全文获取类型
收费全文 | 236篇 |
免费 | 15篇 |
出版年
2023年 | 3篇 |
2022年 | 4篇 |
2021年 | 22篇 |
2020年 | 4篇 |
2019年 | 5篇 |
2018年 | 6篇 |
2017年 | 10篇 |
2016年 | 8篇 |
2015年 | 18篇 |
2014年 | 14篇 |
2013年 | 17篇 |
2012年 | 36篇 |
2011年 | 31篇 |
2010年 | 10篇 |
2009年 | 6篇 |
2008年 | 9篇 |
2007年 | 14篇 |
2006年 | 10篇 |
2005年 | 3篇 |
2004年 | 2篇 |
2003年 | 1篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1997年 | 1篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1991年 | 1篇 |
1985年 | 1篇 |
1983年 | 1篇 |
1982年 | 4篇 |
1981年 | 1篇 |
排序方式: 共有251条查询结果,搜索用时 46 毫秒
11.
Archana Aggarwal Man Mohan Misro Ankur Maheshwari Neeta Sehgal Deoki Nandan 《Molecular reproduction and development》2010,77(10):900-909
We have earlier reported that following persistent stimulation with hCG, oxidative stress‐induced apoptosis in rat Leydig cells was mainly achieved through the extrinsic pathway. In the present study, the role of N‐acetylcysteine (NAC) in counteracting the oxidative stress and the mechanisms of inhibition of apoptosis under such conditions were investigated. NAC (1 mM) intervention with repeated hCG stimulation (50 ng/ml, four times, each with 30 min challenge) prevented the decline in Leydig cell viability and the rise in lipid peroxidation and reactive oxygen species. Simultaneously, the activities of the enzymes glutathione‐S‐transferase, catalase, superoxide dismutase and the intracellular glutathione and antioxidant capacity of the treated cells improved significantly. Apoptotic markers Fas, FasL, and caspase‐8, up‐regulated following repeated hCG exposure, were significantly down‐regulated following NAC co‐incubation. While Bcl‐2 expression was fully restored, Bax and caspase‐9 remained unchanged. NAC treatment induced down‐regulation of upstream JNK/pJNK and down‐stream caspase‐3 in the target cells. Taken together, the above findings indicate that NAC counteracted the oxidative stress in Leydig cells induced as a result of repeated hCG stimulation, and inhibited apoptosis by mainly regulating the extrinsic and JNK pathways of metazoan apoptosis. Mol. Reprod. Dev. 77:900–909, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
12.
Although many bacteria with two chromosomes have been sequenced, the roles of such complex genome structuring are still unclear. To uncover levels of chromosome I (CI) and chromosome II (CII) sequence divergence, Mauve 2.2.0 was used to align the CI- and CII-specific sequences of bacteria with complex genome structuring in two sets of comparisons: the first set was conducted among the CI and CII of bacterial strains of the same species, while the second set was conducted among the CI and CII of species in Alphaproteobacteria that possess two chromosomes. The analyses revealed a rapid evolution of CII-specific DNA sequences compared with CI-specific sequences in a majority of organisms. In addition, levels of protein divergence between CI-specific and CII-specific genes were determined using phylogenetic analyses and confirmed the DNA alignment findings. Analysis of synonymous and nonsynonymous substitutions revealed that the structural and functional constraints on CI and CII genes are not significantly different. Also, horizontal gene transfer estimates in selected organisms demonstrated that CII in many species has acquired higher levels of horizontally transferred segments than CI. In summary, rapid evolution of CII may perform particular roles for organisms such as aiding in adapting to specialized niches. 相似文献
13.
Thommey P. Thomas Baohua Huang Ankur Desai Hong Zong Xue-min Cheng Alina Kotlyar Pascale R. Leroueil Thomas Dunham Abraham van der Spek Brent B. Ward James R. Baker 《Bioorganic & medicinal chemistry letters》2010,20(21):6250-6253
Two morphine prodrugs (‘PDA’ and ‘PDB’) were synthesized and the kinetics of esterase-mediated morphine release from these prodrugs were determined when incubated with plasma from different animal species. Morphine was rapidly released from PDA by all species plasma with the maximum reached within 5–10 min; the released morphine was biologically active as determined by an in vitro cAMP assay. The morphine was released from PDB at a slower and species-dependent rate (mouse > rat > guinea pig > human). Morphine’s release from PDB appeared to be mediated by carboxyl esterases as the release was inhibited by the carboxyl esterase inhibitor benzil. PDA nor PDB induce cytotoxicity in the neuronal cell lines SK-NSH and SH-SY5Y. The carboxyl and amino functional moieties present on the linker portions of PDA and PDB, respectively, may facilitate their conjugation to nanoparticles to tailor morphine pharmacokinetics and specific targeting. These studies suggest the potential clinical utility of these prodrugs for morphine release at desired rates by administration of their mixture at selected ratios. 相似文献
14.
A tyrosine-based signal plays a critical role in the targeting and function of adenovirus RIDalpha protein 下载免费PDF全文
Early region 3 genes of human adenoviruses contribute to the virus life cycle by altering the trafficking of cellular proteins involved in adaptive immunity and inflammatory responses. The ability of early region 3 genes to target specific molecules suggests that they could be used to curtail pathological processes associated with these molecules and treat human disease. However, this approach requires genetic dissection of the multiple functions attributed to early region 3 genes. The purpose of this study was to determine the role of targeting on the ability of the early region 3-encoded protein RIDalpha to downregulate the EGF receptor. A fusion protein between the RIDalpha cytoplasmic tail and glutathione S-transferase was used to isolate clathrin-associated adaptor 1 and adaptor 2 protein complexes from mammalian cells. Deletion and site-directed mutagenesis studies showed that residues 71-AYLRH of RIDalpha are necessary for in vitro binding to both adaptor complexes and that Tyr72 has an important role in these interactions. In addition, RIDalpha containing a Y72A point mutation accumulates in the trans-Golgi network and fails to downregulate the EGF receptor when it is introduced into mammalian cells as a transgene. Altogether, our data suggest a model where RIDalpha is trafficked directly from the trans-Golgi network to an endosomal compartment, where it intercepts EGF receptors undergoing constitutive recycling to the plasma membrane and redirects them to lysosomes. 相似文献
15.
Oral vaccines: new needs, new possibilities 总被引:1,自引:0,他引:1
Aziz MA Midha S Waheed SM Bhatnagar R 《BioEssays : news and reviews in molecular, cellular and developmental biology》2007,29(6):591-604
Vaccination is an important tool for handling healthcare programs both in developed and developing countries. The current global scenario calls for a more-efficacious, acceptable, cost-effective and reliable method of immunization for many fatal diseases. It is hoped that the adoption of oral vaccines will help to provide an effective vaccination strategy, especially in developing countries. Mucosal immunity generated by oral vaccines can serve as a strong first line of defense against most of the pathogens infecting through the mucosal lining. Advances in elucidating the mechanism of action of oral vaccines will facilitate the design of more effective, new generation vaccines. There are promising developments in the use of different agents to effectively deliver the vaccine candidate. It is hoped that ongoing research may be able to set another cardinal point, after polio vaccine, in eradicating infectious diseases. 相似文献
16.
Gadd45alpha is shown to be induced by a wide spectrum of DNA-damaging agents and implicated in negative regulation of cell growth by causing G2-M arrest or induction of apoptosis. In the present study, we explored the involvement of p53 in the promoter activation of Gadd45alpha as well as the role of Gadd45alpha in carboplatin (Carb) or 5-fluorouracil (5-FU)-induced apoptosis in human papillomavirus virus (HPV)-positive HEp-2 and HeLa cells. We report that Carb or 5-FU upregulate Gadd45alpha and p53 in both these cells. Transient transfection of chloramphenicol acetyl transferase (CAT)-reporter construct driven by Gadd45alpha promoter clearly indicated that Gadd45alpha upregulation was mediated through activation of its promoter. Inhibition of p53 function by dominant-negative-p53 expression partially suppressed the activation of Gadd45alpha promoter. Further, the induction of apoptosis was assessed by detection of poly (ADP-ribose) polymerase (PARP) cleavage by Western blot analysis. Inhibition of upregulated Gadd45alpha expression by antisense expression vector did not modulate the Carb or 5-FU-induced apoptosis. Overall, we conclude that Gadd45alpha promoter activation partially depends on p53 function in HPV-positive cells. Moreover, Gadd45alpha protein does not modulate Carb or 5-FU-induced apoptosis in these cells. 相似文献
17.
Lipase-catalyzed terpolymerizations were performed with the monomers trimethylolpropane (B3), 1,8-octanediol (B2), and adipic acid (A2). Polymerizations were performed in bulk, at 70 degrees C, for 42 h, using immobilized lipase B from Candida antartica (Novozyme-435) as a catalyst. To determine the substitution pattern of trimethylolpropane (TMP) in copolymers, model compounds with variable degrees of acetylation were synthesized. Inverse-gated 13C NMR spectra were recorded to first determine the chemical shift positions for mono-, di-, and trisubstituted TMP units and, subsequently, to determine substitution of TMP units along chains. Variation of TMP in the monomer feed gave copolymers with degrees of branching (DB) from 20% to 67%. In one example, a hyperbranched copolyester with 53 mol % TMP adipate units was formed in 80% yield, with Mw 14 100 (relative to polystyrene standards), Mw/Mn 5.3, and DB 36%. Thermal and crystalline properties of the copolyesters were studied by thermogravimetric analysis and differential scanning calorimetry. 相似文献
18.
The purpose of this research was to compare the viscoelastic properties of several neutral and anionic polysaccharide polymers
with their mucociliary transport rates (MTR) across explants of ciliated bovine tracheal tissue to identify rheologic parameters
capable of predicting the extent of reduction in mucociliary transport. The viscoelastic properties of the polymer gels and
gels mixed with mucus were quantified using controlled stress rheometry. In general, the anionic polysaccharides were more
efficient at decreasing the mucociliary transport rate than were the neutral polymers, and a concentration threshold, where
no further decreases in mucociliary transport occurred with increasing polymer concentration, was observed for several of
the neutral polysaccharides. No single rheologic parameter (ν, G′, G″, tan δ, G*) was a good predictor of the extent of mucociliary transport reduction, but a combination of the apparent viscosity (ν),
tangent to the phase angle (tan δ), and complex modulus (G*) was found to be useful in the identification of formulations capable of decreasing MTR. The relative values of each of the
rheologic parameters were unique for each polymer, yet once the relationships between the rheologic parameters and mucociliary
transport rate reduction were determined, formulations capable of resisting mucociliary clearance could be rapidly optimized.
Published: April 20, 2007 相似文献
19.
20.
Michael C Madigan Ryan M McEnaney Ankur J Shukla Guiying Hong Eric E Kelley Margaret M Tarpey Mark Gladwin Brian S Zuckerbraun Edith Tzeng 《Molecular medicine (Cambridge, Mass.)》2015,21(1):313-322
Chronic, nonhealing wounds result in patient morbidity and disability. Reactive oxygen species (ROS) and nitric oxide (NO) are both required for normal wound repair, and derangements of these result in impaired healing. Xanthine oxidoreductase (XOR) has the unique capacity to produce both ROS and NO. We hypothesize that XOR contributes to normal wound healing. Cutaneous wounds were created in C57Bl6 mice. XOR was inhibited with dietary tungsten or allopurinol. Topical hydrogen peroxide (H2O2, 0.15%) or allopurinol (30 μg) was applied to wounds every other day. Wounds were monitored until closure or collected at d 5 to assess XOR expression and activity, cell proliferation and histology. The effects of XOR, nitrite, H2O2 and allopurinol on keratinocyte cell (KC) and endothelial cell (EC) behavior were assessed. We identified XOR expression and activity in the skin and wound edges as well as granulation tissue. Cultured human KCs also expressed XOR. Tungsten significantly inhibited XOR activity and impaired healing with reduced ROS production with reduced angiogenesis and KC proliferation. The expression and activity of other tungsten-sensitive enzymes were minimal in the wound tissues. Oral allopurinol did not reduce XOR activity or alter wound healing but topical allopurinol significantly reduced XOR activity and delayed healing. Topical H2O2 restored wound healing in tungsten-fed mice. In vitro, nitrite and H2O2 both stimulated KC and EC proliferation and EC migration. These studies demonstrate for the first time that XOR is abundant in wounds and participates in normal wound healing through effects on ROS production. 相似文献