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91.
Somers KL Royals MA Carstea ED Rafi MA Wenger DA Thrall MA 《Molecular genetics and metabolism》2003,79(2):99-103
Niemann-Pick C (NPC) disease is an autosomal recessive neurovisceral lysosomal storage disorder that results in defective intracellular transport of cholesterol. The major form of human NPC (NPC1) has been mapped to chromosome 18, the NPC1 gene (NPC1) has been sequenced and several mutations have been identified in NPC1 patients. A feline model of NPC has been characterized and is phenotypically, morphologically, and biochemically similar to human NPC1. Complementation studies using cultured fibroblasts from NPC affected cats and NPC1 affected humans support that the gene responsible for the NPC phenotype in this colony of cats is orthologous to human NPC1. Using human-based PCR primers, initial fragments of the feline NPC cDNA were amplified and sequenced. From these sequences, feline-specific PCR primers were generated and designed to amplify six overlapping bands that span the entire feline NPC1 open reading frame. A single base substitution (2864G-C) was identified in NPC1 affected cats. Obligate carriers are heterozygous at the same allele and a PCR-based assay was developed to identify the geneotype of all cats in the colony. The mutation results in an amino acid change from cysteine to serine (C955S). Several of the mutations identified in people occur in the same region. Marked similarity exists between the human and feline NPC1 cDNA sequences, and is greater than that between the human and murine NPC1 sequences. The human cDNA sequence predicts a 1278aa protein with a lysosomal targeting sequence, several trans-membrane domains and extensive homology with other known mediators of cholesterol homeostasis. 相似文献
92.
Novel Brugada syndrome-causing mutation in ion-conducting pore of cardiac Na+ channel does not affect ion selectivity properties 总被引:2,自引:0,他引:2
AIM: Brugada syndrome is an inherited cardiac disease with an increased risk of sudden cardiac death. Thus far Brugada syndrome has been linked only to mutations in SCN5A, the gene encoding the alpha-subunit of cardiac Na+ channel. In this study, a novel SCN5A gene mutation (D1714G) is reported, which has been found in a 57-year-old male patient. Since the mutation is located in a segment of the ion-conducting pore of the cardiac Na+ channel, which putatively determines ion selectivity, it may affect ion selectivity properties. METHODS: HEK-293 cells were transfected with wild-type (WT) or D1714G alpha-subunit and beta-subunit cDNA. Whole-cell configuration of the patch-clamp technique was used to study biophysical properties at room temperature (21 degrees C) and physiological temperature (36 degrees C). This study represents the first measurements of human Na+ channel kinetics at 36 degrees C. Ion selectivity, current density, and gating properties of WT and D1714G channel were studied. RESULTS: D1714G channel yielded nearly 80% reduction of Na+ current density at 21 and 36 degrees C. At both temperatures, no significant changes were observed in V(1/2) values and slope factors for voltage-dependent activation and inactivation. At 36 degrees C, but not at 21 degrees C, D1714G channel exhibited more slow inactivation compared with WT channel. Ion selectivity properties were not affected by the mutation at both temperatures, as assessed by either current or permeability ratio. CONCLUSION: This study shows no changes in ion selectivity properties of D1714G channel. However, the profoundly decreased current density associated with the D1714G mutation may explain the Brugada syndrome phenotype in our patient. 相似文献
93.
A. S. Amin A. O. Verkerk Z. A. Bhuiyan A. A. M. Wilde H. L. Tan 《Acta physiologica (Oxford, England)》2005,185(4):291-301
Aim: Brugada syndrome is an inherited cardiac disease with an increased risk of sudden cardiac death. Thus far Brugada syndrome has been linked only to mutations in SCN5A, the gene encoding the α‐subunit of cardiac Na+ channel. In this study, a novel SCN5A gene mutation (D1714G) is reported, which has been found in a 57‐year‐old male patient. Since the mutation is located in a segment of the ion‐conducting pore of the cardiac Na+ channel, which putatively determines ion selectivity, it may affect ion selectivity properties. Methods: HEK‐293 cells were transfected with wild‐type (WT) or D1714G α‐subunit and β‐subunit cDNA. Whole‐cell configuration of the patch‐clamp technique was used to study biophysical properties at room temperature (21 °C) and physiological temperature (36 °C). This study represents the first measurements of human Na+ channel kinetics at 36 °C. Ion selectivity, current density, and gating properties of WT and D1714G channel were studied. Results: D1714G channel yielded nearly 80% reduction of Na+ current density at 21 and 36 °C. At both temperatures, no significant changes were observed in V1/2 values and slope factors for voltage‐dependent activation and inactivation. At 36 °C, but not at 21 °C, D1714G channel exhibited more slow inactivation compared with WT channel. Ion selectivity properties were not affected by the mutation at both temperatures, as assessed by either current or permeability ratio. Conclusion: This study shows no changes in ion selectivity properties of D1714G channel. However, the profoundly decreased current density associated with the D1714G mutation may explain the Brugada syndrome phenotype in our patient. 相似文献
94.
A C-Terminal Hydrophobic Region is Required for Homo-Oligomerization of the Hepatitis E Virus Capsid (ORF2) Protein 总被引:1,自引:0,他引:1 下载免费PDF全文
Hepatitis E virus (HEV) is the causative agent of hepatitis E, anacute form of viral hepatitis. The open reading frame 2 (ORF2) of HEV encodes the viral capsid protein, which can self-oligomerize into virus-like particles. To understand the domains within this protein important for capsid biogenesis, we have carried out in vitro analyses of association and folding patterns of wild type and mutant ORF2 proteins. When expressed in vitro or in transfected cells, the ORF2protein assembled as dimers, trimers and higher order forms. WhileN-terminal deletions up to 111 amino acids had no effect, the deletion of amino acids 585–610 led to reduced homo-oligomerization. This deletion also resulted in aberrant folding of the protein, as determined by its sensitivity to trypsin. This study suggests that a C-terminal hydrophobic region encompassing amino acids 585–610 of the ORF2 protein might be critical for capsid biogenesis. 相似文献
95.
Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis 总被引:1,自引:0,他引:1 下载免费PDF全文
Arbiser JL Govindarajan B Bai X Onda H Kazlauskas A Lim SD Amin MB Claesson-Welsh L 《The American journal of pathology》2002,161(3):781-786
A ubiquitous herpesvirus that establishes life-long infection, the Epstein-Barr virus (EBV) has yielded little insight into how a single agent in general accord with its host can produce diverse pathologies ranging from oral hairy leukoplakia to nasopharyngeal carcinoma, from infectious mononucleosis to Hodgkin's disease (HD) and Burkitt's lymphoma. Its pathogenesis is further confounded by the less than total association of virus with histologically similar tumors. In other viral systems, defective (interfering) viral genomes are known to modulate outcome of infection, with either ameliorating or intensifying effects on disease processes initiated by prototype strains. To ascertain whether defective EBV genomes are present in HD, we examined paraffin-embedded tissue from 56 HD cases whose EBV status was first determined by cytohybridization for nonpolyadenylated EBV RNAs (EBERs). Using both standard polymerase chain reaction (PCR) and PCR in situ hybridization, we successfully amplified sequences that span abnormally juxtaposed BamHI W and Z fragments characteristic of defective heterogeneous (het) EBV DNA from 10 of 32 (31%) EBER-positive tumors. Of 24 EBER-negative HD, 8 yielded PCR products indicating presence of het EBV DNA. Two of these contained defective EBV in the apparent absence of the prototype virus. Of the 42 tumors analyzed for defective EBV by both PCR techniques, there was concordance of results in 38 (90%). Detection of defective EBV genomes with the potential to disrupt viral gene regulation suggests one mechanism for pathogenic diversity that may also account for loss of prototypic EBV from individual tumor cells. 相似文献
96.
Effects of heparin on platelet aggregation and release and thromboxane A2 production. 总被引:1,自引:0,他引:1 下载免费PDF全文
S. F. Mohammad W. H. Anderson J. B. Smith H. Y. Chuang R. G. Mason 《The American journal of pathology》1981,104(2):132-141
Heparin, when added to citrated platelet-rich plasma (PRP), caused potentiation of platelet aggregation and the release reaction induced by the aggregating agents adenosine diphosphate (ADP), arachidonic acid, collagen, and epinephrine. At low concentrations (4.7 x 10(-5) M) arachidonic acid failed to cause aggregation of platelets in citrated PRP. However, in the presence of heparin, the same concentration of arachidonic acid caused aggregation. Examination of PRP for the presence of thromboxane A2 (TxA2) by use of a bioassay revealed that heparin also stimulated release of TxA2. This finding indicated that platelets released more TxA2 when they were challenged by low concentrations of arachidonic acid in the presence of heparin than in its absence. Platelets were labeled with 3H-arachidonic acid and 14C-serotonin, and attempts were made to determine whether heparin stimulated the platelet release reaction first with subsequent increased production of TxA2, or alternatively, whether heparin stimulated TxA2 production first with subsequent enhancement of the release reaction. In view of the demonstrated simultaneous release of 14C-serotonin and 3H-arachidonic acid metabolites, it appeared that either release of 14C and 3H occurs concurrently or, even if one of these events is dependent on the other, both events take place in rapid succession. Timed sequential studies revealed that in the presence of arachidonic acid, the addition of heparin hastened the apparently simultaneous release of both 14C and 3H. 相似文献
97.
Maria Shahmoradgoli Najafabadi Mina Ohadi Mohammad Taghi Joghataie Faraz Valaie Yasser Riazalhosseini Hamid Mostafavi Fariba Mohammadbeigi Hossein Najmabadi 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2005,(1):39-41
Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of certain neuropsychiatric disorders such as drug abuse. It has been shown that the dopamine D2 receptor (DRD2) gene dysfunction is associated with multi-drug addiction. Addiction to opium is the most common form of drug abuse in Iran. We studied the allelic association between DRD2 Taq I A polymorphism in 100 opium-dependent Iranian patients and 130 unrelated controls. A 310 bp (base pair) region surrounding Taq I site at the DRD2 locus was amplified by polymerase chain reaction (PCR) and the PCR product was incubated with Taq I restriction enzyme. The A1 allele remained intact while the A2 allele was cut. Significant association was observed between A1 allele and addiction in the patients group (P < 0.0001). Moreover, the frequency of A1A1 genotype was significantly higher in opium users than controls (P < 0.0001). Our result indicates that DRD2 might be involved in the pathophysiology of opium addiction. 相似文献
98.
Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells 总被引:6,自引:0,他引:6
Thant AA Nawa A Kikkawa F Ichigotani Y Zhang Y Sein TT Amin AR Hamaguchi M 《Clinical & experimental metastasis》2000,18(5):423-428
Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown
that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion
and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated
the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and
PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, PI-3 kinase inhibitors, Wortmannin and
LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast,
a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that
both the MEK1 inhibitor and the PI3-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells.
Taken together, our results suggest that activation of dual signaling pathways, MEK1-MAPK and PI3K-Akt, is required for the
FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic
target for cancer.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
99.
Coprological examination of 40 Apodemus mystacinus Danford and Alston 1877 from Jordan revealed oocysts of three species of genus Eimeria. Two species are described as new. Eimeria zuhairamri sp. n. has broadly ellipsoidal oocysts 29.6 (27.0–34.0)×23.3 (22.0–25.0) m with distinctly granulated wall and oocyst residuum. Endogenous development occurs in jejunum and ileum. Eimeria alorani sp. n. has oocysts 26.9 (23.0–29.0)×19.3 (18.0–22.0) m with smooth wall and absent residuum. Endogenous development is confined to the caecum. The third species, developing in jejunum, has oocysts morphologically indistinguishable from Eimeria uptoni. The identity of E. uptoni and the taxonomy of Eimeria of Apodemus are discussed. 相似文献
100.
Najmabadi H Nishimura C Kahrizi K Riazalhosseini Y Malekpour M Daneshi A Farhadi M Mohseni M Mahdieh N Ebrahimi A Bazazzadegan N Naghavi A Avenarius M Arzhangi S Smith RJ 《American journal of medical genetics. Part A》2005,(2):132-137
Hereditary hearing loss (HHL) is a very common disorder. When inherited in an autosomal recessive manner, it typically presents as an isolated finding. Interestingly and unexpectedly, in spite of extreme heterogeneity, mutations in one gene, GJB2, are the most common cause of congenital severe-to-profound deafness in many different populations. In this study, we assessed the contributions made by GJB2 mutations and chromosome 13 g.1777179_2085947del (the deletion more commonly known as del (GJB6-D13S1830) that includes a portion of GJB6 and is hereafter called Delta(GJB6-D13S1830)) to the autosomal recessive non-syndromic deafness (ARNSD) genetic load in Iran. Probands from 664 different nuclear families were investigated. GJB2-related deafness was found in 111 families (16.7%). The carrier frequency of the 35delG mutation showed a geographic variation that is supported by studies in neighboring countries. Delta(GJB6-D13S1830) was not found. Our prevalence data for GJB2-related deafness reveal a geographic pattern that mirrors the south-to-north European gradient and supports a founder effect in southeastern Europe. 相似文献