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41.
Bengt Fellström Faiez Zannad Roland Schmieder Hallvard Holdaas Alan Jardine Helen Rose Wim Wilpshaar 《Trials》2005,6(1):1-8
Background
Patients with end-stage renal disease (ESRD) are at high risk of cardiovascular events. Multiple risk factors for atherosclerosis are present in ESRD and may contribute to the increased risk of cardiovascular mortality in this population. In contrast to patients with normal renal function, the benefits of modifying lipid levels on cardiovascular outcomes in patients with ESRD on haemodialysis have yet to be confirmed in large prospective randomised trials. A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events (AURORA) will be the first large-scale international trial to assess the effects of statin therapy on cardiovascular morbidity and mortality in ESRD patients on chronic haemodialysis.Methods
More than 2,750 ESRD patients who have been receiving chronic haemodialysis treatment for at least 3 months have been randomised (1:1), irrespective of baseline lipid levels, to treatment with rosuvastatin 10 mg or placebo. The primary study endpoint is the time to a major cardiovascular event (first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Secondary endpoints include all-cause mortality, major cardiovascular event-free survival time, time to cardiovascular death, time to non-cardiovascular death, cardiovascular interventions, tolerability of treatment and health economic costs per life-year saved. Study medication will be given until 620 subjects have experienced a major cardiovascular event.Conclusion
Our hypothesis is that results from AURORA will establish the clinical efficacy and tolerability of rosuvastatin in patients with ESRD receiving chronic haemodialysis and guide the optimal management of this expanding population. 相似文献42.
Marten Veenhuis Klaas Sjollema Birgit Nordbring-Hertz Wim Harder 《Antonie van Leeuwenhoek》1989,55(4):361-368
A method is presented that enables studies to be made of single nematode-fungal interactions under conditions where fungal growth at the expense of external nutrients is prevented. The nematophagous fungus Arthrobotrys ologospora was used as a model organism in these studies. The method is based on removal of the traps from the vegetative mycelium, immediately after a nematode was captured and transfer of the trap with the captured nematode into a droplet of sterile distilled water placed in a moisture chamber. In the absence of external nutrients, such isolated traps of A. oligospora were fully effective in penetrating and subsequently digesting the captured nematode. Solely vegetative mycelium was formed at the expense of the digested nematode; this developed from the trap that originally had captured the nematode. One advantage of the present method is that studies on various stages of the nematode-fungal interaction can now be performed under conditions that exclude major influences of external nutrients which otherwise could be communicated to the trap cells by way of the vegetative mycelium. 相似文献
43.
Vermeulen W Van Troys M Bourry D Dewitte D Rossenu S Goethals M Borremans FA Vandekerckhove J Martins JC Ampe C 《Journal of molecular biology》2006,359(5):1277-1292
The HeadPiece (HP) domain, present in several F-actin-binding multi-domain proteins, features a well-conserved, solvent-exposed PXWK motif in its C-terminal subdomain. The latter is an autonomously folding subunit comprised of three alpha-helices organised around a hydrophobic core, with the sequence motif preceding the last helix. We report the contributions of each conserved residue in the PXWK motif to human villin HP function and structure, as well as the structural implications of the naturally occurring Pro to Ala mutation in dematin HP. NMR shift perturbation mapping reveals that substitution of each residue by Ala induces only minor, local perturbations in the full villin HP structure. CD spectroscopic thermal analysis, however, shows that the Pro and Trp residues in the PXWK motif afford stabilising interactions. This indicates that, in addition to the residues in the hydrophobic core, the Trp-Pro stacking within the motif contributes to HP stability. This is reinforced by our data on isolated C-terminal HP subdomains where the Pro is also essential for structure formation, since the villin, but not the dematin, C-terminal subdomain is structured. Proper folding can be induced in the dematin C-terminal subdomain by exchanging the Ala for Pro. Conversely, the reverse substitution in the villin C-terminal subdomain leads to loss of structure. Thus, we demonstrate a crucial role for this proline residue in structural stability and folding potential of HP (sub)domains consistent with Pro-Trp stacking as a more general determinant of protein stability. 相似文献
44.
Esmeralda N Blaney Davidson Elly L Vitters Wim B van den Berg Peter M van der Kraan 《Arthritis research & therapy》2006,8(3):R65-8
Cartilage damage in osteoarthritis (OA) is considered an imbalance between catabolic and anabolic factors, favoring the catabolic
side. We assessed whether adenoviral overexpression of transforming growth factor-β (TGFβ) enhanced cartilage repair and whether
TGFβ-induced fibrosis was blocked by local expression of the intracellular TGFβ inhibitor Smad7. We inflicted cartilage damage
by injection of interleukin-1 (IL-1) into murine knee joints. After 2 days, we injected an adenovirus encoding TGFβ. On day
4, we measured proteoglycan (PG) synthesis and content. To examine whether we could block TGFβ-induced fibrosis and stimulate
cartilage repair simultaneously, we injected Ad-TGFβ and Ad-Smad7. This was performed both after IL-1-induced damage and in
a model of primary OA. In addition to PG in cartilage, synovial fibrosis was measured by determining the synovial width and
the number of procollagen I-expressing cells. Adenoviral overexpression of TGFβ restored the IL-1-induced reduction in PG
content and increased PG synthesis. TGFβ-induced an elevation in PG content in cartilage of the OA model. TGFβ-induced synovial
fibrosis was strongly diminished by simultaneous synovial overexpression of Smad7 in the synovial lining. Of great interest,
overexpression of Smad7 did not reduce the repair-stimulating effect of TGFβ on cartilage. Adenoviral overexpression of TGFβ
stimulated repair of IL-1- and OA-damaged cartilage. TGFβ-induced synovial fibrosis was blocked by locally inhibiting TGFβ
signaling in the synovial lining by simultaneously transfecting it with an adenovirus overexpressing Smad7. 相似文献
45.
van der Steeg WA Hovingh GK Klerkx AH Hutten BA Nootenboom IC Levels JH van Tol A Dallinga-Thie GM Zwinderman AH Kastelein JJ Kuivenhoven JA 《Journal of lipid research》2007,48(3):674-682
It is unclear whether cholesteryl ester transfer protein (CETP) contributes to high density lipoprotein cholesterol (HDL-C) levels in hyperalphalipoproteinemia (HALP) in Caucasians. Moreover, even less is known about the effects of hereditary CETP deficiency in non-Japanese. We studied 95 unrelated Caucasian individuals with HALP. No correlations between CETP concentration or activity and HDL-C were identified. Screening for CETP gene defects led to the identification of heterozygosity for a novel splice site mutation in one individual. Twenty-five heterozygotes for this mutation showed reduced CETP concentration (-40%) and activity (-50%) and a 35% increase of HDL-C compared with family controls. The heterozygotes presented with an isolated high HDL-C, whereas the remaining subjects exhibited a typical high HDL-C/low-triglyceride phenotype. The increase of HDL-C in the CETP-deficient heterozygotes was primarily attributable to increased high density lipoprotein containing apolipoprotein A-I and A-II (LpAI:AII) levels, contrasting with an increase in both high density lipoprotein containing apolipoprotein A-I only and LpAI:AII in the other group. This study suggests the absence of a relationship between CETP and HDL-C levels in Caucasians with HALP. The data furthermore indicate that genetic CETP deficiency is rare among Caucasians and that this disorder presents with a phenotype that is different from that of subjects with HALP who have no mutation in the CETP gene. 相似文献
46.
Wim P. Burmeister Marlyse Buisson Leandro F. Estrozi Guy Schoehn Olivier Billet Zahia Hannas Cécile Sigoillot Hervé Poulet 《PloS one》2015,10(3)
The vesivirus feline calicivirus (FCV) is a positive strand RNA virus encapsidated by an icosahedral T=3 shell formed by the viral VP1 protein. Upon its expression in the insect cell - baculovirus system in the context of vaccine development, two types of virus-like particles (VLPs) were formed, a majority built of 60 subunits (T=1) and a minority probably built of 180 subunits (T=3). The structure of the small particles was determined by x-ray crystallography at 0.8 nm resolution helped by cryo-electron microscopy in order to understand their formation. Cubic crystals belonged to space group P213. Their self-rotation function showed the presence of an octahedral pseudo-symmetry similar to the one described previously by Agerbandje and co-workers for human parvovirus VLPs. The crystal structure could be solved starting from the published VP1 structure in the context of the T=3 viral capsid. In contrast to viral capsids, where the capsomers are interlocked by the exchange of the N-terminal arm (NTA) domain, this domain is disordered in the T=1 capsid of the VLPs. Furthermore it is prone to proteolytic cleavage. The relative orientation of P (protrusion) and S (shell) domains is alerted so as to fit VP1 to the smaller T=1 particle whereas the intermolecular contacts around 2-fold, 3-fold and 5-fold axes are conserved. By consequence the surface of the VLP is very similar compared to the viral capsid and suggests a similar antigenicity. The knowledge of the structure of the VLPs will help to improve their stability, in respect to a use for vaccination. 相似文献
47.
Wim E. J. M. Ghijsen Elly Besselsen Vincent Geukers Willem Kamphuis Fernando H. Lopes da Silva 《Journal of neurochemistry》1992,59(2):482-486
The effect of long-term potentiation (LTP) on endogenous amino acid release from rat hippocampus slices was studied. LTP was induced in vivo by application of a tetanus (200 Hz, 200 ms) to the Schaffer collateral fibers in unanesthetized rats. Endogenous release of glutamate and gamma-aminobutyric acid (GABA) was investigated 60 min after tetanization in CA1 subslices of potentiated and control rats. No significant effects of LTP were observed in basal and K(+)-induced Ca(2+)-independent release components of these amino acids. In contrast, K(+)-induced Ca(2+)-dependent release of both glutamate and GABA increased approximately 100% in slices from potentiated rats. No differences were observed in total content of glutamate and GABA between the subslices from control and LTP animals. These results suggest a persistent increase in the recruitment of the presynaptic vesicular pool of glutamate and GABA during LTP. 相似文献
48.
49.
Ethan A. Merritt Tracy L. Arakaki J. Robert Gillespie Eric T. Larson Angela Kelley Natascha Mueller Alberto J. Napuli Jessica Kim Li Zhang Christophe L.M.J. Verlinde Erkang Fan Frank Zucker Frederick S. Buckner Wesley C. Van Voorhis Wim G.J. Hol 《Journal of molecular biology》2010,397(2):481-494
Crystal structures of histidyl-tRNA synthetase (HisRS) from the eukaryotic parasites Trypanosoma brucei and Trypanosoma cruzi provide a first structural view of a eukaryotic form of this enzyme and reveal differences from bacterial homologs. HisRSs in general contain an extra domain inserted between conserved motifs 2 and 3 of the Class II aminoacyl-tRNA synthetase catalytic core. The current structures show that the three-dimensional topology of this domain is very different in bacterial and archaeal/eukaryotic forms of the enzyme. Comparison of apo and histidine-bound trypanosomal structures indicates substantial active-site rearrangement upon histidine binding but relatively little subsequent rearrangement after reaction of histidine with ATP to form the enzyme's first reaction product, histidyladenylate. The specific residues involved in forming the binding pocket for the adenine moiety differ substantially both from the previously characterized binding site in bacterial structures and from the homologous residues in human HisRSs. The essentiality of the single HisRS gene in T. brucei is shown by a severe depression of parasite growth rate that results from even partial suppression of expression by RNA interference. 相似文献
50.