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81.
82.
Di Benedetto G Zoccarato A Lissandron V Terrin A Li X Houslay MD Baillie GS Zaccolo M 《Circulation research》2008,103(8):836-844
Protein kinase A (PKA) is a key regulatory enzyme that, on activation by cAMP, modulates a wide variety of cellular functions. PKA isoforms type I and type II possess different structural features and biochemical characteristics, resulting in nonredundant function. However, how different PKA isoforms expressed in the same cell manage to perform distinct functions on activation by the same soluble intracellular messenger, cAMP, remains to be established. Here, we provide a mechanism for the different function of PKA isoforms subsets in cardiac myocytes and demonstrate that PKA-RI and PKA-RII, by binding to AKAPs (A kinase anchoring proteins), are tethered to different subcellular locales, thus defining distinct intracellular signaling compartments. Within such compartments, PKA-RI and PKA-RII respond to distinct, spatially restricted cAMP signals generated in response to specific G protein-coupled receptor agonists and regulated by unique subsets of the cAMP degrading phosphodiesterases. The selective activation of individual PKA isoforms thus leads to phosphorylation of unique subsets of downstream targets. 相似文献
83.
Sonia Gutiérrez Silvia Guillemi Natalie Jahnke Valentina Montessori P Richard Harrigan Julio S G Montaner 《Clinical infectious diseases》2008,46(3):e28-e30
We summarize the clinical history and laboratory results following the introduction of tenofovir among 6 patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) who presented with severe liver disease while receiving lamivudine-based highly active antiretroviral therapy. In all cases, the introduction of tenofovir led to a sustained undetectable HBV and HIV loads, with marked clinical and laboratory improvement in liver function. We provide supporting evidence for the role of tenofovir in the management of advanced HBV infection in HIV-positive patients after the development of lamivudine resistance. 相似文献
84.
Silvia Angela Debonis Alberto Bongiovanni Federica Pieri Valentina Fausti Alessandro De Vita Nada Riva Lorena Gurrieri Silvia Vanni Danila Diano Laura Mercatali Toni Ibrahim 《Medicine》2021,100(20)
Rationale:Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that is prevalent among children and adolescents. Surgery is the most important therapeutic approach for IMT and complete resection is recommended. Although 50% of IMTs show anaplastic lymphoma kinase (ALK) rearrangements, crizotinib has proven an effective therapeutic approach. However, the genetic landscape of this tumor is still not fully understood and treatment options are limited, especially in the majority of ALK-negative tumors.Patient concerns:We describe the clinical case of a healthy 18-year-old female in whom a pulmonary nodule was incidentally detectedDiagnoses:Following a small increase in the size of the nodule, the patient underwent both 18FDG-PET/CT and 68Ga-PET/CT, resulting in a suspicion of bronchial hamartoma.Interventions:The patient underwent surgery and a salivary gland-like lung tumor was diagnosed.Outcomes:After surgery, the patient was referred to our cancer center, where a review of the histology slides gave a final diagnosis of ALK-negative lung IMT. Given the histology, it was decided not to administer adjuvant therapy and the patient was placed in a 3-monthly follow-up program. The patient is still disease-free 2 years post-surgery.Lessons:Although there is no standard of care for the treatment of IMT, identifying genomic alterations could help to redefine the management of patients with negative-ALK disease. Our review of the literature on IMT and other kinase fusions revealed, in addition to ALK rearrangements, the potential association of ROS1, NTRK, RET, or PDGFR beta alterations with the tumor. 相似文献
85.
86.
87.
Vincenzo Dario Mandato Valentina Mastrofilippo Andrea Palicelli Monica Silvotti Silvia Serra Lucia Giaccherini Lorenzo Aguzzoli 《Medicine》2021,100(22)
Rationale:Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. It is usually diagnosed at early-stage and presents a favorable prognosis. Conversely, advanced or recurrent disease shows poor outcome. Most recurrences occur within 2 years postoperatively, typically in pelvic and para-aortic lymph nodes, vagina, peritoneum, and lungs. Vulvar metastasis (VM) is indeed anecdotal probably because of the different regional lymphatic drainage from corpus uteri.Patient concerns:A 3 cm, reddish, bleeding lesion of the posterior commissura/right labia was found in a 74-year-old woman treated with radical hysterectomy, surgical staging, and adjuvant radiotherapy 1 year before for a grade 2 endometrioid type, International Federation of Gynecology and Obstetrics Stage IB. Vulvar biopsy confirmed the EC recurrence. Pelvic magnetic resonance imaging and positron emission tomography excluded other metastases so VM was radically resected.Diagnosis:Postoperative histopathology confirmed the diagnosis of grade 2 EC VM.Interventions:A radical excision of VM was performed.Outcomes:Patient died from a severe sepsis 27 months after first surgery.Lessons:Vulvar metastases can show different appearance, occurring as single or diffuse lesions on healthy or injured skin. The surgical approach seems not to influence the metastatic risk, but tumor seeding and vaginal injuries should be avoided. Whether isolated or associated with recurrence in other locations, vulvar metastases imply poor prognosis despite radical treatment. Therefore, any suspected vulvar lesion arisen during EC follow-up should be biopsied and monitored closely, despite that the vulva represents an unusual metastatic site. 相似文献
88.
Valentina Pinna Valentina Lanari Paola Daniele Federica Consoli Emanuele Agolini Katia Margiotti Irene Bottillo Isabella Torrente Alessandro Bruselles Caterina Fusilli Anna Ficcadenti Sara Bargiacchi Eva Trevisson Monica Forzan Sandra Giustini Chiara Leoni Giuseppe Zampino Maria Cristina Digilio Bruno Dallapiccola Maurizio Clementi Marco Tartaglia Alessandro De Luca 《European journal of human genetics : EJHG》2015,23(8):1068-1071
Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management. 相似文献
89.
Fofanova OV Evgrafov OV Polyakov AV Poltaraus AB Peterkova VA Dedov II 《The Journal of clinical endocrinology and metabolism》2003,88(2):820-826
Isolated GH deficiency (IGHD) is characterized by genetic heterogeneity, both in familial and sporadic cases. To determine if this statement can be applied to the Russian population, we performed screening for mutations in the GH-1 gene in children living in Russia with IGHD. Twenty-eight children from 26 families with total IGHD were studied. DNA fragments, covering each of four (2-5) exons of GH-1 were amplified using PCR. Single-strand conformation polymorphism analysis followed by direct DNA sequencing identified five heterozygous mutations of splicing in intron 2, intron 3, and exon 4 of GH-1; three of them were not previously reported. We concentrated here on dominant-negative mutations causing IGHD type II, which were as follows: 1) A>T transversion of the second base of the 3'-acceptor splice site of intron 2 (IVS2 -2A>T); 2) T>C transition of the second base of the 5'-donor splice site of intron 3 (IVS3 +2T>C); 3) G>A transition of the first base of the 5'-donor splice site of intron 3 (IVS3 +1G>A). Our data indicate allelic heterogeneity of IGHD type II (IGHD II). However, all mutations in Russian IGHD II patients affect splicing, a striking difference from the mutation spectrum of other IGHD forms. The IVS2 -2A>T mutation is the first identified mutation in intron 2 of GH-1. The 5'-donor splice site of intron 3 of GH-1 is a mutational hot spot, and the IVS3 +1G>A mutation can be considered to be a common molecular defect in IGHD II in Russian patients. 相似文献
90.
Tatjana Janzen Yuri Gaponenko Aliaksandr Mialdun Gabriela Guevara-Carrion Jadran Vrabec Valentina Shevtsova 《RSC advances》2018,8(18):10017
With laboratory and numerical work, we demonstrate that one of the main diffusion coefficients and the smaller eigenvalue of the Fick diffusion matrix are invariant to the number of methylene groups of the alcohol in ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol). A critical analysis of the relationship between the kinetic and thermodynamic contributions to the diffusion coefficients allows us to explain this intriguing behaviour of this class of mixture. These findings are reflected by the diffusive behaviour of the according binary subsystems. Our approach provides a promising systematic framework for future investigations into the important and challenging problem of transport diffusion in multicomponent liquids.The Fick diffusion coefficient matrix of three ternary mixtures composed of an aromatic (benzene), a ketone (acetone) and one of three different alcohols (methanol, ethanol or 2-propanol) is investigated with laboratory and numerical work.Multicomponent diffusion plays a crucial role in various natural and industrial processes involving mass transfer.1–3 Liquids appearing in nature and technical applications are essentially multicomponent. However, only data on binary diffusion coefficients are relatively abundant because the diffusion behavior of ternary and higher mixtures is much more complex.4,5 Describing the isothermal–isobaric diffusion of a ternary mixture by Fick’s law requires four different diffusion coefficients that are composition dependent. The presence of cross diffusion coefficients aggravates the interpretation and data processing in experimental work, resulting in large uncertainties.6,7 Thus, efforts are being made to develop new methods for analysis of multicomponent diffusion explicitly addressing various degrees of complexity.8–10 Predictive equations for multicomponent diffusion of liquids mostly rely on extensions of the Darken relation,11–13 which is only valid for ideal mixtures.14 The underlying physical phenomena in non-ideal mixtures are not well understood and the lack of experimental data impedes the development and verification of new predictive equations.The objective of this study was not only to measure and predict the Fick diffusion coefficient matrix for a series of ternary liquid mixtures, rather, the emphasis lied on understanding common features and whether they can be related to the behavior of the pure components and binary subsystems. Three ternary mixtures that are composed of organic compounds were selected, i.e. an aromatic, a ketone and an alcohol. Throughout, the first two components were benzene (1) and acetone (2) and the third component was one of the alcohols, methanol, ethanol or 2-propanol. For each mixture, nine state points along a composition path with a constant content of benzene, x1 = 0.33 mol mol−1, were studied under ambient conditions (298.15 K and 0.1 MPa). Seven of the state points were ternary mixtures and two were binary subsystems. To obtain reliable results for the Fick diffusion coefficient matrix, two complementary approaches were used, i.e. experiments and predictive molecular simulations. This combination allows for a critical analysis and leads to a deeper understanding of the underlying phenomena.14,15The Taylor dispersion technique was utilized for the experiments.16,17 In this method, a small quantity of mixture with a slightly different composition is injected into a laminar stream. It disperses due to convection and diffusion while flowing through a capillary tube and the refractive index is measured at its end to sample the concentration distribution. We have used the same apparatus as in previous works.6,7 The Fick diffusion matrix is obtained by fitting working equations to the measured signal, i.e. the Taylor peak. The mathematical model of the Taylor dispersion technique was originally developed on the basis of Fick’s law in the volume reference frame. In a ternary mixture, two molar fluxes Jvi relative to a volume averaged velocity are related to gradients of molar concentration ∇Ci with four diffusion coefficients Dvij. Alternatively, fluxes expressed in the molar reference frame Ji are relative to a molar averaged velocity and the mole fraction gradients ∇xi act as a driving force1with molar density ρ. The fluxes of all three components are constrained by ΣJi = 0. The main diffusion coefficients D11 and D22 relate the flux of one component to its own mole fraction gradient and the cross diffusion coefficients D12 and D21 describe the coupling of the flux of one component with the gradient of the other. The third component does not appear in eqn (1) explicitly, but in general it affects all four diffusion coefficients. The transformation of experimental data from the volume to the molar reference frame (Dvij to Dij) could be done here on the basis of the pure component volumes (see the ESI†).Equilibrium molecular dynamics (MD) simulations were employed in this work, allowing for examination at the microscopic scale. The underlying molecular models were rigid, non-polarizable force fields of united atom type, consisting of a varying number of Lennard–Jones, point charge, dipole and quadrupole sites (see the ESI†). Note that the force field parameters were adjusted to pure fluid properties only so that all simulation results for the mixtures are strictly predictive. Diffusion coefficients were sampled with the Green–Kubo formalism, based on integrated correlation functions of net velocities of the contained species.11,15 Thereby, phenomenological coefficients Δij were obtained, associating the diffusive fluxes with the chemical potential gradients ∇μi2with gas constant R and temperature T. Fluxes Ji correspond to the molar reference frame as in eqn (1).The diffusion coefficients from experiment and simulation are related to different driving forces so that the chemical potential gradients have to be transformed to the mole fraction gradients for their comparison.18 This transformation is contained in the thermodynamic factor matrix Γ3with the activity coefficient of species i being γi, which expresses the non-ideality of a mixture with respect to the composition. This relationship shows that the Fick diffusion coefficients are actually the product of two contributions, a kinetic Δij and a thermodynamic Γij. The separate observation of these two contributions promotes understanding of the underlying physical phenomena. In the present study, the thermodynamic factor was calculated using the Wilson excess Gibbs energy (gE) model, using parameters fitted to experimental vapor–liquid equilibrium data of the binary subsystems (see the ESI†). This combination of MD simulation results with a gE model was successfully used in previous work to predict Fick diffusion coefficients, including several binary subsystems of the ternary mixtures studied here.19The four elements of the Fick diffusion coefficient matrix were determined for the three ternary mixtures, benzene + acetone + methanol/ethanol/2-propanol, for nine different compositions, each at ambient temperature and pressure.Results for the first main element of the diffusion matrix D11, which relates the flux of benzene to its own mole fraction gradient, are shown in Fig. 1(a). The experimental data agree quantitatively with the molecular simulation data. D11 increases with the acetone content in the ternary mixture. Since mixtures with a constant mole fraction of benzene (x1 = 0.33 mol mol−1) were studied throughout, the left edge of Fig. 1(a) corresponds to the binary limit of benzene + alcohol, while the right edge corresponds to that of benzene + acetone. Analysis of the ternary diffusive fluxes implies the following asymptotic behavior of the diffusion coefficients towards the binary limits:7 (i) at the infinite dilution limit, x2 → 0, the ternary coefficient D11 tends to the binary Fick diffusion coefficient of benzene + alcohol; (ii) at the other limit, x3 → 0, D11 − D12 = D22 − D21 → Dbin (benzene + acetone) should hold. The present experimental and simulation results for D11 are consistent with these asymptotic limits.Open in a separate windowFig. 1Top: The main Fick diffusion coefficient (molar reference frame) of benzene D11 in the three ternary mixtures benzene (1) + acetone (2) + alcohol (3) at a constant benzene mole fraction x1 = 0.33 mol mol−1 from experiment (triangles) and MD simulation combined with the Wilson gE model (circles). Both data sets were sampled at the same compositions, but are slightly shifted in the plot for visibility reasons. The symbols at the edges of this plot are the binary diffusion coefficients of benzene + alcohol (x2 → 0) and of benzene + acetone (x3 → 0). Bottom: The binary Fick diffusion coefficient of the subsystems benzene + alcohol and benzene + acetone. Most of the binary experimental data were taken from the literature.20–27An inspection of Fig. 1(a) provides an unexpected finding: the main element D11 is almost identical for all three mixtures along the examined composition path, i.e. it is independent of the contained type of alcohol. To explain this intriguing behavior of D11, the properties of the pure components are considered first (see M (g mol−1) ρ (mol l−1) ρ m (g l−1) D 0 10−9 (m2 s−1) Benzene 78.11 11.147 (2) 870.6 (1) 2.226 (4) Acetone 58.08 13.536 (3) 786.2 (2) 4.538 (8) Methanol 32.04 24.541 (6) 786.3 (2) 2.449 (6) Ethanol 46.07 17.132 (4) 789.3 (2) 0.974 (3) 2-Propanol 60.10 12.803 (1) 769.5 (1) 0.604 (7)