全文获取类型
收费全文 | 1049篇 |
免费 | 124篇 |
出版年
2023年 | 5篇 |
2022年 | 5篇 |
2021年 | 25篇 |
2020年 | 16篇 |
2019年 | 23篇 |
2018年 | 26篇 |
2017年 | 19篇 |
2016年 | 46篇 |
2015年 | 56篇 |
2014年 | 67篇 |
2013年 | 91篇 |
2012年 | 93篇 |
2011年 | 85篇 |
2010年 | 60篇 |
2009年 | 38篇 |
2008年 | 69篇 |
2007年 | 52篇 |
2006年 | 41篇 |
2005年 | 49篇 |
2004年 | 51篇 |
2003年 | 51篇 |
2002年 | 54篇 |
2001年 | 12篇 |
2000年 | 14篇 |
1999年 | 11篇 |
1998年 | 12篇 |
1997年 | 13篇 |
1996年 | 7篇 |
1995年 | 7篇 |
1994年 | 2篇 |
1993年 | 8篇 |
1992年 | 9篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1989年 | 2篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1979年 | 5篇 |
1977年 | 5篇 |
1976年 | 2篇 |
1932年 | 3篇 |
1931年 | 2篇 |
1929年 | 3篇 |
1925年 | 1篇 |
1924年 | 1篇 |
1920年 | 2篇 |
排序方式: 共有1173条查询结果,搜索用时 31 毫秒
111.
The field of tissue engineering has made considerable strides since it was first described in the late 1980s. The advent and subsequent boom in stem cell biology, emergence of novel technologies for biomaterial development and further understanding of developmental biology have contributed to this accelerated progress. However, continued efforts to translate tissue-engineering strategies into clinical therapies have been hampered by the problems associated with scaling up laboratory methods to produce large, complex tissues. The significant challenges faced by tissue engineers include the production of an intact vasculature within a tissue-engineered construct and recapitulation of the size and complexity of a whole organ. Here we review the basic components necessary for bioengineering organs-biomaterials, cells and bioactive molecules-and discuss various approaches for augmenting these principles to achieve organ level tissue engineering. Ultimately, the successful translation of tissue-engineered constructs into everyday clinical practice will depend upon the ability of the tissue engineer to "scale up" every aspect of the research and development process. 相似文献
112.
Hansen L Hare KJ Hartmann B Deacon CF Ugleholdt RK Plamboeck A Holst JJ 《Regulatory peptides》2007,138(2-3):126-132
Little is known about the metabolism of the intestinotropic factor glucagon-like peptide-2 (GLP-2); except that it is a substrate for dipeptidyl peptidase IV (DPP-IV) and that it appears to be eliminated by the kidneys. We, therefore, investigated GLP-2 metabolism in six multicatheterized pigs receiving intravenous GLP-2 infusions (2 pmol/kg/min) before and after administration of valine-pyrrolidide (300 mumol/kg; a well characterized DPP-IV inhibitor). Plasma samples were analyzed by radioimmunoassays allowing determination of intact, biologically active GLP-2 and the DPP-IV metabolite GLP-2 (3-33). During infusion of GLP-2 alone, 30.9+/-1.7% of the infused peptide was degraded to GLP-2 (3-33). After valine-pyrrolidide, there was no significant formation of the metabolite. Significant extraction of intact GLP-2 was observed across the kidneys, the extremities (represented by a leg), and the splanchnic bed, resulting in a metabolic clearance rate (MCR) of 6.80+/-0.47 ml/kg/min and a plasma half-life of 6.8+/-0.8 min. Hepatic extraction was not detected. Valine-pyrrolidide addition did not affect extraction ratios significantly, but decreased (p=0.003) MCR to 4.18+/-0.27 ml/kg/min and increased (p=0.052) plasma half-life to 9.9+/-0.8 min. The metabolite was eliminated with a half-life of 22.1+/-2.6 min and a clearance of 2.07+/-0.11 ml/kg/min. In conclusion, intact GLP-2 is eliminated in the peripheral tissues, the splanchnic bed and the kidneys, but not in the liver, by mechanisms unrelated to DPP-IV. However, DPP-IV is involved in the overall GLP-2 metabolism and seems to be the sole enzyme responsible for N-terminal degradation of GLP-2. 相似文献
113.
Adams WW Watson AM Mueh KE Amiard V Turgeon R Ebbert V Logan BA Combs AF Demmig-Adams B 《Photosynthesis research》2007,94(2-3):455-466
The potential role of foliar carbon export features in the acclimation of photosynthetic capacity to differences and changes
in light environment was evaluated. These features included apoplastic vs. symplastic phloem loading, density of loading veins,
plasmodesmatal frequency in intermediary cells, and the ratio of loading cells to sieve elements. In initial studies, three
apoplastic loaders (spinach, pea, Arabidopsis thaliana) exhibited a completely flexible photosynthetic response to changing light conditions, while two symplastic loaders (pumpkin,
Verbascum phoeniceum), although able to adjust to different long-term growth conditions, were more limited in their response when transferred
from low (LL) to high (HL) light. This suggested that constraints imposed by the completely physical pathway of sugar export
might act as a bottleneck in the export of carbon from LL-acclimated leaves of symplastic loaders. While both symplastic loaders
exhibited variable loading vein densities (low in LL and high in HL), none of the three apoplastic loaders initially characterized
exhibited such differences. However, an additional apoplastic species (tomato) exhibited similar differences in vein density
during continuous growth in different light environments. Furthermore, in contrast to the other apoplastic loaders, photosynthetic
acclimation in tomato was not complete following a transfer from LL to HL. This suggests that loading vein density and loading
cells per sieve element, and thus apparent loading surface capacity, play a major role in the potential for photosynthetic
acclimation to changes in light environment. Photosynthetic acclimation and vein density acclimation were also characterized
in the slow-growing, sclerophytic evergreen Monstera deliciosa. This evergreen possessed a lower vein density during growth in LL compared to HL and exhibited a more severely limited potential
for photosynthetic acclimation to increases in light environment than the rapidly-growing, mesophytic annuals. 相似文献
114.
Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF=4.70) when compared to normal peripheral nerve and brain (MF=2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity. 相似文献
115.
Castellano JM Batrynchuk J Dolbeare K Verma V Mann A Skoblenick KJ Johnson RL Mishra RK 《Peptides》2007,28(10):2009-2015
Two melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) also known as L-prolyl-L-leucyl-glycinamide (PLG) peptidomimetic analogs, 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]-amino]-3-(butyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (A) and 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]amino]-3-(benzyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (B), were evaluated for their ability to modulate dopaminergic activity by measuring apomorphine-induced rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats, and haloperidol (HP)-induced vacuous chewing movements (VCMs) in rats; animal models of Parkinson's disease (PD) and human tardive dyskinesia (TD), respectively. In the 6-OHDA model, both analogs were found to potentiate the contralateral rotational behavior induced by apomorphine dose-dependently and with approximately the same potency. Furthermore, each analog was able to significantly attenuate HP-induced VCMs with almost equal efficacy. The potency and efficacy of these analogs were significantly greater than their parent compound, PLG. These results suggest that both analogs can modulate dopaminergic activity in vivo, likely by the same mechanisms recruited by PLG previously reported. 相似文献
116.
117.
118.
Chiappelli F Prolo P Cajulis KD Angeli A Dovio A Perotti P Pautasso M Sartori ML Saba L Mussino S Fraccalini T Fanto F Manfrini E Mocellini C Rosso MG Grasso E 《Bioinformation》2007,2(1):1-4
The emerging domain of epigenetics in molecular medicine finds application for a variety of patient populations. Here, we present fundamental neuroendocrine immune evidence obtained in patients with senile dementia of the Alzheimer's type (sDAT), and discuss the implications of these data from the viewpoint of translational epigenetics of Alzheimer's disease. We followed 18 subjects with mild sDAT treated with acetylcholinesterase inhibitors, and 10 control subjects matched for age in a repeated measure design every six months for 18 months. We monitored psychosocial profile (Mini-Mental State Examination, Functional Assessment Staging, Independence in Activities of Daily Living, Depression, Profile of Moods States) in parallel to immunophenotypic parameters of T cell subpopulations by flow cytometry. Based on change in the mini-mental state score at entry and at 18 months, patients with sDAT were assigned to a "fast progression" (delta greater than 2 points) or to a "slow progression" group (delta less than or equal to 2 points). The change in circulating activated T cells (CD3+Dr+) with time in patients with sDAT was significantly inversely correlated with the change in time in natural killer (NK) cytotoxic activity to cortisol modulation in these patients, which was greater in patients with fast progression, compared to slow progression sDAT. These data indicate underlying neuroendocrine immune processes during progression of sDAT. Our observations suggest that psychoimmune measures such as those we have monitored in this study provide relevant information about the evolving physiological modulation in patients with sDAT during progression of Alzheimer's disease, and point to new or improved translational epigenetic treatment interventions. 相似文献
119.
120.
Nickel is a cofactor for various microbial enzymes, yet as a trace element, its scavenging is challenging. In the case of the pathogen Helicobacter pylori, nickel is essential for the survival in the human stomach, because it is the cofactor of the important virulence factor urease. While nickel transport across the cytoplasmic membrane is accomplished by the nickel permease NixA, the mechanism by which nickel traverses the outer membrane (OM) of this Gram-negative bacterium is unknown. Import of iron-siderophores and cobalamin through the bacterial OM is carried out by specific receptors energized by the TonB/ExbB/ExbD machinery. In this study, we show for the first time that H. pylori utilizes TonB/ExbB/ExbD for nickel uptake in addition to iron acquisition. We have identified the nickel-regulated protein FrpB4, homologous to TonB-dependent proteins, as an OM receptor involved in nickel uptake. We demonstrate that ExbB/ExbD/TonB and FrpB4 deficient bacteria are unable to efficiently scavenge nickel at low pH. This condition mimics those encountered by H. pylori during stomach colonization, under which nickel supply and full urease activity are essential to combat acidity. We anticipate that this nickel scavenging system is not restricted to H. pylori, but will be represented more largely among Gram-negative bacteria. 相似文献