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101.
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103.
Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane 总被引:16,自引:0,他引:16
Rius M Nies AT Hummel-Eisenbeiss J Jedlitschky G Keppler D 《Hepatology (Baltimore, Md.)》2003,38(2):374-384
The liver is the major source of reduced glutathione (GSH) in blood plasma. The transport protein mediating the efflux of GSH across the basolateral membrane of human hepatocytes has not been identified so far. In this study we have localized the multidrug resistance protein 4 (MRP4; ABCC4) to the basolateral membrane of human, rat, and mouse hepatocytes and human hepatoma HepG2 cells. Recombinant human MRP4, expressed in V79 hamster fibroblasts and studied in membrane vesicles, mediated ATP-dependent cotransport of GSH or S-methyl-glutathione together with cholyltaurine, cholylglycine, or cholate. Several monoanionic bile salts and the quinoline derivative MK571 were potent inhibitors of this unidirectional transport. The K(m) values were 2.7 mmol/L for GSH and 1.2 mmol/L for the nonreducing S-methyl-glutathione in the presence of 5 micromol/L cholyltaurine, and 3.8 micromol/L for cholyltaurine in the presence of 5 mmol/L S-methyl-glutathione. Transport of bile salts by MRP4 was negligible in the absence of ATP or without S-methyl-glutathione. These findings identify a novel pathway for the efflux of GSH across the basolateral hepatocyte membrane into blood where it may serve as an antioxidant and as a source of cysteine for other organs. Moreover, MRP4-mediated bile salt transport across the basolateral membrane may function as an overflow pathway during impaired bile salt secretion across the canalicular membrane into bile. In conclusion, MRP4 can mediate the efflux of GSH from hepatocytes into blood by cotransport with monoanionic bile salts. 相似文献
104.
Rittersma SZ van der Wal AC Koch KT Piek JJ Henriques JP Mulder KJ Ploegmakers JP Meesterman M de Winter RJ 《Circulation》2005,111(9):1160-1165
105.
Po Wei Kang Nourdine Chakouri Johanna Diaz Gordon F. Tomaselli David T. Yue Manu Ben-Johny 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(21)
In cardiomyocytes, NaV1.5 channels mediate initiation and fast propagation of action potentials. The Ca2+-binding protein calmodulin (CaM) serves as a de facto subunit of NaV1.5. Genetic studies and atomic structures suggest that this interaction is pathophysiologically critical, as human mutations within the NaV1.5 carboxy-terminus that disrupt CaM binding are linked to distinct forms of life-threatening arrhythmias, including long QT syndrome 3, a “gain-of-function” defect, and Brugada syndrome, a “loss-of-function” phenotype. Yet, how a common disruption in CaM binding engenders divergent effects on NaV1.5 gating is not fully understood, though vital for elucidating arrhythmogenic mechanisms and for developing new therapies. Here, using extensive single-channel analysis, we find that the disruption of Ca2+-free CaM preassociation with NaV1.5 exerts two disparate effects: 1) a decrease in the peak open probability and 2) an increase in persistent NaV openings. Mechanistically, these effects arise from a CaM-dependent switch in the NaV inactivation mechanism. Specifically, CaM-bound channels preferentially inactivate from the open state, while those devoid of CaM exhibit enhanced closed-state inactivation. Further enriching this scheme, for certain mutant NaV1.5, local Ca2+ fluctuations elicit a rapid recruitment of CaM that reverses the increase in persistent Na current, a factor that may promote beat-to-beat variability in late Na current. In all, these findings identify the elementary mechanism of CaM regulation of NaV1.5 and, in so doing, unravel a noncanonical role for CaM in tuning ion channel gating. Furthermore, our results furnish an in-depth molecular framework for understanding complex arrhythmogenic phenotypes of NaV1.5 channelopathies.Voltage-gated sodium channels (NaV) are responsible for the initiation and spatial propagation of action potentials (AP) in excitable cells (1, 2). NaV channels undergo rapid activation that underlie the AP upstroke while ensuing inactivation permits AP repolarization. The NaV1.5 channel constitutes the predominant isoform in cardiomyocytes, whose pore-forming α-subunit is encoded by the SCN5A gene. NaV1.5 dysfunction underlies diverse forms of cardiac disease including cardiomyopathies, arrhythmias, and sudden death (3–6). Human mutations in NaV1.5 are associated with two forms of inherited arrhythmias–congenital long QT syndrome 3 (LQTS3) and Brugada syndrome (BrS) (7). LQTS3 stems from delayed or incomplete inactivation of NaV1.5 that causes persistent Na influx that prolongs AP repolarization—a “gain-of-function” phenotype (7–9). BrS predisposes patients to sudden death and is associated with a reduction in the peak Na current that may slow cardiac conduction or cause region-specific repolarization differences—a “loss-of-function” phenotype (10, 11). Genetic studies have identified an expanding array of mutations in multiple NaV1.5 domains, including the channel carboxy-terminus (CT) that is a hotspot for mutations linked to both LQTS3 and BrS (12, 13). This domain interacts with the Ca2+-binding protein calmodulin (CaM), suggesting that altered CaM regulation of NaV1.5 may be a common pathophysiological mechanism (12, 14–16). More broadly, human mutations in the homologous regions of neuronal NaV1.1 (17, 18), NaV1.2 (19, 20), and NaV1.6 (21) as well as skeletal muscle NaV1.4 (22) are linked to varied clinical phenotypes including epilepsy, autism spectrum disorder, neurodevelopmental delay, and myotonia (23). Taken together, a common NaV mechanistic deficit—defective CaM regulation—may underlie these diverse diseases.CaM regulation of NaV channels is complex, isoform specific, and mediated by multiple interfaces within the channel (14–16). The NaV CT consists of a dual vestigial EF hand segment and a canonical CaM-binding “IQ” (isoleucine–glutamine) domain (24, 25) (Fig. 1A). The IQ domain of nearly all NaV channels binds to both Ca2+-free CaM (apoCaM) and Ca2+/CaM, similar to CaV channels (26–31). As CaM is typically a Ca2+-dependent regulator, much attention has been focused on elucidating Ca2+-dependent changes in NaV gating. For skeletal muscle NaV1.4, transient elevation in cytosolic Ca2+ causes a dynamic reduction in the peak current, a process reminiscent of Ca2+/CaM-dependent inactivation of CaV channels (32). Cardiac NaV1.5 by comparison exhibits no dynamic effect of Ca2+ on the peak current (32–34). Instead, sustained Ca2+ elevation has been shown to elicit a depolarizing shift in NaV1.5 steady-state inactivation (SSI or h∞), although the magnitude and the presence of a shift have been debated (32, 35). Additional CaM-binding sites have been identified in the channel amino terminus domain (36) and the III-IV linker near the isoleucine, phenylalanine, and methionine (IFM) motif that is well recognized for its role in fast inactivation (35, 37). However, recent cryogenic electron microscopy structures, biochemical, and functional analyses suggest that both the III-IV linker and the Domain IV voltage-sensing domain might instead interact with the channel CT in a state-dependent manner (38–43).Open in a separate windowFig. 1.Absence of dynamic Ca2+/CaM effects on WT NaV1.5 SSI. (A, Left) Structure of NaV1.5 transmembrane domain (6UZ3) (70) juxtaposed with that of NaV1.5 CT–apoCaM complex (4OVN) (28). (Right) Arrhythmia-linked CT mutations highlighted in NaV1.5 CT–apoCaM structure (LQTS3, blue; BrS, magenta; mixed syndrome, purple). (B) Dynamic Ca2+-dependent changes in NaV1.5 SSI probed using Ca2+ photouncaging. Na currents specifying h∞ at ∼100 nM (Left) and ∼4 μM Ca2+ step (Right). (C) Population data for NaV1.5 SSI under low (black, Left) versus high (red, Right) intracellular Ca2+ reveal no differences (P = 0.55, paired t test). Dots and bars are mean ± SEM (n = 8 cells). (D) FRET two-hybrid analysis of Cerulean-tagged apoCaM interaction with various Venus-tagged NaV1.5 CT (WT, black; IQ/AA, red; S[1904]L, blue). Each dot is FRET efficiency measured from a single cell. Solid line fits show 1:1 binding isotherm.Beyond Ca2+-dependent effects, the loss of apoCaM binding to the NaV1.5 IQ domain increases persistent current (34, 44), suggesting that apoCaM itself may be pathophysiologically relevant. Indeed, NaV1.5 mutations in the apoCaM-binding interface are associated with LQTS3 and atrial fibrillation (7), as well as a loss-of-function BrS phenotype and a mixed-syndrome phenotype whereby some patients present with BrS while others with LQTS3 (Fig. 1A) (13, 45). How alterations in CaM binding paradoxically elicits both gain-of-function and loss-of-function effects is not fully understood, though important to delineate pathophysiological mechanisms and for personalized therapies.Here, using single- and multichannel recordings, we show that apoCaM binding elicits two distinct effects on NaV1.5 gating: 1) an increase in the peak channel open probability (PO/peak) and 2) a reduction in the normalized persistent channel open probability (Rpersist), consistent with previous studies (34, 44). The two effects may explain how mixed-syndrome mutations in the NaV1.5 CT produce either BrS or LQTS3 phenotypes. On one hand, the loss of apoCaM association may diminish PO/peak and induce BrS by shunting cardiac AP. On the other hand, increased Rpersist may prevent normal AP repolarization, resulting in LQTS3. Analysis of elementary mechanisms suggests that these changes relate to a switch in the state dependence of channel inactivation. Furthermore, dynamic changes in Ca2+ can inhibit persistent current for certain mutant NaV1.5 owing to enhanced Ca2+/CaM binding that occurs over the timescale of a cardiac AP. This effect may result in beat-to-beat variability in persistent Na current for some mutations. In all, these findings explain how a common deficit in CaM binding can contribute to distinct arrhythmogenic mechanisms. 相似文献
106.
Rissanen TT Korpisalo P Markkanen JE Liimatainen T Ordén MR Kholová I de Goede A Heikura T Gröhn OH Ylä-Herttuala S 《Circulation》2005,112(25):3937-3946
107.
Peak oxygen intake and cardiac mortality in women referred for cardiac rehabilitation 总被引:3,自引:0,他引:3
Kavanagh T Mertens DJ Hamm LF Beyene J Kennedy J Corey P Shephard RJ 《Journal of the American College of Cardiology》2003,42(12):2139-2143
OBJECTIVES: This study investigated the prognostic importance of measured peak oxygen intake (VO(2peak)) in women with known coronary heart disease referred for outpatient cardiac rehabilitation. BACKGROUND: Exercise capacity is a powerful predictor of prognosis in men with known or suspected coronary disease. Similar findings are described in women, but fewer studies have utilized measured VO(2peak), the most accurate measure of exercise capacity. METHODS: A single-center design took data from 2,380 women, age 59.7 +/- 9.5 years (1,052 myocardial infarctions, 620 coronary bypass procedures, and 708 with proven ischemic heart disease), who underwent cardiorespiratory exercise testing. They were followed for an average of 6.1 +/- 5 years (median 4.5 years, range 0.4 to 25 years) until cardiac and all-cause death. RESULTS: We recorded 95 cardiac deaths and 209 all-cause deaths. Measured VO(2peak) was an independent predictor of risk, values > or =13 ml/kg/min (3.7 multiples of resting metabolic rate) conferring a 50% reduction in cardiac mortality (hazard ratio [HR] 0.5, p = 0.001). Considered as a continuous variable, a 1 ml/kg/min advantage in initial VO(2peak) was associated with a 10% lower cardiac mortality. Adverse predictors were diabetes (HR 2.73, p = 0.0005) and antiarrhythmic therapy (HR 3.93, p = 0.0001). CONCLUSIONS: As in men, measured VO(2peak) is a strong independent predictor of cardiac mortality in women referred for cardiac rehabilitation. 相似文献
108.
Marko Lempinen Leena Halme Kirsti Numminen Johanna Arola Arno Nordin Heikki Mäkisalo 《Journal of hepato-biliary-pancreatic sciences》2005,12(5):409-414
Hepatobiliary cystadenomas and cystadenocarcinomas are rare tumors. Differentiating between these tumors and benign hepatic cysts may be difficult. Because of their rarity, diagnosis is often delayed and may result in inaccurate treatment, resulting in unnecessary morbidity and mortality. The purpose of this report is to draw attention to these entities and their complications. We report on two cases with spontaneous rupture of hepatobiliary cystadenoma and cystadenocarcinoma cysts, initially treated as simple hepatic cysts by aspiration, or by aspiration combined with sclerotherapy. The spontaneous rupture of the cysts appeared years after the initial treatment of the cysts, leading in one case to a prolonged stay in an intensive care unit. In both cases, a formal liver resection was carried out and microscopic investigations revealed a mucinous cystadenocarcinoma and cystadenoma. In conclusion, although hepatobiliary cystadenomas and cystadenocarcinomas are rare findings, they should not be forgotten in the diagnostic workshop when examining patients with hepatic cysts. If hepatobiliary cystadenomas and cystadenocarcinomas cannot be excluded following radiological imaging, surgery is recommended. 相似文献
109.
110.
Kwun Lam Anneli Peolsson Emiliano Soldini Hkan Lfgren Johanna Wibault sa Dedering Birgitta
berg Peter Zsigmond Marco Barbero Deborah Falla 《Medicine》2021,100(8)
Pain as a result of cervical radiculopathy (CR) can be widespread, nondermatomal and individually specific, but the association between pain extent and other clinical features has never been explored. The objective of this study is to investigate whether pain extent relates to clinical variables including pain intensity in addition to health indicators including disability, general health, depression, somatic anxiety, coping strategies or self-efficacy.An observational cohort study was conducted. Participants were recruited from 4 hospital spinal centres in Sweden. Pain extent was quantified from the pain drawings of 190 individuals with cervical disc disease, verified with magnetic resonance imaging (MRI) and compatible with clinical findings (examined by a neurosurgeon), that show cervical nerve root compression. Pain extent was evaluated in relation to neck pain, arm pain, and headache intensity. Multiple linear regression analysis were then used to verify whether pain extent was associated with other health indicators including disability, health-related quality of life, depression, somatic anxiety, coping strategies and self-efficacy.Pain extent was directly related to neck, arm and headache pain intensity (all P < .01). Multiple linear regression revealed that pain extent was significantly associated only to the level of perceived disability (P < .01).Increased pain extent in people with CR is associated with higher headache, neck and arm pain intensity, and disability but not measures of general health, depression, somatic anxiety, coping strategies or self-efficacy. 相似文献