全文获取类型
收费全文 | 247篇 |
免费 | 14篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2021年 | 1篇 |
2020年 | 2篇 |
2019年 | 4篇 |
2018年 | 3篇 |
2016年 | 2篇 |
2015年 | 12篇 |
2014年 | 15篇 |
2013年 | 13篇 |
2012年 | 23篇 |
2011年 | 32篇 |
2010年 | 14篇 |
2009年 | 16篇 |
2008年 | 14篇 |
2007年 | 14篇 |
2006年 | 10篇 |
2005年 | 13篇 |
2004年 | 14篇 |
2003年 | 10篇 |
2002年 | 9篇 |
2001年 | 3篇 |
1999年 | 3篇 |
1998年 | 5篇 |
1997年 | 1篇 |
1996年 | 2篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1993年 | 7篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 1篇 |
排序方式: 共有261条查询结果,搜索用时 31 毫秒
81.
Lifeguard/neuronal membrane protein 35 regulates Fas ligand-mediated apoptosis in neurons via microdomain recruitment 总被引:1,自引:0,他引:1
Fernández M Segura MF Solé C Colino A Comella JX Ceña V 《Journal of neurochemistry》2007,103(1):190-203
Fas ligand (FasL)-receptor system plays an essential role in regulating cell death in the developing nervous system, and it has been implicated in neurodegenerative and inflammatory responses in the CNS. Lifeguard (LFG) is a protein highly expressed in the hippocampus and the cerebellum, and it shows a particularly interesting regulation by being up-regulated during postnatal development and in the adult. We show that over-expression of LFG protected cortical neurons from FasL-induced apoptosis and decreased caspase-activation. Reduction of endogenous LFG expression by small interfering RNA sensitized cerebellar granular neurons to FasL-induced cell death and caspase-8 activation, and also increased sensitivity of cortical neurons. In differentiated cerebellar granular neurons, protection from FasL-induced cell death could be attributed exclusively to LFG and appears to be independent of FLICE inhibitor protein. Thus, LFG is an endogenous inhibitor of FasL-mediated neuronal death and it mediates the FasL resistance of CNS differentiated neurons. Finally, we also demonstrate that LFG is detected in lipid rafts microdomains, where it may interact with Fas receptor and regulate FasL-activated signaling pathways. 相似文献
82.
In general, the structural requirements postulated for a high brassinolide activity are: 2alpha,3alpha-diol, 6-ketone or better 7-oxalactone in B-ring, A/B trans fused ring junction, a cis C-22,C-23-diol preferentially with RR configurations, and a C-24 methyl or ethyl substituent [Takatsuto S, Yazawa N, Ikekawa N, Takematsu T, Takeuchi Y, Koguchi M. Structure-activity relationship of brassinosteroids. Phytochemistry 1983;22:2437-41; Thompson MJ, Meudt WJ, Mandava NB, Dutky SR, Lusby WR, Spaulding DW. Synthesis of brassinosteroids and relationship of structure to plant growth-promoting effects. Steroids 1982;39:89-105]. We found that the 3alpha,4alpha-diols 4, 6 and 8 are more active than the 2alpha,3alpha-diols 3, 5 and 7 [Sísa M, Budesínsky M, Kohout L. Synthesis of 7a-homo and 7a,7b-dihomo-5alpha-cholestane analogues of brassinolide. Collect Czech Chem Commun 2003;68:2171-89]. This fact is in strong contrast with the structure requirements mentioned above. Our hypothesis suggests that the lower activity of 2alpha,3alpha-diols and/or the higher activity of 3alpha,4alpha-diols could be explained by twisting and distortion of the molecule due to the seven- or eight-membered B-ring and also by the position of a carbonyl group relative to the A-ring diol. 3D-SAR computer methodologies as alignments and overlaps of GRID maps and 3D-QSAR analysis GRID-GOLPE (CoMFA-like) were used as an effort to explain the higher bioactivity of 3alpha,4alpha-diols 4, 6 and 8 in comparison with the 2alpha,3alpha-diols 3, 5 and 7 of B-ring enlarged brassinosteroids. 相似文献
83.
84.
Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation 总被引:2,自引:0,他引:2
85.
Ecosystems - Temporary streams make up the majority of river networks in many regions around the world. Although they are known to have non-flow periods, it is uncertain in what ways the temporal... 相似文献
86.
In this paper we present a comparative study of supported lipid bilayers (SLBs) and proteolipid sheets (PLSs) obtained from deposition of lactose permease (LacY) of Escherichia coli proteoliposomes in plane. Lipid matrices of two components, phosphatidylethanolamine (PE) and phosphatidylglycerol (PG), at a 3:1, mol/mol ratio, were selected to mimic the inner membrane of the bacteria. The aim was to investigate how species of different compactness and stiffness affect the integration, distribution and nanomechanical properties of LacY in mixtures of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) or 1,2-palmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) with 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG). Both compositions displayed phase separation and were investigated by atomic force microscopy (AFM) imaging and force-spectroscopy (FS) mode. PLSs displayed two separated, segregated domains with different features that were characterised by FS and force-volume mode. We correlated the nanomechanical characteristics of solid-like gel phase (Lβ) and fluid liquid-crystalline phase (Lα) with phases emerging in presence of LacY. We observed that for both compositions, the extended PLSs showed a Lβ apparently formed only by lipids, whilst the second domain was enriched in LacY. The influence of the lipid environment on LacY organisation was studied by performing protein unfolding experiments using the AFM tip. Although the pulling experiments were unspecific, positive events were obtained, indicating the influence of the lipid environment when pulling the protein. A possible influence of the lateral surface pressure on this behaviour is suggested by the higher force required to pull LacY from DPPE:POPG than from POPE:POPG matrices. This is related to higher forces governing protein–lipid interaction in presence of DPPE. 相似文献
87.
M. Carme Coll Ferrer Vladimir V. Shuvaev Blaine J. Zern Russell J. Composto Vladimir R. Muzykantov David M. Eckmann 《PloS one》2014,9(7)
Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with “stealth” properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti-inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (∼120% ID/g vs ∼15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro-inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation. 相似文献
88.
Antoine Adenis Mathieu Nacher Matthieu Hanf Vincent Vantilcke Rachida Boukhari Denis Blachet Magalie Demar Christine Aznar Bernard Carme Pierre Couppie 《PLoS neglected tropical diseases》2014,8(8)
Background
Histoplasmosis is an endemic fungal infection in French Guiana. It is the most common AIDS-defining illness and the leading cause of AIDS-related deaths. Diagnosis is difficult, but in the past 2 decades, it has improved in this French overseas territory which offers an interesting model of Amazonian pathogen ecology. The objectives of the present study were to describe the temporal trends of incidence and mortality indicators for HIV-associated histoplasmosis in French Guiana.Methods
A retrospective study was conducted to describe early mortality rates observed in persons diagnosed with incident cases of HIV-associated Histoplasma capsulatum var. capsulatum histoplasmosis admitted in one of the three main hospitals in French Guiana between 1992 and 2011. Early mortality was defined by death occurring within 30 days after antifungal treatment initiation. Data were collected on standardized case report forms and analysed using standard statistical methods.Results
There were 124 deaths (45.3%) and 46 early deaths (16.8%) among 274 patients. Three time periods of particular interest were identified: 1992–1997, 1998–2004 and 2005–2011. The two main temporal trends were: the proportion of early deaths among annual incident histoplasmosis cases significantly declined four fold (χ2, p<0.0001) and the number of annual incident histoplasmosis cases increased three fold between 1992–1997 and 1998–2004, and subsequently stabilized.Conclusion
From an occasional exotic diagnosis, AIDS-related histoplasmosis became the top AIDS-defining event in French Guiana. This was accompanied by a spectacular decrease of early mortality related to histoplasmosis, consistent with North American reference center mortality rates. The present example testifies that rapid progress could be at reach if awareness increases and leads to clinical and laboratory capacity building in order to diagnose and treat this curable disease. 相似文献89.
L Zubiaurre-Elorza S Soria-Pastor C Junque R Sala-Llonch D Segarra N Bargallo A Macaya 《PloS one》2012,7(7):e42148
Aim
To identify long-term effects of preterm birth and of periventricular leukomalacia (PVL) on cortical thickness (CTh). To study the relationship between CTh and cognitive-behavioral abnormalities.Methods
We performed brain magnetic resonance imaging on 22 preterm children with PVL, 14 preterm children with no evidence of PVL and 22 full-term peers. T1-weighted images were analyzed with FreeSurfer software. All participants underwent cognitive and behavioral assessments by means of the Wechsler Intelligence Scales for Children-Fourth Edition (WISC-IV) and the Child Behavior Checklist (CBCL).Results
We did not find global CTh differences between the groups. However, a thinner cortex was found in left postcentral, supramarginal, and caudal middle rostral gyri in preterm children with no evidence of PVL than in the full-term controls, while PVL preterm children showed thicker cortex in right pericalcarine and left rostral middle frontal areas than in preterm children with no evidence of PVL. In the PVL group, internalizing and externalizing scores correlated mainly with CTh in frontal areas. Attentional scores were found to be higher in PVL and correlated with CTh increments in right frontal areas.Interpretation
The preterm group with no evidence of PVL, when compared with full-term children, showed evidence of a different pattern of regional thinning in the cortical gray matter. In turn, PVL preterm children exhibited atypical increases in CTh that may underlie their prevalent behavioral problems. 相似文献90.
Cleofé Pe?a-Gomez Cristina Solé-Padullés Imma C. Clemente Carme Junqué Núria Bargalló Beatriz Bosch José Luis Molinuevo Josep Valls-Solé Alvaro Pascual-Leone David Bartrés-Faz 《PloS one》2012,7(12)
Behavioral consequences of a brain insult represent an interaction between the injury and the capacity of the rest of the brain to adapt to it. We provide experimental support for the notion that genetic factors play a critical role in such adaptation. We induced a controlled brain disruption using repetitive transcranial magnetic stimulation (rTMS) and show that APOE status determines its impact on distributed brain networks as assessed by functional MRI (fMRI).Twenty non-demented elders exhibiting mild memory dysfunction underwent two fMRI studies during face-name encoding tasks (before and after rTMS). Baseline task performance was associated with activation of a network of brain regions in prefrontal, parietal, medial temporal and visual associative areas. APOE ε4 bearers exhibited this pattern in two separate independent components, whereas ε4-non carriers presented a single partially overlapping network. Following rTMS all subjects showed slight ameliorations in memory performance, regardless of APOE status. However, after rTMS APOE ε4-carriers showed significant changes in brain network activation, expressing strikingly similar spatial configuration as the one observed in the non-carrier group prior to stimulation. Similarly, activity in areas of the default-mode network (DMN) was found in a single component among the ε4-non bearers, whereas among carriers it appeared disaggregated in three distinct spatiotemporal components that changed to an integrated single component after rTMS.Our findings demonstrate that genetic background play a fundamental role in the brain responses to focal insults, conditioning expression of distinct brain networks to sustain similar cognitive performance. 相似文献