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11.
The effects of recombinant-DNA-derived interferons on the growth of myeloid progenitor cells 总被引:5,自引:0,他引:5
Interferons (IFNs) have been shown to have significant effects on hematopoietic cell growth. Previous studies defining these effects have utilized mouse and human alpha-, beta-, and gamma-IFN isolated from supernatants of stimulated cells. Despite purification, the possible presence of other lymphokines and soluble factors remains a concern. In this study, the effects of gene-cloned alpha- and gamma-IFN on colony- forming units of granulocyte/macrophage (CFU-GM) progenitors cultured from the peripheral blood of normal volunteers were examined. In addition, blast cell colonies from one patient with acute myelogenous leukemia (AML) were studied. The growth of normal CFU-GM and AML blast cell colonies was inhibited in a dose-dependent manner by gamma- and alpha-IFN. gamma-IFN was ten to 100 times more potent than alpha-IFN in that this species of IFN reduced colony formation by greater than 50% at concentrations of less than 15 antiviral U/mL. The effects of gamma- IFN were neutralized by a monoclonal antibody specific for gamma-IFN. These in vitro studies indicate that human gamma-IFN may be an important modulator of myelopoiesis. Although these data indicate a possible efficacy of gamma-IFN in the treatment of AML, the in vitro results should be considered for their in vivo significance. 相似文献
12.
目的数值模拟抗血管生成因子Angiostatin和Endostatin对肿瘤血管生成的影响。方法建立肿瘤内外血管生成的二维离散数学模型。模型耦合两种抗血管生成因子Angiostatin和Endostatin的抑制效应,数值模拟在促血管生成因子诱导下肿瘤微血管网生成,讨论血管生成抑制因子的影响。结果抗血管生成因子Angiostatin对肿瘤内外血管网络生成的速度和成熟度有抑制作用。抗血管生成因子Angiostatin和Endostatin耦合作用时,在肿瘤血管生成的早期有明显的抑制效应;在肿瘤血管生成的中后期,它们可以降低肿瘤血管化程度。结论本文模型能够较好的模拟抗血管生成因子Angiostatin和Endostatin对内皮细胞迁移和增殖的抑制作用。 相似文献
13.
Burwinkel B; Maichele AJ; Aagenaes O; Bakker HD; Lerner A; Shin YS; Strachan JA; Kilimann MW 《Human molecular genetics》1997,6(7):1109-1115
Glycogen storage disease due to phosphorylase kinase deficiency occurs in
several variants that differ in mode of inheritance and tissue-
specificity. This heterogeneity is suspected to be largely due to mutations
affecting different subunits and isoforms of phosphorylase kinase. The gene
of the ubiquitously expressed beta subunit, PHKB, was a candidate for
involvement in autosomally transmitted phosphorylase kinase deficiency of
liver and muscle. To identify such mutations, the complete PHKB coding
sequence was amplified by RT-PCR of RNA isolated from blood samples of
patients and analyzed by direct sequencing of PCR products. The
characterization of mutations was complemented by PCR of genomic DNA. In
one female and four male patients, we identified five independent nonsense
mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), one
single-base insertion in codon N421, one splice-site mutation affecting
exon 31, and a large deletion involving the loss of exon 8. Although these
severe translation-disrupting mutations occur in constitutively expressed
sequences of the only known beta subunit gene of phosphorylase kinase,
PHKB, they are associated with a surprisingly mild clinical phenotype,
affecting virtually only the liver, and relatively high residual enzyme
activity of approximately 10%.
相似文献
14.
Delivery of a hammerhead ribozyme specifically down-regulates the production of fibrillin-1 by cultured dermal fibroblasts 总被引:4,自引:1,他引:4
Kilpatrick MW; Phylactou LA; Godfrey M; Wu CH; Wu GY; Tsipouras P 《Human molecular genetics》1996,5(12):1939-1944
The hammerhead ribozyme is a small catalytic RNA molecule. Potential
hammerhead ribozymes that possess a catalytic domain and flanking sequence
complementary to a target mRNA can cleave in trans at a putative cleavage
site within the target molecule. We have investigated the potential of
hammerhead ribozymes to down-regulate the product of the fibrillin-1 gene
(FBN1). Fibrillin is a 347 kDa glycoprotein that is a major constituent of
the elastin-associated microfibrils. Mutations in the FBN1 gene are
responsible for Marfan syndrome (MFS), a common systemic disorder of the
connective tissue. Many FBN1 mutations responsible for MFS appear to act in
a dominant-negative fashion, raising the possibility that reduction of the
amount of product from the mutant FBN1 allele might be a valid therapeutic
approach for MFS. A trans-acting hammerhead ribozyme (FBN1-RZ1) targeted to
the 5' end of the human FBN1 mRNA has been designed and synthesized, and
shown to cleave its target efficiently in vitro. FBN1-RZ1 cleavage is
magnesium dependent and efficient at both 37 and 50 degrees C. Delivery of
the FBN1-RZ1 ribozyme into cultured dermal fibroblasts, by receptor-
mediated endocytosis of a ribozyme-transferrin-polylysine complex,
specifically reduces both cellular FBN1 mRNA and the deposition of
fibrillin in the extracellular matrix. These results suggest that the use
of hammerhead ribozymes is a valid approach to the study of fibrillin gene
expression and possibly to the development of a therapeutic approach to
MFS.
相似文献
15.
Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning 总被引:8,自引:0,他引:8
Weaver TE Maislin G Dinges DF Bloxham T George CF Greenberg H Kader G Mahowald M Younger J Pack AI 《Sleep》2007,30(6):711-719
STUDY OBJECTIVES: Evidence suggests that, to maintain treatment effects, nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA) needs to be used every night. What remains unknown is the nightly duration of use required to normalize functioning. This study, employing probit analyses and piecewise regression to estimate dose-response functions, estimated likelihoods of return to normal levels of sleepiness and daily functioning relative to nightly duration of CPAP. DESIGN: Multicenter, quasi-experimental study. SETTING: Seven sleep centers in the United States and Canada. PARTICIPANTS: Patients with severe OSA (total cohort n = 149; the numbers of included participants from 85 - 120, depending on outcome analyzed.) Interventions: CPAP. MEASUREMENTS AND RESULTS: Before treatment and again after 3 months of therapy, participants completed a day of testing that included measures of objective and subjective daytime sleepiness and functional status. There were significant differences in mean nightly CPAP duration between treatment responders and nonresponders across outcomes. Thresholds above which further improvements were less likely relative to nightly duration of CPAP were identified for Epworth Sleepiness Scale score (4 hours), Multiple Sleep Latency Test (6 hours), and Functional Outcomes associated with Sleepiness Questionnaire (7.5 hours). A linear dose-response relationship (P < 0.01) between increased use and achieving normal levels was shown for objective and subjective daytime sleepiness, but only up to 7 hours use for functional status. CONCLUSIONS: Our analyses suggest that a greater percentage of patients will achieve normal functioning with longer nightly CPAP durations, but what constitutes adequate use varies between different outcomes. 相似文献
16.
A DNA endonuclease, isolated from the nuclei of normal human and xeroderma
pigmentosum complementation group A (XPA) cells, which recognizes
predominately pyrimidine dimers, was examined for the mechanism by which it
locates sites of damage on UVC-irradiated DNA. In reaction mixtures with
low ionic strengths (i.e. lacking KCl), the normal and XPA endonuclease
locate sites of UV damage on both naked and reconstituted nucleosomal DNA
by different mechanisms. On both of these substrates, the normal
endonuclease acts by a processive mechanism, meaning that it binds
non-specifically to DNA and scans the DNA for sites of damage, whereas the
XPA endonuclease acts by a distributive one, meaning that it randomly
locates sites of damage on DNA. However, while both the normal and XPA
endonucleases can incise UVC irradiated naked DNA, they differ in ability
to incise damaged nucleosomal DNA. The normal endonuclease showed increased
activity on UVC treated nucleosomal DNA compared with naked DNA, whereas
the XPA endonuclease showed decreased activity on the damaged nucleosomal
substrate. Since a processive mechanism of action is sensitive to the ionic
strength of the micro-environment, the KCl concentration of the reaction
was increased. At 70 mM KCI, the normal endonuclease switched to a
distributive mechanism of action and its ability to incise damaged
nucleosomal DNA also decreased. These studies show that there is a
correlation between the ability of these endonucleases to act by a
processive mechanism and their ability to incise damaged nucleosomal DNA;
the normal endonuclease, which acts processively, can incise damaged
nucleosomal DNA, whereas the XPA endonuclease, which acts distributively,
is defective in ability to incise this substrate.
相似文献
17.
Epidemiological evidence indicates that aflatoxin B1 (AFB1) intake is
associated with an increased risk of hepatocellular carcinoma (HCC). The
hepatocarcinogenesis is initiated by covalent binding of AFB1 to cellular
DNA. To determine whether nutritional factors and hormonal status may
influence the binding of AFB1 to hepatic DNA, a cross- sectional study was
performed on a total of 42 male asymptomatic hepatitis B surface antigen
(HBsAg) carriers and 43 male non-carriers in a cohort study on the
multistage development of HCC in Taiwan. The major AFB1-DNA adduct in vivo,
AFB1-N7-guanine, was measured by high- performance liquid chromatography in
urine. Urinary AFB1-N7-guanine was detectable in 40% of the subjects. HBsAg
carriers had a higher detection rate of urinary AFB1-DNA adducts than
non-carriers and the difference was statistically significant after
multivariate adjustment. After taking into account the total AFB1 urinary
metabolite level, chronic HBsAg carrier status, and other potential
confounders, plasma levels of cholesterol, alpha-tocopherol, and alpha- and
beta-carotene were positively associated with the detection rate of the
AFB1-DNA adducts in a dose-dependent manner, whereas plasma lycopene level
was inversely related to the presence of the adducts in urine. The
association of urinary AFB1-DNA adducts with the plasma levels of
cholesterol, alpha-tocopherol, lycopene, and alpha- and beta-carotene was
observed at both low and high exposure levels of AFB1. There was a
synergistic interaction of plasma alpha-tocopherol with alpha- and beta-
carotene on the adduct levels. No association with the adducts was found
for plasma levels of retinol and testosterone. This study demonstrated
different associations of antioxidant vitamins with AFB1- DNA adduct
formation. The data consistent with our previous finding in cultured
woodchuck hepatocytes that alpha-tocopherol and beta-carotene enhanced
AFB1-DNA adduct formation suggest that prospective investigation of the
relationship between plasma micronutrients and risk of AFB1-related HCC is
warranted.
相似文献
18.
LO Larsson MW Bentzon K Berg Kelly L Mellander B-E Skoogh I-L Strannegård A Lind 《Acta paediatrica (Oslo, Norway : 1992)》1994,83(10):1091-1094
We studied 3592 Swedish schoolchildren, 8 or 9 years old, examined for palpable submandibular, cervical and supraclavicular lymph nodes. All children were skin tested with 2 TU PPD RT23 and with 0.1 μ g of Mycobacterium avium sensitin or 0.1 μ g of M. scrofulaceum sensitin. A total of 991 children had palpable lymph nodes in any of the three locations. Among them, 811 had lymph nodes in one location, 162 in two locations and 18 in three. In 312 children, the lymph nodes were ± 5 mm in size in any location. The most common location was submandibular. Boys had a significantly higher prevalence of palpable lymph nodes than girls. There was also seasonal variation. Children infected by atypical mycobacteria (sensitin reaction ±6 mm) did not have a higher prevalence of palpable lymph nodes than those not infected. 相似文献
19.
Rodney J. Douglas Misha Mahowald Kevan A. C. Martin Kenneth J. Stratford 《Journal of neurocytology》1996,25(1):893-911
Summary The synapse, first introduced as a physiological hypothesis by C. S. Sherrington at the close of the nineteenth century, has, 100 years on, become the nexus for anatomical and functional investigations of interneuronal communication. A number of hypotheses have been proposed that give local synaptic interactions specific roles in generating an algebra or logic for computations in the neocortex. Experimental work, however, has provided little support for such schemes. Instead, both structural and functional studies indicate that characteristically cortical functions, e. g., the identification of the motion or orientation of objects, involve computations that must be achieved with high accuracy through the collective action of hundreds or thousands of neurons connected in recurrent microcircuits. Some important principles that emerge from this collective action can effectively be captured by simple electronic models. More detailed models explain the nature of the complex computations performed by the cortical circuits and how the computations remain so remarkably robust in the face of a number of sources of noise, including variability in the anatomical connections, large variance in the synaptic responses and in the tria-to-trial output of single neurons, and weak or degraded input signals. 相似文献
20.
Gross and microscopic lesions of the corpus callosum and neighboring structures are common in severe closed head injury. This report is the first, to our knowledge, to confirm neuropathologically the occurrence of extensive traumatic destruction of the corpus callosum in a patient with left-sided apraxia and agraphia. It also demonstrates that large traumatic lesions of the corpus callosum may occur without prolonged posttraumatic coma, vegetative state, or death. In our patient, coexisting extracallosal hemispheric lesions may have modified the effects of callosal pathology. Cases of this type may be more common than generally appreciated, but since symptoms of hemispheric disconnection are not apparent in ordinary behavior, specific tests of callosal function must be employed if disconnection phenomena are to be detected in the posttraumatic period. 相似文献