全文获取类型
收费全文 | 1852篇 |
免费 | 128篇 |
国内免费 | 2篇 |
专业分类
1982篇 |
出版年
2022年 | 27篇 |
2021年 | 27篇 |
2020年 | 35篇 |
2019年 | 25篇 |
2018年 | 42篇 |
2017年 | 33篇 |
2016年 | 57篇 |
2015年 | 87篇 |
2014年 | 88篇 |
2013年 | 112篇 |
2012年 | 123篇 |
2011年 | 143篇 |
2010年 | 94篇 |
2009年 | 72篇 |
2008年 | 115篇 |
2007年 | 115篇 |
2006年 | 110篇 |
2005年 | 97篇 |
2004年 | 75篇 |
2003年 | 89篇 |
2002年 | 61篇 |
2001年 | 22篇 |
2000年 | 14篇 |
1999年 | 22篇 |
1998年 | 23篇 |
1997年 | 16篇 |
1996年 | 16篇 |
1995年 | 10篇 |
1994年 | 19篇 |
1993年 | 10篇 |
1992年 | 5篇 |
1991年 | 10篇 |
1990年 | 9篇 |
1986年 | 7篇 |
1985年 | 6篇 |
1984年 | 8篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1981年 | 6篇 |
1980年 | 10篇 |
1979年 | 5篇 |
1978年 | 5篇 |
1977年 | 9篇 |
1976年 | 10篇 |
1975年 | 14篇 |
1974年 | 13篇 |
1973年 | 9篇 |
1968年 | 11篇 |
1966年 | 4篇 |
1956年 | 4篇 |
排序方式: 共有1982条查询结果,搜索用时 15 毫秒
991.
Kawai M Breggia AC DeMambro VE Shen X Canalis E Bouxsein ML Beamer WG Clemmons DR Rosen CJ 《The Journal of biological chemistry》2011,286(16):14670-14680
Insulin-like growth factor-binding protein 2 (IGFBP-2) is a member of a family of six highly conserved IGFBPs that are carriers for the insulin-like growth factors (IGFs). IGFBP-2 levels rise during rapid neonatal growth and at the time of peak bone acquisition. In contrast, Igfbp2(-/-) mice have low bone mass accompanied by reduced osteoblast numbers, low bone formation rates, and increased PTEN expression. In the current study, we postulated that IGFBP-2 increased bone mass partly through the activity of its heparin-binding domain (HBD). We synthesized a HBD peptide specific for IGFBP-2 and demonstrated in vitro that it rescued the mineralization phenotype of Igfbp2(-/-) bone marrow stromal cells and calvarial osteoblasts. Consistent with its cellular actions, the HBD peptide ex vivo stimulated metacarpal periosteal expansion. Furthermore, administration of HBD peptide to Igfbp2(-/-) mice increased osteoblast number, suppressed marrow adipogenesis, restored trabecular bone mass, and reduced bone resorption. Skeletal rescue in the Igfbp2(-/-) mice was characterized by reduced PTEN expression followed by enhanced Akt phosphorylation in response to IGF-I and increased β-catenin signaling through two mechanisms: 1) stimulation of its cytosolic accumulation and 2) increased phosphorylation of serine 552. We conclude that the HBD peptide of IGFBP-2 has anabolic activity by activating IGF-I/Akt and β-catenin signaling pathways. These data support a growing body of evidence that IGFBP-2 is not just a transport protein but rather that it functions coordinately with IGF-I to stimulate growth and skeletal acquisition. 相似文献
992.
Use of the Pirt and Luedeking-Piret equations permits the determination of the effect of medium composition on the metabolic patterns of Megasphaera elsdenii grown in minimal and complex media with lactate as the major carbon source. To establish the significance of the parameters involved in the Pirt and Luedeking-Piret equations, a quantitative statistical criterion was proposed. In the complex medium, lactate was completely used for growth and product formation, whereas in the minimal medium a fraction of the energy obtained from lactate was used for maintenance purposes. Modeling of VFA production by the Luedeking-Piret equation showed that, independent of the type of medium, acetate and propionate are growth-associated products, while butyrate and valerate are only partially growth-associated. The growth-associated products are related to energy-yielding metabolism and the non-growth-associated products are related to the consumption of reducing equivalents. 相似文献
993.
Chiara D'Ambrosio Mariangela Succoio Luigi Formisano Lucia Nappi Maria Fiammetta Romano Andrea Scaloni Nicola Zambrano 《Proteomics》2013,13(5):866-877
Cetuximab is a chimeric antibody approved for the treatment of metastatic colorectal cancer that selectively targets epidermal growth factor receptor (EGFR) signaling. Treatment efficacy with this drug is often impaired by acquired resistance and poor information has been accumulated on the mechanisms underlying such a phenomenon. By taking advantage of a syngenic cellular system of sensitivity and acquired resistance to anti‐EGFR therapy in the colorectal carcinoma GEO cell line, we profiled protein expression differences between Cetuximab‐sensitive and ‐resistant cells. Combined 2D DIGE and MS analyses revealed a main proteomic signature resulting from selective deregulation of various metabolic enzymes, including glucose‐6‐phosphate dehydrogenase, transketolase, lactate dehydrogenase B, and pyruvate dehydrogenase E1, which was also confirmed by Western blotting experiments. Lactate dehydrogenase B downregulation has been already related to an increased anaerobic utilization of glucose by tumor cells; accordingly, we verified that Cetuximab‐resistant cells have a significantly higher production of lactate. Resistant cells also showed decreased nicotinamide adenine dinucleotide phosphate (NADPH) levels. Observed protein deregulations were not related to functional alterations of the hypoxia‐inducible factor 1‐associated pathways. Our data demonstrate that increased anaerobic metabolism is a prominent feature observed in the GEO syngenic model of acquired resistance to anti‐EGFR therapy in colorectal cancer. 相似文献
994.
995.
Ernesto?Soto-Reyes Luz?María?Del Razo Mahara?Valverde Emilio?RojasEmail author 《Biometals》2005,18(5):493-506
In the last decade arsenic metabolism has become an important matter of discussion. Methylation of inorganic arsenic (iAs)
to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) is considered to decrease arsenic toxicity. However, in addition to these pentavalent metabolites, the trivalent metabolites
monomethylarsonous (MMAIII) and dimethylarsinous acid (DMAIII) have been identified recently as intermediates in the metabolic pathway of arsenic in cultured human cells. To examine the
role of oxidative damage in the generation of DNA strand breaks by methylated trivalent arsenic metabolites, we treated human
lymphocytes with both metabolites at non-cytotoxic concentrations. We further tested whether these effects are sensitive to
modulation by the antioxidants ascorbate (Vitamin C) and selenomethionine (Se-Met). Both trivalent metabolites produced oxidative
stress related DNA damage, consisting of single strand breaks and alkali-labile sites, with MMAIII being more potent at low concentrations than DMAIII. Neither MMAIII nor DMAIII induced DNA-double strand breaks. The oxidative stress response profiles of the metabolites were parallel as determined by
lipid peroxidation induction. MMAIII induced peroxidation from the lowest concentration tested, while effects of DMAIII were apparent only at concentrations above 10 μM. The antioxidant Se-Met exhibited a more pronounced inhibition of trivalent
arsenic metabolite-induced oxidative-DNA damage than did vitamin C. The present findings suggest that DNA damage by methylated
trivalent metabolites at non-cytotoxic concentrations may be mediated by a mix of reactive oxygen and nitrogen oxidized species. 相似文献
996.
Lloret L Ormeño-Orrillo E Rincón R Martínez-Romero J Rogel-Hernández MA Martínez-Romero E 《Systematic and applied microbiology》2007,30(4):280-290
A new lineage of Ensifer nodulating the American legume Acacia angustissima in the tropical forest of Chiapas and Morelos, Mexico is described. Bacteria were identified as Ensifer with ssb or nolR specific primers. Phylogenetic analysis with partial sequences of the five chromosomal genes gyrA, nolR, recA, rpoB and rrs revealed that this new lineage is related to African Ensifer terangae. The results of total DNA-DNA hybridization and selected phenotypic tests among the A. angustissima strains and E. terangae indicated that they belong to different species. The phylogeny with the symbiotic nifH gene also separates this group as a different clade but with close affinities to bacteria belonging to the genus Ensifer isolated from American hosts. ITTG R7(T) (=CFN ER1001, HAMBI 2910, CIP 109033, ATCC BAA-1312, DSM18446) is the type strain of a new species for which the name Ensifer mexicanus sp. nov. is proposed. 相似文献
997.
Giacomello M De Mario A Primerano S Brini M Carafoli E 《The international journal of biochemistry & cell biology》2012,44(5):679-683
Hearing relies on the ability of the inner ear to convert sound waves into electrical signals. The main actors in this process are hair cells. Their stereocilia contain a number of specific proteins and a scaffold of actin molecules. They are organized in bundles by tip-link filaments composed of cadherin 23 and protocadherin 15. The bundle is deflected by sound waves leading to the opening of mechano-transduction channels and to the influx of K(+) and Ca(2+) into the stereocilia. Cadherin 23 and the plasma membrane calcium ATPase isoform 2 (PMCA2) are defective in human and murine cases of deafness. While the involvement of cadherin 23 in deafness/hearing could be expected due to its structural role in the tip-links, that of PMCA2 has been discovered only recently. This review will summarize the structural and functional characteristics of hair cells, focusing on the proteins whose mutations may lead to a deafness phenotype. 相似文献
998.
Mirian Domenech Diana Damián Carmen Ardanuy Josefina Li?ares Asunción Fenoll Ernesto García 《PloS one》2015,10(4)
Background
Since the use of pneumococcal conjugate vaccines PCV7 and PCV13 in children became widespread, invasive pneumococcal disease (IPD) has dramatically decreased. Nevertheless, there has been a rise in incidence of Streptococcus pneumoniae non-vaccine serotypes (NVT) colonising the human nasopharynx. Nasopharyngeal colonisation, an essential step in the development of S. pneumoniae-induced IPD, is associated with biofilm formation. Although the capsule is the main pneumococcal virulence factor, the formation of pneumococcal biofilms might, in fact, be limited by the presence of capsular polysaccharide (CPS).Methodology/Principal Findings
We used clinical isolates of 16 emerging, non-PCV13 serotypes as well as isogenic transformants of the same serotypes. The biofilm formation capacity of isogenic transformants expressing CPSs from NVT was evaluated in vitro to ascertain whether this trait can be used to predict the emergence of NVT. Fourteen out of 16 NVT analysed were not good biofilm formers, presumably because of the presence of CPS. In contrast, serotypes 11A and 35B formed ≥45% of the biofilm produced by the non-encapsulated M11 strain.Conclusions/Significance
This study suggest that emerging, NVT serotypes 11A and 35B deserve a close surveillance. 相似文献999.
Fabio Cafini Jose Yuste Maria-Jose Giménez David Sevillano Lorenzo Aguilar Luis Alou Elisa Ramos-Sevillano Martha Torrico Natalia González Ernesto García Pilar Coronel Jose Prieto 《PloS one》2010,5(8)
Background
Specific antibodies are likely to be present before S. pneumoniae infection. We explored cefditoren (CDN) total and free values of serum concentrations exceeding the MIC (t>MIC) related to efficacy in a mice sepsis model, and the effect of specific gammaglobulins on in-vitro phagocytosis and in-vivo efficacy.Methodology/Principal Findings
We used three pneumococcal isolates (serotype, MIC of CDN): Strain 1 (6B, 1 µg/ml), Strain 2 (19F, 2 µg/ml) and Strain 3 (23F, 4 µg/ml). Hyperimmune serum (HS) was obtained from mice immunized with heat-inactivated strains. In-vitro, phagocytosis by HS diluted 1/10 in presence/absence of sub-inhibitory concentrations was measured by flow cytometry including fluorescent bacteria and a neutrophil cell line. In-vivo dose-ranging experiments with HS (dilutions 1/2–1/16) and CDN (6.25 mg/kg–100 mg/kg tid for 48 h) were performed to determine the minimal protective dilution/dose (highest survival) and the non-protective highest dilution/dose (highest mortality: HS-np dilution and CDN-np dose) over 7 days. Efficacy of CDN-np in animals pre-immunized with HS-np (combined strategy) was explored and blood bacterial clearance determined. The CDN measured protein binding was 86.9%. In-vitro, CDN significantly increased phagocytosis (vs. HS 1/10). In non pre-immunized animals, t>MIC values for CDN of ≈35% (total) and ≈19% (free) were associated with 100% survival. Significant differences in survival were found between HS-np alone (≤20%) or CDN-np alone (≤20%) vs. the combined strategy (90%, 60% and 60% for Stains 1, 2 and 3), with t>MIC (total/free) of 22.8%/14.3%, 26.8%/16.0%, and 22.4%/12.7% for Strains 1, 2 and 3, respectively. Prior to the second dose (8 h), median bacterial counts were significantly lower in animals surviving vs. dead at day 7.Conclusions/Significance
In mice (CDN protein binding similar to humans) total t>MIC values of ≈35% (≈19% free) were efficacious, with a decrease in the required values in pre-immunized animals. This reinforces that immunoprotection to overcome resistance may provide lifesaving strategies. 相似文献1000.