全文获取类型
收费全文 | 570篇 |
免费 | 47篇 |
出版年
2022年 | 6篇 |
2021年 | 16篇 |
2020年 | 14篇 |
2019年 | 7篇 |
2018年 | 10篇 |
2017年 | 10篇 |
2016年 | 14篇 |
2015年 | 25篇 |
2014年 | 32篇 |
2013年 | 43篇 |
2012年 | 38篇 |
2011年 | 39篇 |
2010年 | 24篇 |
2009年 | 25篇 |
2008年 | 25篇 |
2007年 | 38篇 |
2006年 | 27篇 |
2005年 | 23篇 |
2004年 | 34篇 |
2003年 | 19篇 |
2002年 | 25篇 |
2001年 | 16篇 |
2000年 | 9篇 |
1999年 | 6篇 |
1998年 | 8篇 |
1996年 | 3篇 |
1995年 | 4篇 |
1994年 | 4篇 |
1993年 | 5篇 |
1992年 | 3篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 2篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 8篇 |
1983年 | 2篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1972年 | 3篇 |
1971年 | 2篇 |
1969年 | 3篇 |
1968年 | 1篇 |
1966年 | 1篇 |
1961年 | 1篇 |
排序方式: 共有617条查询结果,搜索用时 31 毫秒
61.
Weigert C Brodbeck K Staiger H Kausch C Machicao F Häring HU Schleicher ED 《The Journal of biological chemistry》2004,279(23):23942-23952
62.
Carneiro FA Lapido-Loureiro PA Cordo SM Stauffer F Weissmüller G Bianconi ML Juliano MA Juliano L Bisch PM Da Poian AT Poian AT 《European biophysics journal : EBJ》2006,35(2):145-154
The entry of enveloped animal viruses into their host cells always depends on membrane fusion triggered by conformational
changes in viral envelope glycoproteins. Vesicular stomatitis virus (VSV) infection is mediated by virus spike glycoprotein
G, which induces membrane fusion between the viral envelope and the endosomal membrane at the acidic environment of this compartment.
In this work, we evaluated VSV interactions with membranes of different phospholipid compositions, at neutral and acidic pH,
using atomic force microscopy (AFM) operating in the force spectroscopy mode, isothermal calorimetry (ITC) and molecular dynamics
simulation. We found that the binding forces differed dramatically depending on the membrane phospholipid composition, revealing
a high specificity of G protein binding to membranes containing phosphatidylserine (PS). In a previous work, we showed that
the sequence corresponding amino acid 164 of VSV G protein was as efficient as the virus in catalyzing membrane fusion at
pH 6.0. Here, we used this sequence to explore VSV–PS interaction using ITC. We found that peptide binding to membranes was
exothermic, suggesting the participation of electrostatic interactions. Peptide–membrane interaction at pH 7.5 was shown to
be specific to PS and dependent on the presence of His residues in the fusion peptide. The application of the simplified continuum
Gouy–Chapman theory to our system predicted a pH of 5.0 at membrane surface, suggesting that the His residues should be protonated
when located close to the membrane. Molecular dynamics simulations suggested that the peptide interacts with the lipid bilayer
through its N-terminal residues, especially Val145 and His148.
Fabiana A.Carneiro and Pedro A. Lapido-Loureiro contributed equally to this work
An erratum to this article can be found at 相似文献
63.
64.
The ultrastructure of spermatozoa of four Plecoptera species, Leuctra fusca Linnaeus, Brachyptera risi (Morton), Taeniopteryx stankovitchi Ikonomov, T. kuehtreiberi (Aubert), was investigated by light microscopy, scanning and transmission electron microscopy, and immunofluorescence microscopy. The spermatozoa of all the species have a complex acrosome, are filiform and flagellate, with a '9+9+2' axoneme flanked by two mitochondrial derivatives. However, the structure shows a certain interspecific heterogeneity. L. fusca has a short conical nucleus in the apical position and an axoneme flanked by two accessory bodies. In the sperm of the Taeniopterygidae, the nucleus is a long cylindrical body which lies between the two mitochondrial derivatives flanking the axoneme for most of its length. Our results suggest a close phylogenetic affinity between Plecoptera and the other orders of Polyneoptera, although the proposed sister-group relationship between Plecoptera and Embioptera cannot be confirmed. 相似文献
65.
Fernando J Sancho P Fernández-Rodriguez CM Lledó JL Caja L Campbell JS Fausto N Fabregat I 《Journal of cellular physiology》2012,227(4):1319-1325
Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC-PRF-5, SK-Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down-regulation. However, sorafenib's main anti-tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro-apoptotic "BH3-domain only" PUMA and BIM, as well as decreased protein levels of the anti-apoptotic MCL1 and survivin. PUMA targeting knock-down, by using specific siRNAs, inhibited sorafenib-induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor-β (TGF-β) through the intrinsic pathway and to tumor necrosis factor-α (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib-induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF-β or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro-apoptotic physiological cytokines. 相似文献
66.
C Daleno A Piralla A Scala F Baldanti V Usonis N Principi S Esposito 《Journal of virology》2012,86(19):10888-10889
The new enterovirus C-117 strain belongs to the human enterovirus C species in the Picornaviridae family. We describe the characterization of the complete genome of this strain identified in a respiratory specimen of a child enrolled in the Community-Acquired Pneumonia Pediatric Research Initiative (CAP-PRI) study evaluating the etiology of community-acquired pneumonia (CAP). 相似文献
67.
Chiaradia E Pepe M Tartaglia M Scoppetta F D'Ambrosio C Renzone G Avellini L Moriconi F Gaiti A Bertuglia A Beccati F Scaloni A 《Journal of Proteomics》2012,75(14):4478-4493
Osteoarthritis (OA) and osteochondrosis (OC) are two of the main challenges in orthopedics, whose definitive diagnosis is usually based on radiographic/arthroscopic evidences. Their early diagnosis should allow preventive or timely therapeutic actions, which are generally precluded from the poor relationships occurring between symptomatologic and radiographic evidences. These limitations should be overcome by improving the knowledge on articular tissue metabolism and on molecular factors regulating its normal homeostasis, also identifying novel OA and OC biomarkers suitable for their earlier diagnoses, whenever clinical/pathological inflammatory scenarios between these joint diseases seem somewhat related. To identify proteins involved in their aetiology and progression, we undertook a differential proteomic analysis of equine synovial fluid (SF), which compared the protein pattern of OA or OC patients with that of healthy individuals. Deregulated proteins in OA and OC included components related to inflammatory state, coagulation pathways, oxidative stress and matrix damage, which were suggestive of pathological alterations in articular homeostasis, plasma-SF exchange, joint nutritional status and vessel permeability. Some proteins seemed commonly deregulated in both pathologies indicating that, regardless of the stimulus, common pathways are affected and/or the animal joint uses the same molecular mechanisms to restore its homeostasis. On the other hand, the increased number of deregulated proteins observed in OA with respect to OC, together with their nature, confirmed the high inflammatory character of this disease. Some deregulated proteins in OA found a verification by analyzing the SF of injured arthritic joints following autologous conditioned serum treatment, an emergent therapy that provides positive results for both human and equine OA. Being the horse involved in occupational/sporting activities and considered as an excellent animal model for human joint diseases, our data provide suggestive information for tentative biomedical extrapolations, allowing to overcome the limitations in joint size and workload that are typical of other small animal models. 相似文献
68.
Scoppetta F Tartaglia M Renzone G Avellini L Gaiti A Scaloni A Chiaradia E 《Journal of Proteomics》2012,75(14):4494-4504
Physical exercise induces various stress responses and metabolic adaptations that have not yet been completely elucidated. Novel biomarkers are needed in sport veterinary medicine to monitor training levels and to detect subclinical conditions that can develop into exercise-related diseases. In this study, protein modifications in horse plasma induced by prolonged, aerobic physical exercise were investigated by using a proteomic approach based on 2-DE and combined mass spectrometry procedures. Thirty-eight protein spots, associated with expression products of 13 genes, showed significant quantitative changes; spots identified as membrane Cu amine oxidase, α-1 antitrypsin, α-1 antitrypsin-related protein, caeruloplasmin, α-2 macroglobulin and complement factor C4 were augmented in relative abundance after the race, while haptoglobin β chain, apolipoprotein A-I, transthyretin, retinol binding protein 4, fibrinogen γ chain, complement factor B and albumin fragments were reduced. These results indicate that prolonged physical exercise affects plasma proteins involved in pathways related to inflammation, coagulation, immune modulation, oxidant/antioxidant activity and cellular and vascular damage, with consequent effects on whole horse metabolism. 相似文献
69.
Clarissa X. R. Valim Luiz Roberto Basso Jr Fausto B. dos Reis Almeida Thaila Fernanda Reis André Ricardo Lima Damásio Luisa Karla Arruda Roberto Martinez Maria Cristina Roque-Barreira Constance Oliver Maria Célia Jamur Paulo Sergio Rodrigues Coelho 《PloS one》2012,7(9)
Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis (PCM), one of the most prevalent mycosis in Latin America. P. brasiliensis cell wall components interact with host cells and influence the pathogenesis of PCM. Cell wall components, such as glycosylphosphatidylinositol (GPI)-proteins play a critical role in cell adhesion and host tissue invasion. Although the importance of GPI-proteins in the pathogenesis of other medically important fungi is recognized, little is known about their function in P. brasiliensis cells and PCM pathogenesis. We cloned the PbPga1 gene that codifies for a predicted GPI-anchored glycoprotein from the dimorphic pathogenic fungus P. brasiliensis. PbPga1 is conserved in Eurotiomycetes fungi and encodes for a protein with potential glycosylation sites in a serine/threonine-rich region, a signal peptide and a putative glycosylphosphatidylinositol attachment signal sequence. Specific chicken anti-rPbPga1 antibody localized PbPga1 on the yeast cell surface at the septum between the mother cell and the bud with stronger staining of the bud. The exposure of murine peritoneal macrophages to rPbPga1 induces TNF-α release and nitric oxide (NO) production by macrophages. Furthermore, the presence of O-glycosylation sites was demonstrated by β-elimination under ammonium hydroxide treatment of rPbPga1. Finally, sera from PCM patients recognized rPbPga1 by Western blotting indicating the presence of specific antibodies against rPbPga1. In conclusion, our findings suggest that the PbPga1gene codifies for a cell surface glycoprotein, probably attached to a GPI-anchor, which may play a role in P. brasiliensis cell wall morphogenesis and infection. The induction of inflammatory mediators released by rPbPga1 and the reactivity of PCM patient sera toward rPbPga1 imply that the protein favors the innate mechanisms of defense and induces humoral immunity during P. brasiliensis infection. 相似文献
70.
van Raalte DH van Leeuwen N Simonis-Bik AM Nijpels G van Haeften TW Schafer SA Boomsma DI Kramer MH J Heine R Maassen JA Staiger H Machicao F Häring HU Slagboom PE Willemsen G de Geus EJ Dekker JM Fritsche A Eekhoff EM Diamant M 't Hart LM 《Diabetic medicine : a journal of the British Diabetic Association》2012,29(8):e211-e216