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101.
Mutations in three different genes of phosphorylase kinase (Phk) subunits,
PHKA2, PHKB and PHKG2, can give rise to glycogen storage disease of the
liver. The autosomal-recessive, liver-specific variant of Phk deficiency is
caused by mutations in the gene encoding the testis/liver isoform of the
catalytic gamma subunit, PHKG2. To facilitate mutation detection and to
improve our understanding of the molecular evolution of Phk subunit
isoforms, we have determined the structure of the human PHKG2 gene. The
gene extends over 9.5 kilonucleotides and is divided into 10 exons;
positions of introns are highly conserved between PHKG2 and the gene of the
muscle isoform of the gamma subunit, PHKG1. The beginning of intron 2
harbors a highly informative GGT/GT microsatellite repeat, the first
polymorphic marker in the PHKG2 gene at human chromosome 16p11.2-p12.1.
Employing the gene sequence, we have identified homozygous
translation-terminating mutations, 277delC and Arg44ter, in the two
published cases of liver Phk deficiency who developed cirrhosis in
childhood. As liver Phk deficiency is generally a benign condition and
progression to cirrhosis is very rare, this finding suggests that PHKG2
mutations are associated with an increased cirrhosis risk.
相似文献
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MW Blom PR Bartel DK Sommers CH Van Der Meyden PJ Becker 《Fundamental & clinical pharmacology》1992,6(1):5-9
This study compares the effects of buspirone (5 mg), chlordiazepoxide (5 mg), hydroxyzine (10 mg) and placebo on psychomotor function and EEG, when taken thrice daily for a period of two weeks, with those after a single dose administration. Nine healthy volunteers participated in the study. The battery of psychomotor tests included peak velocity of saccadic eye movements (SEM), a Sternberg memory scanning and choice reaction time test (SMS-CRT) and critical flicker fusion frequency (CFFF). The peak velocity of saccadic eye movements was significantly impaired by the single dose of hydroxyzine (P = 0.03) in comparison to the multidose results. A similar comparison regarding buspirone only approached significance (P = 0.07). The SMS-CRT and CFFF did not reveal any difference between the multi and single dose regimens. Spectral analysis of the EEG did not distinguish between the multi and single dosage schedules regarding the respective drugs in the low doses administered. 相似文献
105.
106.
Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells 总被引:3,自引:0,他引:3
Schütt BS Langkamp M Rauschnabel U Ranke MB Elmlinger MW 《Journal of molecular endocrinology》2004,32(3):859-868
The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added (125)I-hIGFBP-2 specifically bound to the cells. Bound (125)I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for alpha5beta1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P<0.01), and of the p42/44 MAP-kinases of up to 40% (P<0.01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P<0.05), and reduced proliferation by 24% (P<0.01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with alpha5beta1-integrin. 相似文献
107.
P-31 MR spectroscopy of normal human brain and brain tumors 总被引:2,自引:0,他引:2
Hubesch B; Sappey-Marinier D; Roth K; Meyerhoff DJ; Matson GB; Weiner MW 《Radiology》1990,174(2):401-409
Image-guided phosphorus-31 magnetic resonance (MR)-localized image-selected in vivo spectroscopy was performed on normal human brain and brain tumors. Peak area ratios, absolute molar concentrations of metabolites, and pH were determined. T1 values in normal brain were measured. The most important finding was that the metabolite concentrations detectable with MR spectroscopy in brain tumors were reduced from 20% to 70%. Phosphomonoesters, phosphodiesters, and phosphocreatine (PCr) showed the greatest decreases, while inorganic phosphate (Pi) showed the least change. The PCr-Pi ratio was significantly reduced in tumors. The pH of brain tumors (7.12 +/- 0.03) was more alkaline than that of normal brain (6.99 +/- 0.01). The authors conclude that the metabolite concentrations and pH in human brain tumors differ significantly from those in normal brain. These differences may be ultimately useful in characterizing tumors in man. 相似文献
108.
109.
Renate RJ de Groot-Besseling Theo JM Ruers Iris L Lamers-Elemans Cathy N Maass Robert MW de Waal Johan R Westphal 《BMC cancer》2006,6(1):149
Background
Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group. In previous studies, it has been demonstrated that administration of PA in combination with the free sulfhydryl donor (FSD) agents captopril or N-acetyl cysteine, resulted in angiostatin generation, and anti-angiogenic and anti-tumour activity in murine models. 相似文献110.
Hoeflich A Bünger L Nedbal S Renne U Elmlinger MW Blum WF Bruley C Kolb HJ Wolf E 《General and comparative endocrinology》2004,136(2):248-259
Transgenic and knockout models have been used successfully in order to attribute specific functions to distinct growth factors. However, it is not clear which from the different IGF-components are actually altered when growth is affected. Furthermore it is not clear if unique or redundant patterns of IGF-component expression are present under conditions of elevated or reduced growth. To address these questions we have used a unique set of mouse models generated by divergent selection for high and low body growth. The set of mouse models consisted of eight mouse lines established in different laboratories. We have studied systemic and local expression of growth relevant genes in these mouse lines highly diverging for body and carcass weights but also for nose-rump lengths. As a strictly conserved pattern, serum IGF-I levels were dramatically increased in all H-lines if compared with the respective L-lines. By contrast serum IGFBP concentrations did not reveal clear patterns of expression in response to growth selection: IGFBP-3 was elevated in some H-lines, IGFBP-2 was increased in H- or L-lines and IGFBP-4 was similar in H- and L-lines. The fact that IGFBP-2 was the only IGFBP elevated in part of the L-lines, identifies IGFBP-2 as an exclusive although facultative negative effector for growth in the circulation among all other IGFBPs. In muscle tissue from selected breeding groups characterized by specific increases of the carcass weights we found redundant patterns of gene expression indicating the absence of tissue-specific or uniquely fixed expression patterns during growth selection within muscle tissue. The finding that serum but not tissue IGF-I levels were strictly positively correlated with growth during growth selection argues for an important role of endocrine IGF-I for postnatal growth in mice. 相似文献