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971.
Emilie Pecchi Sabrina Priam Marjolaine Gosset Audrey Pigenet Laure Sudre Marie-Charlotte Laiguillon Francis Berenbaum Xavier Houard 《Arthritis research & therapy》2014,16(1):R16
Introduction
Nerve growth factor (NGF) level is increased in osteoarthritis (OA) joints and is involved in pain associated with OA. Stimuli responsible for NGF stimulation in chondrocytes are unknown. We investigated whether mechanical stress and proinflammatory cytokines may influence NGF synthesis by chondrocytes.Methods
Primary cultures of human OA chondrocytes, newborn mouse articular chondrocytes or cartilage explants were stimulated by increasing amounts of IL-1β, prostaglandin E2 (PGE2), visfatin/nicotinamide phosphoribosyltransferase (NAMPT) or by cyclic mechanical compression (0.5 Hz, 1 MPa). Before stimulation, chondrocytes were pretreated with indomethacin, Apo866, a specific inhibitor of NAMPT enzymatic activity, or transfected by siRNA targeting visfatin/NAMPT. mRNA NGF levels were assessed by real-time quantitative PCR and NGF released into media was determined by ELISA.Results
Unstimulated human and mouse articular chondrocytes expressed low levels of NGF (19.2 ± 8.7 pg/mL, 13.5 ± 1.0 pg/mL and 4.4 ± 0.8 pg/mL/mg tissue for human and mouse articular chondrocytes and costal explants, respectively). Mechanical stress induced NGF release in conditioned media. When stimulated by IL-1β or visfatin/NAMPT, a proinflammatory adipokine produced by chondocytes in response to IL-1β, a dose-dependent increase in NGF mRNA expression and NGF release in both human and mouse chondrocyte conditioned media was observed. Visfatin/NAMPT is also an intracellular enzyme acting as the rate-limiting enzyme of the generation of NAD. The expression of NGF induced by visfatin/NAMPT was inhibited by Apo866, whereas IL-1β-mediated NGF expression was not modified by siRNA targeting visfatin/NAMPT. Interestingly, PGE2, which is produced by chondrocytes in response to IL-1β and visfatin/NAMPT, did not stimulate NGF production. Consistently, indomethacin, a cyclooxygenase inhibitor, did not counteract IL-1β-induced NGF production.Conclusions
These results show that mechanical stress, IL-1β and extracellular visfatin/NAMPT, all stimulated the expression and release of NGF by chondrocytes and thus suggest that the overexpression of visfatin/NAMPT and IL-1β in the OA joint and the increased mechanical loading of cartilage may mediate OA pain via the stimulation of NGF expression and release by chondrocytes. 相似文献972.
973.
Sophie Halliez Emilie Jaumain Alvina Huor Jean-Yves Douet Séverine Lugan Hervé Cassard Caroline Lacroux Vincent Béringue Olivier Andréoletti Didier Vilette 《PloS one》2014,9(8)
Prion transmission can occur by blood transfusion in human variant Creutzfeldt-Jakob disease and in experimental animal models, including sheep. Screening of blood and its derivatives for the presence of prions became therefore a major public health issue. As infectious titer in blood is reportedly low, highly sensitive and robust methods are required to detect prions in blood and blood derived products. The objectives of this study were to compare different methods - in vitro, ex vivo and in vivo assays - to detect prion infectivity in cells prepared from blood samples obtained from scrapie infected sheep at different time points of the disease. Protein misfolding cyclic amplification (PMCA) and bioassays in transgenic mice expressing the ovine prion protein were the most efficient methods to identify infected animals at any time of the disease (asymptomatic to terminally-ill stages). However scrapie cell and cerebellar organotypic slice culture assays designed to replicate ovine prions in culture also allowed detection of prion infectivity in blood cells from asymptomatic sheep. These findings confirm that white blood cells are appropriate targets for preclinical detection and introduce ex vivo tools to detect blood infectivity during the asymptomatic stage of the disease. 相似文献
974.
Background
New melanoma therapies, like e.g. ipilimumab, improve survival. However, only a small subset of patients benefits while 60% encounter side effects. Furthermore, these marginal benefits come at a very high price of €110’000 per treatment. This study examines attitudes towards melanoma therapy options of physicians, healthy individuals and patients, their willingness to pay and preference of quality versus length of life.Methods
Based on findings from a focus group questionnaires were developed and pretested. After obtaining ethical approval and informed consent surveys were conducted in a total of 90 participants (n = 30 for each group). Statistical analyses were conducted using R.Findings
Attitudes vastly differed between healthy participants, physicians and melanoma patients. Whereas melanoma patients show a high willingness to endure side effects despite very small survival gains (down to 1 extra week) or even only hope with no survival benefit, healthy controls are more critical, while physicians are the most therapy adverse. Consequently, if given €100’000 and the free decision what to spend the money on the willingness to pay for therapy was much higher in the patient group (68%) compared to 28% of healthy controls and only 43% of the physicians, respectively. When lowering the amount of cash that could be received instead of ipilimumab to €50’000 or €10’000 to test price sensitivity 69% (+1%) and 76% (+8%) of melanoma patients, respectively, preferred ipilimumab over cash. When judging on societal spending even melanoma patients opted for spending on ipilimumab in only 21%.Conclusion
The judgment about the benefits of new treatment options largely differs between groups, physicians being the most critical against therapy. Price elasticity was low. 相似文献975.
Aleksander Krag Flemming Bendtsen Emilie Kristine Dahl Andreas Kj?r Claus Leth Petersen S?ren M?ller 《PloS one》2014,9(10)
Background and aim
Cardiac dysfunction in patients with early cirrhosis is debated. We investigated potential cardiac dysfunction by assessing left ventricular systolic performance during a dobutamine stress test in patients with early cirrhosis.Patients and methods
Nineteen patients with Child A and B cirrhosis (9 with non-alcoholic cirrhosis) and 7 matched controls were included. We used cardiac magnetic resonance imaging to assess left ventricular volumes and cardiac output (CO) at rest and during maximal heart rate induced by increasing dosages of dobutamine and atropine.Results
Patients with cirrhosis and controls had an equal stress response, the heart rate and ejection fraction increased similarly and maximal heart rate was reached in all. At rest CO was higher in Child B patients than controls. During maximal stress, Child B patients had higher CO (10.6±2.7 vs. 8.0±1.8 L/min), left ventricle end diastolic volume (90±25 vs. 67±16 mL), left ventricular end diastolic volume (10±4 vs. 6±2 mL) and stroke volume (80±23 vs. 61±15 mL) than Child A patients. The systemic vascular resistance was lower in Child B than Child A patients (670±279 vs. 911±274 dyne*s*cm−5). The left ventricle mass increased by 5.6 gram per model for end stage liver disease (MELD) point. MELD score correlated with the end diastolic and systolic volume, CO, and stroke volume at rest and at stress (all p<0.05).Conclusion
In patients with early cirrhosis the chronotropoic and inotropic response to pharmacological stress induced by dobutamine is normal. With progression of the disease, the mass of the heart increases along with increase in cardiac volumes. 相似文献976.
Eli?ka Pot??ková Kate?ina Hru?ková Jan Bure? Petra Kova?íková Iva A. ?pirková Kate?ina Pravdíková Lucie Kolbabová Tereza Hergeselová Pavlína Ha?ková Hana Jansová Miloslav Machá?ek Anna Jirkovská Vera Richardson Darius J. R. Lane Danuta S. Kalinowski Des R. Richardson Kate?ina Vávrová Tomá? ?im?nek 《PloS one》2014,9(11)
Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects. 相似文献
977.
Marine Gilabert Simon Launay Christophe Ginestier Fran?ois Bertucci Stéphane Audebert Mathieu Pophillat Yves Toiron Emilie Baudelet Pascal Finetti Tetsuro Noguchi Hagay Sobol Daniel Birnbaum Jean-Paul Borg Emmanuelle Charafe-Jauffret Anthony Gon?alves 《PloS one》2014,9(8)
Background
Breast cancer stem cells (BCSCs) have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL), BrCA-MZ-01.Methods
ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+) and mature cancer (ALDH−) cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE). Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS.Results
2-D DIGE identified poly(ADP-ribose) polymerase 1 (PARP1) as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor.Conclusion
An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors. 相似文献978.
Robert Hinch William J. M. Probert Anel Nurtay Michelle Kendall Chris Wymant Matthew Hall Katrina Lythgoe Ana Bulas Cruz Lele Zhao Andrea Stewart Luca Ferretti Daniel Montero James Warren Nicole Mather Matthew Abueg Neo Wu Olivier Legat Katie Bentley Thomas Mead Kelvin Van-Vuuren Dylan Feldner-Busztin Tommaso Ristori Anthony Finkelstein David G. Bonsall Lucie Abeler-Drner Christophe Fraser 《PLoS computational biology》2021,17(7)
SARS-CoV-2 has spread across the world, causing high mortality and unprecedented restrictions on social and economic activity. Policymakers are assessing how best to navigate through the ongoing epidemic, with computational models being used to predict the spread of infection and assess the impact of public health measures. Here, we present OpenABM-Covid19: an agent-based simulation of the epidemic including detailed age-stratification and realistic social networks. By default the model is parameterised to UK demographics and calibrated to the UK epidemic, however, it can easily be re-parameterised for other countries. OpenABM-Covid19 can evaluate non-pharmaceutical interventions, including both manual and digital contact tracing, and vaccination programmes. It can simulate a population of 1 million people in seconds per day, allowing parameter sweeps and formal statistical model-based inference. The code is open-source and has been developed by teams both inside and outside academia, with an emphasis on formal testing, documentation, modularity and transparency. A key feature of OpenABM-Covid19 are its Python and R interfaces, which has allowed scientists and policymakers to simulate dynamic packages of interventions and help compare options to suppress the COVID-19 epidemic. 相似文献
979.
Protein interaction data curation: the International Molecular Exchange (IMEx) consortium 总被引:1,自引:0,他引:1
Orchard S Kerrien S Abbani S Aranda B Bhate J Bidwell S Bridge A Briganti L Brinkman FS Brinkman F Cesareni G Chatr-aryamontri A Chautard E Chen C Dumousseau M Goll J Hancock RE Hancock R Hannick LI Jurisica I Khadake J Lynn DJ Mahadevan U Perfetto L Raghunath A Ricard-Blum S Roechert B Salwinski L Stümpflen V Tyers M Uetz P Xenarios I Hermjakob H 《Nature methods》2012,9(4):345-350
The International Molecular Exchange (IMEx) consortium is an international collaboration between major public interaction data providers to share literature-curation efforts and make a nonredundant set of protein interactions available in a single search interface on a common website (http://www.imexconsortium.org/). Common curation rules have been developed, and a central registry is used to manage the selection of articles to enter into the dataset. We discuss the advantages of such a service to the user, our quality-control measures and our data-distribution practices. 相似文献
980.
Mária Filková Hana Hulejová Klára Kuncová Lenka Ple?tilová Lucie Andrés Cerezo He?man Mann Martin Klein Josef Záme?ník Steffen Gay Ji?í Vencovsky Ladislav ?enolt 《Arthritis research & therapy》2012,14(3):R111-9