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21.
Lymphocytes infiltrating the CNS during inflammation display a distinctive phenotype and bind to VCAM-1 but not to MAdCAM-1 总被引:3,自引:0,他引:3
Engelhardt Britta; Conley Frances K.; Kilshaw Peter J.; Butcher Eugene C. 《International immunology》1995,7(3):481-491
The nature of inflammatory lymphocytes recruited to the CNShas been studied in a model of chronic inflammation. Injectionof killed Corynebacterlum parvum into the cortex of the mousebrain produces a circumscribed inflammatory cellular infiltratearound the injection site, and recruited mononuclear inflammatorycells (IC) can be isolated for flow cytometric analysis. Themajority of IC were T cells. In comparison with the predominantnaive population of mesenteric lymph node T cells, IC T cellsexpress much higher levels of CD44, LFA-1 and ICAM-1, and lowerlevels of CD45RB, features commonly associated with memory (previouslyactivated) cells. In addition, in contrast to the L-selectin+6-integrinlow phenotype of naive lymph node T cells, IC T cellslacked L-selectin and were 6-integrin–. Mac-1, recentlyproposed as another marker of memory T cell differentation,was not displayed by IC T cells, suggesting that Mac-1 expressionmay be heterogeneous among memory T cell subsets. A subset ofmesenteric lymph node (MLN) T cells, probably representing activatedT cells undergoing the naive to memory transition, but not ofIC T cells, expressed high levels of 6-, ß7- and E-integrin.IC and MLN naive T cells expressed comparable levels of 4-integrin,but IC T cells stain poorly with anti-ß7 mAbs andwith mAb DATK 32, specific for the 4ß7 heterodimericlymphocyte homing receptor for the mucosal addressin MAdCAM-1,suggesting that these inflammatory cells express more 4ß1than 4ß7. Consistent with this, in in vitro adhesionassays, brain IC bound better than MLN cells to the 4ß1integrin ligand VCAM-1 and the LFA-1 ligand ICAM-1 but adheredvery poorly to the 4ß7 ligand MAdCAM-1. These findingsare consistent with and extend previous immunohistological studiesof T cells in murine experimental autoimmune encephalomyelitis,and demonstrate a distinctive phenotype for lymphocytes beingpresent in the chronically inflamed brain. 相似文献
22.
Altered calcium homeostasis has been demonstrated in human spinal cord motor axon terminals of ALS patients, in spinal motor neurons of mutant SOD transgenic mice and following injection of ALS immunoglobulins. In all three paradigms oculomotor neurons are relatively spared. To explore mechanisms of selective resistance, we applied similar calcium localization techniques to terminals of oculomotor neurons in the two animal models. In both cases large vacuoles, which connect with the extracellular space, accumulated the majority of intracellular calcium, while terminals of vulnerable neurons (e.g. innervating interosseus muscle), which possess no such vacuoles, displayed evenly distributed calcium. These relatively unique membrane enveloped structures may permit neurons to control their cytoplasmic Ca2+ concentration and contribute to selective resistance. 相似文献
23.
Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR 总被引:8,自引:0,他引:8
Yang Yiping; Devor Daniel C.; Engelhardt John F.; Ernst Stephen A.; Strong Theresa V.; Collins Francis S.; Cohn Jonathan A.; Frizzell Raymond A.; Wilson James M. 《Human molecular genetics》1993,2(8):1253-1261
Cystic fibrosis (CF) is caused by mutations in the gene encodinga chloride channel called the CF transmembrane conductance regulator(CFTR). A single mutation in this gene, deletion of three nucleotidesthat leads to the absence of phenylalanine 508 (i.e., F508),is found on 70% of all CF chromosomes. To explore the molecularmechanism(s) responsible for defective chloride transport inpatients with CF, we have studied the processing, localization,and function of wild type (W.T.), F508 and G551D CFTR (a GDmissense mutation at position 551) in retrovirus transducedL cells. Cell transduced with W.T. CFTR expressed a 170 kd CFTRprotein that was endoglycosidase H (Endo H) resistant, localizedto the plasma membrane, and generated a cAMP-mediated anionconductance (GCl) when stimulated with standard concentrationsof forskolin (5 µM), cpt cAMP (400 µM) and IBMX(100 µM). The G551D CFTR was indistinguishable from W.T.CFTR with respect to post-translational processing and localization,but it did not produce a cAMP-activated GCI in response to thestandard stimulation cocktail. However, raising the IBMX concentrationto 4 mM produced Gc, in G551D expressing cells. Cells transducedwith F508 CFTR expressed an Endo H sensitive CFTR protein (140kd) that was found in a cytosolic, perinuclear location. Thesecells did not respond to the standard cocktail, but 20% of cellsincreased GCI when the cocktail contained 4 mM IBMX. Incubationof cells at 26°C for 48 hours prior to analysis elicitedresponses in F508 expressing cells at low IBMX concentrations,but had no effect on the responses of cells expressing W.T.or G551D CFTR. The response of F508 to 26°C was associatedwith plasma membrane localization of CFTR protein. These resultssuggest that there are two mechanisms whereby CFTR mutationslead to loss of cAMP-responsive GCI. First, shown by G551D CFTR,the protein can be processed and targeted to the plasma membranecorrectly, but lack full responsiveness to stimulation by cAMP.Second, as examplified by F508 CFTR, a partially functionalprotein which is not targeted to its correct cellular locationcan also lead to loss of the cAMP, responsive GCI. 相似文献
24.
25.
M. E. Nava F. R. Engelhardt 《Archives of environmental contamination and toxicology》1982,11(2):141-145
American eels,Anguilla rostrata, were exposed to crude oil by ingestion of a 10, 100, or 500 l/kg fish dose per day for five days. Depuration was followed for an additional twelve days. All oil doses caused an induction of hepatic microsomal enzymes, maximally by three days of exposure. Benzo(a)pyrene hydroxylase (BaPH) showed a dose related response, with greater induction at 100 l/kg than at the other doses. The highest dose was hepatotoxic. Cytochrome P-450 induction was dose independent, and remained induced maximally for the entire experimental period, in contrast to BaPH which declined in activity. Reaction optimum for BaPH was at pH 7.5 and 27°C. A study of tissue distribution showed the liver to account for nearly all BaPH activity. A significant increase in the protein content of the hepatic postmitochondrial fraction of oil-exposed fish was also observed. 相似文献
26.
Bailey AR von Engelhardt N Von Englehardt N Leng G Smith RG Dickson SL 《Journal of neuroendocrinology》2000,12(3):191-197
Noradrenergic systems are integrally involved in the release of growth hormone (GH) from the anterior pituitary gland and in regulating the activity of hypothalamic growth hormone-releasing hormone (GHRH) neurones. GH secretagogues act at both the pituitary and the hypothalamus to facilitate the release of GH. In male rats, using the induction of Fos protein as an indicator of neuronal activation, we examined whether neurones in the brainstem, the main noradrenergic input to the hypothalamus, were activated by systemic administration of peptide and non-peptide GH secretagogues. In addition, we examined the effects of chronic central noradrenaline depletion upon GH secretagogue-induced activation of the arcuate nucleus. Systemic injection of the GH secretagogues, GHRP-6 and MK-0677 induced Fos protein expression in a population of area postrema cells, but less than 10% of these cells were noradrenergic. Depletion of hypothalamic noradrenaline by the specific neurotoxin, 5-ADMP, did not alter GH secretagogue-induced activation of Fos protein in the arcuate nucleus compared to vehicle-treated controls. We conclude that the central actions of GH secretagogues involve the activation of non-noradrenergic cells in the area postrema and that GH secretagogue-induced activation of the arcuate nucleus occurs independently of noradrenergic tone. 相似文献
27.
Pelinkovic D Martinek V Engelhardt M Lee JY Fu F Huard J 《Zeitschrift für Orthop?die und ihre Grenzgebiete》2000,138(5):402-406
AIM: Muscle-based somatic gene therapy is a novel way to alleviate a biochemical deficiency. METHOD: Muscle-derived cells are very promising in the field of gene therapy and tissue engineering. First, most muscle tissue is accessible by injection. Second, muscle tissue consists of multinucleated, postmitotic myofibers, which enable a long-term expression of the transduced gene. Third, muscle tissue can be biopsied easily. It is available in abundance and the biopsy does not compromise the health and function of the patient. Finally, muscle tissue is highly vascularized, which makes systemic delivery feasible. RESULTS: Muscle-derived cells can promote muscle healing and bone healing. Implanted cells maintain a long-term transgene expression of therapeutic proteins. Isolated, muscle-derived stem cells can differentiate in osteoblasts. CONCLUSION: Based on these characteristics, we present four possible applications: inherited muscular diseases, muscle injury, bone healing, and intraarticular disorders. 相似文献
28.
Based on the observation that antibodies directed against alpha4-integrin and its counterreceptor VCAM-1 inhibit inflammatory cell recruitment into the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), it has been concluded that alpha4-integrin/VCAM-1 interaction plays a critical role in T cell interaction with the blood-brain barrier (BBB) endothelium. In order to define the exact role of alpha4-integrin and VCAM-1 in T cell recruitment across the BBB endothelium we set up in vitro studies, where we investigated the interaction of freshly activated autoaggressive T cell blasts with the brain endothelial cell line bEnd5. A large panel of blocking antibodies directed against the alpha4-, beta1- and beta7-integrin subunits or against the alpha4beta7-heterodimer and against endothelial VCAM-1 significantly reduced adhesion of encephalitogenic T cell blasts to brain endothelium. However, the very same antibodies did not influence transendothelial migration of autoaggressive T cell blasts across a bEnd5 monolayer. Our in vitro observations, therefore, suggest that in vivo alpha4/VCAM-1 interactions are not involved in transendothelial migration of encephalitogenic T cells across the BBB but rather mediate earlier steps of T cell/BBB-interaction such as firm adhesion. 相似文献
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30.