全文获取类型
收费全文 | 247篇 |
免费 | 26篇 |
出版年
2023年 | 2篇 |
2022年 | 7篇 |
2021年 | 22篇 |
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 11篇 |
2017年 | 7篇 |
2016年 | 8篇 |
2015年 | 16篇 |
2014年 | 18篇 |
2013年 | 19篇 |
2012年 | 26篇 |
2011年 | 15篇 |
2010年 | 20篇 |
2009年 | 5篇 |
2008年 | 11篇 |
2007年 | 11篇 |
2006年 | 15篇 |
2005年 | 12篇 |
2004年 | 14篇 |
2003年 | 6篇 |
2002年 | 5篇 |
2001年 | 1篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1995年 | 1篇 |
1993年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1966年 | 2篇 |
排序方式: 共有273条查询结果,搜索用时 46 毫秒
41.
Singh AM Reynolds D Cliff T Ohtsuka S Mattheyses AL Sun Y Menendez L Kulik M Dalton S 《Cell Stem Cell》2012,10(3):312-326
A general mechanism for how intracellular signaling pathways in human pluripotent cells are coordinated and how they maintain self-renewal remain to be elucidated. In this report, we describe a signaling mechanism where PI3K/Akt activity maintains self-renewal by restraining prodifferentiation signaling through suppression of the Raf/Mek/Erk and canonical Wnt signaling pathways. When active, PI3K/Akt establishes conditions where Activin A/Smad2,3 performs a pro-self-renewal function by activating target genes, including Nanog. When PI3K/Akt signaling is low, Wnt effectors are activated and function in conjunction with Smad2,3 to promote differentiation. The switch in Smad2,3 activity after inactivation of PI3K/Akt requires the activation of canonical Wnt signaling by Erk, which targets Gsk3β. In sum, we define a signaling framework that converges on Smad2,3 and determines its ability to regulate the balance between alternative cell states. This signaling paradigm has far-reaching implications for cell fate decisions during early embryonic development. 相似文献
42.
Rab1 interacts directly with the β2-adrenergic receptor to regulate receptor anterograde trafficking
Very little is understood about the trafficking of G protein-coupled receptors (GPCRs) from the endoplasmic reticulum (ER) to the plasma membrane. Rab guanosine triphosphatases (GTPases) are known to participate in the trafficking of various GPCRs via a direct interaction during the endocytic pathway, but whether this occurs in the anterograde pathway is unknown. We evaluated the potential interaction of Rab1, a GTPase known to regulate β2-adrenergic receptor (β2AR) trafficking, and its effect on export from the ER. Our results show that GTP-bound Rab1 interacts with the F(x)(6)LL motif of β2AR. Receptors lacking the interaction motif fail to traffic properly, suggesting that a direct interaction with Rab1 is required for β2AR anterograde trafficking. 相似文献
43.
Rosypal AC Werbovetz KA Salem M Stephens CE Kumar A Boykin DW Hall JE Tidwell RR 《The Journal of parasitology》2008,94(3):743-749
Old World cutaneous leishmaniasis is caused by infection with Leishmania major and Leishmania tropica. Pentamidine and related dications exhibit broad spectrum antiprotozoal activity. Based on the previously reported efficacy of these compounds against related organisms, 18 structural analogs of pentamidine were evaluated for in vitro antileishmanial activity, using pentamidine as the standard reference drug for comparison. Furan analogs and reversed amidine compounds were examined for activity against L. major and L. tropica promastigotes. The most active compounds against both Leishmania species were in the reversed amidine series. DB745 and DB746 exhibited the highest activity against L. major and DB745 was the most active compound against L. tropica. Both of these compounds exhibited 50% inhibitory concentrations (IC50) below 1 nM for L. major. Ten reversed amidines were also tested for their ability to inhibit growth in an axenic amastigote model. Nine of 10 reversed amidine analogs were active at concentrations below 1 nM. These results justify further study of dicationic compounds as potential new agents for treating cutaneous leishmaniasis. 相似文献
44.
45.
Mercado-Gómez O Hernández-Fonseca K Villavicencio-Queijeiro A Massieu L Chimal-Monroy J Arias C 《Neurochemical research》2008,33(8):1599-1609
Glycogen synthase kinase GSK-3β has been identified as one of the major candidates mediating tau hyperphosphorylation at the
same sites as those present in tau protein in brain from Alzheimer′s disease (AD) patients. However, the signal transduction
pathways involved in the abnormal activation of GSK-3β, have not been completely elucidated. GSK-3β activity is repressed
by the canonical Wnt signaling pathway, but it is also modulated through the PI3K/Akt route. Recent studies have suggested
that Wnt signaling might be involved in the pathophysiology of AD. On the other hand, modulators of the PI3K pathway might
be reduced during aging leading to a sustained activation of GSK-3β, which in turn would increase the risk of tau hyperphosphorylation.
The role of Wnt and PI3K signaling inhibition on the extent of tau phosphorylation and neuronal morphology has not been completely
elucidated. Thus, in the present investigation we analyzed the effects of different negative modulators of the Wnt and the
PI3K pathways on GSK-3β activation and phosphorylation of tau at the PHF-1 epitope in cortical cultured neurons and hippocampal
slices from adult rat brain. Changes in the microtubule network were also studied. We found that a variety of Wnt and PI3K
inhibitors, significantly increased tau phosphorylation at the PHF-1 site, induced the disarrangement of the microtubule network
and the accumulation of tau within cell bodies. These changes correlated with alterations in neuronal morphology.
Special issue article in honor of Dr. Ricardo Tapia. 相似文献
46.
Annika Jagels Yannick Hövelmann Alexa Zielinski Melanie Esselen Jens Köhler Florian Hübner Hans-Ulrich Humpf 《Mycotoxin Research》2018,34(3):179-185
In the course of gaining new insights into the secondary metabolite profile of various Stachybotrys strains, in particular concerning triprenyl phenol-like compounds, so far, unknown metabolites with analogous structural features were discovered. Three novel meroterpenoids containing a chromene ring moiety, namely stachybotrychromenes A–C, were isolated from solid culture of the filamentous fungus Stachybotrys chartarum DSMZ 12880 (chemotype S). Their structures were elucidated by means of comprehensive spectroscopic analysis (1D and 2D NMR, ESI-HRMS, and CD) as well as by comparison with spectroscopic data of structural analogues described in literature. Stachybotrychromenes A and B exhibited moderate cytotoxic effects on HepG2 cells after 24 h with corresponding IC50 values of 73.7 and 28.2 μM, respectively. Stachybotrychromene C showed no significant cytotoxic activity up to 100 μM. Moreover, it is noteworthy that stachybotrychromenes A–C are produced not only by S. chartarum chemotype S but also S. chartarum chemotype A and Stachybotrys chlorohalonata. 相似文献
47.
48.
Lindsay DS Goodwin DG Zajac AM Cortés-Vecino JA Gennari SM Rosypal AC Dubey JP 《The Journal of parasitology》2009,95(3):760-763
There are 3 strains of Encephalitozoon cuniculi that occur in mammals. Strain III is associated with clinical disease in dogs, although some can be asymptomatic carriers and excrete spores in their urine. Several cases of human E. cuniculi infection caused by strain III have been observed in immunocompromised patients, indicating that E. cuniculi should be considered a zoonotic agent. Encephalitozoon cuniculi can cause fatal disease in maternally-infected or young dogs. Clinical signs in these animals included blindness, encephalitis, retarded growth rate, and nephritis. Encephalitozoon cuniculi has also been associated with primary renal failure in adult dogs. The present study used the direct agglutination test (DAT, cut-off 1:50) and the indirect fluorescent antibody test (IFAT, cut-off 1:10) to examine the prevalence of antibodies to E. cuniculi in dogs from Brazil and Colombia. Using the DAG, 31 (27.4%) of 113 dogs from Brazil and 47 (18.5%) of 254 dogs from Colombia were seropositive. Nine (14.3%) of 63 dogs from Brazil and 18 (35.3%) of the 51 dogs from Colombia were seropositive by indirect immunofluorescent antibody test. These results indicate that dogs from Brazil and Colombia are exposed to E. cuniculi. 相似文献
49.
Strobl JS Seibert CW Li Y Nagarkatti R Mitchell SM Rosypal AC Rathore D Lindsay DS 《The Journal of parasitology》2009,95(1):215-223
We searched the National Cancer Institute (NCI) compound library for structures related to the antitumor quinoline NSC3852 (5-nitroso-8-quinolinol) and used a computer algorithm to predict the antiprotozoan activity for each of 13 structures. Half of these compounds inhibited Toxoplasma gondii tachyzoite propagation in human fibroblasts at =1 muM. The active compounds comprise a series of low-molecular-weight quinolines bearing nitrogen substituents in the ring-5 position. NSC3852 (EC(50) 80 nM) and NSC74949 (EC(50) 646 nM) were the most potent. NSC3852 also inhibited Plasmodium falciparum growth in human red blood cells (EC(50) 1.3 muM). To investigate the mechanism for NSC3852's anti-T. gondii activity, we used chemiluminescence assays to detect reactive oxygen species (ROS) formation in freshly isolated tachyzoites and in infected host cells; the absence of ROS generation by NSC3852 in these assays indicated NSC3852 does not redox cycle in T. gondii. Inhibitors of enzyme sources of free radicals such as superoxide anion, nitric oxide (NO), and their reaction product peroxynitrite did not interfere with the anti-T. gondii activity of NSC3852. However, inhibition of T. gondii tachyzoite propagation by NSC3852 involved redox reactions because tachyzoites were protected from NSC3852 by inclusion of the cell permeant superoxide dismutase mimetic, MnTMPyP, or N-acetylcysteine in the culture medium. We conclude that the Prediction of Activity Spectra for Substances (PASS) computer program is useful in finding new compounds that inhibit T. gondii tachyzoites in vitro and that NSC3852 is a potent T. gondii inhibitor that acts by indirect generation of oxidative stress in T. gondii. 相似文献
50.
Steven Arcidiacono Jason W. Soares Alexa M. Meehan Patrick Marek Romy Kirby 《Journal of peptide science》2009,15(6):398-403
The interaction of cecropin P1 (CP1) with Escherichiacoli was investigated to gain insight into the time‐dependent antimicrobial action. Biophysical characterizations of CP1 with whole bacterial cells were performed using both fluorescent and colorimetric assays to investigate the role of membrane permeability and lipopolysaccharide (LPS) binding in lytic behavior. The kinetics of CP1 growth inhibition assays indicated a minimal inhibitory concentration (MIC) of 3 µM . Bactericidal kinetics at the MIC indicated rapid killing of E.coli (<30 min). Membrane permeability studies illustrated permeation as a time‐dependent event. Maximum permeability at the MIC occurred within 30 min, which correlates to the bactericidal action. Further investigation showed that the immediate permeabilizing action of CP1 is concentration‐dependent, which correlates to the concentration‐dependent nature of the inhibition assays. At the MIC and above, the immediate permeability was significant enough that the cells could not recover and exhibit growth. Below the MIC, immediate permeability was evident, but the level was insufficient to inhibit growth. Dansyl polymyxin B displacement studies showed LPS binding is essentially the same at all concentrations investigated. However, it does appear that only the immediate interaction is important, because binding continued to increase over time beyond cell viability. Our studies correlated CP1 bactericidal kinetics to membrane permeability suggesting CP1 concentration‐dependent killing is driven by the extent of the immediate permeabilizing action of the peptide. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. 相似文献