jadid Fatima-Zahra Zaidane Imane Chihab Hajar Tahiri Mohamed Kabine Mostafa Badre Wafaa Chemin Isabelle Marchio Agnes Pineau Pascal Ezzikouri Sayeh Benjelloun Soumaya 《中国病毒学》2020,35(5):566-574
Virologica Sinica - Hepatitis C virus (HCV) is still one of the main causes of liver disease worldwide. Metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), induced by HCV have... 相似文献
37.
Kawecki TJ Lenski RE Ebert D Hollis B Olivieri I Whitlock MC 《Trends in ecology & evolution》2012,27(10):547-560
Experimental evolution is the study of evolutionary processes occurring in experimental populations in response to conditions imposed by the experimenter. This research approach is increasingly used to study adaptation, estimate evolutionary parameters, and test diverse evolutionary hypotheses. Long applied in vaccine development, experimental evolution also finds new applications in biotechnology. Recent technological developments provide a path towards detailed understanding of the genomic and molecular basis of experimental evolutionary change, while new findings raise new questions that can be addressed with this approach. However, experimental evolution has important limitations, and the interpretation of results is subject to caveats resulting from small population sizes, limited timescales, the simplified nature of laboratory environments, and, in some cases, the potential to misinterpret the selective forces and other processes at work. 相似文献
38.
Kjølbye AL Dikshteyn M Eloff BC Deschênes I Rosenbaum DS 《American journal of physiology. Heart and circulatory physiology》2008,294(1):H41-H49
Discordant action potential alternans creates large gradients of refractoriness, which are thought to be the mechanisms linking T-wave alternans to cardiac arrhythmogenesis. Since intercellular coupling acts to maintain synchronization of repolarization between cells, we hypothesized that intercellular uncoupling, such as during ischemia, would initiate discordant alternans and that restoration of intercellular coupling by the gap junction opener rotigaptide may provide a novel approach for suppressing arrhythmogenic discordant alternans. Optical mapping was used to record action potentials from ventricular epicardium of Langendorff-perfused guinea pig hearts. Threshold for spatially synchronized (i.e., concordant) alternans and discordant alternans was determined by increasing heart rate step-wise during 1) baseline, 2) treatment with rotigaptide or vehicle, and 3) global low-flow ischemia + rotigaptide or vehicle. Ischemia reduced the threshold for concordant alternans in both groups from 362 +/- 8 to 305 +/- 9 beats/min (P < 0.01) and for discordant alternans from 423 +/- 6 to 381 +/- 7 beats/min (P < 0.01). Interestingly, rotigaptide also increased the threshold for discordant alternans relative to vehicle both before (438 +/- 7 vs. 407 +/- 8 beats/min, P < 0.05) and during (394 +/- 7 vs. 364 +/- 9 beats/min, P < 0.05) ischemia. Rotigaptide increased conduction velocity and prevented conduction slowing and dispersion of repolarization during ischemia. Confocal immunofluorescence revealed that total connexin43 quantity and cellular distribution were unchanged before or after low-flow ischemia, with and without rotigaptide. However, connexin43 dephosphorylation in response to low-flow ischemia was significantly prevented by rotigaptide (15.9 +/- 7.0 vs. 0.3 +/- 6.4%, P < 0.001). These data suggest that intercellular uncoupling plays an important role in the transition from concordant to discordant alternans. By suppressing discordant alternans, repolarization gradients, and connexinx43 dephosphorylation, rotigaptide may protect against ischemia-induced arrhythmias. Drugs that selectively open gap junctions offer a novel strategy for antiarrhythmic therapy. 相似文献
39.
Characterization of the Tomato ARF Gene Family Uncovers a Multi-Levels Post-Transcriptional Regulation Including Alternative Splicing 总被引:1,自引:0,他引:1
40.
Marine Bretou Ouardane Jouannot Isabelle Fanget Paolo Pierobon Nathana?l Larochette Pierre Gestraud Marc Guillon Valentina Emiliani Stéphane Gasman Claire Desnos Ana-Maria Lennon-Duménil Fran?ois Darchen 《Molecular biology of the cell》2014,25(20):3195-3209
Membrane fusion underlies multiple processes, including exocytosis of hormones and neurotransmitters. Membrane fusion starts with the formation of a narrow fusion pore. Radial expansion of this pore completes the process and allows fast release of secretory compounds, but this step remains poorly understood. Here we show that inhibiting the expression of the small GTPase Cdc42 or preventing its activation with a dominant negative Cdc42 construct in human neuroendocrine cells impaired the release process by compromising fusion pore enlargement. Consequently the mode of vesicle exocytosis was shifted from full-collapse fusion to kiss-and-run. Remarkably, Cdc42-knockdown cells showed reduced membrane tension, and the artificial increase of membrane tension restored fusion pore enlargement. Moreover, inhibiting the motor protein myosin II by blebbistatin decreased membrane tension, as well as fusion pore dilation. We conclude that membrane tension is the driving force for fusion pore dilation and that Cdc42 is a key regulator of this force. 相似文献