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11.
《Drug discovery today》2022,27(1):246-256
Bromodomain-containing protein 4 (BRD4) is emerging as a therapeutic target that acts synergistically with other targets of small-molecule drugs in cancer. Therefore, the discovery of potential new dual-target inhibitors of BRD4 may be a promising strategy for cancer therapy. In this review, we highlight a series of strategies to design therapeutic dual-target inhibitors of BRD4 that focus on the synergistic functions of this protein. Drug combinations that exploit synthetic lethality, protein–protein interactions, functional complementarity, and blocking of resistance mechanisms could ultimately overcome the barriers inherent to the development of BRD4 inhibitors as future cancer drugs. 相似文献
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《Gait & posture》2022
BackgroundStair ascending and descending are common in daily life activities which are challenging for blind individuals. Visual information plays an important role in controlling an individual's movements. However, the relationship between visual information and stair ascending and descending is poorly understood.ObjectiveThe aim of this study was to investigate how blindness alters the ground reaction force (GRF) components during ascending and descending the stairs.MethodsTen individuals with congenital blindness and 10 able-bodied sighted individuals were served as experimental (EG) and control groups (CG), respectively. The GRFs were recorded during stair ascending and descending tasks using a portable 40 × 40 cm Kistler force plate which was placed on a firm stair. CG repeated the ascending/descending tasks in both open and closed-eyes conditions. For within and between groups comparisons the repeated measure ANOVA and MANOVA tests were used, respectively. The significance level was set at p < 0.05 for all comparisons.ResultsIn ascending task, there was not any significant between group differences on GRF components. However, closing the eyes in CG resulted in a significant decrease in some GRF components in the stair descending (p < 0.05). The GRF components of the stair descending in CG with open and closed-eyes were significantly different from those in the blind group; however, the differences were less in closed-eyes.SignificanceThe GRF in the stair descent was similar in both blind and sighted individuals with closed-eyes condition, that it can increase the risk of falling in blind people. As a result, the provision of tools and equipment for the blind in descent conditions is essential. 相似文献
15.
Keith P. Reber John D. Sivey Matthew Vollmuth Priyansh D. Gujarati 《Journal of labelled compounds & radiopharmaceuticals》2022,65(9):254-263
Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon-13 at specific positions within the benzene ring was developed. This efficient two-step procedure starts from commercially available 13C-labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding 13C-labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including 13C- and deuterium-labeled esters. In addition, 4-hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing 13C-labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form the para-disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters. 相似文献
16.
抗体药物具有特异性高、不良反应少的特点,已成为肿瘤治疗的热点。双特异性抗体(双抗)是指同时结合2个不同抗原或同一抗原2个表位的抗体。与单特异性抗体相比,双抗具有高度特异性,增强了治疗有效性和安全性,同时减少了不良反应。已有多种双抗药物获批上市,进入临床研究的双抗药物数量不断增加。双抗药物的形式持续在更新,应用范围也在扩大,在未来具有非常好的应用前景。此文就目前已有的双抗类型、作用机制及目前双抗制备上面临的困难等进行概述。 相似文献
17.
《Journal of vascular and interventional radiology : JVIR》2022,33(3):249-254.e1
An ovine iliac vein thrombosis model was devised to test a wall-contacting rotational thrombectomy device. Thrombosis was successfully induced in 9 sheep with an average clot length of 31 mm ± 12 and >60% vessel occlusion on angiography. The thrombus was subsequently removed, maintaining normal intraoperative pulmonary arterial pressure (5.9 mm Hg ± 3.6) and complete distal reperfusion after thrombectomy. Additionally, the sheep were without signs of vascular trauma or embolic complications on gross necropsy and histopathologic analysis. The findings from this study support the use of an ovine iliac deep vein thrombosis model for testing of a lower extremity thrombectomy device. 相似文献
18.
Suicides by pentobarbital overdose have increased since about 2012, which appear to be influenced by technical information on active euthanasia that has spread over the Internet. We encountered a pentobarbital poisoning case of a patient with amyotrophic lateral sclerosis. A caregiver found the patient unconscious immediately after two visitors left the room. The patient was immediately transferred to the emergency hospital but eventually declared dead. A fatal concentration of pentobarbital was detected in peripheral blood samples collected in the emergency hospital and during autopsy (53.8 μg/mL and 29.4 μg/mL, respectively). Because the ratios of pentobarbital concentrations between the gastric contents and peripheral blood were 35 and 29 in the hospital and autopsy samples, respectively, it is likely that pentobarbital was administered via the gastrostomy tube. The patient had contacted the visitors through social media. Although the patient had requested the doctor perform active euthanasia and expressed a desire to end their life on social media, nobody had noticed the plan to commit suicide. 相似文献
19.
Yicheng Chen Ozan Genc Clare B. Poynton Suchandrima Banerjee Christopher P. Hess Janine M. Lupo 《NMR in biomedicine》2022,35(5):e4666
Quantitative susceptibility mapping (QSM) has the potential for being a biomarker for various diseases because of its ability to measure tissue susceptibility related to iron deposition, myelin, and hemorrhage from the phase signal of a T2*-weighted MRI. Despite its promise as a quantitative marker, QSM is faced with many challenges, including its dependence on preprocessing of the raw phase data, the relatively weak tissue signal, and the inherently ill posed relationship between the magnetic dipole and measured phase. The goal of this study was to evaluate the effects of background field removal and dipole inversion algorithms on noise characteristics, image uniformity, and structural contrast for cerebral microbleed (CMB) quantification at both 3T and 7T. We selected four widely used background phase removal and five dipole field inversion algorithms for QSM and applied them to volunteers and patients with CMBs, who were scanned at two different field strengths, with ground truth QSM reference calculated using multiple orientation scans. 7T MRI provided QSM images with lower noise than did 3T MRI. QSIP and VSHARP + iLSQR achieved the highest white matter homogeneity and vein contrast, with QSIP also providing the highest CMB contrast. Compared with ground truth COSMOS QSM images, overall good correlations between susceptibility values of dipole inversion algorithms and the COSMOS reference were observed in basal ganglia regions, with VSHARP + iLSQR achieving the susceptibility values most similar to COSMOS across all regions. This study can provide guidance for selecting the most appropriate QSM processing pipeline based on the application of interest and scanner field strength. 相似文献
20.
《HPB : the official journal of the International Hepato Pancreato Biliary Association》2022,24(10):1780-1788
BackgroundWe assessed whether or not covalently closed circular DNA (cccDNA) levels in the background liver influence the recurrence of hepatocellular carcinoma (HCC) in patients with resolved hepatitis B virus (HBV) infection.MethodsAmong 425 patients who underwent initial hepatectomy for HCC between 2010 and 2018, a retrospective review was performed in 44 with resolved HBV infection. The clinicopathologic characteristics were analyzed for correlation with tumor recurrence. The HBV cccDNA levels were tested via a droplet digital polymerase chain reaction assay.ResultsHBV cccDNA was detected in 27 of 44 patients (61%), and the median level was 1.0 copies/1000 ng (range, 0-931.3 copies/1000 ng). Anti-HBc ≥8.9 S/CO was associated with cccDNA detection (odds ratio, 11.08; 95% confidence interval [95% CI], 2.48-49.46; P = 0.002). Twenty-eight patients (64%) developed HCC recurrence after hepatectomy. The overall 3- and 5-year recurrence-free survival rates were 45.7% and 34.3%, respectively.19 HBV cccDNA levels was not significantly associated with HCC recurrence, while the presence of multiple tumors was an independent risk fact or (hazard ratio, 6.53; 95% CI, 2.48-17.19; P < 0.001.ConclusionHBV cccDNA levels did not influence HCC recurrence after hepatectomy. Anti-HBc levels may be used as a surrogate marker for cccDNA. 相似文献